Facile Route to 3,5-Disubstituted Morpholines: Enantioselective Synthesis of O-Protected trans-3,5-Bis(hydroxymethyl)morpholines

Article abstract of DOI:10.1021/ol035998s

(Equation presented) trans-3,5-Bis(benzyl/terf-butyldiphenylsilyloxymethyl) morpholines, promising candidates for the C₂-symmetric class of chiral reagents, were prepared with excellent optical purity. A key step in the synthesis is the couplin

Full text of DOI:10.1021/ol035998s

ORGANIC
LETTERS
2004
Vol. 6, No. 1
15-18
Facile Route to 3,5-Disubstituted
Morpholines: Enantioselective
Synthesis of O-Protected
trans-3,5-Bis(hydroxymethyl)morpholines
Rajesh Dave and N. Andre´ Sasaki*
Institut de Chimie des Substances Naturelles, CNRS, AVenue de la Terrasse,
91198 Gif-sur-YVette, France
andre.sasaki@icsn.cnrs-gif.fr
Received October 14, 2003
ABSTRACT
trans-3,5-Bis(benzyl/tert-butyldiphenylsilyloxymethyl)morpholines, promising candidates for the C -symmetric class of chiral reagents, were
2
prepared with excellent optical purity. A key step in the synthesis is the coupling of a serinol derivative with 2,3-O-isopropylideneglycerol
triflate or its equivalent. This methodology was extended to the synthesis of chiral trans-3-(benzyloxymethyl)-5-(tert-butyldiphenylsilyloxymethyl)-
morpholine, a potentially useful chiral building block.
C2-symmetric trans-R,R′-bis(alkyl/silyloxymethyl)-azacy-
cloalkanes of different ring sizes are emerging as efficient
chiral auxiliaries/ligand catalysts in asymmetric transforma-
tions.1 The presence of a C2 symmetry axis in the chiral
directors often offers unique advantages in achieving asym-
metric induction by reducing the number of competing
undesired diastereomeric transition states.2 However, there
is little information on the synthesis and application profile
of C2-symmetric trans-R,R′-disubstituted cyclic amines bear-
ing a heteroatom such as the oxygen of morpholines. The
presence of such an atom might influence the chirality
induction and the ligand catalytic properties. It has been
reported that a morpholine amide can be cleaved with
nucleophiles such as hydride and various alkyl/alkynyl
carbanions to give chiral aldehydes, ketones, and ynones,
respectively.3 Recently, Jacobsen and Goodman used a
morpholine amide in an acyl transfer reaction to synthesize
a HMG-CoA reductase inhibitor intermediate.4
To the best of our knowledge, there exist only two
enantioselective synthetic routes to trans-3,5-disubstituted
morpholines: the first by Enders et al.5 provides trans-3,5-
dimethylmorpholine, while the other by Takahata et al.6 gives
trans-3,5-bis(tert-butyldiphenylsilyloxymethyl)morpholine 1.
(3) (a) Douat, C.; Heitz, A.; Martinez, J.; Fehrentz, J.-A. Tetrahedron
Lett. 2000, 41, 37. (b) Anderson, J. C.; Flaherty, A.; Swarbrick, M. E. J.
Org. Chem. 2000, 65, 9152. (c) Sengupta, S.; Mondal, S.; Das, D.
Tetrahedron Lett. 1999, 40, 4107. (d) Badioli, M.; Ballini, R.; Bartolacci,
M.; Bosica, G, Torregiani, E.; Marcantoni, E. J. Org. Chem. 2002, 67, 8938.
(e) Jackson, M. M.; Leverett, C.; Toczko, J. F.; Roberts, J. C. J. Org. Chem.
2002, 67, 5032.
(4) Goodman, S. N.; Jacobsen, E. Angew. Chem., Int. Ed. 2002, 41, 4703.
(5) Enders, D.; Meyer, O.; Raabe, G.; Runsink, J. Synthesis 1994, 66.
(6) Takahata, H.; Takahashi, S.; Kouno, S.; Momose, T. J. Org. Chem.
1998, 63, 2224.
(1) (a) Tanner, D.; Birgersson, C.; Gogoll, A.; Luthman, K. Tetrahedron
1994, 50, 9797. (b) Tanner, D.; Korno, H. T.; Guijarro, D.; Andersson, P.
