Dynamic kinetic resolution: Asymmetrie transfer hydrogenation of α-alkyl-substituted β-ketoamides

Article abstract of DOI:10.1021/ol902715d

[Chemical equation presented] Dynamic kinetic resolution (deracemization) of various a-alkyl-substituted β-ketoamides 1 via asymmetric transfer hydrogenation proceeded efficiently to give the corresponding syn-β-hydroxy amides 3 in high diastereo- and enantioselectivities. Specifically, subjection of 1 to HCO₂H and Et₃N in the presence of 0.5-1 mol % of pentafluorobenzenesulfonyl-DPEN-Ru catalyst 2b at 30-40 °C in either PhCH₃ or CH₂Cl₂ generated the syn-hydroxy product 3 selectively in 15-33:1 dr, 93-97% ee, and 75-88% isolated yields.

Full text of DOI:10.1021/ol902715d

ORGANIC
LETTERS
2010
Vol. 12, No. 3
512-515
Dynamic Kinetic Resolution: Asymmetric
Transfer Hydrogenation of
r-Alkyl-Substituted ꢀ-Ketoamides
John Limanto,* Shane W. Krska,* Benjamin T. Dorner, Enrique Vazquez,
Naoki Yoshikawa, and Lushi Tan
Merck & Company, Inc., Merck Research Laboratories, Department of Process
Research, P.O. Box 2000, Rahway, New Jersey 07065
john_limanto@merck.com; shane_krska@merck.com
Received November 24, 2009
ABSTRACT
Dynamic kinetic resolution (deracemization) of various r-alkyl-substituted ꢀ-ketoamides 1 via asymmetric transfer hydrogenation proceeded
efficiently to give the corresponding syn-ꢀ-hydroxy amides 3 in high diastereo- and enantioselectivities. Specifically, subjection of 1 to HCO2H
and Et3N in the presence of 0.5-1 mol % of pentafluorobenzenesulfonyl-DPEN-Ru catalyst 2b at 30-40 °C in either PhCH3 or CH2Cl2 generated
the syn-hydroxy product 3 selectively in 15-33:1 dr, 93-97% ee, and 75-88% isolated yields.
The fields of dynamic kinetic resolution (DKR) and asym-
metric transfer hydrogenation (ATH) have each sparked
extensive interest and found numerous applications in both
academic and industrial arenas. While DKR is a powerful
method for converting a racemic starting material into an
enantio- and/or diastereopure product in a quantitative
theoretical yield,1 ATH has proven to be a useful strategy
for metal- or enzyme-catalyzed enantioselective reduction
of prochiral ketones using suitable hydrogen donors (i.e.,
formic acid or 2-propanol) as a practical alternative to
conventional molecular hydrogen.2
initially reported by Noyori et al.3 and later exploited by
others.4 While there have been several reports on DKR-ATH
of chirally labile ketones, the scope of the substrate is
generally limited to cyclic aliphatic ꢀ-ketoesters or R-het-
eroatom-substituted ꢀ-ketoesters.5
To the best of our knowledge, the concept of metal-
catalyzed DKR-ATH has never been applied to R-alkyl-
substituted ꢀ-ketoamides for the preparation of optically
(2) (a) Wu, X.; Xiao, J. Chem. Commun. 2007, 2449. (b) Ikariya, T.;
Murata, K.; Noyori, R. Org. Biomol. Chem. 2006, 4, 393. (c) Gladiali, S.;
Alberico, E. Chem. Soc. ReV. 2006, 35, 226. (d) Clapham, S. E.; Hadzovic,
A.; Morris, R. H. Coord. Chem. ReV. 2004, 248, 2201. (e) Everaere, K.;
Mortreux, A.; Carpentier, J. F. AdV. Synth. Catal. 2003, 345, 67. (f) Saluzzo,
C.; Lemaire, M. AdV. Synth. Catal. 2002, 344, 915. (g) Noyori, R.;
Yamakawa, M.; Hashiguchi, S. J. Org. Chem. 2001, 66, 7931. (h) Palmer,
M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045. (i) Murata, K.;
Ikariya, T.; Noyori, R. J. Org. Chem. 1999, 64, 2186. (j) Noyori, R.;
Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (k) Zassinovich, G.; Mestroni,
G.; Gladiali, S. Chem. ReV. 1992, 92, 1051.
