Synthesis of planar chiral phosphapalladacycles by N-Acyl amino acid mediated enantioselective palladation

Article abstract of DOI:10.1021/om9005356

Reaction of 2-(dicyclohexylphosphino)phenylferrocene with sodium tetrachloropalladate in the presence of 1 equiv of (R)-N-acetylphenylalanine in MeOH/H₂O/CH₂Cl₂ at pH 8 resulted in the formation of bis(μ-chloro)bis[2-(2-(d

Full text of DOI:10.1021/om9005356

Organometallics 2009, 28, 5833–5836 5833
DOI: 10.1021/om9005356
Synthesis of Planar Chiral Phosphapalladacycles by N-Acyl Amino Acid
Mediated Enantioselective Palladation
€
M. Emin Gunay and Christopher J. Richards*
School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR4 7TJ, U.K.
Received June 19, 2009
Summary: Reaction of 2-(dicyclohexylphosphino)phenylferr-
ocene with sodium tetrachloropalladate in the presence of
1 equiv of (R)-N-acetylphenylalanine in MeOH/H2O/CH2Cl2
at pH 8 resulted in the formation of bis(μ-chloro)bis-
[2-(2-(dicyclohexylphosphino)phenyl)ferrocene-C1,P]dipallad-
ium(II) with a 59% enantiomeric excess of the pS planar chiral
palladacycle. Similarly, (dimethylaminomethyl)ferrocene gave
(pS)-bis(μ-chloro)bis[2-(dimethylaminomethyl)ferrocene-C1,P]-
dipalladium(II) in 96% ee. An intramolecular isotope effect of
2.3 was observed for the palladation of 2-(diphenylphosphino)-
phenylferrocene under these conditions.
Figure 1. Metallocene-based planar chiral palladacycles.
Scheme 1. Known Methods for the Generation of Planar Chiral
Metallocenes by Enantioselective Palladation
Metallocene-based planar chiral palladacycles are of in-
creasing importance in asymmetric organic synthesis, prin-
cipally due to the application of complexes 1 and 2 (Figure 1)
and similar systems as highly enantioselective catalysts for
the allylic imidate rearrangement1 and related reactions.2
The majority of scalemic planar chiral palladacycles are
obtained by resolution or by the use of a chiral auxiliary to
control diastereoselective palladadation,3 the synthesis of 1
and 2 falling into this latter category.1e,4 In contrast, exam-
ples of enantioselective palladation are rare. One of us
recently reported the application of 1a as a reagent for the
transcyclopalladation of prochiral ferrocenes 3, resulting in
the highly enantioselective generation of phosphapallada-
cycles 4 (Scheme 1).5,6 In 1979 Sokolov and others described
*To whom correspondence should be addressed. E-mail: Chris.
Richards@uea.ac.uk.
(1) Cobalt metallocene based palladacycles: (a) Overman, L. E.;
Owen, C. E.; Pavan, M. M.; Richards, C. J. Org. Lett. 2003, 5, 1809.
(b) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003, 125, 12412. (c)
Nomura, H.; Richards, C. J. Chem. Eur. J. 2007, 13, 10216. Ferrocene based
palladacycles: (d) Anderson, C. E.; Donde, Y.; Douglas, C. J.; Overman, L. E.
J. Org. Chem. 2005, 70, 648. (e) Weiss, M. E.; Fischer, D. F.; Xin, Z.; Jautze,
S.; Schweizer, W. B.; Peters, R. Angew. Chem., Int. Ed. 2006, 45, 5694. (f)
Fischer, D. F.; Xin, Z.; Peters, R. Angew. Chem., Int. Ed. 2007, 46, 7704.
(2) (a) Lee, E. E.; Batey, R. A. J. Am. Chem. Soc. 2005, 127, 14887. (b)
Kirsch, S. F.; Overman, L. E. J. Am. Chem. Soc. 2005, 127, 2866. (c) Binder,
J. T.; Kirsch, S. F. Chem. Commun. 2007, 4164. (d) Kirsch, S. F.; Overman,
L. E.; White, N. S. Org. Lett. 2007, 9, 911. (d) Kirsch, S. F.; Overman, L. E. J.
Org. Chem. 2005, 70, 2859. (e) Overman, L. E.; Roberts, S. W.; Sneddon, H.
