Enantioselective chemoenzymatic synthesis of cis- and trans -2,5-disubstituted morpholines

Article abstract of DOI:10.1021/jo1003295

A versatile synthesis of enantiomerically pure cis- and trans-2,5-disubstituted morpholines is described. Hydroxynitrile lyase-mediated cyanide addition onto aldehydes provided cyanohydrins in virtually quantitative yield and excellent enantioselectivity.

Full text of DOI:10.1021/jo1003295

pubs.acs.org/joc
emetogenic chemotherapy in adults.3 The morpholine skele-
Enantioselective Chemoenzymatic Synthesis
of cis- and trans-2,5-Disubstituted Morpholines
ton is also of importance for the construction of a large
class of agrochemical fungicides and bactericides. Fenpro-
pimorph and tridemorph, for example, both ergosterol
biosynthesis inhibitors, are used as agricultural fungicides
in cereals.4 Furthermore, morpholines have been applied as
chiral auxiliaries in asymmetric synthesis,5 although that
general application is somewhat limited due to restricted
access to stereoselective entries into these kinds of molecules.
Despite their importance, applications in organic synthesis
are most frequently restricted to simple bases or N-alkylating
agents. Less attention has been devoted to the synthesis of
C-funtionalized morpholine derivatives, a compound class
that may have important applications in the ongoing search
to new pharmaceutically active compounds. As a con-
sequence, the development of efficient synthetic routes to
C-funtionalized morpholines has been an important subject
of investigation over the past decades. Various classes of
chiral C-functionalized disubstituted morpholine derivatives
have been synthesized.1,5,6 To the best of our knowledge,
only two enantioselective synthetic routes to trans-2,5-di-
substituted morpholines exist,1b,7 and only one that provides
access to both cis- and trans-2,5-disubstituted morpholines.8
However, all three strategies are rather limited in their
substitution pattern or produce the target morpholines with
modest diastereoselectivity.
We recently reported a concise asymmetric synthesis of
2,3-disubstituted trans-aziridines starting from enantiomeri-
cally pure cyanohydrins.9 Considering the general value of
morpholines, we felt that a similar cyanohydrin-based stra-
tegy could be applied to the construction of both cis- and
trans-2,5-disubstituted morpholines. The retrosynthetic plan
is outlined in Scheme 1. We envisioned obtaining the mor-
pholines 1 in enantiopure form starting from cyanohydrins 4
and amino esters as building blocks, which are readily
available in both enantiomeric forms. The target molecules
1 could arise via ring-closure of the amino diols 2, followed
by deprotection under mild reductive conditions. The inter-
mediates 2, in turn, might be accessed by coupling amino acid
methyl esters with cyanohydrins 4 in a transimination reac-
tion. Finally, chemoenzymatic cyanohydrin formation was
envisioned to provide the starting compounds 4 with high
enantioselectivity using aldehydes as substrates.
ꢀ
Bas Ritzen, Steven Hoekman, Elena Duran Verdasco,
Floris L. van Delft, and Floris P. J. T. Rutjes*
Radboud University Nijmegen, Institute for Molecules and
Materials, Heyendaalseweg 135, NL-6525 AJ Nijmegen,
The Netherlands
f.rutjes@science.ru.nl
Received February 22, 2010
A versatile synthesis of enantiomerically pure cis- and
trans-2,5-disubstituted morpholines is described. Hydro-
xynitrile lyase-mediated cyanide addition onto aldehydes
provided cyanohydrins in virtually quantitative yield and
excellent enantioselectivity. Subsequent formation of dia-
stereomerically pure amino esters via a three-step, one-pot
reduction-transimination-reduction sequence followed
by reduction and simultaneous protection provided cycliza-
tion precursors. Finally, cyclization and SmI2-mediated
reductive detosylation completed the synthesis of cis- and
trans-2,5-disubstituted morpholines in good yields and ex-
cellent diastereoselectivities.
