Concise synthesis of C 2-symmetrical 2,6-disubstituted morpholines by N → O Boc migration under SL-PTC conditions

Article abstract of DOI:10.1021/op1000435

A novel, straightforward synthesis of enantiomerically pure 2,6-disubstituted morpholines has been developed. The ring-opening of epoxides with TsNHBoc under solid-liquid phase transfer catalysis conditions occurred with N → O migration of the Boc group, affording an intermediate carbonate that has been easily transformed to morpholines.

Full text of DOI:10.1021/op1000435

Organic Process Research & Development 2010, 14, 705–711
Concise Synthesis of C2-Symmetrical 2,6-Disubstituted Morpholines by N f O Boc
Migration under SL-PTC Conditions
Domenico Albanese,*,† Dario Landini,† Michele Penso,‡ Aaron Tagliabue,† and Emanuele Carlini†
Dipartimento di Chimica Organica e Industriale, UniVersita` degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy,
Istituto di Scienze e Tecnologie Molecolari-CNR (CNR-ISTM), Via Golgi 19, 20133 Milano, Italia
Scheme 1
Abstract:
A novel, straightforward synthesis of enantiomerically pure 2,6-
disubstituted morpholines has been developed. The ring-opening
of epoxides with TsNHBoc under solid-liquid phase transfer
catalysis conditions occurred with N f O migration of the Boc
group, affording an intermediate carbonate that has been easily
transformed to morpholines.
Scheme 2
Introduction
Substituted morpholines have received considerable attention
due to their wide range of biological and therapeutic properties.1
2,6-Disubstituted morpholines are also used as active ingredients
in agricultural formulations for the control of disease in cereal
crops.2 Enantiomerically enriched 2-vinyl morpholines have
been generated in moderate to good ee through palladium-
catalyzed tandem allylic substitution.3 However, excellent
stereoselectivity has only been obtained by using a xylofuranose-
based phosphinooxazinane as ligand.4 Moreover, C2-sym-
metrical morpholines have been used as chiral auxiliaries.5
Optically pure 2,6-disubstituted morpholines could also be
prepared by diastereoselective alkylation of 6-substituted 3-oxo
morpholines, followed by reduction of the carbonyl moiety and
removal of the chiral auxiliary.6
transfer catalyzed bis-alkylation of 4-methyl-benzenesulfona-
mide (2) by oxiranes 1, followed by cyclization of hydroxysul-
fonamides 3 thus obtained (Scheme 1).7
Enantiomerically pure 2,6-disubstituted morpholines 4 have
also been generated through acid-catalyzed cyclization of epoxy
alcohols 5 derived from the ring-opening of enantiopure
glycidols with a solketal-derived sulfonamide (Scheme 2).8
Chiral, 2,6-disubstituted morpholines were later prepared
through the same procedure by using protecting group chem-
istry9 or through regioselective functionalization of unsym-
metrical diols 3 with 2,4,6-tris-isopropylbenzenesulfonyl chlo-
ride (Tris-Cl), followed by cyclization (Scheme 3).10
In the context of our recent interest in the synthesis of
enantiomerically pure morpholines, we focused on the ring-
opening of epoxides 1 with N-(tert-butoxycarbonyl)-4-methyl-
benzenesulfonamide (7) (TsNHBoc) as nucleophile under SL-
PTC conditions. The tert-butoxycarbonyl (Boc) substituent is
one of the most widely used protecting groups in synthetic
organic chemistry. However, under certain reaction conditions,
migration of the Boc group has been observed, thus expanding
its synthetic utility if controllable.11
In a previous paper we reported the concise synthesis of
racemic 2,6-disubstituted morpholines 4 through the phase
* Corresponding author. Fax: +390250314159. E-Mail: domenico.albanese@
unimi.it.
† Universita` degli Studi di Milano.
‡ Istituto di Scienze e Tecnologie Molecolari-CNR (CNR-ISTM).
(1) (a) Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; Van Delft, F. L.;
Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641–662. (b) Lanman,
B. A.; Myers, A. G. Org. Lett. 2004, 6, 1045–1047.
(2) Forsyth, S. A.; Gunaratne, H. Q. N.; Hardacre, C.; McKeown, A.;
Rooney, D. W. Org. Process Res. DeV. 2006, 10, 94–102.
(3) (a) Uozumi, Y.; Tanahashi, A.; Hayashi, T. J. Org. Chem. 1993, 58,
6826–6832. (b) Yamazaki, A.; Achiwa, K. Tetrahedron: Asymmetry
1995, 5, 1021–1024. (c) Ito, K.; Imahayashi, Y.; Kuroda, T.; Eno, S.;
Saito, B.; Katsuki, T. Tetrahedron Lett. 2004, 45, 7277–7281. (d)
Massacret, M.; Lakhmiri, R.; Lhoste, P.; Nguefack, C.; Ben Abdel-
ouahab, F. B.; Fadel, R.; Sinou, D. Tetrahedron: Asymmetry 2000,
11, 3561–3568. (e) Wilkinson, M. C. Tetrahedron Lett. 2005, 46,
4773–4775.
Here we report a new pathway for the efficient synthesis of
enantiomerically pure, 2,6-disubstituted C2 symmetric morpholines.
(4) Nakano, H.; Yokoyama, J.-i.; Fujita, R.; Hongo, H. Tetrahedron Lett.
2002, 43, 7761–7764.
(7) Lupi, V.; Albanese, D.; Landini, D.; Scaletti, D.; Penso, M. Tetrahe-
dron 2004, 60, 11709–11718.
(5) (a) Enders, D.; Meyer, O.; Raabe, G.; Runsink, J. Synthesis 1994,
66–72. (b) Baldoli, C.; Del Buttero, P.; Licandro, E.; Maiorana, S.;
Papagni, A.; Zanotti Gerosa, A. J. Organomet. Chem. 1995, 486, 279–
282. (c) Licandro, E.; Maiorana, S.; Capella, L.; Manzotti, R.; Papagni,
A.; Pryce, M.; Graiff, C.; Tiripicchio, A. Eur. J. Org. Chem. 1998,
212, 7–2133. (d) Dave, R.; Sasaki, N. A. Org. Lett. 2004, 6, 15–18.
(6) Bouron, E.; Goussard, G.; Marchand, C.; Bonin, M.; Pannecoucke,
X.; Quirion, J.-C.; Husson, H.-P. Tetrahedron Lett. 1999, 40, 7227–
7230.
