Novel catalytic synthetic route to protected α-methyl threonine and the first asymmetric acetyl migration in a steglich rearrangement reaction

Article abstract of DOI:10.1055/s-2008-1032104

A short synthetic route to protected α-methyl threonine 5 as a representative example for (protected) α-methylated α-amino-β- hydroxy acids bearing a stereogenic quaternary carbon center in α-position was developed. This multistep synthesis is based on th

Full text of DOI:10.1055/s-2008-1032104

LETTER
663
Novel Catalytic Synthetic Route to Protected a-Methyl Threonine and the First
Asymmetric Acetyl Migration in a Steglich Rearrangement Reaction
S
ynthetic Rou
r
te to
P
ro
i
tected
α
e
-Methyl
T
d
hreonine rich R. Dietz, Harald Gröger*
Department of Chemistry and Pharmacy, University of Erlangen-Nuremberg, Henkestr. 42, 91054 Erlangen, Germany
E-mail: harald.groeger@chemie.uni-erlangen.de
Received 27 October 2007
Dedicated to Professor Dr. Dr. Heribert Offermanns on the occasion of his 70th birthday
OH
*
OH
*
OH
*
Abstract: A short synthetic route to protected α-methyl threonine
5 as a representative example for (protected) α-methylated α-ami-
no-β-hydroxy acids bearing a stereogenic quaternary carbon center
in α-position was developed. This multistep synthesis is based on
the use of an easily accessible prochiral starting material in the pres-
ence of an organocatalyst, and allows the access to all four types of
stereoisomers. In addition, the first enantioselective acetyl migra-
tion in a Steglich rearrangement reaction as a key step in this multi-
step synthesis of 5 was achieved. The heterocycle 12, which was
used in Steglich rearrangement reaction for the first time, turned out
to be an efficient organocatalyst leading to an enantioselectivity of
up to 63% ee.
R
CO2H
*
CO2H
CO2H
CO2H
*
*
*
R
R
Me
Me NH2
Me NH2
Me NH2
NH2
1
2
3
4
Figure 1 Structure of different types of amino acids 1–3 and α-me-
thyl threonine (4)
Me
Me
O
diastereo-
selective
reduction
O
OH
*
O
O
O
ring
*
opening
*
*
N
O
Me
Oi-Pr
Me
Oi-Pr
Key words: acylation, amino acids, asymmetric catalysis, rear-
rangements, stereoselective synthesis
Me NHCOPh
Me NHCOPh
Ph
6
5
7
O
Me
O
Me
O
Steglich
rearrangement
rac
The use of α-methylated α-amino acids 1 in pharmaceuti-
cals is of wide importance, and numerous synthetic meth-
ods for their preparation exist.1 Another important class of
nonproteinogenic amino acids are α-amino-β-hydroxy ac-
ids 2 bearing two stereogenic centers, which can be also
synthesized efficiently by chemocatalytic as well as enzy-
matic methods.2 A particular challenge still is the synthe-
sis of α-methylated α-amino-β-hydroxy acids 3 which
combine both of the above-mentioned structural motifs.
Me
N
O
N
O
Ph
Ph
9
8
Scheme 1 Retrosynthetic concept for the new access based on Steg-
lich rearrangement
stereomers. In the following we report the development of
One of the most important representatives of this class is a short synthetic route based on the use of an easily acces-
α-methyl threonine (4, Figure1), which is used as a key sible, prochiral starting material using organocatalytic
building block for the preparation of pharmaceutically rel-
evant molecules such as potential enzyme inhibitors.3
methodologies. This new synthetic approach, which is ex-
emplified for the synthesis of protected α-methyl threo-
nine 5, fulfils both the criteria of (i) having the potential to
be extended to an enantioselective catalytic version, as
well as (ii) being suitable to get access to all four types of
stereoisomer (via a sequential construction of the stereo-
genic centers).