Substituted morpholines have attracted considerable in-
terest due to their presence in a vast number of therapeuti-
cally and biologically active compounds.1 For instance,
reboxetine, a potent antidepressant drug, selectively inhibits
the norepinephrine reuptake and is widely studied for its
pharmacological properties.2 Aprepitant has recently been
approved in combination with other agents as an effective
treatment for preventing acute and delayed chemotherapy-
induced nausea and vomiting (CINV) resulting from highly
The synthesis commenced with the preparation of enantio-
merically pure cyanohydrins. Hydroxynitrile lyases (HNL)
(4) Dieckmann, H.; Strockmaier, M.; Kreuzig, R.; Bahadir, M. Fesenius’
J. Anal. Chem. 1993, 345, 784–786.
(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, 5, 641–662. (b) Myers,
A. G.; Lanman, B. A. Org. Lett. 2004, 6, 1045–1047. (c) D’hooghe, M.;
€
Vanlangendonck, T.; Tornroos, K. W.; De Kimpe, N. J. Org. Chem. 2006,
71, 4678–4681.
(2) (a) Hajos, M.; Fleishaker, J. C.; Filipiak-Reisner, J. K.; Brown, M. T.;
Wong, E. H. F. CNS Drug Rev. 2004, 10, 23–44. (b) Versiani, M.; Cassano,
G.; Perugi, G.; Benedetti, A; Mastalli, L.; Nardi, A.; Savino, M. J. Clin.
Psychiatry 2002, 63, 31–37.
(3) (a) Dando, T. M.; Perry, C. M. Drugs 2004, 64, 777–794. (b) Hale, J. J.;
Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri, M. A.; Sadowski, S.;
Ber, E.; Chicchi, G. G.; Kurtz, M.; Metzger, J.; Eiermann, G.; Tsou, N. N.;
Tattersall, F. D.; Rupniak, N. J. M.; Williams, A. R.; Rycroft, W.;
Hargreaves, R.; MacIntyre, D. E. J. Med. Chem. 1998, 41, 4607–4614.
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66–72. (b) Dave, R.; Sasaki, N. A. Org. Lett. 2004, 6, 15–18.
(6) (a) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Angew. Chem., Int.
Ed. 2008, 47, 1–4. (b) Lupi, V.; Albanese, D.; Landini, D.; Scaletti, D.; Penso,
M. Tetrahedron 2004, 60, 11709–11718. (c) Albanese, D.; Salsa, M.; Landine,
D.; Lupi, V.; Penso, M. Eur. J. Org. Chem. 2007, 2107–2113. (d) Sladojevich,
F.; Trabocchi, A.; Guarna, A. J. Org. Chem. 2007, 72, 4254–4257.
(7) Leathen, M. L.; Rosen, B. R.; Wolfe, J. P. J. Org. Chem. 2009, 74,
5107–5110.
(8) Breuning, M.; Winnacker, M.; Steiner, M. Eur. J. Org. Chem. 2007,
13, 2100–2106.
(9) Ritzen, B.; van Oers, M. C. M.; van Delft, F. L.; Rutjes, F. P. J. T.
J. Org. Chem. 2009, 74, 7548–7551.
DOI: 10.1021/jo1003295
r
Published on Web 04/12/2010
J. Org. Chem. 2010, 75, 3461–3464 3461
2010 American Chemical Society

Ritzen et al.
JOCNote
SCHEME 1. Retrosynthetic Route to Chiral Morpholines
TABLE 2. Three-Step, One-Pot Coupling and Reduction
methyl
ester
yielda
(%)
amino
alcohol
yielda
(%)
entry s.m.