G. Tetrahedron 1998, 54, 14213. (c) Shi, M.; Jiang, J.-K.; Feng, Y.-S.
Tetrahedron: Asymmetry 2000, 11, 4923. (d) Shi, M.; Jiang, J.-K.
Tetrahedron: Asymmetry 1999, 10, 1673. (e) Hoshino, J.; Hiraoka, J.; Hata,
Y.; Sawada, S.; Yamamoto, Y. J. Chem. Soc., Perkin Trans. 1 1995, 693.
(f) Donohoe, T. J.; Guillermin, J.-B.; Frampton, C.; Walter, D. S. Chem.
Commun. 2000, 465. (g) Najdi, S.; Reichlin, D.; Kurth, M. J. J. Org. Chem.
1990, 55, 6241.
(2) Whitesell, J. K. Chem. ReV. 1989, 89, 1581.
10.1021/ol035998s CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/10/2003

The latter strategy exploited the double Sharpless asymmetric
dihydroxylation of R,ω-terminal dienes. The major problem
associated with this approach was the efficient separation7
of the enantiomerically pure morpholine derivative from its
meso-isomer. Moreover, the methodology was not general
and could not be used for the synthesis of trans-3,5-bis-
(benzyloxymethyl)morpholine 3 or other differently O-
protected derivatives of trans-3,5-bis(hydroxymethyl)-
morpholine. Thus, it is of great interest that practical and
efficient synthetic methods are developed for the construction
of 3,5-disubstituted chiral morpholines. Herein, we report a
novel synthetic approach to a range of conveniently protected
chiral morpholines that have excellent optical purity; our
strategy utilizes optically pure serine and solketal8 as key
starting materials.
Scheme 1
L-N-Boc-serine methyl ester (S)-4, obtained from L-serine,
was treated with TBDPSCl to give the O-silyl derivative 5
in 95% yield. Ester 5 was then reduced with LiBH4 in ether
to alcohol 6, and the latter was subjected to a coupling with
(R)-2,3-O-isopropylideneglycerol triflate9 (R)-7 mediated by
2 equiv of NaH in THF to furnish 8. Acid hydrolysis10 of 8,
followed by regioselective O-silylation of the primary
hydroxyl in diol 9 with TBDPSCl, gave 10. Conversion of
the alcohol in 10 to a triflate and subsequent deprotection
of the amino group followed by cyclization with triethyl-
amine in methanol (0-5 °C, 15 min) gave (3R,5R)-3,5-bis-
(tert-butyldiphenylsilyloxymethyl)morpholine (3R,5R)-1 in
90% yield, but with only 70% diastereomeric excess.
However, changing the leaving group to a mesylate circum-
vented this problem. Thus, 10 was converted to (3R,5R)-111
(de > 97%, ee > 99% by chiral HPLC analysis) by the three-
step sequence of O-mesylation, removal of the Boc-group
from mesylate derivative 11, and finally base-mediated
cyclization at reflux in methanol (Scheme 1). The overall
yield of (3R,5R)-1 starting from (S)-4 was 45%. Likewise,
(3S,5S)-1 (de > 94%, ee > 99%) was prepared from D-N-
Boc-serine methyl ester (R)-4 and (S)-2,3-O-isopropylidene-
glycerol triflate (S)-7 in 44% overall yield.
The same synthetic protocol was attempted for the
preparation of (3S,5S)-3,5-bis(benzyloxymethyl)morpholine
(3S,5S)-3 from D-N-Boc-serine methyl ester (R)-4 and (R)-
2,3-O-isopropylideneglycerol triflate (R)-7. (R)-4 was con-
verted12 to alcohol (R)-12 by a four-step sequence involving
protection of the hydroxyl group as an O-THP ether,
reduction of the ester to the alcohol with LiBH4 in ether,
O-benzylation of the resulting alcohol with benzyl bromide
in the presence of NaH and catalytic TBAI, and removal of
the O-THP group. Coupling of (R)-12 with (R)-7 in the
presence of 2 equiv of NaH in THF gave 13. Acid hydrolysis
of 13 and subsequent reaction of the resulting diol 14 with
triphenylphosphine and DEAD afforded epoxide 15 (Scheme
2). To our surprise, the known procedures13 to open an
epoxide with a benzyloxide/benzyl alcohol nucleophile failed
to afford 16. Furthermore, regioselective O-benzylation of
the primary alcoholic group of diol 14 gave the desired
compound 16 at best in 20% yield. Therefore, this approach
for the preparation of trans-3,5-bis(benzyloxymethyl)mor-
pholine 3 was abandoned. Instead, application of diol 14 to
the synthesis of trans-3-(benzyloxymethyl)-5-(tert-butyl-
diphenylsilyloxymethyl)morpholine 2, a potentially useful
chiral building block in peptide and chelate chemistry,14 was
pursued.
