Synthesis of new oxathiazinane dioxides and their in vitro cancer cell growth inhibitory activity

Article abstract of DOI:10.1016/j.bmcl.2009.09.019

New oxathiazinane dioxides derived from d- and l-serine have been tested for their in vitro cell growth inhibitory activity toward SKBR3 breast cancer cells. Compound (R)-24 (R′ = BrCH₂C₆H ₄-C₆H₄CH₂) showed a cytotoxicity with IC₅₀ ≈ 10 μM.

Full text of DOI:10.1016/j.bmcl.2009.09.019

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5353–5356
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of new oxathiazinane dioxides and their in vitro cancer cell
growth inhibitory activity
Françoise Borcard a, Matthias Baud a, Claudia Bello a, Giovanna Dal Bello b, Francesco Grossi b,
Paolo Pronzato b, Michele Cea c, Alessio Nencioni c, Pierre Vogel a,
*
a Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Institute of Technology (EPFL), CH 1015 Lausanne, Switzerland
b Italian National Cancer Institute, Genoa, Italy
c Department of Internal Medicine, University of Genoa, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2009
Revised 3 September 2009
Accepted 4 September 2009
Available online 10 September 2009
New oxathiazinane dioxides have been derived from D- and L-serine and tested for their in vitro cell
growth inhibitory activity toward SKBR3 breast cancer cells. (5R)-5-(4-(40-Bromomethyl)phenyl)benzyl-
oxymethyl-[1,3,4]-oxathiazinane-3,3-dioxide showed a cytotoxicity of IC50 ꢀ 10
lM.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Benzyl ethers
Cancer
Cytotoxicity
Oxasultams
Sultams
O
O
Sultams (cyclic sulfonamides) have shown potent biological
activity.1,2 For instance, sultam (1) is an antileptic agent,3 brinzola-
mide (2) has been used for the treatment of glaucoma,4 ampiroxi-
cam (3),5 and S-2474 (4) are COX-2 inhibitors,6 benzodithiazine
dioxide 5 has both antiviral and anticancer activities,7 derivative
6 is a selective calpain I inhibitor,8 7 inhibits the binding of MIP-
O
O
S
Me
SO2NH2
N
O
H2NS
O
S
O
O
H
S
N
N
N
S
N
OMe
Me
O
O
NHEt
OCO2Et
1
2
3
Me
O
O
S
O O
O
O
S
N
3b (macrophage inflammatory protein 3b) to CCR7 receptor,9
8
t
-Bu
O
O
S
N
N
O
H
inhibits mitotic kinesin KSP (anti-cancer),10 9 is a metalloprotease
inhibitor (can be use to inhibit tumor metastasis),11 and 10 inhibits
JAK kinase (can be used against solid and hematological malignan-
cies such as leukemia and lymphomas).12 Aminobenzosultams
have been found to be lipoxygenase inhibitors13 and other cyclic
sulfonamides are herbicides.14
N
HO
Cl
S
N
S
H
t
-Bu
O
4
5
6
Ph
H
N
H
O
S
O
N
O
S O
O
O
N
H
O
O
N
F3C
We report here the synthesis of new oxasultams of the type 5-
hydroxymethyl-1,3,4-oxathiazinane-3,3-dioxide and disclose that
some derivatives display in vitro growth inhibitory activity toward
breast cancer (SKBR3) cell line. Our working hypothesis was that
non-annulated oxathiazinane dioxides could imitate the polar moi-
eties of anti-tumor compounds such as Edelfosine (11),15 jaspine B
7
8
O
H
H
N
H
H
H
N
O
S
O
S
N
N
O
N
N
N
N
N
H
O
O
NH
N
Me
Me
O
O
F
O
S
9
10
(12),16 or oleyl 2-acetamido-2-deoxy-
a-D-glucopyranosides (e.g.,
13),17 and that attaching a less polar side-chain through a 5-
hydroxymethyl group could generate new cytotoxic agents.
Our scaffolds are chloromethanesulfonamide (R)-and (S)-16 ob-
tained from (R)- and (S)-14, both commercially available serine
derivatives. Conversion of (R)-14 into its methyl ester and subse-
quent reduction with LiAlH4 in THF at 0 °C gave (R)-15 in 94%
and no epimerization (see below). Treatment of (R)-15 with
* Corresponding author. Tel.: +41 21 693 93 71; fax: +41 21 693 93 75.