(8) Albanese, D.; Salsa, M.; Landini, D.; Lupi, V.; Penso, M. Eur. J. Org.
Chem. 2007, 210, 7–2113.
(9) Penso, M.; Lupi, V.; Albanese, D.; Foschi, F.; Landini, D.; Tagliabue,
A. Synlett 2008, 2451–2454.
(10) Albanese, D.; Foschi, F.; Penso, M. Catal. Today 2009, 140, 100–
104.
(11) (a) Agami, C.; Couty, F. Tetrahedron 2002, 58, 2701–2724. (b)
Hodgson, D. M.; Humphreys, P. G.; Miles, S. M.; Brierley, C. A. J.;
Ward, J. G. J. Org. Chem. 2007, 72, 10009–10021.
10.1021/op1000435  2010 American Chemical Society
Published on Web 04/22/2010
Vol. 14, No. 3, 2010 / Organic Process Research & Development
•
705

Scheme 3
the amount of TsNHBoc. Indeed, 71% of 9a could be isolated
by using 0.75 mol of TsNHBoc per mole of epoxide (entry 7).
Although reactions carried out with excess K2CO3 proceeded
in the absence of solvent, best results as regards to reaction
time and reproducibility have been obtained by using small
volumes of dioxane in order to maintain an efficient strirring
of the heterogeneous reaction mixture (entries 6-13). Under
these reaction conditions, diol 11a was the main byproduct. The
latter can be formed through the ring-opening of 1a by TsNH2,
deriving from partial degradation of TsNHBoc, even though
partial deprotection of carbamate 9a can not be ruled out.
The substitution of K2CO3 for KHCO3 or use of less polar
solvents such as toluene instead of dioxane did not improve
results. The use of minor amounts of base led to very low
conversions.
It is worth noting that both mono-alkylated compounds 8a
and 10a can be quickly converted to 9a in quantitative yields
by treating them with 1,2-epoxy-3-phenoxypropane (1a) (1
equiv) in the presence of a catalytic amount of K2CO3 and
TEBA at 90 °C without solvent. A fast N f O migration of
the Boc group occurred, followed by the ring-opening of the
epoxide by the aza anion B (Scheme 4).
Benzyl glycidol (1b), 1,2-epoxyoctane (1c) and allyl glycidol
(1d) have also been reacted with TsNHBoc (7), generating the
corresponding carbonates 9b-d in 72-75% yield (Table 1).
On the other hand, styrene oxide afforded a complex reaction
mixture since the nucleophilic attack can occur on both carbon
atoms of the oxirane ring.
The 2,6-disubstituted morpholine synthesis could be easily
completed by conversion of the hydroxy group of monopro-
tected diols 9 into a good leaving group through standard
mesylation with methanesulfonyl chloride. After aqueous
workup of the reaction mixture, crude methanesulfonates
12a-d have been converted to morpholines 4a-d in 80-88%
overall yield by treating with K2CO3 in refluxing methanol
(Scheme 5, Table 2). Cyclization occurred through nucleophilic
displacement of the leaving group by the alkoxide generated
from the removal of the Boc protecting group.
Although the ring-opening of (S)-1,2-epoxy-3-phenoxypro-
pane (1a) afforded the enantiomerically pure monoprotected
diol (S,S)-9a in 75% yield (Table 1, entry 9), the latter could
only generate the achiral meso-morpholine (S,R)-4a since the
cyclization proceeds through inversion of configuration of the
stereocenter bearing the mesylate leaving group. However,
the same pathway could be successfully adapted to generate
the non-meso compound, an enantiomerically pure morpholine,
through prior inversion of the stereocenter bearing the hydroxy
group of (S,S)-9a by Mitsunobu conditions (Scheme 6).
Thus, (S,S)-9a was treated with PPh3, diisopropyl azodicar-
boxylate (DIAD), and 4-nitrobenzoic acid in toluene at 25 °C.
The reaction was completed after 2 h in toluene, whereas it
reached 66% conversion only after 3 h in THF. After purifica-
tion through column chromatography, the hydrolysis of the
benzoate (S,R)-14a thus obtained was carried out in aq NaOH/
THF/MeOH mixture affording the desired (S,R)-9a in a 86%
overall yield from (S,S)-9a.
Results and Discussions
In order to study the reactivity of TsNHBoc 7 in the ring-
opening of epoxides under SL-PTC conditions, a series of
experiments were carried out by using 1,2-epoxy-3-phenoxy-
propane (1a) as a model compound under various reaction
conditions (Scheme 4). In particular, the effect of the amount
and nature of the base as well as the amount of TsNHBoc 7
has been investigated (Table 1).
When the reaction was carried out by stirring at 90 °C a
heterogeneous mixture of 1a, TsNHBoc (1.2 equiv), solid,
anhydrous K2CO3 (0.1 equiv), and tetrabutylammonium hy-
drogensulfate (0.1 equiv) as a phase transfer catalyst, a 75%
yield of carbonate 10a, derived from the epoxide ring-opening
followed by N f O migration of the Boc group, was obtained
(entry 1). Lower yields were obtained by using t-BuOK or
K3PO4 as base under the same reaction conditions (entries 2,
3). The reaction did not proceed without base, whereas it was
unacceptably slow in the absence of the phase transfer catalyst.
On the other hand, the use of 2 mol equiv of TsNHBoc led to
51% of compound 8a, without migration of the Boc moiety
(entry 4). Similar results were obtained with benzyltriethylam-
monium chloride (TEBA), that was preferred to Bu4N+HSO4-
in all subsequent experiments due to its lower atomic mass
(ensuring higher atomic efficiency). Moreover, in reactions
carried out with Bu4N+HSO4- an additional amount of base
was required to neutralize the acidic hydrogensulfate anion.
When the ring-opening was carried out in the presence of
excess K2CO3, 9a was generated as the main compound (entry
6). In order to confirm the structure of 9a, the latter has been
converted into diol 11a by removal of the Boc moiety with
K2CO3 in methanol at 25 °C.12
The nitrogen to oxygen (N f O) migration of the Boc group
is likely to proceed through nucleophilic attack of the alkoxide
anion A, generated from the ring-opening of epoxide, to the
N-bonded carboxylic group, thus generating the aza anion B
(Scheme 4). The latter can subsequently undergo protonation,
leading to 10a, or can act itself as a nucleophile in the ring-
opening of a second epoxide molecule, in such case giving
access to compound 9a, formally deriving from the bis-
alkylation of the nitrogen atom of TsNHBoc. Results show that
pathway b is favored over pathway a in the presence of a greater
quantity of base.
