Stereoselective synthesis of c-substituted morpholine derivatives using reductive etherification reaction: Total synthesis of chelonin C

Article abstract of DOI:10.1021/jo201975b

A general strategy is developed for the stereoselective synthesis of C-substituted morpholine derivatives using intramolecular reductive etherification reaction. The method is extended to the first stereoselective total synthesis of (±)-chelonin C.

Full text of DOI:10.1021/jo201975b

Note
pubs.acs.org/joc
Stereoselective Synthesis of C-Substituted Morpholine Derivatives
using Reductive Etherification Reaction: Total Synthesis
of Chelonin C
Santosh J. Gharpure* and J. V. K. Prasad
Department of Chemistry, Indian Institute of Technology Madras, Chennai-600036, Tamil Nadu, India
S
* Supporting Information
ABSTRACT: A general strategy is developed for the stereoselective synthesis of C-substituted morpholine derivatives using
intramolecular reductive etherification reaction. The method is extended to the first stereoselective total synthesis of
(±)-chelonin C.
enantiomerically enriched forms or a mixture of stereoisomers
is obtained. Further, very few reports described in the literature
provide a general, highly stereoselective access to differently
substituted morpholines.6
ecently, morpholines or 1,4-oxazine derivatives have
Rattracted considerable attention owing to the biological
activity associated with this motif.1 Morpholine derivatives have
also found application in the enantioselective synthesis as chiral
organocatalysts,2 chiral auxiliaries,3 and chiral templates in the
synthesis of α-hydroxy acids and oxacycles.4 Among morpho-
lines, 2,5- and 2,6-disubstituted morpholines are particularly
important as they are found in many biologically important
natural products (Figure 1).
In continuation of our program directed at developing
stereoselective synthesis of oxa- and azacycles,7 herein, we
report a concise strategy which is applicable to the stereo-
selective synthesis of a broad range of C-substituted morpho-
line derivatives using reductive etherification as a key reaction.
We envisioned a general approach for the synthesis of
morpholines 1 by disconnecting the C−O bond similar to
many other approaches but relying on reductive etherification
reaction8 rather than the Williamson’s etherification reaction. It
was argued that the oxocarbenium ion intermediate derived
from keto alcohol 2 using an appropriate Lewis acid could be
reduced in a highly stereoselective fashion using triethylsilane
to generate morpholines. The keto alcohol 2 in turn could be
rapidly assembled from readily available N-protected 1,2-amino
alcohols 3 and α-bromo ketones 4 (Scheme 1).
Scheme 1. Retrosynthesis for the Synthesis of Morpholine
Derivatives
Figure 1. Bioactive compounds bearing a morpholine moiety.
Not surprisingly, some progress has been made on the
synthesis of 2,5- and 2,6-disubstituted morpholine derivatives.5
However, there are still some challenges; e.g., typically 2,5- and
2,6-disubstituted morpholine derivatives are prepared by a two-
component disconnection involving C−O ether bond for-
mation, typically by Williamson’s etherification reaction. Here,
both the fragments required have to be prepared in
In order to test the strategy, the N-tosylethanolamine (3a)
was reacted with bromoacetone (4a) to furnish the keto alcohol
Received: October 2, 2011
Published: November 7, 2011
© 2011 American Chemical Society
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Note
2aa.9 Treatment of keto alcohol 2aa with TMSOTf and Et3SiH
for 1 h gratifyingly furnished the morpholine derivative 1aa5g in
good yield (Scheme 2). Similarly, reaction of the keto alcohol
was tolerated under these reaction conditions and the
morpholine 1ga was obtained in good yield. Not only the
tosyl but even nosyl protection was found to be stable under
the reaction conditions employed (cf. morpholine 1fa). The
ester moiety too was unaffected under the reaction conditions,
furnishing the morpholine 1ha in very good yield and
diastereoselectivity. It is pertinent to mention here that the
morpholine 1ha was obtained in 98% ee, clearly suggesting that
no epimerization of the center α to the ester took place either
under basic alkylation conditions or under the influence of the
strong Lewis acid used for the reductive etherification. It should
be noted that the stereochemistry of the morpholine 1ha is
antipodal to the other cases. The stereochemistry of the
morpholine 1ha was assigned on the basis of single-crystal X-
ray diffraction studies.10 In the other cases, the stereochemistry
was assigned by analogy to this example and by comparison
with the literature report (for the trans isomer of the
morpholine 1bb5h).
Table 1 outlines the utility of this reductive etherification
based strategy for the stereoselective synthesis of cis-2,6-
disubstituted morpholine derivatives. The required keto
alcohols 2ia−ma were readily prepared from racemic N-
tosylamino alcohols 3i−m and α-bromo ketones 4a−c. Both
symmetrically and unsymmetrically substituted morpholine
derivatives could be prepared in excellent yield and
diastereoselectivity (Table 1, entries 1−7).
Scheme 2. Synthesis of Monosubstituted Morpholine
Derivatives
2ab derived from N-tosylethanolamine (3a) and phenacyl
bromide (4b) gave the morpholine 1ab5h in excellent yield.
Encouraged by these results, we embarked on the synthesis
of 2,5-disubstituted morpholines. Toward this end, the keto
alcohols 2ba−ha were prepared by N-alkylation of enantiomeri-
cally enriched amino alcohols 3b−h with α-bromo ketones 4a−
b. Scheme 3 outlines the scope of this reductive etherification
Scheme 3. Stereoselective Synthesis of cis-2,5-Disubstituted
a
Morpholines
Benzyl ether as well as the heteroaromatic thiophene moiety
were found to be unaffected under the reaction conditions used
(Table 1, entries 5 and 6). For the keto alcohol 2ma, the
reaction furnished the morpholine 1ma as the only detectable
product, and none of the oxazepine formation was observed
(Table 1, entry 7). The cis stereochemistry of the 2,6-
substitutents was ascertained on the basis of the NOE
experiments and by comparison with literature data (for
morpholine 1jb6 and for trans isomer of 1ja5g).