Although numerous elegant diastereoselective synthetic
routes to molecules of type 3 or protected derivatives
thereof are known, these often require long multistep syn-
theses as well as the use of stoichiometric amount of chiral
auxiliaries as starting materials.4 In contrast synthetic
routes to 3 starting from prochiral compounds and using
asymmetric chemocatalytic methodologies are rare.5 So
far, chemocatalytic multistep syntheses are based on met-
al-catalyzed key steps,5 whereas to the best of our knowl-
edge a synthetic approach to the target products 3 using an
organocatalytic key step is not known. Recently, an effi-
cient biocatalytic synthetic route to α-methylated α-ami-
no-β-hydroxy acids 3 has been developed,6 which,
As a solution for the preparation of protected α-methyl
threonine 5 as a target molecule we envisioned the follow-
ing retrosynthetic concept (Scheme1): The final step con-
sists of a diastereoselective reduction of chiral ketone 6
bearing a quaternary stereogenic center. Since numerous
stereoselective asymmetric catalytic reductions are
known, this step should enable the selective reduction of
the C=O bond in either the R- or the S-direction, depend-
however, is limited to the synthesis of very specific dia- ing on the absolute configuration of the catalyst. The
chiral ketone 6 was planned to be prepared by means of a
catalytic ring opening of the heterocycle 7, which is
formed in a Steglich rearrangement reaction starting from
a prochiral O-acylated azlactone derivative 8. The
SYNLETT 2008, No. 5, pp 0663–0666
Advanced online publication: 26.02.2008
DOI: 10.1055/s-2008-1032104; Art ID: G35107ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8

664
F. R. Dietz, H. Gröger
LETTER
Me
Me
Table 1 Enantioselective Acetyl Migration in Steglich Rearrange-
ment
N
N
(Me)2N
O
O
Me
Me
O
N
rac
10 (7.5 mol%)
CH2Cl2, r.t., 3 h
Et3N, AcCl
Me
Fe
Ph
THF, 0 °C, 1 h
Ph
Ph
N
O
N
H
N
O
or
step A
step B
Ph
Ph
S
N
Ph
Ph
Ph
(S)-11
8
rac-9
(S)-12
81% yield
O
O
Me
O
(S)-11 or (S)-12
solvent, temp, time
O
Me
O
Me
10 (10 mol%)
i-PrOH
r.t., 16 h
*
Me
NaBH4
i-PrOH, 0 °C, 2 h;
then r.t., 2 h
O
O
O
Me
Me
*
O
N
N
O
*
Me
Oi-Pr
O
N
Me NHCOPh
step C
step D
Ph
Ph
Ph
rac-7
89% conversion
8
65 % conversion
d.r. 60:40
7
rac-6
84% yield
Entry15 Cat.
Solvent
Temp Time Conversion ee (%)
(%)
98% yield
(mol%)
11 (2)
11 (2)
11 (2)
11 (2)
OH
O
OH
*
O
1
2
3
4
5
6
CH2Cl2
toluene
MTBE
THF
r.t.
r.t.
r.t.
3 h
3 h
3 h
84
80
78
71
80
82
25
23
24
18
63
59
+
*
*
*
Me
Oi-Pr
Me
Oi-Pr
Me NHCOPh
Me NHCOPh
rac-l-5
major diastereomer
rac-u-5
minor diastereomer
(18% yield)
(18% yield)
0 °C 3 h
(only one enantiomer shown)
12 (32) CDCl3
12 (32) CHCl2
r.t.
r.t.
2 d
3 d
Scheme 2 Multistep synthesis of protected α-methylthreonine
prochiral substrate 8 can be easily synthesized from azlac-
tone 9 via acylation. Steglich rearrangement reactions are
typically catalyzed by an organic base. Thus, stereocon-
trol of this Steglich rearrangement should be possible
when using suitable chiral bases as organocatalysts, albeit
so far asymmetric migration of the acetyl group has not
been reported.
