Origins of stereoselectivity in the α-alkylation of chiral hydrazones

Article abstract of DOI:10.1021/jo1019877

Density functional theory calculations and experiment reveal the origin of stereoselectivity in the deprotonation-alkylation of chiral N-amino cyclic carbamate (ACC) hydrazones. When the ACC is a rigid, camphor-derived carbamate, the two conformations of the azaenolate intermediate differ in energy due to conformational effects within the oxazolidinone ring and steric interactions between the ACC and the azaenolate. An electrophile adds selectively to the less-hindered π-face of the azaenolate. Although it was earlier reported that use of ACC auxiliaries led to α-alkylated ketones with er values of 82:18 to 98:2, B3LYP calculations predict higher stereoselectivity. Direct measurement of the dr of an alkylated hydrazone prior to removal of the auxiliary confirms this prediction; the removal of the auxiliary under the reported conditions can compromise the overall stereoselectivity of the process.

Full text of DOI:10.1021/jo1019877

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Origins of Stereoselectivity in the r-Alkylation of Chiral Hydrazones
Elizabeth H. Krenske,†,‡ K. N. Houk,*,† Daniel Lim,§ Sarah E. Wengryniuk,§ and
Don M. Coltart*,§
†Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United
States, ‡School of Chemistry, The University of Melbourne, VIC 3010, Australia, and Australian Research
Council Centre of Excellence for Free Radical Chemistry and Biotechnology, and Department of Chemistry,
§
Duke University, Durham, North Carolina 27708, United States
houk@chem.ucla.edu; don.coltart@duke.edu
Received October 7, 2010
Density functional theory calculations and experiment reveal the origin of stereoselectivity in the
deprotonation-alkylation of chiral N-amino cyclic carbamate (ACC) hydrazones. When the ACC is
a rigid, camphor-derived carbamate, the two conformations of the azaenolate intermediate differ in
energy due to conformational effects within the oxazolidinone ring and steric interactions between the
ACC and the azaenolate. An electrophile adds selectively to the less-hindered π-face of the azaenolate.
Although it was earlier reported that use of ACC auxiliaries led to R-alkylated ketones with er values of
82:18 to 98:2, B3LYP calculations predict higher stereoselectivity. Direct measurement of the dr of an
alkylated hydrazone prior to removal of the auxiliary confirms this prediction; the removal of the
auxiliary under the reported conditions can compromise the overall stereoselectivity of the process.
Introduction
have been many studies, both experimental and theoretical, of
the mechanisms and stereoselectivities of alkylations of azae-
nolates derived from dialkylhydrazones, imines, and oximes.2
We recently discovered that chiral N-amino cyclic carba-
mate (ACC) auxiliaries are convenient alternatives for ketone
R-alkylations (Scheme 2).3 ACCs react easily with ketones to
The R-alkylation of ketones is a useful synthetic operation,
most often achieved via electrophilic addition to a derived
azaenolate. Compared with enolates, azaenolates provide
improved reactivities, yields, and regioselectivities and can
incorporate nitrogen-based chiral auxiliaries.1 Enders’ SAMP/
RAMP auxiliaries, the proline-based (S)- and (R)-1-amino-2-
methoxymethylpyrrolidines (Scheme 1), are widely used.1f,g
An attractive feature of the SAMP/RAMP methodology is the
well-defined stereochemical predictability; the appropriate
enantiomer of the auxiliary can be chosen in advance. There
(2) (a) Dialkylhydrazones: Boche, G. Angew. Chem., Int. Ed. Engl. 1989,
28, 277–297. Collum, D. B.; Kahne, D.; Gut, S. A.; DePue, R. T.; Mohamadi,
F.; Wanat, R. A.; Clardy, J.; Van Duyne, G. J. Am. Chem. Soc. 1984, 106,
4865–4869. Enders, D.; Eichenauer, H.; Baus, U.; Schubert, H.; Kremer,
K. A. M. Tetrahedron 1984, 40, 1345–1359. Ludwig, J. W.; Newcomb, M.;
Bergbreiter, D. E. J. Org. Chem. 1980, 45, 4666–4669. Lazny, R.; Nodzewska,
A. Chem. Rev. 2010, 110, 1386–1434. (b) Imines: Fraser, R. R.; Banville, J.;
Dhawan, K. L. J. Am. Chem. Soc. 1978, 100, 7999–8001. Hosomi, A.;