E-mail address: pierre.vogel@epfl.ch (P. Vogel).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.019

5354
F. Borcard et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5353–5356
HO
HO
(80 °C, 15 h) to give sultam (R)-33 (48%, two steps). Hydrogenolysis
O
O
C18H37
O
C14H29
OH
O
MeO
of the benzyl ether (H-Cube, Pd–C/EtOH, 30 bar, 45 °C) provided
alcohol (R)-3421 in 85% yield. It was converted into its (Z)-oleyl
ether (R)-35 (57%), 4-phenylbenzyl ether (R)-36 (52%) and b-naph-
thylmethyl ether (R)-37 (75%) by treatment with (Z)-oleyl
methanesulfonate (Bu4NI, 50% aq NaOH, 23 °C, 15 h), with
4-PhC6H4CH2Br (Bu4NI, MeCN, 50% aq NaOH, 23 °C, 15 h) and with
2-bromomethyl-naphthalene (Bu4NI, 50% aq NaOH, 23 °C, 15 h),
respectively.
As we found that oxasultams (R)-17 and (R)-24 inhibited the
growth of breast cancer cells (see below), we decided to prepare
also a few (S)-derivatives. Thus following the route shown in
Scheme 1, (2S)-2-amino-3-benzyloxypropane-1-ol ((S)-15) was
treated with ClCH2SO2Cl/Et3N in CH2Cl2 to generate the corre-
sponding sulfonamide (S)-16. On staying with Et3N polymerization
occurred together with the formation of (S)-17 (33%). N-Benzyla-
tion of (S)-16 followed by treatment with Cs2CO3/DMF gave (S)-
25 (45%, two steps). Selective hydrogenolysis of the benzyl ether
of (S)-25 furnished alcohol (S)-26 that was converted into oleyl
ether (S)-28. Protection of the sulfonamide group in (S)-16 with
PMB followed by treatment with Cs2CO3/DMF and selective
hydrogenolysis of the benzyl group gave (S)-20. Alcohol (S)-20
was transformed into 4-(4-bromomethylphenyl)benzyl ether (S)-
23 that was deprotected into (S)-24.
Me(CH2)7
(CH2)8
H
H
NMe3
HO
P
O
11
H
NAc
O
H2N
O
12
13
ClCH2SO2Cl (1.2 equiv)/Et3N (2 equiv) at 0 °C gave sulfonamide (R)-
16 in 63% yield. When stirred at 25 °C for several hours, (R)-16 was
converted into sultam (R)-1718 (isolated in 28%) and polymeric
material. As this latter base-induced HCl elimination was sluggish
we protected the sulfonamide with a 4-methoxybenzyl group
applying standard conditions. Thus (R)-16 was treated with PMBBr
(1.1 equiv) and K2CO3 (3 equiv) in DMF at 20 °C giving (R)-18 in
73% yield. Heating (R)-18 with Cs2CO3 (2 equiv) in DMF to 80 °C
overnight produced sultam (R)-19 (73%).
Hydrogenolysis of the benzyl ether moiety with H2/Pd–C
(H-Cube, 50 °C, 30 bar) gave (R)-20 (85%). The latter alcohol dis-
placed para-phenylbenzyl bromide in the presence or 50% aqueous
NaOH and Bu4NI/CH3CN at 20 °C furnishing (R)-21 (65%). Selective
hydrolysis of the PMB ether was induced with CF3COOH/CH2Cl2 at
ꢁ5 °C giving (R)-22 (68%). Similarly (R)-20 reacted with 4,40-
bis(bromomethyl)biphenyl in excess to give (R)-23 that was depro-
tected into (R)-2419 (Scheme 1).
N-Benzyl derivatives were prepared as shown in Scheme 2. Treat-
ment of (R)-16 with BnBr/K2CO3/DMF at 23 °C gave a crude N-ben-
zylsulfonamide that was heated to 80 °C in DMF containing
2 equiv of Cs2CO3. This provided sultam (R)-25 in 45% (two steps).