(7) In ref 27 of their article, Takahata et al. mentioned the separation of
the morpholine enantiomer from its meso-isomer by the fractionation
procedure.
(8) R)- and (S)-Solketal was purchased in kilogram scale from CHEMI
S. p. A. (Via del Lavoratori 54, 20092 Cinisello Balsamo (MI), Italy).
(9) Cassel, S.; Debaig, C.; Benvegnu, T.; Chaimbault, P.; Laffose, M.;
Plusquellec, P. R. Eur. J. Org. Chem. 2001, 875. Pyridine was used as a
base instead of triethylamine.
(10) Lewbart, M. L.; Schneider, J. J. J. Org. Chem. 1969, 34, 3505.
1
(11) (3R,5R)-1: H NMR (300 MHz, CDCl3) δ 1.05 (18H, s, 2 × SiC-
(CH3)3), 3.11 (2H, m, 2 × CHN), 3.41 (2Ha, dd, J ) 12, 6 Hz, 2 × CHaHb-
OC), 3.56 (2Ha, dd, J ) 9, 6 Hz, 2 × CHaHbOSi), 3.74 (4Hb, m, 2 ×
CHaHbOC, 2 × CHaHbOSi), 7.4 (12H, m, ArH), 7.66 (8H, m, ArH); 13C
NMR (75.5 MHz, CDCl3) δ 19.2, 26.8, 51.7, 63.9, 68.7, 127.7, 129.7, 133.2,
135.5; IR (neat) 3338, 2930, 2857, 1740, 1471, 1427, 1112, 824, 740, 702
cm-1; HRMS (ESI) (M + H)+ m/z calcd for C38H50NO3Si2 624.3324, found
624.3324. Anal. Calcd for C38H49NO3Si2: C, 73.15; H, 7.92; N, 2.24.
Regioselective O-silylation of diol 14 with TBDPSCl,
followed by activation of the hydroxyl group of 17 with
(12) Sasaki, N. A.; Hashimoto, C.; Potier, P. Tetrahedron Lett. 1987,
28, 6069.
Found: C, 73.18; H, 8.12; N, 2.23. [R]24D 10.7 (c 1.1, CHCl3) [lit.6 [R]26
D
10.3 (c 0.87, CHCl3); de > 97%, ee > 99%; (i) HPLC analysis at 265 nm,
symmetry column C18 (5 µm) 4.6 × 150 mm, H2O/CH3CN 40/60 + 0.1%
HCO2H, 1 mL/min, rt, retention time ) 7.0 and 10.9 min for the two
diastereomers, respectively; (ii) HPLC analysis at 220 nm, Chiralcel OD
column (5 µm) 4.6 × 250 mm, hexane/2-propanol 99/1, 1 mL/min, rt,
retention time ) 5.1, 6.4 and 8.6 min for the (3S,5S)-, (3R,5R)-, and meso-
isomers, respectively. (()-1 was prepared from racemic serine and solketal.
(3S,5S)-1: [R]25 -10.1 (c 1, CHCl3) [lit.6 [R]26 -10.6 (c 0.74, CHCl3);
(13) (a) Abushanab, E.; Vemishett, P.; Leiby, R. W.; Singh, H. K.;
Millilineni, A. B.; Wu, D. C.-J.; Saibaba, R.; Panzica, R. P. J. Org. Chem.
1988, 53, 2598. (b) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.;
Pedrini, P. Synthesis 1988, 685. (c) Guivisdalsky, P. N.; Bittman, R. J.
Am. Chem. Soc. 1989, 111, 3077.
(14) (a) Kozlomski, M. C.; Bartlett, P. A. J. Org. Chem. 1996, 61, 7681.
(b) Klaveness, J.; Rongved, P.; Berg, A. Patent No. WO 9110669, July 25,
1991. (c) Almen, T.; Berg, A.; Dugstag, H.; Klaveness, J.; Krautwurst, K.
D.; Rongved, P. Patent No. WO 9008138, July 26, 1990.