We envisioned that synthesis of morpholine moiety fused to
a cyclic system will further enhance the utility of the present
strategy. Thus, reaction of the keto alcohol 2na under
optimized conditions yielded the morpholine 1na in good
yield and excellent diastereoselectivity (Scheme 4). Similarly,
when the keto alcohol 2oa derived from the cis-amino alcohol
moiety was subjected to reductive etherification reaction, the
morpholine 1oa was obtained in comparable yield with good
diastereoselectivity. The reactions of keto alcohols 2pa−2ra
bearing either a five-membered ring or an eight-membered ring
a
Isolated yield is shown. In all the cases, dr was determined on the
1
crude reaction mixtures by H NMR and was found to be ≥19:1.
for the synthesis of 2,5-disubstituted morpholines. The keto
alcohols 2ba−ea bearing alkyl or aryl substituents gave the
corresponding cis-2,5-disubstituted morpholines 1ba−ea in
excellent yield and diastereoselectivity. The thioether moiety
Table 1. Stereoselective Synthesis of cis-2,6-Disubstituted Morpholines
ab
,
entry
R1
R2
product
yield (%)
1
2
3
4
5
6
7
Me
Ph
Ph
Cy
Me
Ph
2ia
2jb
2ja
2ka
2la
1ia
1jb
1ja
1ka
1la
82
80
86
92
70
72
92
Me
Me
Me
BnOCH2
Me
thiophene-2-yl
Me
2ic
1ic
CH2OH
2ma
1ma
a
b
1
Isolated yield. In all cases, dr was determined on the crude reaction mixtures by H NMR and was found to be ≥19:1.
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Note
Scheme 4. Stereoselective Synthesis of Fused Bicyclic
a c
−
Morpholines
Figure 2. Origin of stereoselectivity for substituted morpholines.
avoid interaction with tosyl group. In both the cases, the
nucleophile traps the oxocarbenium from the axial direction to
lead to chair rather than the twist-boat conformation as
proposed by Woerpel in the tetrahydropyran systems, thus
resulting in the cis stereochemistry of the product.11 Finally, for
the morpholine 1sa, in the major conformer of the
oxocarbenium ion, both the alkyl groups (R1 and R2) would
occupy pseudoaxial orientation4a and thus lead to the trans-1sa
as the major product, albeit with diminished stereoselectivity.
After successfully demonstrating the scope of the strategy, we
turned our attention to applying this strategy for the total
synthesis of rac-chelonin C (5). Chelonin C (5) belongs to the
family of 2,6-disubstituted morpholines and was isolated from the
marine sponge Chelonaplysilla sp.12 This family of alkaloids have
been reported to exhibit antimicrobial activity against Bacillus
subtilis and in vivo anti-inflammatory activity. The synthesis
began with the alkylation of the amino alcohol 6 with the
bromide 7 to furnish the keto-alcohol 8. The keto alcohol 8
under reductive etherification conditions furnished the protected
chelonin C 9 in 81% yield and with excellent cis diastereose-
lectivity (Scheme 6). Deprotection of tosyl and benzoate groups
a
b
Isolated yield. In all cases, dr was determined on the crude reaction
c
1
mixtures by H NMR and was found to be ≥19:1. All products are
racemic.
were uneventful, and the corresponding morpholines 1pa−ra
were formed in good to excellent yield.
The strategy was also extended to the synthesis of other
C-substituted morpholines. When the keto alcohol 2sa was
subjected to reductive etherification reaction, the 2,3,6-
trisubstituted morpholine 1sa was formed in excellent yield
but only with moderate diastereoselectivity (ca. 4:1) favoring
trans stereochemistry for 2,6-substitution (Scheme 5). The keto
Scheme 6. Stereoselective Synthesis of Chelonin C
Scheme 5. Synthesis of 2,3,6-Tri-, 2,2,3,6-Tetrasubstituted,
and Spirocyclic Morpholines
was accomplished in the same pot on treatment with sodium
napthalide to give rac-chelonin C (5) in good yield. The data for
the synthetic chelonin C was found to be in good agreement with
that reported for natural product. This constitutes the stereo-
selective, first total synthesis of rac-chelonin C (5).
In conclusion, we have developed a new reductive ether-
ification-based strategy for the synthesis of diversely substituted
morpholines. 2-Substituted, cis-2,5-disubstituted, cis-2,6-disub-
stituted, 2,3,6-trisubstituted, 2,2,3,6-tetrasubstituted, bicyclic,
and spirocyclic morpholines were prepared with good yields
and excellent diastereoselectivities by utilizing this strategy. The
noted feature of this approach is that only one of the amino
alcohol starting material needs to be prepared in enantiopure
form. The developed strategy was also successfully applied in
the stereoselective first total synthesis of marine natural product
chelonin C.
alcohol 2ta bearing tertiary alcohol moiety yielded the
corresponding 2,2,3,6-tetrasubstituted morpholine derivative
1ta in good yield and excellent diastereoselectivity. Even
spirocyclic morpholine 1ua could be prepared from keto
alcohol 2ua in excellent yield.
The stereochemical outcome of these reactions is dependent
on the conformational stability of the oxocarbenium ion
intermediate. The tosyl substitution on nitrogen prefers to be in
the equatorial orientation (Figure 2). In the case of 2,6-
disubstituted morpholines (R1 = alkyl, R2 = H), the alkyl group
occupies the pseudoequatorial position. On the contrary, in the
case of 2,5-disubstituted morpholine (R1 = H, R2 = alkyl), the
alkyl substitution prefers to be in the axial direction perhaps to
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Note
143.6 (C), 139.0 (C), 137.6 (C), 130.0 (2CH), 128.7 (2CH), 128.4
(CH), 127.2 (2CH), 126.1 (2CH), 78.0 (CH), 71.8 (CH2), 48.3
(CH), 46.2 (CH2), 21.6 (CH3), 13.8 (CH3); HRMS (ESI, M + H+)
m/z calcd for C18H22NO3S 332.1320, found 332.1318.
EXPERIMENTAL SECTION
■
General Materials and Methods. 1H and 13C NMR spectra
were recorded using CDCl3 and C6D6 as solvents on a 400 MHz
1
spectrometer. For H NMR spectra, signals arising from the residual
(2S,5S)-2-Methyl-5-phenyl-4-tosylmorpholine (1ea): colorless
proton from the solvent were used as the internal standards. In the 13
C
liquid; yield 70%; [α]23 58.4 (c 1.00, CHCl3); IR (neat) 3058,
D
NMR spectra, the nature of the carbons (C/CH/CH2/CH3) was
determined by recording the DEPT-135 experiment. Infrared spectra
are reported in cm−1. Melting points are uncorrected. Dry CH2Cl2 was
prepared by distilling over calcium hydride. All the commercial
reagents were used as such without further purification.
