Catalytic enantioselective synthesis of key intermediates for NET inhibitors using atropisomeric lactam chemistry

Article abstract of DOI:10.1016/j.tetlet.2007.11.101

An atropisomeric lactam which was prepared with high enantioselectivity by catalytic asymmetric intramolecular N-arylation, was efficiently converted to synthetic intermediates for NET inhibitors through highly diastereoselective α-alkylation followed by

Full text of DOI:10.1016/j.tetlet.2007.11.101

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 471–474
Catalytic enantioselective synthesis of key intermediates for
NET inhibitors using atropisomeric lactam chemistry
*
*
Osamu Kitagawa , Daisuke Kurihara, Hajime Tanabe, Taichi Shibuya, Takeo Taguchi
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 17 October 2007; revised 12 November 2007; accepted 19 November 2007
Available online 22 November 2007
Abstract
An atropisomeric lactam which was prepared with high enantioselectivity by catalytic asymmetric intramolecular N-arylation, was
efficiently converted to synthetic intermediates for NET inhibitors through highly diastereoselective a-alkylation followed by hydration
and trans-tert-butylation.
ꢀ 2007 Elsevier Ltd. All rights reserved.
N-Substituted ortho-tert-butylanilide derivatives have
received much attention as novel atropisomeric compounds
possessing an N–C chiral axis.1 The synthesis of such opti-
cally active atropisomeric anilides and their application to
asymmetric reactions have been reported by many groups.2
On the other hand, there have been very few reports on the
synthesis of natural products and biologically active com-
pounds using these atropisomeric anilides.2n
In the course of our study on optically active atropiso-
meric anilide chemistry,2b,k we recently succeeded in highly
enantioselective synthesis of atropisomeric anilides and lac-
tams through chiral Pd-catalyzed inter- and intramolecular
N-arylation (catalytic asymmetric Buchwald–Hartwig
amination3) of achiral NH-anilides.4,5 Furthermore, highly
diastereoselective a-monoalkylation with lithium enolates
prepared from these anilides and lactams was also found.4
In this Letter, we report catalytic asymmetric synthesis of
biologically active dihydroquinolin-2-one derivatives using
our atropisomeric lactam chemistry. This work shows a
new utility of atropisomeric anilide derivatives.
a-substituted dihydroquinolin-2-one derivatives I having
potent norepinephrine transporter (NET) inhibitory activ-
ity.7 An enantiomer of I (R0 = H) was also found to be 20-
fold more NET active than the antipode, while the absolute
configurations were not determined. We expected that cata-
lytic asymmetric synthesis of key intermediates II for such
NET inhibitors I may be achieved through our enantio-
selective intramolecular N-arylation followed by diastereo-
selective a-alkylation of the resulting atropisomeric lactam
2 and the removal of the tert-butyl group by trans-tert-
butylation (retro-Friedel–Crafts reaction)8 (Scheme 1).
To realize the synthetic pathway shown in Scheme 1, N-
(ortho-mono-tert-butylphenyl)lactam III (R = H) having
high optical purity is essential, because the meta-tert-butyl
group in 2,5-di-tert-butyl derivative III (R = t-Bu) is diffi-
cult to remove.8b However, as described in a previous
paper,4 the intramolecular N-arylation of the ortho-
mono-tert-butylanilide 1 (R = H) resulted in a considerable
decrease in enantioselectivity in comparison with that of
2,5-di-tert-butyl derivative 1 (R = t-Bu) (R = H: 70% ee,
R = t-Bu: 96% ee, Scheme 1). In addition, stereoselective
construction of quaternary a-carbon in III (R0 = Me) and
efficient removal of the ortho-tert-butyl group in III, which
have not yet been examined, are necessary.
Various biologically active compounds possessing a
dihydroquinolin-2-one skeleton have been found so far.6
For example, Camp and co-workers reported N-phenyl-
Initially, the improvement of the enantioselectivity in
the reaction with mono-tert-butylanilide 1a was investi-
gated. After reinvestigation of the chiral phosphine ligands,
*
Corresponding authors. Tel.: +81 42 676 3274; fax: +81 42 676 3257
(O.K.).
E-mail address: kitagawa@ps.toyaku.ac.jp (O. Kitagawa).
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.101