In accordance with the proposed mechanism, the yield of
the bis-alkylation product 9a could be increased by reducing
(12) 1H NMR of 11a proved to be identical to that previously published
(ref 7).
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Vol. 14, No. 3, 2010 / Organic Process Research & Development

Scheme 4. Ring-opening of epoxide 1a with TsNHBoc (7)
Table 1. Ring-opening of epoxides 1a-d with TsNHBoc (7) under SL-PTC conditions at 90 °C
epoxide
7 (equiv)
base (equiv)
cat.a
dioxane (M)
t (h)
8
9
10
11
1
1a
1.2
K2CO3 (0.2)
t-BuOK (0.2)
K3PO4 (0.2)
K2CO3 (0.2)
K2CO3 (0.1)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
A
A
A
A
B
B
B
B
B
B
B
B
B
-
-
-
-
-
5
2
7
24
2
2
-
-
-
51
-
-
-
-
-
-
-
-
-
6
75
53
50
-
76
28
8
8
-
20
-
9
20
10
10
8
-
-
-
-
2
1a
1.2
-
3
1a
1.2
-
4
1a
2
-
5
1a
1.2
5
6
1a
1.2
24
5
50
71
72
75
75
72
64
75
7
1a
0.75
0.75
0.75
0.75
0.75
0.75
0.75
5
8
1b
5
5
8
9
(S)-1a
(S)-1b
1c
5
6
5
10
11
12
13
5
6
-
-
-
-
5
20
14
18
1d
(R)-1d
5
5
a A ) Bu4N+HSO4-, B ) TEBA (0.1 equiv).
Scheme 5. Conversion of mono-protected diols into
2,6-disubstituted morpholines
Scheme 6. Generation of (S,S)-9a by ring-opening,
Mitsunobu inversion, and cyclization
Table 2. Synthesis of morpholines 4a-d from
mono-protected diols 9a-da
b
c
substrate
t1 (h)
t2 (h)
yield (%)
product
1
2
3
4
5
6
7
9a
(S,R)-9a
9b
(S,R)-9b
9c
9d
(R,S)-9d
22
24
18
10
24
15
18
6
7
6
5
9
5
4
88
85
82
85
81
85
80
4a
(S,S)-4a
4b
(S,S)-4b
4c
4d
(R,R)-4d
but using the opposite epoxide enantiomer in the second step
(Scheme 7). In this case the intermediate monoprotected diol
(S,R)-9b has the correct absolute configuration to generate the
desired C2-symmetric morpholine (S,S)-4b through the cycliza-
tion protocol previously described. The benzyl groups could
be removed by hydrogenolysis of morpholine (S,S)-4b thus
generating C2-symmetric 2,6-bis-hydroxymethylmorpholine (S,S)-
13, a key intermediate for making a variety of C2-symmetric
morpholines through standard functional group chemistry.8
The enantiomeric morpholine (R,R)-4b can be obtained by
simply reversing the charging order of two epoxide enantiomers.
The same procedure can also be exploited for the synthesis
of a variety of chiral, nonsymmetric morpholines by using
different chiral epoxides in the two ring-opening steps instead
of the two opposite enantiomers of the same epoxide.
a Reaction conditions: (1) MsCl (1.5 equiv), Et3N (1.5 equiv), CH2Cl2, 25 °C;
(2) K2CO3 (5 equiv), MeOH, reflux. b Time for the mesylation step. c Time for the
cyclization step.
The monoprotected diols (S,R)-9a,b and (R,S)-9d, obtained
by Mitsunobu inversion, have been converted to C2-symmetric
morpholines (S,S)-4a,b and (R,R)-4d in 80-85% overall yield
(Table 2).13
A more efficient synthesis of these enantiopure morpholines
4 is possible through two sequential epoxide ring-opening steps,
(13) Morpholines have been shown to be enantiomerically pure by HPLC
on chiral column. Racemic morpholines have been prepared as
analytical standards from the ring opening of racemic epoxides.
Vol. 14, No. 3, 2010 / Organic Process Research & Development
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707

Scheme 7. Alternative synthesis of (S,S)-2,6-disubstituted morpholines
Conclusion
In summary, enantiopure 2,6-disubstituted morpholines 4
have been prepared in a straightforward manner through the
ring-opening of epoxides with TsNHBoc under SL-PTC
conditions.
mixture of TsNHBoc (540 mg, 2 mmol), K2CO3 (28 mg, 0.2
mmol), and Bu4N+HSO4- (34 mg, 0.1 mmol). After heating at
90 °C for 2 h, the reaction mixture was directly purified by
column chromatography (AcOEt/PE, 1:6) to generate 215 mg
1
of 8a, 51% yield. H NMR (300 MHz, CDCl3) δ 7.95-7.90
The migration of the Boc group from the incoming nucleo-
phile to the hydroxy group generated during the oxirane ring-
opening enables the sequential double alkylation of TsNHBoc.
Standard synthetic elaboration of the mono-protected diols 9
thus obtained generates C2-symmetric morpholines 4 in high
yields.
Since the Boc protecting group of carbonates 9 originates
from the incoming nucleophile, this new procedure does not
require additional steps of introduction and removal of external
protecting groups in order to set the stage for the cyclization
by differentiating two chemically equivalent hydroxy groups.
The crucial epoxide ring-opening step has been carried out
under SL-PTC conditions in the presence of a small amount of
solvent, and the following operations leading to the morpholine
skeleton are high-yielding reactions and proceed under mild
conditions.
Moreover, when two opposite enantiomers of the same
epoxide are used in two sequential ring-opening steps under
SL-PTC conditions without solvent (Scheme 7), C2-symmetric
morpholines 4 have been generated without the requirement of
prior Mitsunobu inversion of one stereocenter. Also, nonsym-
metrical, enantiopure 2,6-disubstituted morpholines can also be
obtained by using two different epoxides in the alternative two
steps protocol (Scheme 7).
Therefore, this new procedure enables the synthesis of a large
number of chiral, symmetrical 2,6-disubstituted morpholines
from a variety of readily available and inexpensive chiral
epoxides by choosing the proper pathway.