R1
config
1
2
3
4
5
6
7
8
6
6
6
6
7
8
8
9
H
Me
Bn
Allyl
Bn
Me
Bn
10
11
12
13
14
15
16
17
48
32
44
34
10
35
34
47
18
19
20
21
22
23
24
25
80
92
89
95
88
87
92
97
(R)
(R,S)
(R,S)
(R,S)
(R,S)
(S,S)
(S,S)
(S,S)
TABLE 1. HNL-Mediated Cyanohydrin Formation and Protection
Allyl
aIsolated yield after chromatography.
Inspired by results from Van der Gen et al.,13 cyanohydrin
6 was reacted in a three-step, one-pot reduction-transimi-
nation-reduction sequence to prepare the N-substituted
β-amino ester 10. Treatment with a 5-fold excess of DIBALH
at -78 °C followed by protonation of the resulting imine-
aluminum complex with dry methanol afforded the inter-
mediate primary imine. Subsequent transimination with an
excess of glycine methyl ester and Et3N led to rapid forma-
tion of the more stable secondary imine upon loss of NH3.
Finally, the transimination product was reduced in situ with
sodium borohydride at 0 °C furnishing 10 in 48% overall
yield (entry 1, Table 2). The somewhat moderate yield for
this reaction sequence can be mainly explained by over-
reduction of the intermediate metallo-imine to the corres-
ponding amine with DIBALH as was shown by mass spec-
trometry analysis. Optimizing the conditions to keep this
side reaction to a minimum proved to be difficult. Changing
the addition speed or lowering the amount of DIBALH gave
lower conversions, while longer exposure of the starting
material under these conditions resulted in increased forma-
tion of the corresponding amine. In the course of determin-
ing the optimal conditions, we noticed that the use of the
MIP protective group turned out to be critical. When the
same sequence was carried out using a TBS protective group,
considerable side-product formation was observed due to
reductive cleavage of the TBS ether by DIBALH.14 Further-
more, we encountered severe difficulties in deprotecting the
hydroxyl group in a later stage of the synthesis. In contrast,
the MIP protective group could be readily removed under
mildly acidic conditions. Pleased with these results, we applied
the one-pot reaction sequence on cyanohydrins 7-9 using
various commercially available (S)-amino acid methyl esters.
Gratifyingly, the desired amino esters could be isolated in fair to
moderate yields for the three-step sequence. In case of entry 5,
only 10% yield was obtained, apparently as a result of increased
reactivity of the 2-furanyl moiety toward DIBALH.
yielda
(%)
ee
(%)
>99b
>99b
>99b
>99c
entry
R
enzyme
product
config
1
2
3
4
Ph
(R)-HNL
(S)-HNL
(S)-HNL
(S)-HNL
6
7
8
9
99
90
99
99
(R)
(R)d
(S)
2-furanyl
4-BrC6H4
4-butenyl
(S)
aIsolated yield after chromatography. bDetermined by HPLC analysis of
the free cyanohydrins 4. cDetermined by derivatization with Mosher’s acid
chloride and comparison with the diastereomeric esters prepared from their
racemic counterparts. dThe stereochemical arrangement is as expected for
the (S)-HNL: however, due to priority changes following the Cahn-
Ingold-Prelog rules, the product has the (R)-configuration.
are enzymes that in nature convert cyanohydrins into the
corresponding aldehydes and hydrogen cyanide. Using a
biphasic aqueous-organic solvent system consisting of cit-
rate buffer (pH 5) and methyl tert-butyl ether (MTBE)
combined with a large excess of KCN, however, the equi-
libria can be directed to the cyanohydrins.10 Starting from
four different aldehydes and using (R)-selective HNL from
Prunus amygdalus (PaHNL)11 and (S)-selective HNL from
Hevea brasiliensis (HbHNL)12 as catalysts, the correspond-
ing cyanohydrins 4 were obtained as crude products. Sub-
sequent protection of the hydroxyl group (MIP protecting
group), mandatory in order to prevent racemization via an
equilibrium with the aldehyde, afforded the cyanohydrins
6-9 (Table 1) in virtually quantitative yield and excellent
enantiomeric access.