Araki, Y.; Sakurai, H. J. Am. Chem. Soc. 1982, 104, 2081–2083. Smith,
J. K.; Bergbreiter, D. E.; Newcomb, M. J. Am. Chem. Soc. 1983, 105, 4396–
4400. Houk, K. N.; Strozier, R. W.; Rondan, N. G.; Fraser, R. R.; Chuaqui-
Offermanns, N. J. Am. Chem. Soc. 1980, 102, 1426–1429. (c)Oximes: Kofron,
W. G.; Yeh, M.-K. J. Org. Chem. 1976, 41, 439–442. Glaser, R.; Streitwieser,
A. J. Am. Chem. Soc. 1987, 109, 1258–1260. Kallman, N.; Collum, D. B.
J. Am. Chem. Soc. 1987, 109, 7466–7472. Glaser, R.; Streitwieser, A., Jr.
J. Am. Chem. Soc. 1989, 111, 7340–7348.
(1) (a) Meyers, A. I.; Williams, D. R.; Druelinger, M. J. Am. Chem. Soc.
1976, 98, 3032–3033. (b) Meyers, A. I.; Williams, D. R. J. Org. Chem. 1978,
43, 3245–3247. (c) Meyers, A. I.; Williams, D. R.; Erickson, G. W.; White, S.;
Druelinger, M. J. Am. Chem. Soc. 1981, 103, 3081–3087. (d) Hashimoto, S.;
Koga, K. Tetrahedron Lett. 1978, 19, 573–576. (e) Hashimoto, S.; Koga, K.
Chem. Pharm. Bull. 1979, 27, 2760–2766. (f) Enders, D. In Asymmetric
Synthesis; Morrison, J. D., Ed.; Academic Press: Orlando, 1984; Vol. 3, Part
B, pp 275-339. (g) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253–2329.
(3) Lim, D.; Coltart, D. M. Angew. Chem., Int. Ed. 2008, 47, 5207–5210.
8578 J. Org. Chem. 2010, 75, 8578–8584
Published on Web 11/11/2010
DOI: 10.1021/jo1019877
r
2010 American Chemical Society

Krenske et al.
JOCArticle
SCHEME 1. Stereoselective R-Alkylation of a RAMP Hydra-
zone1g
FIGURE 1. Conformers of the ACC hydrazone 11 (ΔH in kcal
mol-1 at 0 K).
evidence1g,4,5 and is depicted in Scheme 1. Kinetic deproto-
nation of hydrazone 1 gives rise to lithium azaenolate 2
which, following equilibration, has the E-configuration at
the CC bond and the Z-configuration at the CN bond.6 The
bottom face of 2 is blocked by the pyrrolidine ring, and
reaction with an electrophile takes place selectively at the top
(β) face.7
SCHEME 2. Asymmetric R-Alkylation of Ketones Mediated by
ACC 4
We proposed3 that a similar mechanism is followed in the
alkylation of an ACC azaenolate but that the formation of
the azaenolate from the hydrazone is controlled by the
orientation of the carbonyl group. As shown in Scheme 3,
the generalized ACC hydrazone 9 would prefer to exist in the
conformation depicted as 9a, where steric interactions be-
tween R2 and the larger substituent (L) on the auxiliary are
minimized. Coordination of LDA to the carbonyl group
would then lead to a “syn-directed” deprotonation,8 giving
the ECC/ZCN-azaenolate 10a as a five-membered chelate.
The bottom face of 10a is sterically blocked, and alkylation
should take place selectively at the top (β) face.