F. Org. Lett. 2008, 10, 1485.
the reaction of (dimethylaminomethyl)ferrocene (5) with
sodium tetrachloropalladate together with 1 equiv of (S)-
N-acetylleucine (7a), which resulted in the isolation of palla-
dacycle 6 in up to 79% ee (Scheme 1).7 There is currently a
great deal of interest in transition-metal C-H activation
chemistry and its application to arene substitution,8 includ-
ing enantioselective functionalization.9 In light of this and
the potential application of phosphapalladacycles 4 in or-
ganic synthesis, we chose to apply the Sokolov protocol to
prochiral substrates 3. The results of this investigation are
reported in this note.
(3) Djukic, J.-P.; Hijazi, A.; Flack, H. D.; Bernardinelli, G. Chem.
Soc. Rev. 2008, 37, 406.
(4) (a) Stevens, A. M.; Richards, C. J. Organometallics 1999, 18, 1346.
(b) Yeamine, M. R.; Richards, C. J. Tetrahedron: Asymmetry 2007, 18,
2613.
(5) Roca, F. X.; Motevalli, M.; Richards, C. J. J. Am. Chem. Soc.
2005, 127, 2388.
(7) Sokolov, V. I.; Troitskaya, L. L.; Reutov, O. A. J. Organomet.
Chem. 1979, 182, 537.
(6) See also: (a) Dunina, V. V.; Razmyslova, E. D.; Gorunova, O. N.;
Livantsov, M. V.; Grishin, Y. K. Tetrahedron: Asymmetry 2003, 14,
2331. (b) Dunina, V. V.; Gorunova, O. N.; Kuznetsova, E. D.; Turubanova, E.
I.; Livantsov, M. V.; Grishin, Y. K.; Kuz'mina, L. G.; Churakov, A. V. Russ.
Chem. Bull., Int. Ed. 2006, 55, 2193.
(8) (a) Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichim. Acta
2007, 40, 35. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174.
(9) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2008, 47, 4882.
r
2009 American Chemical Society
Published on Web 09/09/2009
pubs.acs.org/Organometallics

5834 Organometallics, Vol. 28, No. 19, 2009
Results and Discussion
Gu€nay and Richards
in contrast to the isopropyl substituent of N-acetylvaline,
which was conspicuously unsuccessful.
Using an adaptation of the Sokolov methodology,7
a
The original Sokolov substrate, (dimethylaminomethyl)-
ferrocene (5), was reinvestigated using the most enantiose-
lective conditions identified for phosphines 3a,b, in order to
see if the previously reported enantiomeric excess of 79%
could be improved. As the ee of the product palladacycle 6
had previously been determined using polarimetry,7 we
sought a more accurate alternative by reacting rac-6 with
(S)-proline, which gave (S,pS)-8 and its S,pR diastereoisomer
with well-separated methyl and cyclopentadienyl singlets in
the resulting 1H NMR spectrum. Using this technique with
the product of (R)-N-acetylphenylalanine-mediated pallada-
tion, obtained in a yield of 88%, resulted in the determina-
tion of an ee of 96% (Scheme 3). The absolute configuration
of the product (pS)-6 was determined by polarimetry.7 Under
otherwise identical conditions (S)-N-acetylleucine gave a
74% yield of (pR)-6 with an ee of 95%.