D
D
de > 94%, ee > 99% (chiral HPLC analysis).
16
Org. Lett., Vol. 6, No. 1, 2004

propyl chloride (R)-22a by treatment with methanesulfonyl
chloride and not the desired (R)-22b. Replacement of
methanesulfonyl chloride by methanesulfonic anhydride
indeed gave the desired triflate derivative (R)-22b, but it
failed to couple with (R)-12, probably because of its
instability under the reaction conditions. Although (2R)-3-
benzyloxy-2-trimethylsilyloxypropyl trifluoromethanesulfonate
(R)-22c was obtained in 79% yield by treatment with
trimethylsilyl trifluoromethanesulfonate (TMSOTf), the yield
of the subsequent coupling step with (R)-12 was at best 20%
under various reaction conditions. Finally, use of the tert-
butyldimethylsilyl group for protection by employing tert-
butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) cir-
cumvented the problem. The resulting (2R)-3-benzyloxy-2-
tert-butyldimethylsilyloxypropyl trifluoromethanesulfonate17
(R)-22d coupled smoothly with (R)-12 to give 23 in 81%
yield (Scheme 4).
Scheme 2
Scheme 4
methanesulfonyl chloride, afforded 18. Deprotection of the
amino group in 18 and subsequent cyclization gave (3S,5R)-
3-(benzyloxymethyl)-5-(tert-butyldiphenylsilyloxymethyl)-
morpholine15 (3S,5R)-2 (de and ee > 99% by chiral HPLC
analysis) (Scheme 3). The overall yield of (3S,5R)-2 starting
Scheme 3
Cleavage of the silyl group from 23 with TBAF and
mesylation of the resulting alcohol 16 with methanesulfonyl
chloride afforded 24. Deprotection of the amino group of
24 and subsequent base-mediated cyclization furnished
(3S,5S)-3,5-bis(benzyloxymethyl)morpholine18 (3S,5S)-3 (de
> 99%, ee > 98% by chiral HPLC analysis) (Scheme 5).
The overall yield of (3S,5S)-3 starting from (R)-19 was 42%.
1
(15) (3S,5R)-2: H NMR (300 MHz, CDCl3) δ 1.1 (9H, s, SiC(CH3)3),
2.74 (1H, br, NH), 3.12 (1H, m, BnOCCHN), 3.24 (1H, m, SiOCCHN),
3.56 (3Ha + 2H, m, CHaHbOSi, 2 × CHaHbO, BnOCH2), 3.77 (3Hb, m, 2
× CHaHbO, CHaHbOSi), 4.59 (2H, s, ArCH2), 7.39 (11H, m, ArH), 7.71
(4H, m, ArH); 13C NMR (75.5 MHz, CDCl3) δ 19.3, 26.9, 48.8, 51.8, 63.5,
68.5, 68.8, 70.1, 73.5, 127.7, 127.8, 128.4, 129.8, 133.4, 135.6, 138.2; IR
(neat) 3070, 2928, 2856, 1589, 1471, 1454, 1427, 1390, 1362, 1335, 1111,
823, 740, 701 cm-1; HRMS (ESI) (M + H)+ m/z calcd for C29H38NO3Si
476.2615, found 476.2610. Anal. Calcd for C29H37NO3Si: C, 73.22; H,
7.84; N, 2.94. Found: C, 73.14; H, 7.91; N, 2.81. [R]24D 12.4 (c 1.4, CHCl3);
de and ee > 99%; (i) HPLC analysis at 220 nm, symmetry column C18 (5
µm) 4.6 × 250 mm, H2O/CH3CN 48/52 + 0.1% HCO2H, 1 mL/min, rt,
retention time ) 30.6 and 33.1 min for the two diastereomers, respectively;
(ii) HPLC analysis at 220 nm, Chiralcel OD column (10 µm) 4.6 × 250
mm, hexane/2-propanol 99/1, 1 mL/min, rt, retention time ) 16.6 and 18.2
min for the pair of cis enantiomers and 13.0 and 18.3 min for the (3R,5S)-
and (3S,5R)-isomers, respectively. (()-2 was prepared from racemic serine
and solketal. (3R,5S)-2: [R]25D -11.9 (c 1.1, CHCl3); de > 97% and ee >
99% (chiral HPLC analysis).
from (R)-4 was 46%. Using the same approach, (3R,5S)-2
(de > 97% and ee > 99%) was prepared from L-N-Boc-
serine methyl ester (S)-4 and (S)-2,3-O-isopropylidene-
glycerol triflate (S)-7 in 45% overall yield.