472
O. Kitagawa et al. / Tetrahedron Letters 49 (2008) 471–474
O
NH2
-Bu
5.0 mol% (S)-BINAP
3.3 mol% Pd(OAc)2
1.4 eq. Cs2CO3
Pd (OAc)2
rac-BINAP
Cs2CO3
O
O
NH
N
O
(S)
I
(S)
I
t
OMe
t-Bu
Me3Al
t-Bu
NH
I
toluene 80 °C
t-Bu
toluene
80 °C
R
(R = t-Bu, 96% ee)
(R = H, 70% ee)
R
2 "axially chiral"
1 "achiral"
(88% ee)
4a (92%)
Ha
Me
(S)
Me
CH2-CH=CH2
(CH2)3NHMe
R'
*
CH2-CH=CH2
(S)
O
R'
R'
*
N
(R)
O
N
*
(S)
+
3a'
(62%)
t
-Bu
ent-3a
N
O
t-Bu
N
O
N
O
trans-
tert-
t-Bu
(30%, 88% ee)
[α]D = +14.9
(c=0.52, CHCl3)
t
-Bu - Me (NOE)
butylation
t-Bu - Ha (no NOE)
R
III
II
I (R' = H, Me)
Scheme 3. Stereochemical assignment of lactam product.
inhibitors of norepinephrine
transporter (NET inhibitors)
R
Scheme 1. Catalytic asymmetric synthesis of atropisomeric lactam and its
conversion to NET inhibitors.
Li-TMP
THF
R-X
N
O
N
OLi
2a
(93% ee)
t-Bu
t
-Bu
it was found that the use of SEGPHOS-like ligands such as
(R)-SEGPHOS, (R)-DIFLUORPHOS and (R)-SYNPHOS
led to a remarkable increase in enantioselectivity (90–93%
ee, Scheme 2).9 This result is in striking contrast to that
of intermolecular N-arylation, which proceeded with poor
enantioselectivity (23% ee) in the presence of the (R)-SEG-
PHOS ligand.4,10
The absolute stereochemistry of the axial chirality in
lactam product 2a was confirmed to be (R)-configuration
by comparison of 3a in Scheme 4 with ent-3a prepared in
accordance with Scheme 3.4b
The a-alkylation with mono-tert-butyl lactam product
2a (93% ee) proceeded with higher diastereoselectivity
(dr = 31:1–50:1) than that with 2,5-di-tert-butyl lactam
(dr = 13:1–48:1), which was previously reported.4,11 The
attack of alkyl halides to the lactam enolate preferentially
occurs from the opposite site of the ortho-tert-butyl group
to afford products 3a–c having a-chiral carbon of (R)-con-
figuration (Scheme 4).
3 (93% ee)
[α]D = -17.0 (c=0.92, CHCl3)
yield (%)
dr
3
R-X
82
83
85
31/1
3a
3b
Me-I
allyl-Br
> 50/1
> 50/1
PhCH2-Br
3c
Scheme 4. Diastereoselective a-alkylation with atropisomeric lactam 2a.
a quaternary carbon. That is, a-allylation and a-methyl-
ation of a-methyl lactam 3a and a-allyl lactam 3b gave dia-
stereomeric a-methyl-a-allyl lactams 5a and 5a0with almost
complete diastereoselectivities, respectively (Scheme 5).
The stereochemistries of products 5a and 5a0 show that
the second alkylation also selectively occurs from the oppo-
site site of the ortho-tert-butyl group.12
For conversion to synthetic intermediates II (Scheme 1),
the removal of the ortho-tert-butyl group in a-allylated lac-
Furthermore, we newly found that the present a-alkyl-
ation can be applied to the stereoselective construction of
Me
Me
1) Li-TMP
2) allyl-Br
O
7.5 mol% ligand
5.0 mol% Pd(OAc)2
2 eq. Cs2CO3
N
O
N
O
NH
N
O
t-Bu
THF
t-Bu
t-Bu
t
-Bu
I
toluene 80 °C, 24 h
1a
2a
3a
5a (86%, dr = > 50/1)
O
O
O
F
F
Me
O
O
O
O
O
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
1) Li-TMP
2) Me-I
O
F
F
N
O
N
O
-Bu
O
O
O
t-Bu
THF
t
(R)-SYNPHOS
(93%, 93% ee)
(R)-SEGPHOS
(95%, 93% ee)
(R)-DIFLUORPHOS
(93%, 90% ee)
3b
5a' (70%, dr = > 50/1)
Scheme 2. Catalytic asymmetric intramolecular N-arylation of ortho-
mono-tert-butyl-NH-anilide 1a.
Scheme 5. Diastereoselective a-alkylation with a-substituted lactams.