SCHEME 3. Model Proposed To Explain Stereoselectivity in
the Alkylation of ACC Hydrazones3
We present here a computational study of the deprotona-
tion of ACC hydrazones and the alkylation of the lithium
azaenolates. Density functional theory calculations provide
information about the transition states that lead to the
selectivities shown in Scheme 2. However, computations
predict even higher stereoselectivities than were originally
reported.3 This discovery prompted us to measure directly
the dr of an alkylated hydrazone, prior to its conversion to
the ketone. Consistent with theoretical predictions, the dr of
the hydrazone was higher than the er of the final ketone,
revealing that the removal of the auxiliary indeed compro-
mised the overall stereoselectivity of the process.
Results and Discussion
To explore the structural properties of ACC hydrazones,
we first examined the parent ACC hydrazone 11 (Figure 1).
At the B3LYP/6-31G(d) level, two isomers of 11 were
located, which differ in the conformation about the N-N
bond. The more stable isomer, 11-syn, has a synclinal
arrangement of the N-CCdO bond and the NdC bond
(CNNCCdO dihedral angle 71°). The other isomer (11-anti)
has an anti arrangement of these bonds (dihedral angle 150°)
and is 4.7 kcal mol-1 less stable (ΔH0K). Its lower stability is
afford hydrazones and can be recovered quantitatively from
the products after alkylation. Deprotonation of an ACC
hydrazone is rapid; the stereoselectivity of alkylation is high
even without the use of extreme low temperature, and yields
are excellent. Among the ACCs that we have investigated to
date, camphor-based auxiliary 4 (Scheme 2) has proven to give
the best yields and enantioselectivities.
(6) Davenport, K. G.; Eichenauer, H.; Enders, D.; Newcomb, M.;
Bergbreiter, D. E. J. Am. Chem. Soc. 1979, 101, 5654–5659.
(7) For an X-ray crystal structure of the lithium azaenolate derived from
treatment of 2-acetylnaphthalene-SAMP hydrazone with LDA, see: Enders,
€
D.; Bachstadter, G.; Kremer, K. A. M.; Marsch, M.; Harms, K.; Boche, G.
Angew. Chem., Int. Ed. Engl. 1988, 27, 1522–1524.
A mechanism for the stereoselective alkylation of a
SAMP/RAMP hydrazone was proposed by Enders on the
basis of crystallographic, spectroscopic, and computational
(4) (a) Enders, D.; Eichenauer, H. Angew. Chem., Int. Ed. Engl. 1976, 15,
549–551. (b) Enders, D.; Eichenauer, H. Tetrahedron Lett. 1977, 18, 191–194.
(5) Enders, D. Chem. Scripta 1985, 25, 139–147.
(8) For a review of metal-mediated complex-induced proximity effects in
deprotonation, see: Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P.
Angew. Chem., Int. Ed. 2004, 43, 2206–2225.
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SCHEME 4. Average Bond Angles at Nitrogen in Model Species
due to repulsive interactions between the CdN and CdO
lone pairs. In both isomers of the hydrazone, the ring
nitrogen is pyramidal with an average bond angle of 114°.
In this respect, the ACC hydrazone differs from simple
carbamates (cf. species 12 and 13, Scheme 4) and instead
resembles an N,N-dialkylhydrazone (14). The NR2 lone pair
in 11 and 14 lies roughly in the same plane as the CdN bond,
as a result of steric effects.9
FIGURE 2. Transition states for deprotonation of 11 by Li(NMe2)-
(THF). THF ligands are fogged out for clarity. The “syn-directed”
deprotonation, leading to the ZCN azaenolate, is favored (ΔHq in
rel
kcal mol-1 at 0 K).
To study the directed deprotonation of 11, Li(NMe2)(THF)
was used as a model for LDA in THF solution. Both 11-syn
and 11-anti can undergo an intramolecular deprotonation
reaction, following coordination of Li(NMe2)(THF) to the
carbonyl oxygen. The transition states, TS-11-syn and TS-11-
anti, are shown in Figure 2. The reaction involving 11-syn
represents the “syn-directed” deprotonation described above
(Scheme 3), whereas the reaction of 11-anti leads to the
opposite result, formation of a carbanion trans to the ACC
group. The “syn-directed” deprotonation pathway is favored:
TS-11-syn lies 1.4 kcal mol-1 lower than TS-11-anti. The
absolute barriers, relative to the reactant complexes, are very
low or negative in the gas phase (ΔHq = 0.3 and -0.6 kcal
mol-1, respectively). Because the lowest-energy TS (TS-11-
syn) appears to have a vacant coordination site on the lithium,
we reoptimized its geometry with a second THF coordinated.