racemic diastereomers rac-l-5 and rac-u-5 were formed
with a conversion of 65% and a diastereomeric ratio of
60:40 (step D).11 Subsequently, the diastereomers were
separated by means of column chromatography, leading
to the isolated two (racemic) diastereomers rac-l-5 and
rac-u-5 in (nonoptimized) yields of 18% in both cases.11
The azlactone rac-9 represents an easily accessible start-
ing material, which has been prepared from DL-alanine as
a readily available and economically attractive raw mate-
rial.7 In a first step the azlactone rac-9 is converted into its
prochiral O-acylated form 8 (Scheme2, step A), followed
by a Steglich rearrangement with 4-dimethylaminopyri-
dine (DMAP, 10) as an organocatalyst under formation of
the racemic intermediate rac-7. This acetyl migration
(step B) was previously reported by Steglich and co-work-
ers.8 When carrying out the reaction according to this pro-
tocol in a somewhat modified form with DMAP as a base
a yield of 98% was obtained for rac-7.9
In addition, preliminary studies with respect to an enan-
tioselective fashion of this type of Steglich rearrangement
under migration of an acetyl functionality as a key step in
the multistep synthesis have been done (Table1). So far,
there are no reports in the literature for the asymmetric mi-
gration of acetyl groups in such a type of reaction, where-
as analogous migration of alkoxycarbonyl and
benzyloxycarbonyl groups is widely known.12 As a chiral
organocatalyst, the commercially available catalyst (S)-
11, developed by the Fu group,13 has been used due to
very successful applications of this and related catalysts in
resolution reactions via acylation and migration of alk-
oxycarbonyl and benzyloxycarbonyl groups in Steglich
rearrangement reactions.12a,13,14 In the presence of (S)-11
with a low catalytic amount of only 2 mol%, the desired
key intermediate 7 was formed with a high conversion of
84% and an enantioselectivity of 25% ee (Table1, entry
1). Albeit the enantioselectivity has only been in a modest
range, this initial result represents a proof of principle that
the migration of the acetyl group as well as the formation
of the key intermediate 7 can be done in an enantioselec-
tive fashion. Reaction conditions such as solvent and tem-
perature have been varied, however, without
improvement of the enantioselective course of the reac-
The subsequent ring opening of rac-7 has been also done
in a catalytic fashion. Notably, the same type of organo-
catalyst as for the Steglich rearrangement was used: In the
presence of 10 mol% of the organocatalyst DMAP (10)
this key reaction step proceeds under formation of the N-
acyl α-amino β-oxobutyrate rac-6 with high conversion
of 89% (step C). After chromatographic purification this
desired key intermediate rac-6 was obtained in 84% yield
with high purity.10 When reducing the aceto moiety in the
racemic intermediate rac-6 with sodium borohydride as a
reducing agent in isopropanol as a solvent, the resulting
Synlett 2008, No. 5, 663–666 © Thieme Stuttgart · New York

LETTER
Synthetic Route to Protected α-Methyl Threonine
665
(2) (a) Jung, M. E.; Young, Y. H. Tetrahedron Lett. 1989, 30,
6637. (b) Blaskovich, M. A.; Evindar, G.; Rose, N. G. W.;
Wilkinson, S.; Lao, Y.; Lajoe, G. A. J. Org. Chem. 1998, 63,
3631. (c) Coppola, G. M.; Schuster, H. F. Asymmetric
Synthesis. Construction of Chiral Molecules Using Amino
Acids; John Wiley and Sons: Toronto, 1987.
(3) (a) Watts, J.; Benn, A.; Flinn, N.; Monk, T.; Ramjee, M.;
Ray, P.; Wang, Y.; Quibell, M. Bioorg. Med. Chem. 2004,
12, 2903. (b) Wei, L.; Steiner, J. P.; Hamilton, G. S.; Wu,
Y.-Q. Bioorg. Med. Chem. Lett. 2004, 12, 4549.
(4) Diastereoselective multistep syntheses with stoichiometric
amount of chiral auxiliaries: (a) Avenoza, A.; Busto, J. H.;
Corzana, F.; Peregrina, J. M.; Sucunza, D.; Zurbano, M. M.
Tetrahedron: Asymmetry 2004, 15, 719. (b) Shao, H.;
Rueter, J. K.; Goodman, M. J. Org. Chem. 1998, 63, 5240.
(c) Ohfune, Y.; Moon, S.-H.; Horikawa, M. Pure Appl.
Chem. 1996, 68, 645. (d) Moon, S.-H.; Ohfune, Y. J. Am.
Chem. Soc. 1994, 116, 7405. (e) Blank, S.; Seebach, D.
Liebigs Ann. Chem. 1993, 8, 889. (f) Seebach, D.; Aebi, J.
D.; Gander-Coquoz, M.; Naef, R. Helv. Chim. Acta 1987,
70, 1194. (g) Seebach, D.; Aebi, J. D. Tetrahedron Lett.