(10) (a) Fechter, M. H.; Griengl, H. In Enzyme Catalysis in Organic
Synthesis; Drauz, K., Waldmann, H., Eds.; Wiley-VHC: Weinheim, 2002;
Vol. 3, pp 974-990. (b) Wijdeven, M. A.; Wijtmans, R.; van den Berg, R. J. F.;
Noorduin, W.; Schoemaker, H. E.; Sonke, T.; van Delft, F. L.; Blaauw, R. H.; Fitch,
R. W.; Spande, T. F.; Daly, J. W.; Rutjes, F. P. J. T. Org. Lett. 2008, 10, 4001–4003.
(c) Wijdeven, M. A.; van den Berg, R. J. F.; Wijtmans, R.; Botman, P. N. M.;
Blaauw, R. H.; Schoemaker, H. E.; van Delft, F. L.; Rutjes, F. P. J. T. Org. Biomol.
Chem. 2009, 7, 2976–2980. (d) Koch, K; van den Berg, R. J. F.; Nieuwland, P. J.;
Wijtmans, R.; Schoemaker, H. E.; van Hest, J. C. M.; Rutjes, F. P. J. T. Biotechnol.
Bioeng. 2008, 99, 1028–1033.
Reduction of methyl esters 10-17 under standard condi-
tions (LiAlH4 in THF, 0 °C) proceeded in all cases to give the
corresponding amino alcohols in high yields. Alternatively,
these amino alcohols might be directly obtained by coupling
(11) Glieder, A.; Weis, R.; Skranc, W.; Poechlauer, P.; Dreveny, I.;
Majer, S.; Wubbolts, M.; Schwab, H.; Gruber, K. Angew. Chem., Int. Ed.
2003, 42, 4815–4818.
(12) Hasslacher, M.; Schall, M.; Hayn, M.; Bona, R.; Rumbold, K.;
Luckl, J.; Griengl, H.; Kohlwein, S. D.; Schwab, H. Protein Expression Purif.
1997, 11, 61–71.
(13) Zandbergen, P.; van den Nieuwendijk, A. M. C. H.; Brussee, J.;
van der Gen, A.; Kruse, C. G. Tetrahedron 1992, 48, 3977–3982.
(14) Corey, E. J.; Jones, G. B. J. Org. Chem. 1992, 57, 1028–1029.
3462 J. Org. Chem. Vol. 75, No. 10, 2010

Ritzen et al.
JOCNote
SCHEME 2. Synthesis of N-Tosyl-Protected 2-Phenylmorpholine
TABLE 4. Ring Closure and SmI2-Mediated Deprotection
yielda
yielda
entry s.m.
1
R
R1 product (%) product (%) config
Ph
H
28
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
80
92
83
86
82
50
56
86
(R)
2
3
4
5
6
7
8
36 Ph
37 Ph
38 Ph
39 2-furanyl Bn
40 4-BrC6H4 Me
41 4-BrC6H4 Bn
42 4-butenyl allyl
Me
Bn
allyl
96
99
97
73
94
93
83
trans
trans
trans
trans
cis
TABLE 3. Simultaneous Sulfonylation and Deprotection
cis
cis
aIsolated yield after chromatography.
sulfonyl chloride. Moreover, in some cases under these
circumstances cleavage of the MIP protective group took
place also (entries 6 and 7). In other cases, subsequent
deprotection of the hydroxyl group proceeded smoothly in
high yields, and the crude morpholine precursors 36-42
were used without further purification for the next step.