2979, 2919, 2865, 1599, 1495, 1451, 1381, 1341, 1299, 1268, 1162,
1
1120, 1096, 1022, 997, 907, 843, 816, 770, 737, 703 cm−1; H NMR
(400 MHz, CDCl3) δ 7.56 (d, J = 8.2 Hz, 2H), 7.45−7.40 (m, 2H),
7.30−7.20 (m, 3H), 7.19 (d, J = 8.2 Hz, 2H), 4.89 (dd, J = 3.4, 0.0 Hz,
1H), 4.25 (ABX, J = 12.0, 0.0 Hz, 1H), 3.78 (ABX, J = 12.0, 3.7 Hz,
1H), 3.57 (ABX, J = 13.8, 2.5 Hz, 1H), 3.55−3.40 (m, 1H), 2.80
(ABX, J = 13.8, 10.9 Hz, 1H), 2.38 (s, 3H), 1.09 (d, J = 6.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 143.4 (C), 138.0 (C), 137.7 (C),
129.8 (2CH), 128.5 (2CH), 128.4 (2CH), 127.7 (CH), 127.2 (2CH),
71.4 (CH), 69.0 (CH2), 54.4 (CH), 47.1 (CH2), 21.6 (CH3), 18.8
(CH3); HRMS (ESI, M + H+) m/z calcd for C18H22NO3S 332.1320,
found 332.1308.
Typical Procedure for Reductive Etherification. (2S,5S)-2,5-
Dimethyl-4-tosylmorpholine (1ba). To a magnetically stirred sol-
ution of keto alcohol 2ba (155 mg, 0.544 mmol) in CH2Cl2 (5 mL) at
0 °C were added successively Et3SiH (95 μL, 0.598 mmol) and
TMSOTf (108 μL, 0.598 mmol), and the reaction mixture was allowed
to warm to rt. After complete consumption of starting material (TLC
control), the reaction mixture was quenched with saturated NaHCO3,
extracted with CH2Cl2, washed with brine, and dried (anhyd Na2SO4).
Evaporation of solvent and purification of residue on silica gel column
using EtOAc−hexanes (1:24) as eluent furnished morpholine 1ba
(114 mg, 78%) as a colorless solid: mp 58−60 °C; [α]23D 46.2 (c 1.00,
CHCl3); IR (KBr) 2982, 2920, 2899, 2861, 1595, 1489, 1447, 1387,
1377, 1340, 1296, 1280, 1184, 1162, 1112, 1053, 1001, 903, 861, 823,
(2S,5S)-5-Benzyl-2-methyl-4-tosylmorpholine (1fa): colorless
liquid; yield 85%; [α]24 71.0 (c 0.3, CHCl3); IR (neat) 3028, 2975,
D
2927, 2863, 1590, 1544, 1452, 1368, 1346, 1276, 1167, 1124, 1058,
999, 941, 909, 854, 777, 740, 702 cm−1; 1H NMR (400 MHz, CDCl3)
δ 7.95 (d, J = 7.6 Hz, 1H), 7.70−7.55 (m, 3H), 7.25−7.10 (m, 5H),
3.95−3.85 (m, 1H), 3.74 (ABX, J = 11.2, 0.0 Hz, 1H), 3.63 (ABX, J =
13.4, 2.5 Hz, 1H), 3.60−3.50 (m, 2H), 3.17 (ABX, J = 9.8, 5.2 Hz,
1H), 3.13 (ABX, J = 11.2, 5.8 Hz, 1H), 2.92 (ABX, J = 13.1, 5.2 Hz,
1H), 1.24 (d, J = 6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 147.6
(C), 137.7 (C), 133.8 (C), 133.6 (CH), 132.2 (CH), 131.0 (CH),
129.6 (2CH), 128.7 (2CH), 126.8 (CH), 124.6 (CH), 72.4 (CH),
67.6 (CH2), 55.2 (CH), 47.1 (CH2), 35.2 (CH2), 18.7 (CH3); HRMS
(ESI, M + H+) m/z calcd for C18H21N2O5S 377.1171, found 377.1165.
(2S,5S)-2-Methyl-5-(2-(methylthio)ethyl)-4-tosylmorpholine
1
769, 709 cm−1; H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz,
2H), 7.30 (d, J = 8.2 Hz, 2H), 4.00−3.90 (m, 1H), 3.63 (ABX, J =
11.2, 2.7 Hz, 1H), 3.59 (ABX, J = 11.2, 0.7 Hz, 1H), 3.52 (ABX, J =
12.7, 2.8 Hz, 1H), 3.50−3.40 (m, 1H), 2.77 (ABX, J = 12.7, 10.6 Hz,
1H), 2.42 (s, 3H), 1.14 (d, J = 6.1 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 143.5 (C), 137.7 (C), 129.9 (2CH),
127.2 (2CH), 72.0 (CH), 71.5 (CH2), 48.3 (CH), 45.9 (CH2), 21.6
(CH3), 18.7 (CH3), 13.8 (CH3); HRMS (ESI, M + H+) m/z calcd for
C13H20NO3S 270.1164, found 270.1152.
(1ga): colorless liquid; yield 75%; [α]23 43.5 (c 1.00, CHCl3); IR
D
(2S,5S)-5-Benzyl-2-methyl-4-tosylmorpholine (1ca): colorless
(neat) 3034, 2971, 2920, 2862, 1598, 1493, 1449, 1339, 1303, 1277,
solid; yield 91%; mp 90−92 °C; [α]23 − 36.6 (c 1.00, CHCl3); IR
1
1214, 1160, 1117, 1042, 997, 907, 814, 733 cm−1; H NMR (400
D
(KBr) 3061, 3026, 2974, 2922, 2866, 1597, 1493, 1455, 1335, 1280,
MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H),
3.87 (td, J = 7.3, 2.8 Hz, 1H), 3.65 (ABX, J = 11.4, 0.0 Hz, 1H), 3.60
(ABX, J = 13.8, 2.8 Hz, 1H), 3.43 (ABX, J = 11.8, 2.6 Hz, 1H), 3.35−
3.25 (m, 1H), 2.82 (ABX, J = 13.8, 11.4 Hz, 1H), 2.50−2.40 (m, 2H),
2.42 (s, 3H), 2.05 (s, 3H),1.95−1.80 (m, 2H), 1.08 (d, J = 6.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 143.6 (C), 138.2 (C), 130.0
(2CH), 127.1 (2CH), 71.2 (CH), 68.5 (CH2), 51.7 (CH), 46.6
(CH2), 30.9 (CH2), 27.7 (CH2), 21.6 (CH3), 18.7 (CH3), 15.5
(CH3); HRMS (ESI, Ms + H+) m/z calcd for C15H24NO3S2 330.1198,
found 330.1201.