1983, 24, 3311. (h) Schöllkopf, U. Tetrahedron 1983, 39,
2085. (i) Schöllkopf, U.; Hartwig, W.; Groth, U. Angew.
Chem. 1980, 92, 205.
tion with this catalyst (S)-11 (entries 2–4). The best sol-
vent in terms of product formation was dichloromethane
(entry 1).
Surprisingly, however, a significant improvement has
been achieved when using the chiral bicyclic isothiourea
(–)-tetramisole [(S)-12] as an organocatalyst. This mole-
cule (S)-12 is economically attractive, produced on large
scale for medicinal and veterinary purposes and commer-
cially available in enantiomerically pure form as a hydro-
chloride under the name Levamisole.16 Very recently it
was applied by the Birman group as a catalyst in kinetic
resolution processes.16 When we used this heterocycle
(S)-12 with a catalytic amount of 32 mol%, the desired
product 7 was formed with a conversion of 80%, and the
enantioselectivity remarkably increased to 63% ee (entry
5). Notably, to the best of our knowledge this type of or-
ganocatalyst has not been used in Steglich rearrangement
reactions so far, thus representing an interesting lead
structure for further catalyst improvement. In particular,
reactivity has to be increased since so far a long reaction
time of 2–3 days is required (entries 5 and 6).
(5) Multistep syntheses with an asymmetric chemocatalytic
reaction as key step: (a) Chiral osmium-complex-catalyzed
dihydroxylation as key step: Shao, H.; Rueter, J. K.;
Goodman, M. J. Org. Chem. 1998, 63, 5240.
In summary, a novel and short multistep synthesis to pro-
tected α-methyl threonine 5 as a representative example
for (protected) α-methylated α-amino-β-hydroxy acids
bearing a stereogenic quaternary carbon center in α-posi-
tion is presented. This synthesis is based on the use of an
easily available and prochiral starting material in the pres-
ence of organocatalysts, and allows the access to all four
types of stereoisomers. Furthermore, the first enantiose-
lective acetyl migration in Steglich rearrangement reac-
tions as a key step in this multistep synthesis of 5 has been
achieved. The heterocycle (S)-12, which was never used
before in Steglich rearrangement reactions, turned out to
be a particular efficient organocatalyst leading to enan-
tioselectivities of up to 63% ee. The development of im-
proved catalysts based on (S)-12 as a lead structure is
planned as a next step, as well as the extension of this syn-
thetic concept towards other (protected) α-methylated α-
amino-β-hydroxy acids.
(b) Asymmetric aldol reaction of isocyano carboxylates
catalyzed by chiral gold(I) complexes as key step: Ito, Y.;
Sawamura, M.; Shirakawa, E.; Hayashizaki, K.; Hayashi, T.
Tetrahedron 1988, 44, 5253.
(6) Enzymatic production of L-serine derivative by using
microbial 2-methylserine hydroxymethyltransferases:
Kuroda, S.; Nozaki, H.; Watanabe, K.; Yokozeki, K.;
Imabayashi, Y. WO 2006123745, 2006.
(7) (a) Obrecht, D.; Altdorfer, M.; Lehmann, C.; Schoenholzer,
P.; Müller, K. J. Org. Chem. 1996, 3, 230. (b) Chen, F. M.
F.; Kuroda, K.; Benoiton, N. L. Synthesis 1979, 230.
(c) Liang, J.; Ruble, J. G.; Fu, G. C. J. Org. Chem. 1998, 63,
3154.
(8) Steglich, W.; Höfle, G. Tetrahedron Lett. 1970, 54, 4727.
(9) Preparation of rac-4-Acetyl-4-methyl-2-phenyloxazol-5-
one (rac-7)
In analogy to a protocol described in ref. 8, 5-acetyloxy-4-
methyl-2-phenyloxazole (8, 2.0 g, 9.3 mmol) and DMAP
(10, 90 mg, 0.7 mmol) were dissolved in CH2Cl2 (50 mL) at
r.t. After 3 h of stirring, the solvent was removed to give 7
(2.05 g, 9.4 mmol, purity >95%) as yellow oil. 1H NMR (400
MHz, CDCl3): δ = 1.69 (3 H, s), 2.27 (3 H, s), 7.45–7.60 (3
H, m), 8.00–8.02 (2 H, m) ppm. 13C NMR (100 MHz,
CDCl3): δ = 20.95, 25.84, 77.96, 125.20,128.10, 128.87,
133.28, 162.61, 174.42, 198.39 ppm. MS–FAB: m/z = 218,
176.