The second THF was found to bind in a slightly endergonic
fashion (ΔG þ2.4 kcal mol-1 relative to TS-11-syn þ THF).
For the anti geometry, the lithium is already 4-coordinate in
TS-11-anti, and a stable structure containing a second THF
could not be located.
For the chiral hydrazone 15, derived from the ACC 4,
there are four classes of conformational isomers. These are
shown in Figure 3a. Unlike the achiral hydrazone 11, 15 can
only adopt a syn conformation. Steric crowding between the
rigid bicycloalkane unit and the hydrazone R-methyl group
is too severe for anti conformers to be energy minima. The
two syn conformers, 15-syn-front and 15-syn-back, corre-
spond to the proposed structures 9a and 9b of Scheme 3,
respectively (the terms “front” and “back” refer to the
orientation of the carbonyl group). Consistent with the
earlier model,3 15-syn-front is 3.5 kcal mol-1 more stable
than 15-syn-back. The destabilization of 15-syn-back can
be traced to the conformation about the N-C4 bond in the
oxazolidinone ring. Although the two conformers of 15-syn
are formally related by rotation about the N-N bond, their
interconversion also induces a change in configuration at the
ring nitrogen. This is depicted in Figure 3b, which shows
Newman projections along the N-C4 bond after the
NdCMe2 group has been replaced by a hydrogen atom
(green). The N-C4 bond in 15-syn-back shows substantial
eclipsing, with CNCC and NNCC dihedral angles of 12° and
22°, respectively. By contrast, the smallest dihedral angles
about N-C4 in 15-syn-front are 29° and 56°. The energy
difference between the two structures in Figure 3b is 2.2 kcal
mol-1 (ΔE).
Transition states for the deprotonation of 15 by coordi-
nated Li(NMe2)(THF) are shown in Figure 4. The relative
energies of the transition states are the same as those of the
hydrazones themselves; TS-15-syn-front is 3.5 kcal mol-1
lower in energy than TS-15-syn-back. The barriers relative to
reactants (0.5 and 1.1 kcal mol-1, respectively) are similar to
those for the achiral TS-11-syn and TS-11-anti. The eclipsing
interactions about N-C4 that were present in 15-syn-back
are also present in TS-15-syn-back. There is also a destabiliz-
ing steric interaction (shown by the red line) between the
hydrazone R-methyl group and the nearby methyl group on
the auxiliary. The chiral ACC effectively blocks anti depro-
tonation and makes the front (β) deprotonation consider-
ably easier than the back (R). The front/back selectivity is
calculated to be only marginally affected by solvation. When
the transition structures were optimized in THF using the
conductorlike polarizable continuum model (CPCM),10,11
the preference for TS-15-syn-front was ΔΔHq = 3.3 kcal
mol-1 (ΔΔGq = 4.2 kcal mol-1 at 298.15 K). A transition
state related to TS-15-syn-front but containing a second
THF in the coordination sphere of Liþ was found to be
1.9 kcal mol-1 less stable (ΔG) in the gas phase.
The overall stereoselectivity of the deprotonation-alkyla-
tion sequence is determined by the addition of the azaenolate
to the electrophile. The geometry of lithium azaenolate 16
and transition states for its reaction with MeCl are shown in
Figure 5. Two THF ligands were included in the coordina-
tion sphere of Liþ. During the alkylation, the ACC can be
oriented with its carbonyl group lying in front of or behind
the plane of the azaenolate. MeCl can add to either con-
former and can approach from either the front or back.
Figure 5 shows four transition states, which correspond to
these four possible arrangements of the ACC and MeCl with
respect to the plane of the azaenolate. The relative enthalpies
and free energies are given below each transition state, both
for the gas phase and with a THF solvent model in addition
to the two explicit THFs.