1153, 1125, 1087, 1050, 1000, 940, 911, 854, 816, 778, 743, 704 cm−1
;
1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 2H), 7.35−7.20
(m, 5H), 7.23 (d, J = 8.2 Hz, 2H), 4.10−3.95 (m, 1H), 3.70 (ABX, J =
11.8, 0.0 Hz, 1H), 3.63 (ABX, J = 13.2, 2.7 Hz, 1H), 3.60−3.50 (m,
1H), 3.47 (ABX, J = 11.8, 2.3 Hz, 1H), 3.07 (ABX, J = 13.1, 10.5 Hz,
1H), 2.95 (ABX, J = 13.2, 10.8 Hz, 1H), 2.73 (ABX, J = 13.1, 4.7 Hz,
1H), 2.45 (s, 3H), 1.24 (d, J = 6.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 143.5 (C), 138.0 (C), 137.7 (C), 130.0 (2CH), 129.6
(2CH), 128.8 (2CH), 127.2 (2CH), 126.7 (CH), 71.8 (CH), 67.3
(CH2), 54.2 (CH), 46.6 (CH2), 34.1 (CH2), 21.6 (CH3), 18.8 (CH3);
HRMS (ESI, M + H+) m/z calcd for C19H24NO3S 346.1477, found
346.1479.
(3S,6R)-Methyl 6-methyl-4-tosylmorpholine-3-carboxylate
(1ha): colorless solid; yield 88%; mp 106−108 °C; [α]23 − 57.6 (c
D
1.00, CHCl3); IR (KBr) 2984, 2971, 2925, 2867, 1750, 1597, 1445,
1344, 1301, 1279, 1213, 1166, 1110, 1094, 1047, 1009, 918, 826, 755
(2S,5S)-5-Isopropyl-2-methyl-4-tosylmorpholine (1da): colorless
liquid; yield 71%; [α]23 20.8 (c 1.00, CHCl3); IR (neat) 2968,
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.9 Hz, 2H), 7.30
D
2924, 2867, 1596, 1455, 1339, 1302, 1277, 1159, 1134, 1092, 1021,
994, 904, 815, 779 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J =
8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 3.83 ABX, J = 11.4, 0.0 Hz, 1H),
3.60 (ABX, J = 14.5, 1.9 Hz, 1H), 3.30−3.20 (m, 2H), 3.20−3.10 (m,
1H), 2.82 (ABX, J = 14.5, 11.2 Hz, 1H), 2.42 (s, 3H), 2.30−2.15 (m,
1H), 1.03 (d, J = 6.2 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 143.3 (C), 138.9 (C), 129.9
(2CH), 127.0 (2CH), 70.6 (CH), 66.4 (CH2), 59.0 (CH), 47.1
(CH2), 25.4 (CH3), 21.6 (CH), 20.1 (CH3), 19.9 (CH3), 18.7 (CH3);
HRMS (ESI, M + H+) m/z calcd for C15H24NO3S 298.1477, found
298.1462.
(d, J = 7.9 Hz, 2H), 4.51 (d, J = 2.2 Hz, 1H), 4.31 (ABX, J = 11.6, 0.0
Hz, 1H), 3.77 (ABX, J = 11.6, 3.3 Hz, 1H), 3.60−3.50 (m, 2H), 3.56
(s, 3H), 3.03 (ABX, J = 12.0, 12.0 Hz, 1H), 2.43 (s, 3H), 1.13 (d, J =
5.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.6 (CO), 143.7 (C),
136.6 (C), 129.7 (2CH), 127.4 (2CH), 72.4 (CH), 69.0 (CH2), 54.6
(CH), 52.4 (CH3), 47.6 (CH2), 21.7 (CH3), 18.6 (CH3); HRMS (ESI,
M + H+) m/z calcd for C14H20NO5S 314.1062, found 314.1052.
(2S*,6R*)-2,6-Dimethyl-4-tosylmorpholine (1ia): colorless solid;
yield 82%; mp 100−102 °C; IR (KBr) 2974, 2931, 2888, 2845, 1599,
1493, 1457, 1380, 1347, 1327, 1300, 1238, 1166, 1137, 1085, 1005,
944, 907, 843, 809, 782 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.62 (d,
J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 3.75−3.60 (m, 2H), 3.54
(ABX, J = 10.7, 0.0 Hz, 2H), 2.43 (s, 3H), 1.91 (ABX, J = 10.7, 10.7
Hz, 2H), 1.12 (d, J = 6.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
144.0 (C), 132.3 (C), 129.9 (2CH), 127.9 (2CH), 71.4 (2CH), 51.0
(2CH2), 21.7 (CH3), 18.8 (2CH3); HRMS (ESI, M + H+) m/z calcd
for C13H20NO3S 270.1164, found 270.1165.