The demonstration of DKR in a metal-catalyzed asym-
metric hydrogenation (AH) of R-substituted ꢀ-keto esters was
(1) (a) Ma´rtin-Matute, B.; Ba¨ckvall, J.-E. Curr. Opin. Chem. Biol. 2007,
11, 226. (b) Turner, N. J. Curr. Opin. Chem. Biol. 2004, 8, 114. (c) Pellisier,
H. Tetrahedron 2003, 59, 8291. (d) Pamies, O.; Ba¨ckvall, J.-E. Chem. ReV.
2003, 103, 3247. (e) Huerta, F. F.; Minidis, A. B. E.; Ba¨ckvall, J.-E. Chem.
Soc. ReV. 2001, 30, 321. (f) Ohkuma, T.; Kitamura, M.; Noyori, R. Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000;
p 1. (g) Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475.
(3) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.;
Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi,
H. J. Am. Chem. Soc. 1989, 111, 9134.
10.1021/ol902715d  2010 American Chemical Society
Published on Web 12/22/2009

Table 1. Initial DKR-ATH Studies of 1a with Catalyst 2aa
entry
solvent
2a (mol %)b
timec (h)
Et3Nd (equiv)
HCO2Hd (equiv)
convne (%)
3a:4af (HPLC)
% eeg 3a
1
2
3
4
5
6
7
8
CH2Cl2
EtOAc
MeCN
PhCH3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2
2
2
2
2
2
2
0.5
0.5
0.5
0.5
20
48
60
20
20
20
20
21
18
15k
40l
5
5
5
5
2
5
5
5
99
97
90
98
100
99
91:9
80:20
77:23
89:11
94:6
94:6
94:6
94:6
95:5
94:6
95:5
84.7
74.2
76.4
81.0
88.0
87.1
88.5
87.3
92.7
87.6
92.3
5
2h
2
2h
2i
2
2i
98
2
100
100
100
96
9
10
11
1
1
1
1.2j
1.2j
1.2j
a [1] ) 10 mL/g of solvent, 200 mg scale. b Isolated or in situ generated catalyst. c Required time to reach the conversion. d Unless noted otherwise,
added all at once in the beginning of the reaction. e HPLC analysis. f Sum of syn-epimers:sum of anti-epimers in the crude reaction mixture as analyzed by
HPLC and confirmed by NMR and X-ray single crystal structure, where the major syn-3a epimer has configuration of (2R,3R,6S) and the major anti-4a
epimer (2R,3S,6S). g See ref 12. h Added over 2 h. i Added as a 1:1 mixture over 2 h. j Added over 8 h. k 40 °C. l 23 °C.
active ꢀ-hydroxyamides.6 These types of products, as well
as their 1,3-amino alcohol derivatives,7 have been widely
used as synthetic building blocks to access many natural
products and advanced pharmaceutical intermediates, includ-
ing various potent ꢀ-lactam (azetidinone) derivatives.8
Herein, we wish to report the first enantio- and diastereo-
selective approach to R-alkyl-substituted syn-ꢀ-hydroxya-
mides via highly efficient catalytic DKR-ATH reactions
from the corresponding racemic ꢀ-ketoamides.9
Using compound 1a as a test substrate,10 our DKR-ATH
studies were initially performed with Noyori’s p-cymene-
TsDPEN ruthenium(II) chloride complex 2a. Considering that
optically active R-substituted ꢀ-ketoamides have been previ-
ously prepared via a chiral auxiliary methodology,11 the rate
of R-epimerization for our ketoamide substrate was unknown
at the time. Gratifyingly, we found that subjection of 1a to 2
mol % of 2a and 5 mol equiv of each Et3N and HCO2H at 30
°C resulted in high conversions to give the corresponding
alcohols in various solvents (entries 1-4, Table 1), with CH2Cl2
yielding the highest diastereoselectivity and enantioselectivity12
for the syn-hydroxyamide (2R,3R,6S)-3a.13 The observed high
enantio- and diastereoselectivity for the syn epimers indicates
that the R-epimerization event certainly takes place under these
conditions. Upon reducing the amounts of base and hydride
donor to 2 equiv each, higher de and ee were both observed,
regardless of the order of addition (entries 5-7). Furthermore,
performing the reaction with a reduced amount of catalyst
(0.5 mol %) did not result in the erosion of de and ee
(entry 8). Better results were obtained when performing
(4) For representatiVe examples, see: (a) Makino, K.; Hiroki, Y.;
Hamada, Y. J. Am. Chem. Soc. 2005, 127, 5784. (b) Makino, K.; Goto, T.;
Hiroki, Y.; Hamada, Y. Angew. Chem., Int. Ed. Engl. 2004, 43, 882. (c)
Lei, A.; Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 9685. (d)
Mordant, C.; Dunkelmann, P.; Ratovelomanana-Vidal, V.; Genet, J.-P. Eur.