Subsequent cyclization under the influence of NaH in
THF at 0 °C successfully provided the N-tosyl-protected
morpholines 28 and 43-49 in high yields (Table 4). Finally,
deprotection completed the synthesis of unprotected cis- and
trans-2,5-disubstituted morpholines 50-57. Generally, the
robustness of sulfonamides can be problematic in the depro-
tection to the free amines. Traditional deprotection methods
involving single electron donors such as lithium or sodium
are often too harsh for these systems. Upon application of
recent methodology developed by Ankner et al.,15 we found
that by using a combination of SmI2/Et3N/H2O, the N-tosyl-
protected morpholines 28 and 43-49 underwent clean and
instantaneous deprotection. Unfortunately, in the case of
entries 6 and 7, lower yields were obtained. Mass spectro-
metry of the reaction mixture showed that under these
reductive conditions partial dehalogenation of the aromatic
ring had occurred.
In summary, we have described a synthetic route that
effectively provides access to diastereomerically pure cis- and
trans-2,5-disubstituted morpholines. Key steps involve
HNL-catalyzed cyanohydrin formation, a three-step, one-
pot coupling sequence, and a SmI2-mediated detosylation.
Important advantages of this sequence are the ready avail-
ability of the two chiral precursors from either simple alde-
hydes or commercially available amino acids and the
relatively mild character of the route which, in principle,
allows for introduction of various functional groups.
yielda
(%)
yielda
(%)
entry s.m.
R
R1
product
product
1
2
3
4
5
6
7
19
20
21
22
23
24
25
Ph
Ph
Ph
Me
Bn
allyl
29
30
31
32
33
34
35
80
74
85
70
36
37
38
39
40
41
42
90
98
95
92
100
96c
80c
2-furanyl Bn
4-BrC6H4 Me
4-BrC6H4 Bn
4-butenyl Allyl
88
n.d.b
n.d.b
aIsolated yield after chromatography. bn.d. = not determined. cYield
over two steps.
the cyanohydrins with the appropriate enantiopure β-amino
alcohols. However, such attempts resulted in considerably
decreased product formation (10-15%) so that we decided
to focus on the amino acid methyl esters.
Exposure of amino alcohol 18 to an excess of o-nitro-
benzenesulfonyl chloride (NsCl) to simultaneously react the
primary alcohol and the secondary nitrogen provided the
desired product in only 35% yield. In contrast, subjection of
18 to p-toluenesulfonyl chloride (1.1 equiv) and triethyl-
amine (2.0 equiv) in dichloromethane at 0 °C afforded
selectively the N-tosylated amino alcohol 26 in 82% yield
(Scheme 2). This product was MIP-deprotected under mild
acidic conditions (pH 2-3) and then cyclized in one step via
selective tosylation of the primary alcohol involving excess
sodium hydride in THF, followed by p-toluenesulfonyl
imidazole at 0 °C. Fortunately, this provided N-tosylmor-
pholine derivative 28 in 83% yield.
Although the sequence summarized in Scheme 2 was
highly efficient, attempts to apply the same sequence to pre-
pare 2,5-disubstituted morpholines (R1 = methyl, benzyl,
allyl; compounds 19-25, Table 3) only provided selective
O-tosylation, apparently as a result of increased steric hind-
rance of the amino group. A more rewarding result was
obtained by stirring compounds 19-25 in the presence of
p-toluenesulfonyl chloride (4.0 equiv) in pyridine containing
triethylamine, thereby providing 29-35 as summarized in
Table 3.1b To facilitate purification of the products, ethyl-
enediamine was added to scavenge the excess of p-toluene-
Experimental Section
Methyl (S)-2[[(R)-2-[(2-methoxypropan-2-yl)oxy]-2-phenylethyl]-
amino]propanoate (11). A solution of 6 (500 mg, 2.44 mmol) in dry
Et2O (75 mL) was cooled to -78 °C, and DIBALH (12.2 mL of a
1.0 M solution in hexane, 12.2 mmol, 5.0 equiv) was added drop-
wise. The reaction mixture was stirred at -78 °C for 30 min.
(15) Ankner, T.; Hilmersson, G. Org. Lett. 2009, 11, 503–506.
J. Org. Chem. Vol. 75, No. 10, 2010 3463

Ritzen et al.