Selective hydrogenolysis of the benzyl ether moiety (H-Cube, EtOH,
45 °C, 40 bar) gave alcohol (R)-26 (74%).20 Debenzylation of (R)-26
into (R)-27 was very sluggish. On increasing H2 pressure to 50 bar,
no more than 10% of (R)-27 was obtained. The latter was converted
into oleyl ether (R)-28 (34%) by reaction with oleyl methanesulfo-
nate in excess at 23 °C (Bu4NI 1 equiv, 50% aq NaOH, 15 h), into 4-flu-
orobenzyl ether (R)-29 (86%) by reaction with 4-FC6H4CH2Br (same
conditions), into 3-methoxybenzyl ether (R)-30 (68%) by reaction
with 3-MeOC6H4CH2Br (as above) and into benzoate (R)-31 (73%)
by reaction with BzCl in CH2Cl2 containing 2 equiv of DMAP (4-
dimethylaminopyridine). Benzylamine derivative (R)-32 (20%, two
steps) was prepared by converting first alcohol (R)-26 into its mesy-
late (MeSO2Cl/Et3N/CH2Cl2, 0 °C, 90 min) and reaction of the latter
(crude) with an excess of benzylamine (MeCN, 60 °C, 15 h).
Mosher’s ester of (R)-26 and (S)-26 obtained by reaction with
(R)-(ꢁ)-
a-methoxy-a
-trifluoromethylacetyl chloride22 gave esters
with 98% and 95% ee, respectively (by 13C–19F satellites), thus dem-
onstrated that less than 2.5% of our compounds have been
epimerized.
Compounds (R)-17, (S)-17, (R)-22, (R)-24, (S)-24, (R)-25, (S)-25,
(R)-28, (S)-28, (R)-29, (R)-30, (R)-31, (R)-33, (R)-35, (R)-36, and (R)-
37 were submitted to the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-
carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)/
PMS(phenazine methosulfate: 5-methylphenazinium methylsul-
fate) assay to determine this inhibitory of the cell growth of SKBR3
cancer cells (breast cancer). Table 1 summarized our results and
Figures 1 and 2 show concentration depending viability for
selected oxasultams. The best cell growth inhibitory activities were
observed for the free sulfonamides (no N-substituents). Interest-
ingly (S)-17 (5-benzyloxymethyl derivative) is slightly more active
than its enantiomer (R)-17 while (S)-24 exhibits similar potency as
its enantiomer (R)-24. These results suggest that the absolute con-
figuration does not play a crucial role in the mode of action of these
compounds. N-substitution of the oxasultams by benzyl or methyl
A number of N-methyl sultams were also prepared as shown in
Scheme 3. Sulfonamide (R)-16 was N-methylated first with MeI/
K2CO3/DMF (23 °C, 10 h) and then treated with Cs2CO3/DMF
Cl
R1 OH
O
OH
ClCH2SO2Cl
SO2N
1. SOCl2
OH 2. MeOH, reflux (76%)
3. LiAlH4, THF, 0°C
H2N
H2N
Et3N/CH2Cl2
0°C (63%)
OBn
(R)-14
OBn
OBn
(94%)
(R)-15
(R)-16 R1 = H
PMBBr, K2CO3
(R)-18 R1 = 4-MeOC6H4CH2
DMF (73%)
R1
N
O
S
R2
5
Et3N
20°C
O
O
(R)-16
(R)-18
3
O1
(R)-17 R1 = H, R2 = Bn
Cs2CO3, DMF
80°C (73%)
(R)-19 R1 = PMB, R2 = Bn
(R)-20 R1 = PMB, R2 = H
(R)-21 R1 = PMB, R2 = 4-PhC6H4CH2
(R)-22 R1 = H, R2 = 4-PhC6H4CH2
H2/Pd-C, EtOH (85%)
4-PhC6H4CH2Br, NaOH
Bu4NI, MeCN, 20°C (65%)
CF3COOH, CH2Cl2
-5°C (68%)
C14H12Br2
NaOH/H2O
Bu4NI, MeCN
20°C (21%)
(R)-20
(R)-23 R1 = PMB, R2
(R)-24 R1 = H, R2 = ArCH2
=
BrH2C
CH2 = ArCH2
CF3COOH, CH2Cl2, -5°C (30%)
Scheme 1. Synthesis of benzyl- and (5R)-5-arylmethyloxymethyl[1,3,4]oxa-thiazinane-3,3-dioxides.