We also investigated the effect of changing the number of
equivalents of the amino acid derivative on the yield and
enantioselectivity of palladation (Table 2). Starting with
phosphine 3b, doubling the amount of N-acetylphenylala-
nine to 200 mol % with respect to the substrate and sodium
tetrachloropalladate resulted in a 81% yield and a small
increase in the ee to 65% (entry 1). Decreasing the amount to
just 10 mol % with 3b resulted in both a low yield and low ee
(entry 2), whereas amine 5 with 10 mol % (R)-N-acetylphe-
nylalanine also gave a poor yield but with little erosion of
enantioselectivity compared to the stoichiometric reaction
MeOH/CH2Cl2 solution of phosphine 3a was added to an
aqueous solution of 1:1 (S)-N-acetylleucine (7a)/sodium hy-
droxide with the pH adjusted to 8.0 using additional sodium
hydroxide. After the mixture was stirred overnight at room
temperature, the product (pR)-4a was isolated from the reac-
tion mixture in 88% yield and 36% ee (Scheme 2 and Table 1,
entry 1). The ee and absolute configuration were determined
as previously described.5 Lowering and increasing the pH of
the reaction mixture to 7.0 and 9.0, respectively, resulted in a
slight decrease in both yield and enantioselectivity (entries 2
and 3). A number of other N-acetyl amino acid derivatives
were screened at pH 8.0 (entries 4-7), and although most
proved inferior to N-acetylleucine, N-acetylphenylalanine
gave a slightly improved ee of 42%. Replacement of the acetyl
group with a p-toluenesulfonyl group (entries 8 and 9), Boc
group(entry10), benzoylgroup(entry11), andtrifluoroacetyl
group (entry 12) all resulted in a lower ee. The carbonyl or
sulfonyl nitrogen substituents are required to solubilize the
amino acid under the conditions used, as revealed by the use
of (S)-phenylalanine (entry 13). The amino acid was found to
be largely insoluble, and (pR)-4a was isolated with an ee of
26% and a significantly reduced yield (also 26%). Of the
nitrogen substituents screened, the acetyl group is clearly the
optimum group; more electron-withdrawing and/or larger
substituents proved inferior.
Repetition of these reactions on dicyclohexylphenylphos-
phine 3b (entries 14-23) resulted in similar trends, albeit
with generally higher enantioselectivities. Again N-acetyl-
phenylalanine proved to be the most selective, resulting in an
ee of 59% (entry 16). These results reveal that amino acid
derivatives containing “long” R-substituents such as isobu-
tyl, and notably benzyl, gave the highest enantioselectivities
Scheme 3. Enantioselective Palladation of
(dimethylaminomethyl)ferrocene (5)
Scheme 2. N-protected Amino Acid Mediated Enantioselective
Palladation of 3a,b
Table 1. N-protected Amino Acid Mediated Enantioselective Palladation of 3a,ba
product 4a
ee, % (confign)
product 4b
ee, % (confign)
entrya
ligand
yield, %
entry
14
yield, %
77
1
(S)-N-acetylleucine (7a)
(S)-N-acetylleucine (7a)
(S)-N-acetylleucine (7a)
(S)-N-acetylvaline (7b)
(R)-N-acetylphenylalanine (7c)
(S)-N-acetyltryptophan (7d)
(S)-N-acetylproline (7e)
(S)-N-(p-toluenesulfonyl)leucine (7f)
(S)-N-(p-toluenesulfonyl)phenylalanine (7g)
(S)-N-Boc-leucine (7h)
88
70
84
69
80
71
77
85
72
78
69
50
26
36 (pR)
29 (pR)
31 (pR)
∼0
31 (pR)
2b
3c
4
15
16
17
18
19
20
21
22
23
72
85
65
69
81
73
82
85
60
∼0
59 (pS)
12 (pR)
8 (pS)
46 (pR)
32 (pR)
8 (pR)
5
6
7
8
42 (pS)
11 (pR)
13 (pS)
18 (pR)
13 (pR)
9 (pR)
9
10
11
12
13
(S)-N-benzoylphenylalanine (7i)
(S)-N-(trifluoroacetyl)phenylalanine (7j)
(S)-phenylalanine (7k)
12 (pS)
5 (pR)
26% (pR)
10 (pS)
8 (pS)
a All reactions at pH 8.0 unless otherwise stated. b pH 7.0. c pH 9.0.

Note
Organometallics, Vol. 28, No. 19, 2009 5835
Table 2. Influence of N-Acetylphenylalanine Equivalency of the Outcome of Enantioselective Palladationa
entry
substrate
amt of (R)-N-acetylphenylalanine, equiv
product/yield, %
ee, %/confign
1
2
3
3b
3b
5
5
5
2
4b/81
4b/10
6/9
6/35
6/51
4b/54
6/20
65/pS
28/pS
95/pS
95/pS
95/pS
0.1
0.1
0.1
0.1
0
4b
5c
6
3b
5
7
0
a All reactions were performed using the standard conditions with a reaction time of 24 h unless otherwise stated. b With 5 equiv of NaCl. c With 5
equiv of LiCl.