(9) (a) Karabatsos, G. J.; Taller, R. A.; Vane, F. M. Tetrahedron Lett.
1964, 5, 1081–1085. (b) Karabatsos, G. J.; Taller, R. A. Tetrahedron 1968, 24,
3923–3937.
(10) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995–2001.
(11) Barone, V.; Cossi, M.; Tomasi, J. J. Comput. Chem. 1998, 19, 404–
417.
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FIGURE 3. (a) Conformers of the hydrazone 15 and (b) Newman projections showing the conformation about the N-C4 bond in the
oxazolidinone ring [NdCMe2 unit has been removed and replaced by H (green) at a distance of 1 A, while the remaining atoms were held fixed].
˚
Only the syn conformation is available to 15, because the anti conformers would be subject to severe steric interactions between the auxiliary
and the nearby alkyl group on the hydrazone. The rigid bicycloalkane moiety enforces destabilizing eclipsing interactions about the N-C4
bond in 15-syn-back.
16-back by 5 kcal mol-1 relative to 16-front. The front-back
difference increases to 7 kcal mol-1 in their TSs for reaction
with MeCl. Additionally, regardless of the conformation of
16, there is also a 7 kcal mol-1 preference for MeCl to add to
the π-face where the carbonyl group (coordinated to Liþ) is
located (TS-16-A, TS-16-D). Addition to the opposite face
(TS-16-B, TS-16-C) is disfavored because of steric repulsion
between MeCl and the bicycloalkane group, as indicated by
the red lines in Figure 5b. Thus, the alkylation of 16 takes
place exclusively through the lower-energy conformer 16-
front, and MeCl adds selectively to the front side (TS-16-A).
The large stereochemical preference is the result of both steric
effects and Liþ Cl- attraction in TS-16-A.
3 3 3
FIGURE 4. Transition states for deprotonation of 15 by Li(NMe2)-
(THF). Deprotonation from the front (β) face is favored. The
transition state for deprotonation from the back is destabilized both
by eclipsing interactions about N-C4 and by steric interactions
between the hydrazone and the auxiliary (red line) (interatomic
˚
distances in A).
The lithium azaenolate 16 is subject to the same conforma-
tional effects described above for the corresponding hydra-
Having established the facial selectivity of alkylation at an
unsubstituted azaenolate terminus, we then investigated the
alkylation of a substituted azaenolate. Deprotonation at a
secondary carbon introduces the additional consideration of
zone 15. The ring nitrogen is less pyramidal than in the
corresponding hydrazone, with an average bond angle of
117° in 16-front and 118° in 16-back. Pyramidalization (109°)
at the ring nitrogen has previously been observed in the
crystal structure of the SAMP hydrazone 17.7 The lithium
azaenolate 16-back, like its hydrazone precursor, is destabi-
lized by eclipsing interactions about the N-C4 bond. 16-back
is also destabilized by steric interactions between the azaeno-
late and one of the methyl groups on the auxiliary (red line in
Figure 5a), similar to those present in the TS for its formation
(TS-15-syn-back, Figure 4). These two effects destabilize
E
CC/ZCC selectivity. We suggested earlier3 that ECC azaeno-
lates are formed preferentially, on the basis that the allylation
of a 3-pentanone-derived hydrazone and a cyclohexanone-
derived hydrazone both led to ketones that had the same
configuration at the newly formed stereocenter. Transition
states for the deprotonation of an unsymmetrical hydrazone
(18) by Li(NMe2)(THF) are shown in Figure 6. The calculated
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FIGURE 5. (a) Conformers of the lithium azaenolate 16 and (b) transition states for alkylation of 16 by MeCl. Both the azaenolate and the TSs
for alkylation prefer the carbonyl-front conformation. Addition of MeCl to the β face of the azaenolate (TS-16-A) is preferred by 6.5 kcal mol-1
over addition to the R face (TS-16-C) in the gas phase. A similar but smaller preference is retained in solution.