(m, 2 H), 7.39-7.30 (m, 5 H), 6.99-6.97 (m, 2 H), 4.40-4.36
(m, 1 H), 4.25-4.05 (m, 4 H), 2.49 (s, 3 H), 1.42 (s, 9 H); 13C
NMR (CDCl3) δ 158.4 (C), 151.5 (C), 149.3 (C), 144.4 (C),
144.2 (C), 137.0 (C), 136.1 (C), 129.3 (CH), 128.0 (CH), 121.1
(CH), 114.5 (CH), 83.6 + 84.8 (C), 69.6 (CH2), 69.5 (CH),
49.3 (CH2), 27.6 (CH3), 21.4 (CH3). ESI-MS: m/z ) 440 [M
+ Na]+.
Synthesis of tert-Butyl 1-(N-4-Methylphenylsulfonamido)-
3-phenoxypropan-2-yl Carbonate (10a). 1,2-Epoxy-3-phe-
noxypropane (1a) (150 mg, 1 mmol) was added to a mixture
of TsNHBoc (326 mg, 1.2 mmol), K2CO3 (28 mg, 0.2 mmol),
and Bu4N+HSO4- (34 mg, 0.1 mmol). After heating at 90 °C
for 2 h the reaction mixture was directly purified through
column chromatography (AcOEt/PE, 1:6) to generate 316 mg
of 10a, 75% yield, mp 94-95 °C. 1H NMR (300 MHz, CDCl3)
δ 7.78-7.75 (d, 2 H, J ) 8.3), 7.33-7.28 (m, 4 H), 7.03-6.98
(m, 1 H), 6.87-6.85 (d, 2 H, J ) 8.1), 5.00-4.97 (m, 1 H),
4.83 (m, 1 H), 4.08 (ddd, 2 H, J ) 5.1, 10.2 and 18.6),
3.47-3.35 (m, 2 H), 2.44 (s, 3 H), 1.52 (s, 9 H); 13C NMR
(CDCl3) δ 152.6 (C), 143.6 (C), 129.8 (CH), 129.5 (CH), 127.1
(CH), 121.4 (CH), 114.6 (CH), 83.2 (C), 73.2 (CH), 66.2 (CH2),
43.5 (CH2), 27.7 (CH3), 21.5 (CH3). ESI-MS: m/z ) 440 [M
+ Na]+.
General Method for the Synthesis of Carbonates 9a-d.
A mixture of TsNHBoc 7 (4.07 g, 15 mmol), epoxide 1 (20
mmol), K2CO3 (0.55 g, 40 mmol), TEBA (0.46 g, 2 mmol),
and dioxane (4 mL) was stirred at 90 °C for the time indicated
in Table 1. Addition of water (2 mL), extraction with CH2Cl2
(2 × 20 mL), drying with MgSO4, filtration, and solvent
removal in Vacuo gave a residue which was purified by flash
column chromatography (eluting solvent mixture listed below)
on silica gel to give carbonates 9a-d.
tert-Butyl 1-(N-(2-hydroxy-3-phenoxypropyl)-4-meth-
ylphenylsulfonamido)-3-phenoxypropan-2-yl carbonate (S,S)-
9a: (AcOEt/PE, 1:4) 4.29 g, 75% yield, [R]23D +19.3 (c 0.85,
CHCl3), HPLC (CHIRALCEL OD, hexane/i-PrOH, 80:20) tR
(S,S) ) 28.7 min, ee 98%.14 (Anal. Calc for C30H37NO8S: C,
63.03; H, 6.52; N, 2.45. Found: C, 63.11; H, 6.53; N, 2.46). 1H
NMR (300 MHz, CDCl3) δ 7.71 (d, 2 H, J ) 8.3), 7.28-7.26
(m, 6 H), 6.95-6.88 (m, 6 H), 5.30 (m, 1 H), 4.31 (m, 1 H),
4.13 (m, 2 H), 3.98 (m, 2 H) 3.60-3.42 (m, 2 H), 2.41 (s, 3
H), 1.47 (s, 9 H); 13C NMR (CDCl3) δ 158.3 (C), 158.10 (C),
152.8 (C), 143.7 (C), 135.1 (C), 129.7 (CH), 129.3 (CH), 127.4
(CH), 121.1 (CH), 121.0 (CH), 114.5 (CH), 82.9 (C) 73.4 (CH),
Experimental Section
General. Anhydrous dioxane and chiral epoxides (ee 98%)
were purchased from Fluka and used without further purifica-
tion. NMR spectra were recorded on Bruker AC 300 or AC
200 spectrometers, operating at 300.13 or 200.13 MHz for 1H
NMR and 75.3 MHz for 13C NMR. Optical rotations were
measured with a Perkin-Elmer 241 polarimeter; the [R]D values
are reported in 10-1 deg cm-2 g-1, concentration (c) is reported
in g per 100 mL. Column chromatography on silica gel
(230-400 mesh) was performed by the flash technique. Chiral
HPLC separations were performed on a Agilent HP 1100
apparatus, equipped with a diode array detector, detection at
230 nm. The flux was set to 1 mL min-1, and the volume of
injection was 20 µL.
Carbamic Acid, [2-Hydroxy-3-phenoxypropane][(4-me-
thylphenyl)sulfonyl]-1,1-dimethylethyl Ester (8a). 1,2-Epoxy-
3-phenoxypropane (1a) (150 mg, 1 mmol) was added to a
(14) Retention times for the racemic mixture: 20.6, 24.2, 28.8, 30.8
min.
708
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Vol. 14, No. 3, 2010 / Organic Process Research & Development

69.4 (CH2), 68.7 (CH), 66.7 (CH2), 53.9 (CH2), 50.8 (CH2),
27.6 (CH3), 21.3 (CH3). ESI-MS: m/z ) 594 [M + Na]+.
tert-Butyl 1-(N-(2-hydroxy-3-benzyloxypropyl)-4-meth-
ylphenylsulfonamido)-3-benzyloxypropan-2-ylcarbonate(S,S)-
3.7, 10.7 and 18.4 Hz), 3.97 (ddd, 2 H, J ) 4.4, 10.7, and 23.5
Hz), 3.75-3.67 (m, 3 H), 3.41 (dd, 1 H, J ) 7.0 and 15.1 Hz),
2.36 (s, 3 H), 1.44 (s, 9 H). 13C NMR (CDCl3) δ 130.9 (CH),
129.9 (CH), 129.5 (CH), 129.3 (CH), 127.5 (CH), 123.4 (CH),
121.5 (CH), 121.2 (CH), 114.7 (CH), 114.3 (CH), 77.0 (CH),
72.1 (CH), 66.8 (CH2), 66.5 (CH2), 50.1 (CH2), 49.8 (CH2),
27.6 (CH3), 2.5 (CH3).