(entry 3). The addition of 5 equiv of NaCl to promote
carboxylate/chloride ligand exchange increased the yield to
35% (entry 4), and the use of 5 equiv of LiCl further
increased the yield to 51% (entry 5). Again in both these
cases no erosion of enantioselectivity was observed. These
results suggest that dissociation of the carboxylate ligand
from the product palladacycle is the factor preventing the
efficient application of N-acetylphenylalanine as a catalyst in
enantioselective palladation. As expected, in the absence of
N-acetylphenylalanine, substrates 3b and 5 both resulted in a
reduced yield of the corresponding palladacycles (entries 6
and 7). The 54% yield obtained with 3b suggests that
competitive achiral palladation of this substrate under the
reaction conditions may, at least in part, be responsible for
the lower enantioselectivities observed with the phosphine
substrates.
Scheme 4. Determination of Intramolecular Isotope Effect for
the Palladation of 3a
The enantioselectivities observed and the requirement for
a stoichiometric quantity of N-acyl amino acid point to these
reactions proceeding via a carboxylate coordinated metal in
which this ligand is intimately involved in the palla-
dium-carbon bond forming step.7 An electrophilic aromatic
substitution pathway (SEAr) has been postulated as the
mechanism of palladation reactions on aryl substrates,10
and ferrocene is a reactive substrate for related SEAr reaction
pathways such as Friedel-Crafts acylation.11 An alternative
concerted metalation-deprotonation (CMD) pathway, also
described as a σ-bond metathesis, has been used to rationa-
lize the acceleration of palladation and other metalation
reactions in the presence of carboxylates and other basic
ligands.12,13 A number of palladium-catalyzed direct aryl-
ation reactions have displayed intramolecular isotope effects
(kH/kD) between 3.5 and 6.5.12d,14 These values are incon-
sistent with a SEAr mechanism for the introduction of
palladium and point to the operation of an alternative
CMD pathway.
To determine the intramolecular isotope effect of N-acetyl
amino acid mediated palladation, racemic 4a15 was first
reacted with lithium aluminum deuteride, resulting in the
isolation of 3a with a 69% deuterium incorporation, as
determined by 1H NMR (Scheme 4). Subsequent palladation
in the presence of N-acetylglycine followed by conversion of
the product chloride-bridged dimer into the monomeric
hexafluoroacetylacetonate complex 9, and 1H NMR analy-
sis, revealed a 48% deuterium incorporation at the 3-posi-
tion of the palladacycle. The calculated kH/kD ratio of 2.3
reveals the involvement of C-H bond cleavage in the rate-
determining step, and the outcome is consistent with the
participation of the carboxylate in a CMD pathway, as
represented in Figure 2. Assuming phosphine coordination
to palladium, which accounts for the R (ortho)-regioselec-
tivity, the reaction is constrained to palladium approach exo
to ferrocene. This is a consequence of the conformational
restriction about the ferrocenyl-aryl σ bond due to the
requirement that the 2-phosphino substituent is oriented
away from the metallocene. A cis-coordinated carboxylate
ligand is then positioned to participate in proton abstraction,
as is also represented in Figure 2. The success of the amino
acid derived ligands may be due to the conformational
restrictions in the torsions designated ψ and φ by analogy
with peptide conformational analysis on examples such as
(10) (a) Canty, A. J.; van Koten, G. Acc. Chem. Res. 1995, 28, 406. (b)
Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org.
Lett. 2004, 6, 1159. (c) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem.
Soc. 2005, 127, 8050.
ꢀ
(11) Mayor-Lopez, M. J.; Weber, J.; Mannfors, B.; Cunningham, A.
F. Organometallics 1998, 17, 4983.
(12) (a) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echa-
varren, A. M. J. Am. Chem. Soc. 2006, 128, 1066. (b) Lafrance, M.;
Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754.
(c) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc.
2005, 127, 13754. (d) Garcia-Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.;
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2007, 129, 6880. (e)
Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
10848.
(13) Other mechanistic pathways for the formation of palla-
dium-carbon bonds in the context of direct arylation reactions include
Heck-like carbopalladation and oxidative C-H insertion; see: (a)
Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko, M.
Org. Lett. 2003, 5, 301. (b) Hughes, C. C.; Trauner, D. Angew. Chem., Int.
Ed. 2002, 41, 1569. (c) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J.
Am. Chem. Soc. 2002, 124, 5286. (d) Mota, A. J.; Dedieu, A.; Bour, C.;
Suffert, J. J. Am. Chem. Soc. 2005, 127, 7171.
(14) (a) Campeau, L.-C.; Parisien, M.; Leblanc, M.; Fagnou, K. J.