O. Kitagawa et al. / Tetrahedron Letters 49 (2008) 471–474
473
Yamamoto, M.; Yamada, K. Chem. Lett. 1994, 1605; (c) Clayden, J.
Angew. Chem., Int. Ed. 1997, 36, 949; (d) Dantale, S.; Reboul, V.;
Metzner, P.; Philouze, C. Chem. Eur. J. 2002, 8, 632; (e) Clayden, J.,
Ed.; Tetrahedron symposium-in-print on axially chiral amides.
Tetrahedron 2004, 60, 4325–4558.
R
R
(CH2)3-OH
AlCl3
1) 9-BBN
N
O
t
N
O
t
C6H6, 80 °C
-Bu
2) NaOH, H2O2
-Bu
2. Typical examples on synthesis of optically active atropisomeric
anilides and their application to asymmetric reaction: (a) Kawamoto,
T.; Tomishima, M.; Yoneda, F.; Hayami, J. Tetrahedron Lett. 1992,
33, 3169; (b) Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.;
Taguchi, T.; Shiro, M. J. Org. Chem. 1998, 63, 2634; (c) Dai, X.;
Wong, A.; Virgil, S. C. J. Org. Chem. 1998, 63, 2597; (d) Hughes, A.
D.; Price, D. A.; Simpkins, N. S. J. Chem. Soc., Perkin Trans. 1 1999,
1295; (e) Kondo, K.; Fujita, H.; Suzuki, T.; Murakami, Y. Tetra-
hedron Lett. 1999, 40, 5577; (f) Curran, D. P.; Liu, W.; Chen, C. H. J.
Am. Chem. Soc. 1999, 121, 11012; (g) Shimizu, K. D.; Freyer, H. O.;
Adams, R. D. Tetrahedron Lett. 2000, 41, 5431; (h) Godfrey, C. R. A.;
Simpkins, N. S.; Walker, M. D. Synlett 2000, 388; (i) Hata, T.; Koide,
H.; Taniguchi, N.; Uemura, M. Org. Lett. 2000, 2, 1907; (j) Ates, A.;
Curran, D. P. J. Am. Chem. Soc. 2001, 123, 5130; (k) Kitagawa, O.;
Kohriyama, M.; Taguchi, T. J. Org. Chem. 2002, 67, 8682; (l)
Sakamoto, M.; Iwamoto, T.; Nono, N.; Ando, M.; Arai, W.; Mino,
T.; Fujita, T. J. Org. Chem. 2003, 68, 942; (m) Sakamoto, M.; Utsumi,
N.; Ando, M.; Saeki, M.; Mino, T.; Fujita, T.; Katoh, A.; Nishio, T.;
Kashima, C. Angew. Chem., Int. Ed. 2003, 42, 4360; (n) Bennett, D. J.;
Pickering, P. L.; Simpkins, N. S. Chem. Commun. 2004, 1392; (o)
Betson, M. S.; Clayden, J.; Helliwell, M.; Mitjans, D. Org. Biomol.
Chem. 2005, 3, 3898; (p) Kamikawa, K.; Kinoshita, S.; Matsuzaka,
H.; Uemura, M. Org. Lett. 2006, 8, 1097; (q) Tokitoh, T.; Kobayashi,
T.; Nakada, E.; Inoue, T.; Yokoshima, S.; Takahashi, H.; Natsugari,
H. Heterocycles 2006, 70, 93.
3. (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1348; (b) Hartwig, J. F.; Loue, J. Tetrahedron Lett.
1995, 36, 3609.
4. (a) Kitagawa, O.; Takahashi, M.; Yoshikawa, M.; Taguchi, T. J. Am.
Chem. Soc. 2005, 127, 3676; (b) Kitagawa, O.; Yoshikawa, M.;
Tanabe, H.; Morita, T.; Takahashi, M.; Dobashi, Y.; Taguchi, T. J.
Am. Chem. Soc. 2006, 128, 12923.
5. Papers on catalytic asymmetric synthesis of atropisomeric anilides by
other groups: (a) Brandes, S.; Bella, M.; Kjoersgaard, A.; Jorgensen,
K. A. Angew. Chem., Int. Ed. 2006, 45, 1147; (b) Tanaka, K.;
Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006, 128, 4586; (c)
Duan, W.; Imazaki, Y.; Shintani, R.; Hayashi, T. Tetrahedron 2007,
63, 8529; (d) Oppenheimer, J.; Hsung, R. P.; Figueroa, R.; Johnson,
W. L. Org. Lett. 2007, 9, 3969.
(93% ee)
6b (89 %)
6a (99 %)
3b (R = H)
5a (R = Me)
R
R
(CH2)3-OH
(CH2)3-NHMe
N
O
N
O
(93% ee)
7b (57 %)
7a (53 %)
NET inhibitor
Scheme 6. Conversion to synthetic intermediates for NET inhibitors.
tams 3b (R = H) and 5a (R = Me) was next investigated. In
accordance with the procedure of trans-tert-butylation