J. Org. Chem. 2004, 3017. (e) Mordant, C.; Dunkelmann, P.; Ratovelo-
manana-Vidal, V.; Genet, J. P. Chem. Commun. 2004, 1296.
(5) (a) Ros, A.; Magriz, A.; Dietrich, H.; Lassaletta, J. M.; Ferna´ndez,
R. Tetrahedron 2007, 63, 7532. (b) Ferna´ndez, R.; Ros, A.; Magriz, A.;
Dietrich, H.; Lassaletta, J. M. Tetrahedron 2007, 63, 6755. (c) Alcock, N. J.;
Mann, I.; Peach, P.; Wills, M. Tetrahedron: Asymmetry 2002, 13, 2485.
(d) Mohar, B.; Valleix, A.; Desmurs, J.-R.; Felemez, M.; Wagner, A.;
Mioskowski, C. Chem. Commun. 2001, 2572.
(6) For an example of enzymatic DKR-ATH of 2-oxocyclopentanecar-
boxamides, see: Quiro´s, M.; Rebolledo, F.; Gotor, V. Tetrahedron:
Asymmetry 1999, 10, 473.
(9) For examples of nonasymmetric, but diastereoselective, reduction
of racemic R-substituted ꢀ-ketoamides, see: (a) Bartoli, G.; Bosco, M.;
Marcantoni, E.; Melchiorre, P.; Rinaldi, S.; Sambri, L. Synlett 2004, 1, 73.
(b) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.; Massaccesi, M.;
Rinaldi, S.; Sambri, L. Tetrahedron Lett. 2001, 42, 8811. (c) Fujita, M.;
Hiyama, T. J. Am. Chem. Soc. 1985, 107, 8294.
(7) For reviews, see: (a) Knapp, S. Chem. ReV. 1995, 95, 1859. (b)
Ohfune, H. Acc. Chem. Res. 1992, 25, 360.
(8) For representatiVe examples, see: (a) Brandi, A.; Cicchi, S.; Cordero,
F. M. Chem. ReV. 2008, 108, 3988. (b) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Chem. ReV. 2007, 107, 4437. (c) Thiruvengadam, T. K.;
Sudhakar, A., R.; Wu, G. Process Chemistry in the Pharmaceutical Industry;
Gadamasetti, K. G., Ed.; Marcel Dekker, Inc.: New York, NY, 1999; p
221. (d) De´ziel, R.; Malenfant, E. Bioorg. Med. Chem. Lett. 1998, 8, 1437.
(e) Clader, J. W.; Burnett, D. A.; Caplen, M. A.; Domalski, M. S.; Dugar,
S.; Vaccaro, W.; Sher, R.; Browne, M. E.; Zhao, H.; Burrier, R. E.;
Salisbury, B.; Davis, H. R. J. Med. Chem. 1996, 39, 3684. (f) Wild, H.;
Kant, J.; Walker, D. G.; Ojima, I.; Ternansky, R. J.; Morin, J. M., Jr.; Georg,
G. I.; Rabikumar, V. T. The Organic Chemistry of ꢀ-Lactams; Georg, G. I.,
Ed.; VCH: New York, 1993.
(10) See Supporting Information for the synthesis of this compound.
(11) Evans, D. A.; Ennis, M. D.; Le, T. J. Am. Chem. Soc. 1984, 106,
1154.