Acknowledgment
The authors would like to thank Evonik-Degussa GmbH for dona-
ting methyl tert-butyl ether (MTBE).
References and Notes
(10) Preparation of rac-2-Benzoylamino-2-methyl-3-
oxobutyric Acid Isopropyl Ester (rac-6)
(1) (a) Maruoka, K.; Ooi, T.; Kano, T. Chem. Commun. 2007,
1487. (b) Cativiela, C.; Diaz-de-Villegas, M. D.
4-Acetyl-4-methyl-2-phenyloxazol-5-one (rac-7, 1.5 g, 6.9
mmol) and DMAP (10, 90 mg, 0.7 mmol) were dissolved in
i-PrOH (40 mL). The reaction mixture was stirred for 16 h
and the excess of i-PrOH was removed in vacuo. The
resulting crude product was purified by column
chromatography [SiO2 60 Å, cyclohexane–EtOAc (3:1)] to
give rac-6 (1.62 g, 5.8 mmol, 84% yield). 1H NMR (400
MHz, CDCl3): δ = 1.18 (3 H, d, J = 6.3 Hz), 1.21 (3 H, d,
J = 6.3 Hz), 1.79 (3 H, s), 2.21 (3 H, s), 5.08 (1 H, sept,
J = 6.3 Hz), 7.40–7.44 (2 H, m), 7.48–7.52 (1 H, m), 7.71 (1
H, br s), 7.78–7.81 (2 H, m) ppm. 13C NMR (100 MHz,
Tetrahedron: Asymmetry 1998, 9, 3517. (c) Huang, Z.; He,
Y.-B.; Raynor, K.; Tallent, M.; Reisine, T.; Goodman, M. J.
Am. Chem. Soc. 1992, 114, 9390. (d) He, Y.-B.; Huang, Z.;
Raynor, K.; Reisine, T.; Goodman, M. J. Am. Chem. Soc.
1993, 115, 8066. (e) Chalmers, D. K.; Marshall, G. J. Am.
Chem. Soc. 1995, 117, 5927.
Synlett 2008, No. 5, 663–666 © Thieme Stuttgart · New York

666
F. R. Dietz, H. Gröger
LETTER
(12) (a) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120,
CDCl3): δ = 19.97, 21.36, 21.39, 23.97, 68.62, 70.51,
127.02, 128.58, 131.84, 133.51, 165.85, 168.56, 200.23
ppm. MS (EI): m/z = 278, 234. IR: 3412, 3327, 2984, 1722,
1664 cm–1. Anal. Calcd (%) for C15H19NO4: C, 64.97; H,
6.91; N, 5.05. Found: C, 64.61; H, 6.88; N, 4.89.
11532. (b) Shaw, S.; Aleman, P.; Vedejs, E. J. Am. Chem.
Soc. 2003, 125, 13368. (c) Shaw, S. A.; Aleman, P.; Christy,
J.; Kampf, J. W.; Va, P.; Vedejis, E. J. Am. Chem. Soc. 2006,
128, 925. (d) Busto, E.; Gotor-Fernandez, V.; Gotor, V. Adv.
Synth. Catal. 2006, 348, 2626.
(11) Preparation of Diastereomers of rac-2-Benzoylamino-3-
hydroxy-2-methylbutyric Acid Isopropyl Ester (rac-l-5,
rac-u-5)
(13) (a) Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230.
(b) For an excellent review about development and
application of these type of catalysts, see: Fu, G. C. Acc.
Chem. Res. 2004, 37, 542.
(14) For an overview about organocatalytic methodologies in
general, see: Berkessel, A.; Gröger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, 2005.
(15) Experimental Procedure (Exemplified for Reaction in
Table 1, Entry 1)
2-Benzoylamino-2-methyl-3-oxobutyric acid isopropyl
ester (rac-6, 200 mg, 0.72 mmol) was dissolved in i-PrOH
(20 mL) and cooled in an ice bath. After adding NaBH4 (13.6
mg, 0.36 mmol) the mixture was stirred at ice-bath
temperature for 2 h, and further 2 h at r.t. Subsequently,
dilute HCl was added until no further hydrogen was evolved.