9b: (AcOEt/PE, 1:4) 4.49 g, 75% yield, [R]23 - 8.5 (c 0.78,
D
CHCl3), HPLC (CHIRALPAK AD; hexane/i-PrOH, 80:20) tR
(S,S) ) 21.0, ee 98%.15 (Anal. Calc for C32H41NO8S: C, 64.09;
H, 6.89; N, 2.34. Found: C, 64.15; H, 6.93; N, 2.32); 1H NMR
(300 MHz, CDCl3) δ 7.69 (m, 2H), 7.35-7.29 (m, 10 H), 5.12
(m, 1 H), 4.56 (m, 4 H), 4.11 (m, 1 H), 3.67-3.65 (m, 2 H),
3.53-3.20 (m, 6 H), 2.44 (s, 3 H), 1.49 (s, 9 H). ESI-MS: m/z
) 622 [M + Na]+.
tert-Butyl 1-(N-(2-hydroxy-3-hexyl)-4-methylphenylsul-
fonamido)-3-hexylpropan-2-yl carbonate 9c (diastereoiso-
meric mixture): (AcOEt/ PE, 1:6) 3.80 g, 72% yield. 1H NMR
(300 MHz, CDCl3) 7.71 (m, 2 H), 7.29 (m, 2 H), 4.90 (m, 1
H), 3.85 (m, 1 H), 3.47-2.96 (m, 4 H), 2.45 (s, 3 H), 1.58-1.29
(m, 29 H), 0.90 (m, 6 H). 13C NMR (CDCl3) 143.5 (C), 135.4
(C), 129.7 (CH), 127.4 (CH), 82.4 (C), 75.9 + 75.8 (CH), 70.1
+ 69.6 (CH), 58.3 + 57.5 (CH), 54.7 + 53.5 (CH2), 34.7 +
34.6 (CH2), 32.0 + 31.7 (CH2), 29.3 + 29.0 (CH2), 27.7 (CH3),
25.5 + 25.0 (CH2), 22.4 (CH2), 21.4 (CH3), 13.9 (CH3). ESI-
MS: m/z ) 550 [M + Na]+.
This was dissolved in 40 mL of a THF/H2O/MeOH mixture
(1:1:2) and solid NaOH (0.19 g, 4.74 mmol) was added. After
20 min (TLC), THF and MeOH were removed at reduced
pressure, and the residue was extracted with CH2Cl2 (3 × 20
mL). The organic phase was evaporated to dryness and the
carbonate (S,R)-9a isolated by column chromatography.
(S,R)-9a (AcOEt/PE, 1:4) 3.67 g, 92% yield, [R]23D: +53.0
(c 1, CHCl3); HPLC (CHIRALCEL OD; hexane/i-PrOH, 80:
1
20) tR (S,R) ) 20.1, ee 98%. H NMR (300 MHz, CDCl3) δ
7.71 (m, 2 H), 7.32-7.23 (m, 6 H), 6.95-6.88 (m, 6 H),
5.32-5.28 (m, 1 H), 4.32 (m, 1 H), 4.16 (m, 2 H), 3.97 (m, 2
H), 3.6-3.2 (m, 4 H), 2.41 (s, 3 H), 1.47 (s, 9 H).
tert-Butyl 1-(N-(2-hydroxy-3-benzyloxypropyl)-4-meth-
ylphenylsulfonamido)-3-benzyloxypropan-2-ylcarbonate(S,R)-
9b. Carbonate (S,S)-9b (3.00 g, 5 mmol), PPh3 (1.97 g, 7.5
mmol) and p-nitrobenzoic acid (1.25 g, 7.5 mmol) were
dissolved in toluene (40 mL) and stirred at room temperature
for 10 min. DIAD (1.62 g, 8 mmol) was added over 10 min
and the reaction stirred until the starting material was no longer
detectable (TLC analysis). After completion (2 h), the reaction
mixture was evaporated to dryness, and the p-nitrobenzoate
(S,R)-14b was isolated through column chromatography.
(R)-1-(N-((S)-2-(tert-Butoxycarbonyloxy)-3-benzyloxypro-
pyl)-4-methylphenylsulfonamido)-3-benzyloxypropan-2-yl
tert-Butyl 1-(N-(2-hydroxy-3-allyloxypropyl)-4-methylphe-
nylsulfonamido)-3-allyloxypropan-2-yl carbonate (R,R)-9d:
(AcOEt/PE, 1:5) 3.75 g, 75% yield, [R]23D +5.7 (c 1.03, CHCl3),
HPLC (CHIRALPAK AD; hexane/i-PrOH, 90:10) tR (R,R) )
20.3, ee 98%. (Anal. Calc for C24H37NO8S: C, 57.70; H, 7.46;
1
N, 2.80. Found: C, 57.78; H, 7.47; N, 2.79); H NMR (300
MHz, CDCl3) δ 7.73 (d, 2 H, J ) 8.1), 7.33 (d, 2 H, J ) 8.1),
5.92-5.85 (m, 2 H), 5.30-5.18 (m, 4 H,), 5.10 (m, 1 H),
4.04-4.02 (m, 5 H), 3.63 (d, 2 H, J ) 4.6), 3.49-3.20 (m, 6
H), 2.44 (s, 3 H), 1.49 (s, 9 H);13C NMR (CDCl3) δ 152.8 (C),
143.6 (C), 135.3 (C), 134.4 (CH), 134.2 (CH), 129.6 (CH),
127.4 (CH), 117.1 (CH2), 117.0 (CH2), 82.6 (C), 74.0 (CH),
72.2 (CH2), 71.7 (CH2), 69.1 (CH), 68.8 (CH2), 54.2 (CH2),
50.9 (CH2), 27.8 (CH3), 21.4 (CH3). ESI-MS: m/z ) 522 [M
+ Na]+.