(2S,5S)-5-Methyl-2-phenyl-4-tosylmorpholine (1bb): colorless
liquid; yield 77%; [α]23 69.5 (c 1.00, CHCl3); IR (neat) 3063,
D
3033, 2978, 2919, 2864, 1599, 1495, 1450, 1342, 1264, 1161, 1111,
1065, 1034, 979, 912, 869, 816, 733 cm−1 1H NMR (400 MHz,
;
CDCl3) δ 7.61 (d, J = 8.2 Hz, 2H), 7.30−7.15 (m, 5H), 7.21 (d, J = 8.2
Hz, 2H), 4.33 (dd, J = 10.9, 2.8 Hz, 1H), 4.05−3.95 (m, 1H), 3.75
(ABX, J = 11.4, 2.3 Hz, 1H), 3.70 (ABX, J = 11.4, 0.0 Hz, 1H), 3.65
(ABX, J = 12.5, 2.9 Hz, 1H), 2.92 (ABX, J = 12.5, 12.5 Hz, 1H), 2.34
(s, 3H), 1.07 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
(2S*,6R*)-2-Cyclohexyl-6-methyl-4-tosylmorpholine (1ka): col-
orless solid; yield 92%; mp 126−128 °C; IR (KBr) 2929, 2849,
1
1595, 1449, 1343, 1161, 1095, 1064, 994, 932, 816, 774 cm−1; H
10328
dx.doi.org/10.1021/jo201975b | J. Org. Chem. 2011, 76, 10325−10331

The Journal of Organic Chemistry
Note
NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2
Hz, 2H), 3.70−3.55 (m, 2H), 3.54 (ABX, J = 11.0, 0.0 Hz, 1H), 3.35−
3.20 (m, 1H), 2.44 (s, 3H), 1.97 (ABX, J = 11.0, 11.0 Hz, 1H), 1.90
(ABX, J = 10.7, 10.7 Hz, 1H), 1.90−1.80 (m, 1H), 1.75−1.50 (m, 4H),
3H); 13C NMR (100 MHz, C6D6) δ 142.7 (C), 139.8 (C), 129.8
(2CH), 127.5 (2CH), 74.3 (CH), 72.0 (CH), 53.9 (CH), 46.1 (CH2),
31.6 (CH2), 24.9 (CH2), 23.4 (CH2), 21.1 (CH3), 19.8 (CH2), 18.7
(CH3); HRMS (ESI, M + H+) m/z calcd for C16H24NO3S 310.1477,
found 310.1484.
1.35−1.10 (m, 4H), 1.11 (d, J = 6.2 Hz, 3H), 1.05−0.90 (m, 2H); 13
C
NMR (100 MHz, CDCl3) δ 143.9 (C), 132.5 (C), 129.9 (2CH), 127.9
(2CH), 79.5 (CH), 71.4 (CH), 51.4 (CH2), 47.8 (CH2), 41.1 (CH),
29.1 (CH2), 28.6 (CH2), 26.5 (CH2), 26.1 (CH2), 26.0 (CH2), 21.7
(CH3), 18.8 (CH3); HRMS (ESI, M + H+) m/z calcd for C18H28NO3S
338.1790, found 338.1786.
(2R*,4aS*,7aS*)-2-Methyl-4-tosyloctahydrocyclopenta[b][1,4]-
oxazine (1pa): colorless solid; yield 60%; mp 132−134 °C; IR (KBr)
2967, 2927, 2876, 1599, 1453, 1400, 1380, 1335, 1308, 1289, 1166,
1123, 1092, 1042, 927, 871, 814, 783, 709 cm−1; 1H NMR (400 MHz,
C6D6) δ 7.66 (d, J = 8.2 Hz, 2H), 6.81 (d, J = 8.2 Hz, 2H), 3.72 (ABX,
J = 11.4, 2.4 Hz, 1H), 3.60−3.50 (m, 1H), 3.35−3.25 (m, 1H), 2.25−
2.20 (m, 1H), 2.10−1.90 (m, 3H), 1.91 (s, 3H), 1.65−1.55 (m, 1H),
1.40−1.15 (m, 3H), 0.87 (d, J = 6.2 Hz, 3H); 13C NMR (100 MHz,
C6D6) δ 143.3 (C), 133.4 (C), 129.7 (2CH), 128.4 (2CH), 83.0
(CH), 72.8 (CH), 62.0 (CH), 54.0 (CH2), 27.1 (CH2), 25.7 (CH2),
21.2 (CH3), 18.4 (CH3), 17.6 (CH2); HRMS (ESI, M + Na+): m/z
calcd for C15H21NO3NaS 318.1140, found 318.1150.
(2R*,4aR*,7aS*)-2-Methyl-4-tosyloctahydrocyclopenta[b][1,4]-
oxazine (1qa): colorless liquid; yield 63%; IR (neat) 2974, 2876,
1599, 1454, 1342, 1267, 1158, 1123, 1092, 1060, 1034, 1000, 927, 872,
816, 737, 706 cm−1; 1H NMR (400 MHz, C6D6) δ 7.73 (d, J = 8.2 Hz,
2H), 6.80 (d, J = 8.2 Hz, 2H), 4.02 (td, J = 9.6, 3.6 Hz, 1H), 3.60−3.50
(m, 2H), 3.30−3.20 (m, 1H), 2.42 (ABX, J = 12.0, 10.7 Hz, 1H), 1.91
(s, 3H), 1.60−1.45 (m, 2H), 1.40−1.30 (m, 2H), 1.30−1.10 (m, 2H),
0.82 (d, J = 6.2 Hz, 3H); 13C NMR (100 MHz, C6D6) δ 142.8 (C),
138.3 (C), 129.7 (2CH), 127.8 (2CH), 78.1 (CH), 70.8 (CH), 56.6
(CH), 45.8 (CH2), 29.8 (CH2), 22.0 (CH2), 21.2 (CH3), 21.0 (CH2),
18.7 (CH3); HRMS (ESI, M + H+) m/z calcd for C15H22NO3S
296.1320, found 296.1333.
(2R*,6R*)-2-(Benzyloxymethyl)-6-methyl-4-tosylmorpholine
(1la): pale yellow liquid; yield 70%; IR (neat) 3062, 3032, 2978, 2869,
2251, 1724, 1599, 1495, 1453, 1347, 1235, 1166, 1089, 1001, 912, 812,
1
783, 734, 703 cm−1; H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.2
Hz, 2H), 7.40−7.25 (m, 7H), 4.52 (s, 2H), 3.85−3.75 (m, 1H), 3.75−
3.65 (m, 1H), 3.64 (ABX, J = 11.0, 2.0 Hz, 1H), 3.56 (ABX, J = 11.0,
2.0 Hz, 1H), 3.48 (ABX, J = 10.2, 5.0 Hz, 1H), 3.40 (ABX, J = 10.2, 5.0
Hz, 1H), 2.44 (s, 3H), 2.12 (ABX, J = 11.0, 11.0 Hz, 1H), 1.96 (ABX, J
= 11.0, 11.0 Hz, 1H), 1.15 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 144.0 (C), 137.9 (C), 132.4 (C), 129.9 (2CH), 128.6 (CH),
128.0 (2CH), 127.9 (2CH), 127.9 (2CH), 74.5 (CH), 73.6 (CH2),
71.7 (CH), 70.6 (CH2), 51.2 (CH2), 47.4 (CH2), 21.7 (CH3), 18.7
(CH3); HRMS (ESI, M + Na+) m/z calcd for C20H25NO4NaS
398.1402, found 398.1414.