barriers confirm the ECC selectivity. The TS leading to azaeno-
late 19-ECC is favored by 2.9 kcal mol-1 over the TS leading to
19-ZCC. Similar selectivity for formation of ECC azaenolates has
previously been established for SAMP/RAMP-hydrazones.6
Once formed, the azaenolate 19-ECC is unlikely to undergo
conversion to the ZCC isomer. We calculate a CdC rota-
tional barrier of 43 kcal mol-1 for the azaenolate derived
from 11, and the barrier for the more-hindered azaenolate
19-ECC is likely quite higher. The reaction of 19-ECC with
MeCl is calculated to have a stereoselectivity similar to that
of 16; front-side addition of MeCl to 19-ECC is favored by 6.9
kcal mol-1 (ΔΔHq0K) over back-side addition (Supporting
Information).
Although the B3LYP gas-phase calculations for alkyla-
tions of 16 and 19-ECC predict the correct major products,3
they also predict higher stereoselectivity compared with that
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FIGURE 6. Transition states for deprotonation of the substituted hydrazone 18 by Li(NMe2)(THF). The TS leading to the ECC isomer of the
azaenolate is 2.9 kcal mol-1 lower in energy than the TS leading to the ZCC azaenolate.
SCHEME 5. Asymmetric R-Allylation of 20
reported previously. For example, the allylation of hydra-
zone 20 with allyl bromide (Scheme 5) was reported to give
ketone 22 with an er of 96:4, but the gas-phase activation
energies for the reactions of the azaenolates 16 or 19-ECC
with MeCl predict the product 22-β would be formed
exclusively. This high selectivity decreases only slightly with
a bulkier electrophile; for example, the alkylation of 16 by
EtCl is calculated to have a stereoselectivity of 5.7 kcal mol-1
(cf. 6.5 kcal mol-1 for MeCl).
The very high predicted gas-phase selectivities prompted
us to reappraise the experimental selectivities. In our initial
study,3 er values were determined for the ketone products,
following hydrolytic cleavage of the auxiliary. We repeated
the allylation of 20 (Scheme 5), and this time measured the
diastereomer ratio of 21-β to 21-R. HPLC analysis revealed
that 21-β and 21-R were formed in a ratio of >99:1.12
Subsequent hydrolysis of the auxiliary led to 22-β and 22-R
in a ratio of 96:4. Thus, despite the reasonably mild condi-
tions and short reaction time, erosion of stereochemical
integrity occurs during the hydrolysis. We are now seeking
improved conditions for auxiliary cleavage.
The predicted stereoselectivity in solution, however, is
nevertheless not as high as in the gas phase. For example,
in the reaction of the azaenolate 16 with MeCl, the TS
leading to the minor product (TS-16-C) has a larger degree
of charge transfer to MeCl (0.35 e) than the lowest-energy TS
(TS-16-A, 0.29 e).13 This would be expected to lead to
enhanced stabilization of the minor TS in solution. We
calculated CPCM free energies of solvation for the gas-phase
structures in THF. The calculated value of ΔΔGq in THF
at -78 °C is only 1.1 kcal mol-1, corresponding to a dr of 95:5.
The same value of ΔΔGq is obtained if the transition structures
are fully optimized in the solvent model. Although this value is
not expected to be quantitatively accurate (an accurate treat-
ment of solvent effects would require more sophisticated mod-
eling, including treatment of different coordination states
for Liþ) and indeed underestimates the experimental dr, it
does indicate that the predicted stereoselectivity is sensitive to
solvation.
Conclusion
B3LYP calculations support the model for the stereose-
lectivity of ketone R-alkylation shown in Scheme 3. The
crucial features are that (i) the conformation of the inter-
mediate azaenolate is controlled by conformational effects in
the oxazolidinone ring and by steric repulsion between the
chiral auxiliary and the deprotonated group, and (ii) an
electrophile reacts preferentially with the lower-energy azae-
nolate, from the side opposite the bulky bicycloalkane
group. These features resemble the mechanism of stereoin-
duction in the alkylation of SAMP/RAMP hydrazones.4,5
ACC hydrazones represent a convenient new complement to
the SAMP/RAMP methodology.