F. Borcard et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5353–5356
5355
BnNH
Bn
Bn
O
S
1. MeSO2Cl, Et3N
CH2Cl2, 0°C
2. BnNH2/MeCN
O
1. BnBr, K2CO3/DMF
23°C
2. Cs2CO3/DMF
80°C (45%, 2 steps)
R2
N
N
O
O
S O
(R)-16
(R)-26
(R)-26
O
O
(R)-25 R2 = Bn
(R)-26 R2 = H
(R)-28 R2 = (Z )-oleyl
(R)-29 R2 = 4-FC6C4CH2
(R)-30 R2 = 3-MeOC6H4CH2
(R)-31 R2 = Bz
(R)-32
H2/Pd-C, 40 bar
45°C, EtOH (85%)
OH
5
H
N
H2/Pd-C
EtOH
50 bar
O
S
O
O
45°C (10%)
(R)-27
Scheme 2. Preparation of (5R)-4-benzyl-5-oxy- and -aminomethyl[1,3,4]oxathiazinane-3,3-dioxide derivatives.
Me
O
R2
N
1. MeI/K2CO3, DMF
2. Cs2CO3, DMF
80°C (48%, 2 steps)
O
S O
(R)-16
O
(R)-33 R2 = Bn
(R)-34 R2 = H
H2/Pd-C, 30 bar
45°C, EtOH (85%)
(R)-35 R2 = (Z )-oleyl
(R)-36 R2 = 4-PhC6H4CH2
(R)-37 R2 = β-naphthylCH2
Scheme 3. Preparationof(5R)-4-methyl-5-oxymethyl[1,3,4]oxathiazinane-3,3-diox-
ide derivatives.
Figure 1. Plot of viability versus concentration for compounds (R)-17, (S)-17, (R)-
24, (S)-24, (R)-25, (S)-25, (R)-28, and (S)-28 toward SKBR3 (breast cancer) cell line.
Viability was determined after 72 h exposure.
group leads to lower inhibitory activity. The best compounds in our
series are the two (4-bromomethylphenyl)-4-benzyloxymethyl
derivatives (R)-24 and (S)-24 with a IC50 value of ca. 10 lM. Con-
trary to our initial working hypothesis (R)- and (S)-28 with the long
alkyl chain (oleyl) are not cytotoxic. The potential alkylation prop-
erties of (R)-24 and (S)-24 could be responsible of their
cytotoxicity.
This work presents new monocyclic oxasultams with poten-
tial anti-cancer activities. They are obtained readily from
D- or
L-serine and their structures can be diversified widely. This
should open the possibility to obtain new leads as anti-tumor
agents. Work is underway with this objective in mind. We are
pursuing studies to establish the biological targets of these
compounds.
Figure 2. Plot of viability versus concentration for compounds (R)-17, (R)-22, (R)-
29, (R)-30, (R)-31, (R)-33, (R)-35, (R)-36, and (R)-37 toward SKBR3 (breast cancer)
cell line. Viability was determined after 72 h exposure. Data for (R)-17 appear again
here as a reference.
Table 1
Viability assays (MTS) on compounds (R)-17, (S)-17, (R)-22, (R)-24, (S)-24, (R)-25, (S)-
25, (R)-28, (S)-28, (R)-29, (R)-30, (R)-31, (R)-33, (R)-35, (R)-36, and (R)-37 toward
SKBR3 (breast cancer) cell line
Product
%Viability
25
Acknowledgments
6.25
l
M
12.5
lM
l
M
50
lM
100 lM
We thank the Swiss National Science Foundation (Bern) for
financial help. We also thank M. Rey, F. Sepúlveda, and L. Menin
for technical help.
(R)-17
(S)-17
(R)-22
(R)-24
(S)-24
(R)-25
(S)-25
(R)-28
(S)-28
(R)-29
(R)-30
(R)-31
(R)-33
(R)-35
(R)-36
(R)-37
100
100
75
66
99
89
81
100
71
93
100
81
85
72
89
100
94
75
34
81
82
80
100
81
86
100
98
81
71
66
82
100
78
75
10
26
88
82
99
81
88
100
88
88
65
60
73
80
16
22
46
10
20
82
96
100
96
96
89
100
82
65
52
74
51
44
10
18
83
87
100
82
99
96
89
83
65
61
74
Supplementary data
Experimental details and spectroscopic characterization of new
compounds are available. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.bmcl.2009.09.019.