(2R*,6R*)-2-Methyl-6-(thiophene-2-yl)-4-tosylmorpholine (1ic): col-
orless liquid; yield 72%; IR (neat) 3107, 3068, 2979, 2874, 2275, 1598,
1493, 1450, 1349, 1234, 1166, 1088, 998, 934, 912, 877, 816, 730
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.2 Hz, 2H), 7.34
(d, J = 8.2 Hz, 2H), δ 7.25 (dd, J = 4.7, 1.1 Hz, 1H), 7.00−6.90 (m,
2H), 4.91 (dd, J = 10.5, 2.5 Hz, 1H), 3.95−3.85 (m, 1H), 3.84 (ABX, J
= 11.2, 2.5 Hz, 1H), 3.64 (ABX, J = 11.2, 2.2 Hz, 1H), 2.44 (s, 3H),
2.31 (ABX, J = 11.2, 10.5 Hz, 1H), 2.08 (ABX, J = 11.2, 10.6 Hz, 1H),
1.22 (d, J = 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.2 (C),
141.4 (C), 132.4 (C), 130.0 (2CH), 127.9 (2CH), 126.8 (CH), 125.3
(CH), 124.7 (CH), 73.8 (CH), 72.2 (CH), 51.4 (CH2), 51.0 (CH2),
21.7 (CH3), 18.8 (CH3); HRMS (ESI, M + H+) m/z calcd for
C16H20NO3S2 338.0885, found 338.0870.
(2R*,4aR*,10aS*)-2-Methyl-4-tosyldecahydro-2H-cycloocta[b]-
[1,4]oxazine (1ra): colorless liquid; yield 75%; IR (neat) 3057, 2927,
2860, 1599, 1448, 1373, 1338, 1268, 1222, 1161, 1118, 1090, 1061,
1020, 924, 893, 861, 813, 738, 707 cm−1; 1H NMR (400 MHz, C6D6)
δ 7.76 (d, J = 8.2 Hz, 2H), 6.81 (d, J = 8.2 Hz, 2H), 4.20−4.15 (m,
1H), 3.59 (ABX, J = 12.4, 2.8 Hz, 1H), 3.55−3.35 (m, 2H), 2.43
(ABX, J = 12.4, 10.7 Hz, 1H), 1.90 (s, 3H), 1.90−1.75 (m, 1H), 1.65−
1.00 (m, 12H), 0.88 (d, J = 6.2 Hz, 3H); 13C NMR (100 MHz, C6D6)
δ 142.8 (C), 139.3 (C), 129.7 (2CH), 127.5 (2CH), 78.8 (CH), 71.9
(CH), 55.0 (CH), 46.6 (CH2), 28.7 (CH2), 28.5 (CH2), 26.9 (CH2),
25.7 (CH2), 24.6 (CH2), 21.5 (CH2), 21.1 (CH3), 18.7 (CH3); HRMS
(ESI, M + H+) m/z calcd for C18H28NO3S 338.1790, found 338.1781.
(2R,3S,6S)-Methyl 2,6-dimethyl-4-tosylmorpholine-3-carboxylate
((2R*,6R*)-6-Methyl-4-tosylmorpholin-2-yl)methanol (1ma): pale
yellow liquid; yield 92%; IR (neat) 3502, 2978, 2925, 2877, 1600,
1
1454, 1341, 1236, 1163, 1090, 1045, 1001, 812, 782 cm−1; H NMR
(400 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz,
2H), 3.80−3.70 (m, 2H), 3.68 (ABX, J = 12.0, 2.4 Hz, 1H), 3.57
(ABX, J = 10.6, 0.0 Hz, 2H), 3.52 (ABX, J = 12.0, 4.9 Hz, 1H), 2.44 (s,
3H), 2.17 (ABX, J = 10.6, 10.6 Hz, 1H), 1.94 (ABX, J = 10.6, 10.6 Hz,
1H), 1.15 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.1
(C), 132.2 (C), 130.0 (2CH), 128.0 (2CH), 75.5 (CH), 71.7 (CH),
63.6 (CH2), 51.2 (CH2), 46.4 (CH2), 21.7 (CH3), 18.7 (CH3); HRMS
(ESI, M + H+) m/z calcd for C13H20NO4S 286.1113, found 286.1106.
(2R*,4aS*,8aS*)-2-Methyl-4-tosyloctahydro-2H-benzo[b][1,4]-
oxazine (1na): colorless solid; yield 80%; mp 84−86 °C; IR (KBr)
2930, 2851, 2814, 1595, 1455, 1383, 1350, 1162, 1092, 1046, 1015,
902, 865, 810, 767, 705 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.64 (d,
J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 3.88 (ABX, J = 11.6, 2.2 Hz,
1H), 3.85−3.75 (m, 1H), 3.30−3.20 (m, 1H), 2.60−2.50 (m, 1H),
2.44 (s, 3H), 2.31 (ABX, J = 11.6, 10.5 Hz, 1H), 2.17 (ddd, J = 12.0,
8.8, 3.7 Hz, 1H), 1.90−1.80 (m, 1H), 1.80−1.60 (m, 2H), 1.50−1.40
(m, 1H), 1.35−1.20 (m, 2H), 1.15 (d, J = 6.2 Hz, 3H), 1.15−1.05 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 143.7 (C), 134.7 (C), 129.9
(2CH), 127.6 (2CH), 79.6 (CH), 71.6 (CH), 62.8 (CH), 54.6 (CH2),
31.7 (CH2), 29.5 (CH2), 25.0 (CH2), 24.1 (CH2), 21.7 (CH3), 18.9
(CH3); HRMS (ESI, M + H+) m/z calcd for C16H24NO3S 310.1477,
found 310.1483.
(cis-1sa): colorless liquid; yield 18%; [α]23 −98.4 (c 1.00, CHCl3);
D
IR (neat) 2981, 2927, 2899, 2854, 1744, 1596, 1492, 1449, 1354, 1278,
1202, 1167, 1139, 1116, 1033, 972, 906, 869, 813 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H),
3.86 (s, 3H), 3.85−3.70 (m, 2H), 3.53 (ABX, J = 11.0, 2.5 Hz, 1H),
2.85 (d, J = 9.0 Hz, 1H), 2.46 (s, 3H), 1.94 (ABX, J = 11.0, 11.0 Hz,
1H), 1.13 (d, J = 6.3 Hz, 3H), 1.12 (d, J = 6.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.1 (CO), 144.7 (C), 130.7 (C), 130.0
(2CH), 128.9 (2CH), 74.1 (CH), 71.0 (CH), 64.4 (CH), 53.0 (CH3),
51.0 (CH2), 21.8 (CH3), 18.8 (CH3), 18.0 (CH3); HRMS (ESI, M +
H+) m/z calcd for C15H22NO5S 328.1219, found 328.1231.