JOCNote
After the mixture was quenched with dry MeOH (70 mL),
(S)-alanine methyl ester hydrochloride (850 mg, 2.5 equiv) and
Et3N (850 μL, 2.5 equiv) were added. The reaction mixture was
allowed to warm to rt and stirred for another 2 h. Then the mixture
wascooledto0°C, and NaBH4 (370 mg, 4.0 equiv) was added. After
2 h at 0 °C, the mixture was quenched with saturated aqueous
NaHCO3 (30 mL) and the product was extracted with EtOAc (3 ꢀ
60 mL). The organic layers were combined, dried (Na2SO4), filtered,
and concentrated in vacuo. The residue was purified by column
chromatography (EtOAc/heptane, 1:2 f 1:1) to afford 11 (233 mg,
32% yield) as a colorless oil: Rf 0.76 (EtOAc/heptane, 1:1); [R]D
1:1 mixture of saturated aqueous NaHCO3 and brine (2 ꢀ 20 mL).
The organic layer was separated, dried (Na2SO4), filtered, and
concentrated in vacuo. The residue was purified by column chro-
matography (EtOAc/heptane, 1:2) to afford 43 (32 mg, 96% yield)
as a colorless oil: Rf 0.44 (EtOAc/heptane, 1:1); [R]D -88.2 (c 1.45,
CH2Cl2); IR (ATR) 2855, 1349, 1166 cm-1; 1H NMR (CDCl3, 400
MHz) δ 7.65-7.63 (m, 2H), 7.35-7.25 (m, 7H), 4.69 (dd J = 2.3,
9.1 Hz, 1H), 3.94 (dd, J = 2.6, 12.1 Hz, 1H), 3.81 (dd, J = 3.2, 11.7
Hz, 1H), 3.47 (dd, J = 9.0, 11.6 Hz, 1H), 2.92-2.84 (m, 1H), 2.66
(dd,J= 9.2, 12.0 Hz, 1H), 2.43 (s, 3H), 1.36 (d, J= 6.4 Hz, 3H); 13
C
NMR (CDCl3, 75 MHz) δ 143.7, 138.4, 133.7, 129.7, 128.4, 128.1,
127.6, 126.1, 77.1, 71.7, 52.3, 51.9, 21.4, 16.1; HRMS (ESI) m/zcalcd
for C18H21NO3S (M þ H)þ 332.1320, found 332.1309.
-96.2 (c 1.21, CH2Cl2); IR (ATR) 2984, 2360, 1738, 1206 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 7.35-7.21 (m, 5H), 4.81 (dd, J =
4.5, 8.1 Hz, 1H), 3.69 (s, 3H), 3.34 (q, J = 6.9 Hz, 1H), 3.14 (s, 3H),
2.85 (dd, J = 8.1, 11.9 Hz, 2H), 2.61 (dd, J= 4.5, 11.9 Hz, 2H), 1.85
(br s, 1H), 1.42, (s, 3H), 1.26 (d, J = 7.0 Hz, 3H), 1.14, (s, 3H);
13C NMR (CDCl3, 75 MHz) δ 175.8, 143.2, 128.1, 127.1, 126.4,
101.1, 73.2, 56.4, 55.1, 51.6, 49.2, 26.0, 25.1, 18.7; HRMS (ESI) m/z
calcd for C16H25NO4 (M þ H)þ 296.1862, found 296.1849.