Am. Chem. Soc. 2004, 126, 9186. (b) Hennessy, E. J.; Buchwald, S. L. J.
Am. Chem. Soc. 2003, 125, 12084.
(15) Prepared by acetate-chloride ligand exchange5 following room-
temperature palladation with palladium acetate; see: Roca, F. X.;
Richards, C. J. Chem. Commun. 2003, 3002.

5836 Organometallics, Vol. 28, No. 19, 2009
Gu€nay and Richards
dried (MgSO4) and filtered and the solvent removed in vacuo
25
to give the product (S,pS)-8 (0.089 g, 87%). [R]D = -123.5
(c 0.003, CHCl3). A dr of 98:2 (and thus a 96% ee for 6) was
determined using the following signals in the 1H NMR spectrum
(δ, 400 MHz, CDCl3): S,pS, 2.81 (3H, s, NCH3), 3.07 (3H, s,
NCH3), 4.12 (5H, s, C5H5); S,pR, 2.82 (3H, s, NCH3), 2.95 (3H,
s, NCH3), 4.23 (5H, s, C5H5).
Synthesis of Deuterated 3a. To a solution of 4a (0.119 g,
0.10 mmol) in Et2O (5 mL) was added an excess of LiAlD4. The
resulting mixture, which immediately turned black, was stirred
at room temperature for 2 h and then quenched with H2O
(20 mL). The organic layer was separated, dried (MgSO4), and
evaporated in vacuo to give 3a as a yellow solid (0.067 g, 74%).
The ratio of deuterated and nondeuterated5 3a was determined
Figure 2. CMD pathway for enantioselective palladation with
(R)-N-acetylphenylalanine.
Ac-ala-NHMe (the alanine dipeptide).16 The extended
β-conformation (j ≈ 120, φ ≈ -120) is the most stable in
water,16b and it is of note that in this conformation the
methine hydrogen of the stereogenic center is oriented
toward the phosphine substituents, which may account for
the preferred formation of the (pS)-palladacycle. A similar
model can be envisaged to account for the enantioselectivity
observed with substrate 5.
In conclusion, we have demonstrated an improvement and
extension of the Sokolov procedure for the enantioselective
synthesis of planar chiral ferrocene palladacycles. The use of
N-acetylphenylalanine as a chiral carboxylic acid additive
resulted in superior enantioselectivities compared to N-acet-
ylleucine, and the methodology is applicable to the synthesis
of scalemic phosphapalladacycles. A kH/kD value of 2.3 is
consistent with a concerted metalation-deprotonation me-
chanism in which a coordinated chiral carboxylate acts as a
base in the enantioselective carbon-palladium bond form-
ing step.
1
as 69:31. H NMR (δ, 400 MHz, CDCl3): 4.00 (5H, s, C5H5),
4.12 (2H, br s, β-FcH), 4.37 (1.31H, br s, R-FcH), 6.77 (1H, t,
J = 8.0, Ph), 7.05 (1H, t, J = 8.0, Ph), 7.18-7.31 (11H, m, Ph),
7.83-88 (1H, m, Ph). High-resolution MS (m/z, ETD): found
for MHþ 448.1018, calcd for C28H23DFeP 448.1022.
Palladation of Deuterated 3a and the Synthesis of 9. A solution
of N-acetylglycine (0.008 g, 0.07 mmol) and NaOH (0.003 g, 0.07
mmol) in water (1.7 mL) was added to a solution of Na2PdCl4
(0.020 g, 0.07 mmol) in MeOH (5.2 mL), and then the pH of the
resulting solution was adjusted to 8.0 with 50% NaOH. A
solution of the deuterated 3a (0.031 g, 0.07 mmol) in MeOH
and CH2Cl2 (5 mL, 4:1) was added to the stirred solution, and a
precipitate began to appear after ∼1 h. The mixture was stirred
at room temperature overnight. The organic solvents were
removed in vacuo, and the aqueous residue was extracted with
CH2Cl2 (3 ꢀ 10 mL). The organic phase was dried (MgSO4) and
filtered and the solvent removed in vacuo to give the crude
palladacycle 4a.
To the palladacycle was added sodium hexafluoroacetylace-
tonate (0.075 g, 0.33 mmol), acetone (5 mL), and water (3 mL).