(2R,3S,6R)-Methyl 2,6-dimethyl-4-tosylmorpholine-3-carboxylate
(trans-1sa): colorless solid; 71%; mp 96−98 °C; [α]23 − 39.4 (c
D
1.00, CHCl3); IR (KBr) 2982, 2954, 2933, 1747, 1598, 1451, 1343,
1
1285, 1164, 1121, 1091, 1040, 1011, 910, 814, 734 cm−1; H NMR
(400 MHz, CDCl3) δ 7.66 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz,
2H), 4.53 (q, J = 6.6 Hz, 1H), 4.29 (s, 1H), 4.05−3.90 (m, 1H), 3.54
(s, 3H), 3.52 (ABX, J = 12.4, 3.1 Hz, 1H), 2.99 (ABX, J = 12.4, 11.0
Hz, 1H), 2.42 (s, 3H), 1.46 (d, J = 6.7 Hz, 3H), 1.06 (d, J = 6.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 169.9 (CO), 143.6 (C), 136.6
(C), 129.6 (2CH), 127.4 (2CH), 70.4 (CH), 63.1 (CH), 58.2 (CH),
52.4 (CH3), 47.3 (CH2), 21.7 (CH3), 18.7 (CH3), 16.9 (CH3); HRMS
(ESI, M + H+) m/z calcd for C15H22NO5S 328.1219, found 328.1231.
(3S*,6S*)-2,2,3,6-Tetramethyl-4-tosylmorpholine (1ta): colorless
solid; yield 70%; mp 72−74 °C; IR (KBr) 2984, 2928, 1597, 1449,
1381, 1334, 1277, 1244, 1154, 1086, 1056, 1000, 924, 882, 843, 814,
(2R*,4aR*,8aS*)-2-Methyl-4-tosyloctahydro-2H-benzo[b][1,4]-
oxazine (1oa): colorless solid; yield 71%; mp 86−88 °C; IR (KBr)
2933, 2862, 1596, 1450, 1376, 1336, 1151, 1104, 1011, 918, 899, 817,
706 cm−1; 1H NMR (400 MHz, C6D6) δ 7.76 (d, J = 8.2 Hz, 2H), 6.80
(d, J = 8.2 Hz, 2H), 3.90−3.80 (m, 1H), 3.54 (ABX, J = 12.8, 2.9 Hz,
1H), 3.50−3.40 (m, 1H), 3.40−3.30 (m, 1H), 2.63 (ABX, J = 12.8,
10.8 Hz, 1H), 1.90 (s, 3H), 1.80−1.70 (m, 1H), 1.65 (qd, J = 12.1, 3.3
Hz, 1H), 1.45−1.30 (m, 3H), 1.15−0.90 (m, 3H), 0.86 (d, J = 6.2 Hz,
1
752, 707 cm−1; H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.2 Hz,
2H), 7.29 (d, J = 8.2 Hz, 2H), 3.95−3.85 (m, 1H), 3.67 (q, J = 6.6 Hz,
10329
dx.doi.org/10.1021/jo201975b | J. Org. Chem. 2011, 76, 10325−10331

The Journal of Organic Chemistry
Note
1H), 3.45 (ABX, J = 12.4, 3.5 Hz, 1H), 2.60 (ABX, J = 12.4, 11.3 Hz,
1H), 2.42 (s, 3H), 1.35 (s, 3H), 1.10 (d, J = 6.6 Hz, 3H), 1.09 (s, 3H),
0.92 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 143.3 (C),
137.8 (C), 129.9 (2CH), 127.1 (2CH), 74.1 (C), 65.0 (CH), 54.5
(CH), 44.8 (CH2), 26.6 (CH3), 23.7 (CH3), 21.7 (CH3), 19.1 (CH3),
10.8 (CH3); HRMS (ESI, M + H+) m/z calcd for C15H24NO3S
298.1477, found 298.1464.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectroscopic data (1H NMR, 13C NMR and NOE’s) of all the
products and HPLC chromatogram for the compound 1ha.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(RS)-2-Methyl-4-tosyl-1-oxa-4-azaspiro[5.5]undecane (1ua): col-
orless liquid; yield 90%; IR (neat) 3058, 2931, 2857, 1599, 1492, 1452,
1344, 1306, 1270, 1215, 1163, 1087, 1049, 1018, 987, 937, 903, 846,
AUTHOR INFORMATION
■
1
815, 738 cm−1; H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.6 Hz,
Corresponding Author
*E-mail: sjgharpure@iitm.ac.in.
2H), 7.32 (d, J = 7.6 Hz, 2H), 3.95−3.90 (m, 1H), 3.54 (ABX, J =
11.0, 0.0 Hz, 1H), 3.50 (AB, J = 11.2 Hz, 1H), 2.43 (s, 3H), 2.05−2.00
(m, 1H), 1.92 (AB, J = 11.2 Hz, 1H), 1.86 (ABX, J = 11.0, 11.0 Hz,
1H), 1.70−1.20 (m, 9H), 1.06 (d, J = 5.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 143.8 (C), 132.7 (C), 129.8 (2CH), 127.8 (2CH),
72.4 (C), 63.8 (CH), 53.1 (CH2), 51.8 (CH2), 36.9 (CH2), 29.7
(CH2), 26.1 (CH2), 21.7 (CH3), 21.6 (CH2), 21.5 (CH2), 19.2
(CH3); HRMS (ESI, M + H+) m/z calcd for C17H26NO3S 324.1633,
found 324.1631.
ACKNOWLEDGMENTS
■
We thank CSIR and DST, New Delhi, for financial support and
Mr. V. Ramkumar of the Department of Chemistry, IIT
Madras, for the crystallographic data. We are grateful to CSIR,
New Delhi, for the award of research fellowship to J.V.K.P.