General Procedure for the Mitsunobu Inversion of Stereo-
center of Carbonates 9a,b,d. tert-Butyl 1-(N-(2-hydroxy-3-
phenoxypropyl)-4-methylphenylsulfonamido)-3-phenoxypro-
pan-2-yl carbonate (S,R)-9a. Carbonate (S,S)-9a (2.86 g, 5.0
mmol), PPh3 (1.97 g, 7.5 mmol) and p-nitrobenzoic acid (1.25
g, 7.5 mmol) were dissolved in toluene (40 mL) and stirred at
room temperature for 10 min. DIAD (1.62 g, 8 mmol) was
added over 10 min and the reaction stirred until the starting
material was no longer detectable (TLC analysis). After
completion (2 h), the reaction mixture was evaporated to dryness
and the p-nitrobenzoate (S,R)-14a isolated through column
chromatography.
4-nitrobenzoate (S,R)-14b: (AcOEt/PE, 1:5) 5.28 g, 94% yield,
1
[R]23 +8.4 (c 0.95, CHCl3); H NMR (300 MHz, CDCl3) δ
D
8.17 (s, 4H), 7.65 (d, 2 H, J ) 8.5), 7.30-7.20 (m, 12 H), 5.57
(m, 1 H), 5.01 (m, 1 H), 4.54 (s, 2 H), 4.39 (s, 2 H), 3.71-3.52
(m, 7 H), 3.28 (dd, 1 H, J ) 6.6 and 14.7), 2.37 (s, 3 H), 1.53
(s, 9 H).
This was dissolved in 40 mL of a THF/H2O/MeOH mixture
(1:1:2), and solid NaOH (0.19 g, 4.79 mmol) was added. After
stirring at room temperature for 20 min and following the
general procedure, the carbonate (S,R)-9b was isolated through
column chromatography.
tert-Butyl (S)-1-(N-((R)-2-hydroxy-3-benzyloxypropyl)-4-
methylphenylsulfonamido)-3-benzyloxypropan-2-yl carbon-
ate (S,R)-9b: (AcOEt/ETP, 1:5) 3.68 g, 87% yield, [R]23D +11.8
(c 1, CHCl3), HPLC (CHIRALCEL OD; hexane/i-PrOH, 80:
1
20) tR (S,R) ) 25.2, ee 98%. H NMR (300 MHz, CDCl3) δ
7.70-7.66 (d, 2 H, J ) 8.3), 7.31-7.26 (m, 10 H), 5.13 (m, 1
H), 4.54 (s, 4 H), 4.10 (m, 1 H), 3.65 (d, 2 H, J ) 7.1),
3.50-3.10 (m, 6 H), 2.41 (s, 3 H), 1.45 (s, 9 H).
(R)-1-(N-((S)-2-(tert-Butoxycarbonyloxy)-3-phenoxypro-
pyl)-4-methylphenylsulfonamido)-3-phenoxypropan-2-yl 4-ni-
trobenzoate (S,R)-14a: 5.03 g, 93% yield, [R]23D +3.2 (c 0.74,
CHCl3). 1H NMR (300 MHz, CDCl3) δ 8.16 (m, 4 H), 7.68 (d,
2 H, J ) 8.5 Hz), 7.25 (m, 6 H), 6.90 (m, 4 H), 6.69 (d, 2 H,
J ) 7.7 Hz), 5.77 (m, 1 H), 5.19 (m, 1 H), 4.25 (ddd, 2 H, J )
tert-Butyl (S)-1-(N-((R)-2-hydroxy-3-allyloxypropyl)-4-
methylphenylsulfonamido)-3-allyloxypropan-2-yl carbonate
(R,S)-9d. Carbonate (R,R)-9d (2.86 g, 5 mmol), PPh3 (1.97 g,
7.5 mmol) and p-nitrobenzoic acid (1.25 g, 7.5 mmol) were
dissolved in toluene (40 mL) and stirred at room temperature
for 10 min. DIAD (1.62 g, 8 mmol) was added over 10 min
and the reaction stirred until the starting material was no longer
detectable (TLC analysis). After completion (2 h), the reaction
(15) Retention times for the racemic mixture: 18.6, 20.2, 22.5, 25.2
min.
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mixture was evaporated to dryness, and the p-nitrobenzoate
(R,S)-14d was isolated through column chromatography.
(R)-1-(N-((S)-2-(tert-Butoxycarbonyloxy)-3-allyloxypropyl)-
4-methylphenylsulfonamido)-3-allyloxypropan-2-yl 4-ni-
trobenzoate (R,S)-14d: (AcOEt/PE, 1:8) 2.92 g (90% yield);
[R]23D: -9.7 (c 1.28, CHCl3); 1H NMR (300 MHz, CDCl3) δ
8.25 (dd, 4 H, J ) 6.6 and 9.1), 7.70 (d, 2 H, J ) 8.1), 7.25 (d,
2 H, J ) 8.1), 5.94-5.73 (m, 2H), 5.55 (m, 1 H), 5.30-5.11
(m, 4 H), 4.98 (m, 1 H), 4.12 (d, 2 H, J ) 7.0), 3.90 (d, 2 H,
J ) 5.5), 3.71-3.51 (m, 8 H), 3.34 (dd, 1 H, J ) 7.0 and 15.0),
2.38 (s, 3H), 1.45 (s, 9 H).
This was dissolved in 40 mL of a THF/H2O/MeOH mixture
(1:1:2), and solid NaOH (0.18 g, 4.44 mmol) was added. After
stirring at room temperature for 20 min and following the
general procedure, the carbonate (R,S)-9d was isolated through
column chromatography.
(S,S)-2,6-Bis-(phenoxymethyl)morpholine (15a). (S,S)-
4a (0.1 mmol, 45 mg) was dissolved in DME (5 mL), cooled
to -70 °C and a freshly prepared 0.06 M sodium naphthalide
DME solution (0.3 mmol, 5 mL) was added over 5 min. After
1 h (CH2Cl2/MeOH, 9:1) the reaction was quenched with sat.
NH4Cl and evaporated to dryness. The title compound (27 mg,
90% yield) was isolated in pure form by column chromatog-
raphy (CH2Cl2/MeOH, 95:5).
(S,S)-15a: HPLC (CHIRALCEL OJ-H; hexane/i-PrOH, 50:
50, 0.7 mL/min); tR (S,S) ) 27.3, tR (R,R) ) 39.6, ee 98%. 1H
NMR (300 MHz, CDCl3) δ 7.31-7.25 (m, 4 H), 6.95-6.92
(m, 6 H), 4.20-4.17 (m, 6 H), 3.12 (dd, 2 H, J ) 2.7 and
12.1), 2.94 (dd, 2 H, J ) 4.9 and 12.1), 2.25 (s, 1 H, NH).13C
NMR (CDCl3) δ 158.7 (C), 129.4 (CH), 121.2 (CH), 114.7
(CH), 70.0 (CH), 67.9 (CH2), 47.0 (CH2). ESI-MS: m/z ) 300
[M + H]+.