(12) For ease of discussion, the term “enantioselectivity” refers to the
absolute configuration at carbon 2 and 3 of the syn-epimer 3a while ignoring
the fixed stereocenter at the benzylic carbon labeled 6 [i.e., (2R,3R,6S) vs
(2S,3S,6S)].
(13) The absolute stereochemistry was confirmed by X-ray single-crystal
structure (see Supporting Information). Additional information can be found
at the Cambridge Crystallographic Data Centre (CCDC) with deposition
code of CCDC 752316.
Org. Lett., Vol. 12, No. 3, 2010
513

% catalyst loading, 0.5 mol equiv of Et3N, and 1.1 mol equiv
of HCO2H. As discovered previously, slow addition of
HCO2H over 8 h was found to be optimal for achieving the
high conversion and selectivity. In CH2Cl2, excellent dias-
tereo- and enantioselectivity of the syn-isomer were obtained
for all catalysts (entries 1-5), with pentafluorobenzenesulfo-
nyl-DPEN Ru catalyst 2e affording the highest dr (97:3) and
ee (96.7%). While performing the reactions in “greener”
solvents, such as iPAc, DME, or iPA, afforded lower dr and
ee with slightly lower conversions and longer reaction times
(entries 6-8), similar results could be favorably obtained in
toluene, in which the reaction could be completed in 23 h to
afford 93% assay yield of the combined products in 96.8:3
dr and 93.6% ee for the syn-epimer (2R,3R)-3a. Upon scale-
up (mol scales), the syn-product (2R,3R)-3a could be
selectively crystallized from iPA:H2O, affording the product
in 90% yield, 98:2 dr, and 99.5% ee.
Table 2. DKR-ATH of 1 with Various Ru Catalysts 2a
timec convnd
solvent (h) (% assay) (HPLC)
3a:4ae % eef
entry
cat. 2b
R
3a
1
2
3
4
5
6
7
8
9
p-Tol (2a)
CH2Cl2
CH2Cl2
18
20
20
21
22
28
48
72
23
100 (88)
100
94.5:5.5
96.2:3.8
96.2:3.8
95.5:4.4
92.5
91.5
94.2
90.9
96.7
88.8
88.9
p-F-Ph (2b)
p-CF3-Ph (2c) CH2Cl2
CF3 (2d)
F5-Ph (2e)
F5-Ph (2e)
F5-Ph (2e)
F5-Ph (2e)
F5-Ph (2e)
100
CH2Cl2
CH2Cl2
iPAc
DME
iPA
PhCH3
100
100 (95) 96.9:2.9
98
99
89
92.1:7.7
90.7:9.2
85.7:14.3 88.6
93.6
With optimized conditions in hand, the substrate scope
and limitation was subsequently explored. The results from
these studies (Table 3) indicate that the current conditions
(0.5-1 mol % 2b, Et3N, HCO2H, PhCH3, or CH2Cl2, 30-40
°C) generally apply to other R-alkyl-substituted (R2) aromatic
ꢀ-ketoamides (1b-h), affording the corresponding syn
ꢀ-hydroxide amides (3b-h) in high yields and good dias-
tereo- and enantioselectivities (entries 2-8). In addition, the
reaction could also be extended to include aliphatic ketones
(entry 9) and aliphatic amides (entry 10), albeit with lower
diastereoselectivities. Nonetheless, the product purity could
be conveniently upgraded by crystallization to afford the syn
diastereomers in high yields, enantio-, and diastereoselec-
tivities.
100 (93) 96.8:3.0
a [1] ) 10 mL/g of solvent, 200 mg scale, 0.5 equiv of Et3N, 1.1 equiv
of HCO2H added over 8 h. b Isolated catalyst or in situ generated from
[RuCl2-p-cymene]2 and the chiral ligands. c Required time to reach the
conversion. d HPLC analysis. e Sum of syn-epimers:sum of anti-epimers in
the crude reaction mixture as analyzed by HPLC and confirmed by NMR,
where the major syn-3a epimer has configuration of (2R,3R,6S) and the
major anti-4a epimer (2R,3S,6S). f See ref 12.
a slow addition of HCO2H (1.2 equiv) over 8 h to a
solution of 1, Et3N (1 equiv), and 2a (0.5 mol %) in
CH2Cl2 at 30 °C (entry 9). On the other hand, erosion of
enantioselectivity was observed at higher temperature
(entry 11), whereas long reaction time and lower conver-
sions were obtained at lower temperature (entry 10).