The resulting mixture was stirred vigorously at room tempera-
ture until a precipitate was formed (24 h). The organic sol-
vent was removed in vacuo, and the aqueous residue was
extracted with CH2Cl2 (2 ꢀ 10 mL). The organic phase was
dried (MgSO4), filtered, and column chromatographed (SiO2,
CH2Cl2) to give 9 as an orange crystalline solid (0.035 g, 66%).
The ratio of deuterated and nondeuterated 9 (see the Supporting
Information) was determined as 48:52.
Data for 9 are as follows. Mp: 140-145 °C. IR (NaCl): νmax
1638, 1589, 1550cm-1. 1H NMR(δ, 400 MHz, CDCl3): 4.10 (5H,
s, C5H5), 4.40 (1H, br s, FcH), 4.74 (1.52H, br s, FcH), 5.94 (1H,
s, COCH), 6.85 (1H, t, J = 8.0, Ph), 7.03 (1H, t, J = 8.0, Ph), 7.19
(1H, t, J = 8.0, Ph), 7.29-7.37 (11 H, m, Ph), 7.45 (1H, br s, Ph).
13C NMR(δ, 100 MHz, CDCl3): 67.5, 70.8, 73.6, 80.0 (d, J = 35),
82.8 (d, J = 17), 89.7, 119.3, 120.2, 125.1, 125.2, 127-129, 129.5,
130.5, 131.2, 131.3, 132.0, 132.8, 134.1, 134.3, 148.7, 149.0, 175.5
(q, J = 50). 31P NMR (δ, 400 MHz, CDCl3): 33.29. MS (m/z, EI):
754 (4%), 755 (6), 756 (25), 757 (64), 758 (100), 759 (74), 760 (64),
761 (60), 762 (38), 763 (28), 764 (10), 765 (2).
Experimental Section
General Procedure for Asymmetric Palladation. A solution
of the amino acid derivative (0.22 mmol) and NaOH (0.009 g,
0.22 mmol) in water (1.7 mL) was added to a solution of
Na2PdCl4 (0.066 g, 0.22 mmol) in MeOH (5.2 mL), and the
pH of the resulting solution was adjusted to 8 with 50% NaOH.
A solution of the ferrocene derivative (3a,b or 5; 0.22 mmol) in
MeOH and CH2Cl2 (5.0 mL, typically 4:1) was added to the
stirred solution, and a precipitate began to appear after ∼15
min. The mixture was stirred overnight (minimum 15 h). The
organic solvents were removed in vacuo, and the aqueous
residue was extracted with CH2Cl2 (3 ꢀ 10 mL). The organic
phase was dried (MgSO4) and filtered and the solvent removed
in vacuo to give the product palladacycles as either an orange-
red (4a) or dark red crystalline solid (4b and 6). The enantio-
meric excess and absolute configuration of 4a,b were determined
as previously reported.5 The absolute configuration of 6 was
determined by polarimetry; the product of the reaction with
(R)-N-acetylphenylalanine gave [R]D25 = -466 (0.08, CH2Cl2)
(lit.7 (pR)-6 [R]D20 = þ461 (c 1.28, CH2Cl2), 68% ee).
Acknowledgment. We thank the Scientific and Tech-
€
_
nological Research Council of Turkey (TUBITAK)
for financial support (M.E.G.) and the EPSRC National
Mass Spectrometry Centre (University of Wales,
Swansea).
Synthesis of 8 and the Determination of the ee of 6. A suspen-
sion of (pS)-6 (0.088 g, 0.11 mmol) in acetone (5 mL) was
combined with an aqueous solution (10 mL) containing (S)-
proline (0.083 g, 0.72 mmol) and NaHCO3 (0.061 g, 0.72 mmol),
and the mixture was stirred for 24 h at room temperature. The
organic solvent was removed in vacuo, and the aqueous residue
was extracted with CH2Cl2 (2 ꢀ 10 mL). The organic phase was
Supporting Information Available: Text and figures giving
details of the origin of 7a-j, further information on the methods
of ee determination for (pS)-4a, (pS)-4b, and (pS)-6, and the
synthesis and characterization of (pS)-H-9. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) (a) Pettitt, B. M.; Karplus, M. J. Phys. Chem. 1988, 92, 3994. (b)
Tobias, D. J.; Brooks, C. L. J. Phys. Chem. 1992, 96, 3864.