4-((2R*,6S*)-6-(3,4-Dimethoxyphenyl)-4-tosylmorpholin-2-yl)-
phenyl Benzoate (9). To a stirred solution of amino alcohol 6 (195
mg, 0.474 mmol) in acetone were added successively K2CO3 (131 mg,
0.948 mmol) and bromide 7 (134 mg, 0.521 mmol), and the resulting
mixture was stirred at rt for 5 h (TLC control). The reaction mixture
was filtered through Celite, concentrated in vacuo, and purified by
silica gel column chromatography using EtOAc−hexanes (1:4) as
eluent to furnish keto alcohol 8 (220 mg, 78%) as a colorless solid.
Reaction of keto alcohol 8 (200 mg, 0.340 mmol) with Et3SiH (60 μL,
0.374 mmol) and TMSOTf (68 μL, 0.374 mmol) in CH2Cl2 (5 mL),
as described for the morpholine 1ba, followed by purification on silica
gel column using EtOAc−hexanes (1:6) as eluent furnished morpho-
line 9 (158 mg, 81%) as a colorless solid: mp 184−186 °C; IR (KBr)
3064, 3001, 2959, 2930, 2845, 1736, 1600, 1513, 1450, 1347, 1264,
DEDICATION
■
Dedicated to Professor V. K. Singh, IIT Bombay, on the occasion
of his 60th birthday.
REFERENCES
■
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Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641.
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1203, 1166, 1085, 1025, 984, 825, 737, 710 cm−1; H NMR (400
(3) (a) Enders, D.; Meyer, O.; Raabe, G.; Runsink, J. Synthesis 1994,
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(4) (a) Pansare, S. V.; Ravi, R. G.; Jain, R. P. J. Org. Chem. 1998, 63,
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V. A. Org. Lett. 2006, 8, 2035.
(5) For 2,6-disubstituted morpholines, see: (a) Albanese, D.; Landini,
D.; Penso, M.; Tagliabue, A.; Carlini, E. Org. Process Res. Dev. 2010, 14,
705. (b) Lupi, V.; Albanese, D.; Landini, D.; Scaletti, D.; Penso, M.
Tetrahedron 2004, 60, 11709. (c) Albanese, D.; Salsa, M.; Landini, D.;
Lupi, V.; Penso, M. Eur. J. Org .Chem. 2007, 2107. (d) Penso, M.;
Lupi, V.; Albanese, D.; Foschi, F.; Landini, D.; Tagliabue, A. Synlett
2008, 2451. (e) Albanese, D.; Foschi, F.; Penso, M. Catal. Today 2009,
140, 100. (f) Bouron, E.; Goussard, G.; Marchand, C.; Bonin, M.;
Pannecoucke, X.; Quirion, J. C.; Husson, H. P. Tetrahedron Lett. 1999,
MHz, CDCl3) δ 8.20 (d, J = 8.0 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.61
(d, J = 8.1 Hz, 2H), 7.52 (t, J = 7.7 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H),
7.32 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.3 Hz,
1H), 6.91 (s, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.88 (d, J = 8.4 Hz, 1H),
4.81 (d, J = 8.4 Hz, 1H), 4.00−3.85 (m, 2H), 3.89 (s, 3H), 3.88 (s,
3H), 2.43 (s, 3H), 2.27 (td, J = 11.5, 2.5 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 165.3 (CO), 150.9 (C), 149.2 (2C), 144.2 (C), 136.4
(C), 133.9 (CH), 132.3 (C), 131.3 (C), 130.3 (2CH), 130.0 (2CH),
129.5 (C), 128.8 (2CH), 128.0 (2CH), 127.4 (2CH), 122.0 (2CH),
118.5 (CH), 111.3 (CH), 109.6 (CH), 77.6 (CH), 77.2 (CH), 56.2
(CH2), 56.1 (CH2), 51.8 (2CH3), 21.7 (CH3); HRMS (ESI, M + H+)
m/z calcd for C32H32NO7S 574.1899, found 574.1876.
rac-Chelonin C (5). To a cold (−78 °C) solution of compound 9
(105 mg, 0.183 mmol) in dry THF (4 mL) was added sodium
naphthalide solution [prepared by adding naphthalene (178 mg, 1.373
mmol) to sodium (25.2 mg, 1.098 mmol) in dry THF (3 mL) at rt and
stirred for 2 h] and the resulting solution stirred for 1 h. The reaction
mixture was quenched by addition of saturated NH4Cl at −78 °C and
warmed to rt. The reaction mixture was extracted with EtOAc (3 × 5
mL), and the combined organic layer was washed with dilute HCl (3 ×
5 mL). The aqueous layer was neutralized with saturated aq NaHCO3
and extracted with EtOAc (3 × 5 mL). The combined organic layer
was washed with brine, dried (anhyd Na2SO4), and evaporated to
furnish chelonin C (5) (42 mg, 72%) as a colorless solid: mp 136−138
°C; IR (KBr) 3441, 3287, 2952, 2917, 2845, 1731, 1609, 1517, 1460,
́
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1
1416, 1262, 1160, 1139, 1089, 1024, 913, 835, 813, 764 cm−1; H
NMR (400 MHz, CD3OD) 7.25 (d, J = 8.4 Hz, 2H), 7.02 (s, 1H),
6.97 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 8.4 Hz,
2H), 4.60 (t, J = 10.2 Hz, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 2.99 (t, J =
11.8 Hz, 2H, 2H), 2.80−2.65 (m, 2H); 13C NMR (100 MHz,
CD3OD) δ 158.3 (C), 150.4 (C), 150.1 (C), 134.6 (C), 132.5 (C),
128.6 (2CH), 119.8 (CH), 116.1 (2CH), 112.8 (CH), 111.3 (CH),
80.2 (CH), 80.2 (CH), 56.5 (2CH3), 52.7 (CH2), 52.7 (CH2); HRMS
(ESI, M + H+) m/z calcd for C18H22NO4 316.1549, found 316.1551.
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10330
dx.doi.org/10.1021/jo201975b | J. Org. Chem. 2011, 76, 10325−10331

The Journal of Organic Chemistry
Note
(e) Gharpure, S. J.; Sathiyanarayanan, A. M. Chem. Commun. 2011, 47,
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(8) (a) Sassaman, M. B.; Surya Prakash, G. K.; Olah, G. A.; Donald,
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equilibrium with the hemiacetal form, predominantly tending towards
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Chem. 2003, 5, 285. (b) Manabu, H.; Takeshi, N.; Katsuhiko, T. Synlett
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(10) CCDC 837982 (1ha) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
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10331
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