To further optimize the transformation, other Ru catalysts,
particularly those bearing electron-deficient aryl sulfonyl
groups on the chiral ligands5d (R in 2), were screened (Table
2). In general, high conversions were obtained using 0.5 mol
As mentioned previously, syn-ꢀ-hydroxyamides can be
readily transformed into synthetically useful trans-ꢀ-lactam
(azetidinone) derivatives via either a Mitsunobu reaction14
or intramolecular displacement of the preactivated alcohols
with the corresponding amide anion.15 In the present case,
Table 3. Substrate Scopea
entry
x
R1
R2
R3
3x:4xb
3x:4xc
% ee 3xd
% yield 3xe
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
p-BrPh
Ph
Ph
Ph
Ph
p-FPhCH-(S)-OTBS-Et-
Et
Et
Bn
allyl
cinnamyl
cinnamyl
p-FPhCH-(S)-OTBS-Et-
cinnamyl
p-IPh
Ph
p-OMePh
Ph
Ph
Ph
p-IPh
p-FPh
Ph
97:3
92:8
91:9
88:12
92:8
93:7
93:7
93:7
83:17
80:20
98:2
99:1
98:2
99:1
92:8
97:3
94:6
99:1
99:1
99:1
99.5
99.5
99
99
98
95
98
92
95
90
80
85
70
74
77
90
90
80
75
Ph
p-BrPh
p-AllylOPh
c-Hex
Ph
10
j
Ph-Pr-
Bn
99.5
a [1] ) 10 mL/g of solvent, 1-50 g scale, 0.5 equiv of Et3N, 1.1-2 equiv of HCO2H added over 8 h, preformed/isolated catalyst 2b. b HPLC ratio of
the crude reaction mixture and confirmed by NMR spectroscopy. c HPLC ratio in the isolated material. d Chiral HPLC analysis (see Supporting Information).
e Isolated by crystallization or SiO2 gel column purification.
514
Org. Lett., Vol. 12, No. 3, 2010

activation of the hydroxyl group in compounds syn-3a and
syn-3c with MsCl and Et3N at -10 °C in toluene cleanly
afforded mesylates 5a and 5c, which were then subsequently
subjected to 35 wt % aqueous KOH and a phase transfer
catalyst, such as BnNEt3Cl, to exclusively afford trans-ꢀ-
lactam 6a and 6c in 94% and 90% isolated yield, respec-
tively, in a one-pot, through process (Scheme 1).16
92:8-99:1 dr.17 An example of the potential utility of this
class of compounds was demonstrated by the preparation of
stereochemically pure, highly functionalized trans-ꢀ-lactams
6a and 6c in high yields.
Acknowledgment. We acknowledge the following Mer-
ck’s analytical group: Mr. Bob Reamer and Ms. Lisa
DiMichele for their assistance with NMR interpretations and
structural assignments, Ms. Mirlinda Biba for her assistance
with HPLC chiral assay method development, and Mr.
Thomas Novak for the HRMS measurements. In addition,
we would also like to thank Dr. Michael McNevin and Dr.
Richard Ball from Merck’s physical characterization group
for generating crystallographic data.