After addition of H2O the reaction mixture was extracted 5
times with MTBE. Removal of the solvent furnished a crude
product of the resulting racemic diastereomers l-5 and u-5
(dr = 60:40), which were separated by column chroma-
tography [SiO2 60 Å, cyclohexane–EtOAc (3:1)] to give rac-
l-5 (36 mg, 0.13 mmol, 18%) and rac-u-5 (37 mg, 0.13
mmol, 18%).
5-Acetyloxy-4-methyl-2-phenyloxazole (8, 500 mg, 2.3
mmol) and 4-dimethylaminopyridinyl-(pentaphenyl-
cyclopentadienyl)iron [(S)-11, 40 mg, 0.06 mmol] were
dissolved in CH2Cl2 (20 mL) and stirred at r.t. for 3 h.
Subsequently the solvent was removed to give 4-acetyl-4-
methyl-2-phenyloxazol-5-one 7 (537 mg) as an oily crude
product. The conversion (84%) and enantioselectivity (25%
ee) were determined by 1H NMR spectroscopy and chiral
HPLC chromatography [after derivatization to 6, Daicel
Chiralcel OD column, hexane/2-PrOH (97:3)], respectively.
The spectroscopic properties are in accordance with those
for the racemic product rac-7. The other reactions with
catalyst (S)-11 (Table1, entries 2–4) as well as the reaction
with (–)-tetramisole [(S)-12] as a catalyst in CH2Cl2 (Table1,
entry 6) were carried out on a 2 mL scale using 100 mg of
substrate 8. The reaction with (S)-12 as a catalyst (Table1,
entry 5) was carried out on a 1 mL scale, and the conversion
was directly determined from the reaction mixture by 1H
NMR spectroscopy in this experiment.
Compound rac-l-5: Rf = 0.16. 1H NMR (400 MHz, CDCl3):
δ = 1.07 (3 H, d, J = 6.5 Hz), 1.25–1.29 (6 H, m), 1.69 (3 H,
s), 4.14–4.22 (1 H, m), 5.05–5.14 (1 H, m), 5.49 (1 H, d,
J = 10.1 Hz), 7.41–7.45 (2 H, m), 7.48–7.53 (1 H, m), 7.61
(1 H, br s), 7.79–7.81 (2 H, m) ppm. 13C NMR (100 MHz,
CDCl3): δ = 18.67, 18.85, 21.49, 65.90, 70.53, 71.19,
127.09, 128.67, 131.99, 133.82, 167.89, 173.42 ppm. MS–
FAB: m/z = 280. IR: 3516, 3242, 2984, 1706, 1633 cm–1.
Anal. Calcd (%) for C15H21NO4: C, 64.50; H, 7.58; N, 5.01.
Found: C, 62.82; H, 7.51; N, 4.75.
Compound rac-u-5: Rf = 0.06. 1H NMR (400 MHz, CDCl3):
δ = 1.20–1.26 (9 H, m), 1.58 (3 H, s), 3.71 (1 H, br s), 4.13–
4.20 (1 H, m), 5.04–5.13 (1 H, m), 6.86 (1 H, br s), 7.38–7.42
(2 H, m), 7.46–7.50 (1 H, m), 7.74–7.77 (2 H, m) ppm. 13
C
(16) (a) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351. (b) The
Birman group also reported that benzotetramisole turned out
to be an improved and very efficient organocatalyst in
resolution processes compared with (–)-tetramisole [(S)-12].
Thus, this catalyst might also give improved
NMR (100 MHz, CDCl3): δ = 17.85, 18.60, 21.63, 21.69,
64.60, 69.57, 71.29, 127.00, 128.56, 131.67, 134.39, 167.83,
172.09 ppm. MS–FAB: m/z = 280. IR: 3412, 3331, 2976,
1733, 1640 cm–1. Anal. Calcd (%) for C15H21NO4: C, 64.50;
H, 7.58; N, 5.01. Found: C, 64.13; H, 7.61; N, 4.87.
enantioselectivities in the synthesis of 7, which is planned to
be studied next.
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