Theoretical Calculations
B3LYP calculations14-16 were performed with Gaussian 0317
and Gaussian 09.18 The nature of each optimized point was
checked by calculation of the vibrational frequencies, and
(14) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
(15) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J.
J. Phys. Chem. 1994, 98, 11623–11627.
(16) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.
(17) Frisch, M. J., et al. Gaussian 03, Revision C.02; Gaussian, Inc.:
Wallingford, CT, 2004.
(18) Frisch, M. J., et al. Gaussian 09, Revision A.02; Gaussian, Inc.:
Wallingford, CT, 2009.
(12) No regioisomeric products corresponding to allylation at the
R0-position were formed.
(13) Mulliken charges at the B3LYP/6-31G(d) level.
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transition states were further verified by IRC calculations.19,20
Zero-point energy and thermal corrections were derived from
the B3LYP/6-31G(d) frequencies, scaled by Radom’s factors.21
The effects of basis set size were investigated through calcula-
tions of the transition states TS-11-syn and TS-11-anti with the
6-311þG(2d,p) basis (leaving frequencies unscaled); this raised
mixture was stirred for 45 min. Allyl bromide (23.7 μL, 0.272
mmol) was then added, and stirring was continued for
5 min. The cold bath was removed, and the mixture was stirred
for an additional 40 min and then partitioned between Et2O and
H2O. The aqueous phase was extracted with Et2O (twice),
and the combined organic extracts were washed with brine, dried
(MgSO4), filtered, and evaporated under reduced pressure to give
the selectivity in favor of TS-11-syn from 1.4 to 2.9 kcal mol-1
,
1
while the bond lengths involving the transferring proton chan-
crude 21. H NMR (CDCl3, 400 MHz): δ 5.90-5.70 (m, 1H),
˚
ged by only 0.01-0.02 A. The effects of solvation were simulated
5.18-4.94 (m, 2H), 4.25 (dd, J = 8.1, 4.1 Hz, 1H), 3.18-3.04 (m,
1H), 2.50-2.24 (m, 4H), 2.14-1.80 (m, 4H), 1.76 (t, J = 4.4 Hz,
1H), 1.26-1.32 (m, 2H), 1.23 (s, 3H), 1.16 (s, 3H), 1.13 (t, J = 7.2
Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H). HPLC analysis of this material
showed a 99.3:0.7 mixture of 21-β/21-R.25
by means of CPCM calculations10,11 using UAKS radii. Free
energies of solvation were calculated for the gas-phase-opti-
mized geometries and were added to the gas-phase free energies
to obtain the solution-phase free energies. We also performed
geometry optimizations for selected species in THF (Gaussian
The crude material was purified via flash chromatography
over silica gel using 10:90 EtOAc/hexanes to give 21 as a pure,
light-yellow oil (66 mg, 96%). 1H NMR (CDCl3, 400 MHz): δ
5.90-5.70 (m, 1H), 5.18-4.94 (m, 2H), 4.25 (dd, J = 8.1, 4.1 Hz,
1H), 3.18-3.04 (m, 1H), 2.50-2.24 (m, 4H), 2.14-1.80 (m, 4H),
1.76 (t, J = 4.4 Hz, 1H), 1.26-1.32 (m, 2H), 1.23 (s, 3H), 1.16 (s,
3H), 1.13 (t, J = 7.2 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H); 13C NMR
(CDCl3, 100 MHz): δ 184.4, 155.5, 136.6, 116.7, 82.9, 73.4, 47.9,
43.1, 37.6, 35.6, 35.1, 26.7, 25.8, 24.8, 21.5, 19.3, 17.3, 10.4; ESI-
MS m/z [M þ H]þ calcd for C18H29N2O2 305.44, found 305.1.
HPLC analysis of this material showed exclusively 21-β.25
09). Solution-phase free energies are quoted at 1 mol L-1
.