References and notes
81
1. Jiménez-Hopkins, M.; Hanson, P. R. Org. Lett. 2008, 10, 2223.
2. Hanessian, S.; Sailes, H.; Therrien, E. Tetrahedron 2003, 59, 7047.
Viability was determined after 72 h exposure.

5356
F. Borcard et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5353–5356
3. Tanimukai, H.;Inui, M.;Hariguchi,S.;Kaneko, Z.Biochem. Pharmacol. 1965, 14, 961.
4. Wroblewski, T.; Graul, A.; Castaner, J. Drugs Future 1998, 23, 365.
5. Rabasseda, X.; Hopkins, S. J. Drugs Today 1994, 30, 557.
6. Inagaki, M.; Tsuri, T.; Jyoyama, H.; Ono, T.; Yamada, K.; Kobayashi, M.; Hori, Y.;
Arimura, A.; Yasui, K.; Ohno, K.; Kakudo, S.; Koizumi, K.; Suzuki, R.; Kato, M.;
Kawai, S.; Matsumoto, S. J. Med. Chem. 2000, 43, 2040.
7. Brzozowski, Z.; Saczewski, F.; Neamati, N. Bioorg. Med. Chem. Lett. 2006, 16,
5298.
8. Wells, G. J.; Tao, M.; Josef, K. A.; Bihovsky, R. J. Med. Chem. 2001, 44, 3488.
9. Gladue, R. P.; Martin, W. H.; Poss. C. S. Eur. Patent Appl. 2002-253019,
20,020,429, 2002; Chem. Abstr. 2002, 137, 333146.
Massiot, G. Tetrahedron Lett. 2002, 44, 225; (c) Vasta, V.; Meacci, E.; Catarzi, S.;
Donati, C.; Farnararo, M.; Bruni, P. Biochim. Biophys. Acta 2000, 1483, 154; (d)
Meacci, E.; Vasta, V.; Moorman, J. P.; Bobak, D. A.; Bruni, P.; Moss, J.; Vaughan,
M. J. Biol. Chem. 1999, 274, 18605; (e) Klionsky, D. J.; Cuervo, A. M.; Seglen, P. O.
Autophagy 2007, 3, 181.
17. (a) García-Alvarez, I.; Corrales, G.; Doncel-Pérez, E.; Muñoz, A.; Nieto-
Sampedro, M.; Fernandez-Mayoralas, A. J. Med. Chem. 2007, 50, 364; (b)
García-Alvarez, I.; Garrido, L.; Doncel-Pérez, E.; Nieto-Sampedro, M.;
Fernández-Mayoralas, A. J. Med. Chem. 2009, 52, 1263; (c) López-Donaire, M.
L.; Parra-Caceres, J.; Vázquez-Lasa, B.; García-Alvarez, L.; Fernández-Mayoralas,
A.; López-Bravo, A.; San Roman, J. Biomaterials 2009, 30, 1613.
25
10. Adams, N. D.; Darcy, M. G.; Dhanak, D.; Duffy, K. J.; Fitch, D. M.; Knight, S. D.;
Newlander, K. A.; Shaw, A. N. PCT Int. Appl. WO2006113432, 2006; Chem. Abstr.
2006, 145, 438652.
18. Data of (R)-17: ½
aꢂ
¼ ꢁ6 (c 0.06, CHCl3); 1H NMR (400 MHz, CDCl3): dH: 7.38–
405
7.32 (m, 4H), 5.09 (d, 3J = 8.9, 1H), 4.57–4.49 (m, 4H), 3.91 (m, 1H), 3.75 (m,
3H), 3.63 (m, 1H); 13C NMR (100 MHz, CDCl3): dC: 137.0 (s), 128.6, 128.1, 127.8
11. Gege, C.; Schneider, M.; Chevrier, C.; Deng, H.; Sucholeiki, I.; Gallagher, B. M.,
Jr.; Bosies, M.; Steeneck, C.; Wu, X.; Hochguertel, M.; Nolte, B.; Taveras, A. PCT
Int. Appl. WO2008063668, 2008; Chem. Abstr. 2008, 149, 10034.
12. Li, H.; Argade, A.; Thota, S.; Carroll, D.; Sran, A.; Cooper, R.; Singh, R.; Tso, K.;
Bhamidipati, S. PCT Int. Appl. WO2008049123, 2008; Chem. Abstr. 2008, 148,
472065.