(S,S)-2,6-Bis-(benzyloxymethyl)-4-tosylmorpholine (4b).
Et3N (0.9 mL, 6.4 mmol) was added to a stirred solution of
carbamate (S,R)-9b (2.40 g, 4 mmol) in CH2Cl2 (20 mL).
Methanesulfonyl chloride (0.46 mL, 6 mmol) was added over
3 min at 0 °C, and the temperature was allowed to reach room
temperature. After 10 h, water (3 mL) was added, and the
separated organic phase was washed with 0.5 M HCl (3 mL)
and brine (2 × 5 mL). After drying over MgSO4, the solvent
was removed at reduced pressure to give crude methane-
sulfonate (S,R)-12b which was dissolved in methanol (20 mL)
and treated with solid K2CO3 (2.76 g, 20 mmol). After heating
at reflux for 5 h, and following the general procedure, mor-
pholine (S,S)-4b was isolated by column chromatography.
(S,S)-4b: 1.64 g (85% yield), (AcOEt/PE, 1:3) [R]23D -23.3
(c 0.79, CHCl3); HPLC (CHIRALPAK AD; hexane/i-PrOH 80:
20; tR (meso) ) 14.0, tR (S,S) ) 16.1, tR (R,R) ) 23.2, ee 98%.
1H NMR identical to that reported in ref 8 for (R,R)-4b.
2,6-Bis-(hexyl)-4-tosylmorpholine (4c). Et3N (1.6 mL, 11.5
mmol) was added to a stirred solution of carbamate (S,R)-9c
(3.69 g, 7 mmol) in CH2Cl2 (20 mL). Methanesulfonyl chloride
(0.85 mL, 11 mmol) was added over 3 min at 0 °C, and the
temperature was allowed to reach room temperature. After 24 h,
water (5 mL) was added, and the separated organic phase was
washed with 0.5 M HCl (5 mL) and brine (2 × 5 mL). After
drying over MgSO4, the solvent was removed at reduced
pressure to give crude methanesulfonate 12c which was
dissolved in methanol (25 mL) and treated with solid K2CO3
(4.84 g, 35 mmol). After heating at reflux for 9 h, and following
the general procedure, morpholine 4c was isolated by column
chromatography.
tert-Butyl (S)-1-(N-((R)-2-hydroxy-3-allyloxypropyl)-4-
methylphenylsulfonamido)-3-allyloxypropan-2-yl carbonate
(R,S)-9d: (AcOEt/ETP, 1:5) 1.93 g, 86% yield, [R]23D: -9.7
(c 1.28, CHCl3); HPLC (CHIRALPAK AD; hexane/i-PrOH,
90:10) tR (R,S) ) 17.8, ee 98%. 1H NMR (300 MHz, CDCl3)
δ 7.74-7.72 (d, 2 H, J ) 8.1), 7.33 (d, 2 H, J ) 8.1), 5.94-5.89
(m, 2 H), 5.31-5.18 (m, 4 H), 5.12-5.08 (m, 1 H), 4.10-4.02
(m, 5 H), 3.66-3.64 (d, 2 H, J ) 4.6), 3.56-3.15 (m, 6 H),
2.44 (s, 3 H), 1.49 (s, 9 H). 13C NMR (CDCl3) δ 152.8 (C),
143.5 (C), 135.4 (C), 134.4 (CH), 134.2 (CH), 129.7 (CH),
127.5 (CH), 117.2 (CH2), 117.1 (CH2), 82.5 (C), 73.9 (CH),
72.2 (CH2), 71.7 (CH2), 68.9 (CH2), 53.8 (CH2), 50.5 (CH2),
27.7 (CH3), 21.4 (CH3).
General Method for the Cyclization of Carbonates 9a-d.
Et3N (0.9 mL, 6.4 mmol) was added to a stirred solution of
carbamate (S,R)-9a (2.29 g, 4 mmol) in CH2Cl2 (20 mL).
Methanesulfonyl chloride (0.46 mL, 6 mmol) was added over
3 min at 0 °C, and the temperature was allowed to reach room
temperature. After 24 h, water (3 mL) was added, and the
separated organic phase was washed with 0.5 M HCl (3 mL)
and brine (2 × 5 mL). After drying over MgSO4, the solvent
was removed at reduced pressure to give crude methane-
sulfonate (S,R)-12a which was dissolved in methanol (20 mL)
and treated with solid K2CO3 (2.76 g, 20 mmol). After heating
at reflux for 7 h, methanol was removed at reduced pressure.
The residue was dissolved in 50-50 AcOEt/H2O mixture (15
mL). The separated aqueous phase was extracted with AcOEt
(2 × 5 mL), and the combined organic phase was dried over
MgSO4, and the solvent was removed at reduced pressure to
give morpholine (S,S)-4a which was purified by column
chromatography.
Two diastereoisomeric morpholines have been separated
(AcOEt/PE, 1:19). 2.32 g (81% yield).
1
(S,S)-2,6-Bis-(phenoxymethyl)-4-tosylmorpholine(4a).(AcO-
(RR+SS)-4c: 1.16 g, mp 39-40 °C; H NMR (300 MHz,
Et/ETP, 1:3) 1.54 g (85% yield), mp 142-143 °C; [R]23
:
D
CDCl3) δ 7.63 (d, 2 H, J ) 8.2), 7.35 (d, 2 H, J ) 8.1), 3.80
(m, 2 H), 2.98 (dd, 2 H, J ) 3.2 and 11.2), 2.71 (dd, 2 H, J )
5.8 and 11.2), 2.45 (s, 3 H), 1.26 (m, 20 H), 0.87 (m, 6 H).13C
NMR (CDCl3) δ 143.6 (C), 132.6 (C), 129.6 (CH), 127.7(CH),
69.6 CH), 49.4 (CH2), 31.7 (CH2), 31.2 (CH2), 29.1 (CH2), 25.2
(CH2), 22.5 (CH2), 21.5 (CH3), 14.0 (CH3).
-47.0 (c 0.6, CHCl3); the optical purity of this compound has
been determined after N-detosylation (see below).