Molecular graphics were produced with the CYLview pro-
gram.22 For simplicity, we have only considered monomeric spe-
cies where the Liþ is coordinated by one NMe2- and one or two
THF ligands (for the deprotonation step), or by two THF
ligands (for the alkylation step). A fuller treatment would
involve adducts having alternative coordination numbers and
aggregation states, as well as multiple conformational isomers.
Collum23 has shown, for example, that at high THF concentra-
tions, the lithium azaenolate derived from cyclohexanone phe-
nylimine exists predominantly as a monomeric species with
three THF ligands coordinated to Liþ. The structures, aggrega-
tion states, and reactivities of lithium enolates and related
species have been studied computationally by Pratt.24 In our
simple model complexes, sampling of different THF conforma-
tions showed energetic variations amounting to a few tenths of a
Hydrolysis of 21-β. p-TsOH H2O (83 mg; 0.436 mmol) was
3
added to a stirred solution of 21-β (66 mg, 0.218 mmol) in
acetone (2 mL). The mixture was stirred for 15 min and then
partitioned between Et2O and saturated aqueous NaHCO3. The
aqueous phase was extracted with Et2O (twice), and the com-
bined organic extracts were washed with brine, dried (MgSO4),
filtered, and evaporated under reduced pressure to give a color-
less oil. GC analysis of this material showed a 96:4 mixture of 22-
β/22-R.25 Flash chromatography of the remaining crude ma-
terial over silica gel using 5:95 Et2O/pentane gave 22 (25.8 mg,
94%) as a pure, colorless oil. Spectroscopic data was identical to
that reported previously.26
kcal mol-1
.
Experimental Methods
Allylation of 20. n-BuLi (2.5 M in hexanes, 100 μL, 0.250
mmol) was added dropwise over ca. 2 min to a stirred and cooled
(-78 °C) solution of diisopropylamine (38.2 μL, 0.272 mmol) in
THF (1.0 mL) (Ar atmosphere). The mixture was cooled for
30 min with an ice-H2O bath and then cooled to -40 °C. A
solution of 20 (60.0 mg, 0.227 mmol) in THF (1.0 mL) was added
by cannula, with additional THF (2 ꢀ 0.3 mL) as a rinse, and the
Acknowledgment. We thank the National Institues of
General Medical Sciences, National Institutes of Health
(GM-36700 to K.N.H.), National Science Foundation
(CHE-0548209 to K.N.H.), Duke University, and Austra-
lian Research Council (DP0985623 to E.H.K.) for generous
financial support, the NCSA, UCLA ATS, UCLA IDRE,
and NCI NF (Australia) for computer resources, and the
NCBC for spectroscopic resources. S.E.W. holds an NSF
graduate fellowship.
(19) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154–2161.
(20) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523–5527.
(21) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502–16513.
ꢀ
(22) Legault, C. Y. CYLview, 1.0b; Universite de Sherbrooke:
Sherbrooke, Canada, 2009; http://www.cylview.org.
(23) Kallman, N.; Collum, D. B. J. Am. Chem. Soc. 1987, 109, 7466–7472.
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(b) Pratt, L. M.; Hogen-Esch, T. E.; Khan, I. M. Tetrahedron 1995, 51, 5955–
5970. (c) Pratt, L. M.; Khan, I. M. J. Mol. Struct.: THEOCHEM 1996, 367,
33–40. (d) Pratt, L. M.; Newman, A.; St. Cyr, J.; Johnson, H.; Miles, B.;
Lattier, A.; Austin, E.; Henderson, S.; Hershey, B.; Lin, M.; Balamraju, Y.;
Sammonds, L.; Cheramie, J.; Karnes, J.; Hymel, E.; Woodford, B.; Carter,
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Supporting Information Available: B3LYP geometries and
energies, complete citations for refs 17 and 18, experimental
procedures, and analytical data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(25) See Supporting Information for details.
(26) Hightower, L. E.; Glasgow, L. R.; Stone, K. M.; Albertson, D. A.;
Smith, H. A. J. Org. Chem. 1970, 35, 1881–1886.
8584 J. Org. Chem. Vol. 75, No. 24, 2010