13. Nakane, M.; Satake, K.; Ando, K.; Wakabayashi, H. Jpn. Kokai Tokkyo Koho Pat.
Appl. JP80-2495535, 1992; Chem. Abstr. 1992, 117, 191879.
14. Kamireddy, B.; Murray, W. M. PCT Int. Appl. WO9533746 A1 19951214, 1995;
Chem. Abstr. 1996, 124, 232492.
15. (a) Busto, J. V.; Sot, J.; Goñi, F. M.; Mollinedo, F.; Alonso, A. Biochim. Biophys. Acta
2007, 1768, 1855; (b) Gajate, C.; Mollinedo, F. Curr. Drug Metab. 2002, 3, 491; (c)
Mollinedo, F.; Fernández-Luna, J. L.; Gajate, C.; Martín-Martín, B.; Benito, A.;
Martínez-Dalmau, R.; Modotell, M. Cancer Res. 1997, 57, 1320; (d) Mollinedo, F.;
Gajate, C.; Martín-Santamaria, S.; Gago, F. Curr. Med. Chem. 2004, 11, 3163; (e)
Nieto-Miguel, T.; Gajate, C.; Mollinedo, F. J. Biol. Chem. 2006, 281, 14833.
16. (a) Canals, D.; Mormeneo, D.; Fabriàs, G.; Llebaria, A.; Casas, J.; Delgado, A.
Bioorg. Med. Chem. 2009, 17, 235; (b) Ledroit, V.; Debitus, C.; Lavaud, C.;
(3d), 73.6, 69.1, 56.5 (3t), 55.1 (d), 44.8 (6).
25
19. Data of (R)-24: ½
aꢂ
¼ ꢁ20 (c 0.06, CHCl3); 1H NMR (400 MHz, CDCl3): dH:
405
7.35–7.61 (m, 8H), 4.76 (m, 2H), 4.58 (m, 4H), 4.45 (d, 3J = 11.6, 1H), 4.04 (m,
1H), 3.98 (dd, 3J = 12.2, 3.1, 1H), 3.73 (br t, 3J = 14.4, 1H), 3.63 (m, 2H); 13C NMR
(100 MHz, CDCl3): dC: 140.7, 140.6, 137.0, 136.1 (4s), 129.5, 129.2, 129.1, 128.4,
127.5, 127.4, 127.3, 127.2 (8d), 82.0, 73.4, 68.9, 68.0 (4t), 56.4 (d), 33.2 (t).
25
20. Data of (R)-26: ½
a
ꢂ
¼ 20 (c 0.05, CHCl3). 1H NMR (400 MHz, CDCl3): dH: 7.38–
405
7.33 (m, 4H, H arom.) 4.69 (d, 2J = 11.3, 1H, HHC(2)) 4.67 (d, 2J = 14.8, 1H, N-
CHH-Ph) 4.55 (d, 2J = 11.3, 1H, HHC(2)) 4.31 (d, 2J = 14.8, 1H, N-CHH-Ph) 4.04
(m, 1H, CH2-C(5)), 3.97 (m, 1H, H2C(7)) 3.91 (dd, 2J = 12.4, 3J = 1.9, 1H, HHC(6))
3.58 (dd, 2J = 12.4, 3J = 3.0 , 1H, HHC(6)) 3.41 (m, 1H, CH-N) 2.42 (s, 1H, OH). 13
C
NMR (100 MHz, CDCl3): dC: 135.68 (s, C arom.) 128.86 (d, 1J = 161.3, CH arom.)
128.50 (d, 1J = 157.6, CH arom.) 128.23 (d, 1J = 167.0, CH arom.) 82.57 (t,
1J = 154.8, C(2)) 66.29 (t, 1J = 146.4, C(7) or CH2(6)) 60.50 (d, 1J = 140.3, C(5))
60.10 (t, 1J = 145.0, C(7) or CH2(6)) 50.39 (t, 1J = 140.3, N-CH2-Ph).
25
405
21. Data of (R)-34: ½
a
ꢂ
¼ ꢁ34 (c 0.06, CHCl3); 1H NMR (400 MHz, CDCl3): dH: 4.60
(m, 2H), 4.06 (dd, 3J = 11.6, 6.5, 1H, 3.94 (m, 3H), 3.61 (m, 1H), 2.96 (s, 3H).
22. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.