1H NMR (300 MHz, CDCl3) δ 7.65 (d, 2 H, J ) 12.3),
7.34-7.24 (m, 6 H), 7.00-6.88 (m, 6 H), 4.29-4.01 (m, 6 H),
3.30-3.22 (dd, 2 H, J ) 5.4 and 11.5), 3.09-3.00 (dd, 2 H, J
) 2.8 and 11.3), 2.43 (s, 3 H). 13C NMR (CDCl3) δ 158.3 (C),
144.1 (C), 129.9 (CH), 129.5 (CH), 127.9 (CH), 121.3 (CH),
114.6 (CH), 69.3 (CH), 66.7 (CH2), 46.9 (CH2), 21.5 (CH3).
(meso)-4c: 1.15 g, mp 55 °C; 1H NMR (300 MHz, CDCl3)
δ 7.63 (d, 2 H, J ) 8.2), 3.59-3.48 (m, 4 H), 2.46 (s, 3 H),
1.96 (dd, 2 H, J ) 10.7 and 10.7), 1.41-1.28 (m, 20 H), 0.90
710
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(m, 6 H). 13C NMR (CDCl3) δ 143.6 (C), 132.6 (C), 129.7
(CH), 127.8 (CH), 75.2 CH), 50.1 (CH2), 33.2 (CH2), 31.6
(CH2), 29.1 (CH2), 25.1 (CH2), 22.5 (CH2), 21.5 (CH3), 14.0
(CH3).
Method B. Epoxide 1a (150 mg, 1 mmol) was added to a
mixture of 10a (420 mg, 1 mmol), K2CO3 (14 mg, 0.1 mmol)
and TEBA (23 mg, 0.1 mmol). After heating at 90 °C for 2 h
the reaction mixture was directly purified by column chroma-
tography (AcOEt/PE, 1:4) to generate 457 mg of the title
compound, 97% yield.
(R,R)-2,6-Bis-(allyloxymethyl)-4-tosylmorpholine (4d).
Et3N (0.80 mL, 5.76 mmol) was added to a stirred solution of
carbamate (R,S)-9d (1.80 g, 3.6 mmol) in CH2Cl2 (20 mL).
Methanesulfonyl chloride (0.42 mL, 5.4 mmol) was added over
3 min at 0 °C, and the temperature was allowed to reach room
temperature. After 18 h, water (5 mL) was added, and the
separated organic phase was washed with 0.5 M HCl (5 mL)
and brine (2 × 5 mL). After drying over MgSO4, the solvent
was removed at reduced pressure to give crude methane-
sulfonate (R,S)-12d which was dissolved in methanol (20 mL)
and treated with solid K2CO3 (2.49 g, 18 mmol). After heating
at reflux for 4 h, and following the general procedure, mor-
pholine (R,R)-4d was isolated by column chromatography.
(R,R)-4d: 0.93 g (80% yield), [R]23D: +22.4 (c 0.97, CHCl3);
HPLC (CHIRALPAK AD; hexane/i-PrOH, 80:20); tR (R,R) )
11.5, tR (S,S) ) 8.2, tR (meso) ) 7.6, ee 98%; 1H NMR (300
MHz, CDCl3) δ 7.66 (d, 2 H, J ) 8.1), 7,37 (d, 2 H, J ) 8.1),
5.96-5.85 (m, 2 H), 5.32-5.20 (m, 4 H), 4.04-3.99 (m, 6 H),
3.66-3.56 (m, 4 H), 3.13-3.08 (dd, 2 H, J ) 3.6 and 11.8),
2.98-2.92 (dd, 2 H, J ) 5.9 and 11.5), 2.47 (s, 3 H). 13C NMR
(CDCl3) δ 143.9 (C), 134.4 (CH), 132.3 (C), 129.7 (CH), 127.8
(CH), 117.4 (CH2), 72.4 (CH2), 69.7 (CH), 68.8 (CH2), 46.7
(CH2), 21.5 (CH3). APCI-MS: m/z ) 322 [M + H]+.
Alternative Synthesis of tert-Butyl 1-(N-(2-Hydroxy-3-
phenoxypropyl)-4-methylphenylsulfonamido)-3-phenoxypro-
pan-2-yl Carbonate 9a. Method A. Epoxide 1a (150 mg, 1
mmol) was added to a mixture of 8a (421 mg, 1 mmol), K2CO3
(14 mg, 0.1 mmol) and TEBA (23 mg, 0.1 mmol). After heating
at 90 °C for 2 h the reaction mixture was directly purified by
column chromatography (AcOEt/PE, 1:4) to generate 434 mg
of the title compound, 96% yield.
Alternative Synthesis of Carbonate (S,R)-9b. Step 1. (S)-
Benzyl glycidol (164 mg, 1 mmol) was added to a mixture of
TsNHBoc (326 mg, 1.2 mmol), K2CO3 (14 mg, 0.1 mmol) and
TEBA (23 mg, 0.1 mmol). After heating at 90 °C for 2 h the
reaction mixture was directly purified by column chromatog-
raphy (AcOEt/PE, 1:4) to generate 318 mg of (S)-10b, 73%
yield. [R]23 + 0.29 (c 1.1, CHCl3).
D
1H NMR (CDCl3) δ, 7.90-7.83 (m, 4 H), 7.36-7.25 (m, 5
H), 4.59 (s, 2 H), 4.18-4.03 (m, 3 H), 3.94 (dd, 1 H, J ) 3.3
and 14.3), 3.61 (dd, 1 H, J ) 4.0 and 9.9), 3.52 (dd, 1 H, J )
4.9 and 9.9), 2.44 (s, 3 H), 1.30 (s, 9 H).
Step 2. (R)-Benzyl glycidol (115 mg, 0.7 mmol) was added
to a mixture of (S)-10b (305 mg, 0.7 mmol), K2CO3 (10 mg,
0.07 mmol) and TEBA (16 mg, 0.07 mmol). After heating at
90 °C for 2 h the reaction mixture was directly purified by
column chromatography (AcOEt/PE, 1:4) to generate 399 mg
of the title compound, 95% yield.
(S,R)-9b: [R]23D: +11.0 (c 0.93, CHCl3), HPLC (CHIRALCEL
OD; hexane/i-PrOH, 80:20) tR (S,R) ) 25.0, ee 98%.
Acknowledgment
Financial support from MIUR (Nuovi metodi catalitici
stereoselettivi e sintesi stereoselettiva di molecole funzionali)
and CNR is gratefully acknowledged.
Received for review February 10, 2010.
OP1000435
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