(S)-2-[[(R)-2-[(2-Methoxypropan-2-yl)oxy]-2-phenylethyl]amino]-
propan-1-ol (19). A suspension of LiALH4 (36 mg, 2.0 equiv) in
dry THF (9 mL) was cooled to 0 °C, and a solution of 11 (0.14 g,
0.47 mmol) in dry THF (5 mL) was added dropwise. The reaction
mixture was stirred at 0 °C for 2 h. After being quenched with water
(42 μL, 5.0 equiv), the mixture was concentrated in vacuo and
purified by column chromatography (CH2Cl2/MeOH, 0.99:0.01 f
0.90:0.10) to afford 19 (0.12 g, 92% yield) as a colorless oil: Rf 0.76
(CH2Cl2/MeOH, 0.9:0.1); [R]D -47.4 (c 1.10, CH2Cl2); IR (ATR)
3304, 2920, 1038 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.36-7.30
(m,4H),7.27-7.23(m,1H),4.81(dd,J= 6.3, 6.3 Hz, 1H), 3.53 (dd,
J = 4.1, 10.6 Hz, 1H), 3.20 (dd, J = 7.2, 10.6 Hz, 1H), 3.13 (s, 3H),
2.93 (dd, J = 5.6, 12.0 Hz, 1H), 2.82-2.75 (m, 2H), 2.07 (br s, 1H),
1.42 (s, 3H), 1.15 (s, 3H), 1.00 (d, J = 6.5 Hz, 3H); 13C NMR
(CDCl3, 75MHz) δ143.0, 128.2, 127.2, 126.5, 101.2, 72.7, 65.2, 54.1,
53.5, 49.3, 25.8, 25.1, 16.9; HRMS (ESI) m/z calcd for C15H25NO3
(M þ H)þ 268.1913, found 268.1909.
(2R,5S)-5-Methyl-2-phenylmorpholine (51). A solution of
SmI2 (8.8 mL of a 0.1 M solution in THF, 0.88 mmol, 10 equiv)
and water (47 μL, 30 equiv) was added to 43 (29 mg, 0.088 mmol)
under an argon atmosphere. Pyrrolidine (0.15 mL, 20 equiv) was
subsequently added. The reaction mixture turned white instan-
taneously upon addition of amine. The resulting mixture was
quenched by blowing air through the mixture. The mixture was
concentrated in vacuo and purified by column chromatography
(CH2Cl2/MeOH, 0.99:0.01 f 0.96:0.04) to afford 51 (14 mg,
92% yield) as a colorless oil: Rf 0.65 (CH2Cl2/MeOH, 0.9:0.1);
[R]D -7.9 (c 0.75, CH2Cl2); IR (ATR) 3434, 2920, 2353, 1453,
1093 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.36-7.32 (m, 5H),
5.98 (br s, 1H), 5.00 (dd, J = 2.2, 11.1 Hz, 1H), 4.10 (dd, J = 3.6,
12.6 Hz, 1H), 3.90 (dd, J = 11.0, 12.4 Hz, 1H), 3.58-3.50 (m,
1H), 3.46 (dd, J = 2.2, 12.7 Hz, 1H), 3.00 (dd, J = 11.2, 12.7 Hz,
1H), 1.47 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ
137.2, 128.6, 126.0, 75.2, 70.4, 51.0, 49.4, 14.8; HRMS (ESI) m/z
calcd for C11H15NO (M þ H)þ 178.1232, found 178.1232.
Acknowledgment. The Council for Chemical Sciences
of The Netherlands Organization for Scientific Research
(NWO-CW) is gratefully acknowledged for financial support.
We thank DSM Pharma Chemicals (Geleen, The Netherlands)
for providing the HNL enzymes.
(2R,5S)-5-Methyl-4-(4-methylbenzenesulfonyl)-2-phenyl-
morpholine (43). A solution of 36 (48 mg, 0.10 mmol) in THF (5 mL)
was cooled to 0 °C, and NaH (3.4 mg of 60% NaH in oil, 1.5 equiv)
was added. The resulting mixture was allowed to warm to rt and
stirred for 1 h. The mixture was cooled to 0 °C and quenched by the
dropwise addition of saturated aqueous NH4Cl (1 mL). The result-
ing solution was diluted with EtOAc (30 mL) and washed with a
Supporting Information Available: Experimental proce-
dures and spectroscopic and analytical data of all compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
3464 J. Org. Chem. Vol. 75, No. 10, 2010