Failure of the above general methodology for the prepara-
tion of trans-3,5-bis(benzyloxymethyl)morpholine 3 prompted
us to modify the solketal substrate before coupling with (R)-
12. In the beginning, we envisaged converting (S)-3-
benzyloxy-propane-1,2-diol16 (S)-20, obtained from (R)-
solketal (R)-19, to (2R)-3-benzyloxy-2-methanesulfonyl-
oxypropyl trifluoromethanesulfonate (R)-22b before subject-
ing it to a coupling reaction. Accordingly, (2R)-3-benzyloxy-
2-hydroxypropyl trifluoromethanesulfonate 21 was prepared
in situ by reaction of (S)-20 with triflic anhydride. Unfor-
tunately, 21 gave (2R)-3-benzyloxy-2-methanesulfonyloxy-
(16) Yamauchi, K.; Une, F.; Tabata, S.; Kinoshita, M. J. Chem. Soc.,
Perkin Trans. 1 1986, 765.
(17) Mori, Y.; Sawada, T.; Furukawa, H. Tetrahedron Lett. 1999, 40,
731.
Org. Lett., Vol. 6, No. 1, 2004
17

In summary, a simple and practical protocol for preparing
C2-symmetric trans-3,5-bis(benzyl/tert-butyldiphenylsily-
loxymethyl)morpholines with excellent optical purity has
been developed by employing commercially available chiral
serine and solketal. The generality of the methodology can
be extended to preparation of other O-protected derivatives
of trans-3,5-bis(hydroxymethyl)morpholines. Use of these
C2-symmetric morpholine entities as chiral auxiliaries/ligand
catalysts in asymmetric syntheses is under progress in our
laboratory.
Scheme 5
Acknowledgment. We thank Benjamin Dumontet and
Marie-The´re`se Adeline for technical assistance in HPLC
analyses and Institut de Chimie des Substances Naturelles
(CNRS, Gif-sur-Yvette) for financial assistance to R.D.
Supporting Information Available: Experimental details
and spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
In the same fashion, (3R,5R)-3 (de and ee > 99%) was
obtained from D-N-Boc-serine methyl ester (R)-4 and (S)-
solketal (S)-19 in 43% overall yield.
OL035998S
12.7 (c 1.1, CHCl3); de > 99%, ee > 98%; (i) HPLC analysis at 258 nm,
symmetry column C18 (5 µm) 4.6 × 250 mm, H2O/CH3CN 70/30 + 0.1%
HCO2H, 1 mL/min, rt, retention time ) 15.6 and 18.3 min for the two
diastereomers; (ii) HPLC analysis at 258 nm, Chiralcel OD column (10
µm) 4.6 × 250 mm, hexane/2-propanol 98/2 + 0.1% HCO2H, 1 mL/min,
rt, retention time ) 16.5, 19 and 21.9 min for the meso-, (3R,5R)-, and
(3S,5S)-isomers, respectively. (()-3 was prepared from racemic serine and
1
(18) (3S,5S)-3: H NMR (300 MHz, CDCl3) δ 2.56 (1H, br, NH), 3.16
(2H, m, 2 × CHN), 3.47 (2Ha + 4H, m, 2 × CHaHbOC, 2 × CH2OBn),
3.73 (2Hb, dd, J ) 12, 3 Hz, 2 × CHaHbOC), 4.51 (2H, s, ArCH2), 4.52
(2H, s, ArCH2), 7.3 (10H, m, ArH); 13C NMR (75.5 MHz, CDCl3) δ 49.8,
68.7, 69.9, 73.4, 127.7, 128.4, 138.1; IR (neat) 3340, 2856, 1736, 1496,
1453, 1366, 1242, 1100, 1028, 738, 698 cm-1; HRMS (ESI) (M + H)+
m/z calcd for C20H25NO3 328.1907, found 328.1911. Anal. Calcd for C20H25-
solketal. (3R,5R)-3: [R]23 -12.3 (c 1, CHCl3); de and ee > 99% (chiral
D
NO3: C, 73.37; H, 7.70; N, 4.28. Found: C, 73.45; H, 7.86; N, 4.22. [R]24
HPLC analysis).
D
18
Org. Lett., Vol. 6, No. 1, 2004