Scheme 1. Diastereoselective Synthesis of trans-ꢀ-Lactam
Supporting Information Available: Experimental pro-
cedures and characterization of new substrates, including
their NMR spectra and single-crystal X-ray structure of
compound 3a. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL902715D
(17) Typical Experimental Procedure: To a solution of keto amide
1a (5 g, 7.04 mmol, 1 equiv) in dry toluene (KF < 50 ppm, 50 mL) was
added the ruthenium catalyst 2b (25 mg, 0.035 mmol, 0.005 equiv) all at
once as a solid at 20-25 °C. The resulting mixture was then purged several
times with N2. Neat triethylamine (0.49 mL, 3.52 mmol, 0.5 equiv) was
then added, and the reaction mixture was warmed to 30-33 °C, at which
neat formic acid (KF ) <1.7 wt %, 0.325 mL, 7.74 mmol, 1.1 equiv) was
charged at a uniform rate over 8 h via a syringe pump. The reaction mixture
was then aged at 30-33 °C for an additional 12 h or until >99.5%
conversion was obtained. Once the reaction was judged complete, the
mixture was then concentrated and solvent switched completely to iPA to
give a thin slurry at 7 mL/g (wrt SM) of final volume (35 mL). The batch
was then warmed to 36-40 °C to give a homogenous solution and cooled
to 25 °C, at which the product started to crystallize. After aging for 10 h at
20-25 °C, water (3 vol. wrt SM, 15 mL) was added as an antisolvent over
1 h. After cooling to 0-5 °C, the resulting slurry was aged for another 2 h
and then filtered. The wetcake was washed with a cold mixture of 1:1 iPA:
H2O (20 mL) and then dried at 40 °C in a vacuum oven. The ꢀ-hydroxy
amide product 3a was typically isolated in 98:2 dr (3a:4a), 99.5% ee, and
90% yield (4.5 g). The absolute stereochemistry of the product was
confirmed by X-ray single crystal structure (see Supporting Information).
In summary, the first enantio- and diastereoselective
synthesis of various syn-R-alkyl-substituted ꢀ-hydroxyamides
via highly efficient Ru-catalyzed DKR-ATH of the corre-
sponding ꢀ-ketoamides has been successfully demonstrated.
Excellent dr and ee were observed when the transformation
was performed in CH2Cl2 or toluene using Ru catalysts
bearing an electron-deficient sulfonyl diamine ligand, such
as 2b. Various types of substrates, including aromatic and
aliphatic R-substituted ꢀ-ketoamides 1, were shown to
selectively yield syn-ꢀ-hydroxyamides 3 in 80:20-97:3
diastereomeric ratio. Upon crystallization or purification by
column chromatography, the desired syn-product 3 could be
obtained in 75-90% isolated yield, 92-99.5% ee, and
(14) (a) Bose, A. K.; Manhas, M. S.; Sahu, D. P.; Hedge, V. R. Can.
J. Chem. 1984, 2498. (b) Miller, M. J.; Mattingly, P. G.; Morrison, M. A.;
Kerwin, J. F. J. Am. Chem. Soc. 1980, 102, 7026.
25
Mp: 122-123 °C. [R]D -67 (c 0.05 M, MeOH). 1H NMR (CDCl3) δ
7.60 (s + d, J ) 8.7 Hz, 3H), 7.44 (d, J ) 8.4 Hz, 2H), 7.23 (t, J ) 8.4 Hz,
4H), 7.15 (m, 2H), 6.95 (t, J ) 8.7 Hz, 2H), 5.08 (s, 1H), 4.57 (m, 1H),
3.42 (s, 1H), 2.50 (m, 1H), 1.66 (m, 4H), 0.82 (s, 9H), -0.04 (s, 3H),
-0.20 (s, 3H). 13C NMR (CDCl3) δ 173.1, 162.1 (d, JCF ) 245.0 Hz),
141.2 (d, JCF ) 3.0 Hz), 140.5, 138.2, 137.2, 131.7, 127.9, 127.4 (d, JCF
) 7.9 Hz), 122.1, 121.8, 115.2 (d, JCF ) 21.3 Hz), 88.1, 75.0, 73.6, 54.2,
38.7, 26.0, 25.9, 22.9, 18.3, -4.4, -4.8. 19F NMR (CDCl3) δ 115.51. Anal.
Calcd for C30H36BrFINO3Si: C, 50.57; H, 5.09; N, 1.97. Found: C, 50.72;
H, 5.10; N, 1.86.
(15) For phase transfer catalyzed cyclization of O-phosphorylated or
O-benzoylated substrates, see ref.8c For a nonphase transfer promoted
process, see: Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1986, 27, 3119.
(16) While executing the mesylation at higher temperatures (>5 °C)
resulted in partial chloride displacement leading to syn ꢀ-lactams, performing
the cyclization under homogenous conditions (KOtBu/THF or LiHMDS/
THF) gave initially the trans-ꢀ-lactam 6, which during the course of the
reaction equilibrated rapidly to a 4:1 mixture of trans:syn ꢀ-lactams.
Org. Lett., Vol. 12, No. 3, 2010
515