reported by Simpkins et al.,8c although 3b and 5a were trea-
ted with AlCl3 (10 equiv) in C6H6 at 80 ꢁC, desired N-phe-
nyl lactams were not obtained. In these reactions, the
formation of complex mixtures accompanied by the disap-
pearance of the alkene part was observed. The tert-butyl
group could be removed by trans-tert-butylation of the
resulting hydroxy lactams 6b and 6a after anti-Markovni-
kov hydration of 3b and 5a (Scheme 6). The obtained N-
phenyl lactams 7b and 7a are also synthetic intermediates
for NET inhibitors, which have been reported by Camp
et. al.7
a-Alkylations in Schemes 4 and 5, and hydration and
trans-tert-butylation in Scheme 6 proceeded without any
racemization to give intermediates 7b and 7a of same ee
as that of starting lactam 2a.
In conclusion, we succeeded in the catalytic asymmetric
synthesis of key intermediates for NET inhibitors using
optically active atropisomeric lactam obtained through
highly enantioselective intramolecular N-arylation.13,14
The present work shows a new development in atropiso-
meric anilide chemistry.
6. Typical examples of biologically active dihydroquinolin-2-one deriv-
atives: (a) Rosauer, K. G.; Ogawa, A. K.; Willoughby, C. A.;
Ellsworth, K. P.; Geissler, W. M.; Myers, R. W.; Deng, Q.; Chapman,
K. T.; Harris, G.; Moller, D. E. Bioorg. Med. Chem. Lett. 2003, 13,
4385; (b) Iyobe, A.; Uchida, M.; Kamata, K.; Hotei, Y.; Kusama, H.;
Harada, H. Chem. Pharm. Bull. 2001, 49, 822; (c) Tzeng, C.; Chen, I.;
Chen, Y.; Wang, T.; Chang, Y.; Teng, C. Helv. Chim. Acta. 2000, 83,
349; (d) Beard, R. L.; Teng, M.; Colon, D. F.; Duong, T. T.; Thacher,
S. M.; Arefieg, T.; Chandraratna, A. S. Bioorg. Med. Chem. Lett.
1997, 7, 2373.
Acknowledgements
7. Beadle, C. D.; Boot, J.; Camp, N. P.; Dezutter, N.; Findlay, J.;
Hayhurst, L.; Masters, J. J.; Penariol, R.; Walter, M. W. Bioorg. Med.
Chem. Lett. 2005, 15, 4432.
8. (a) Tashiro, M. Synthesis 1979, 921; (b) Bigi, F.; Conforti, M. L.;
Maggi, R.; Mazzacani, A.; Sartori, G. Tetrahedron Lett. 2001, 42,
6543; (c) Bennett, D. J.; Blake, A. J.; Cooke, P. A.; Godfrey, C. R. A.;
Pickering, P. L.; Simpkins, N. S.; Walker, M. D.; Wilson, C.
Tetrahedron 2004, 60, 4491.
9. (a) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. Adv. Synth. Catal. 2001, 343, 264; (b) Duprat de
Paule, S.; Jeulin, S.; Ratovelomanana-Vidal, V.; Genet, J.-P.; Cham-
pion, N.; Dellis, P. Tetrahedron Lett. 2003, 44, 823; (c) Jeulin, S.;
Duprat de Paule, S.; Ratovelomanana-Vidal, V.; Genet, J.-P.;
Champion, N. Angew. Chem., Int. Ed. 2004, 43, 320.
We gratefully acknowledge Takasago International
Corporation for supplying (R)-SEGPHOS. This work
was partly supported by a Grant-in-Aid from The
Research Foundation for Pharmaceutical Sciences, and a
Grant-in-Aid [(C) Grant No. 18590018] for Scientific Re-
search and the Ministry of Education, Science, Sports
and Culture of Japan.
References and notes
1. (a) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem.
Soc. 1994, 116, 3131; (b) Kishikawa, K.; Tsuru, I.; Kohomoto, S.;

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O. Kitagawa et al. / Tetrahedron Letters 49 (2008) 471–474
10. Interestingly, the use of (R)-DTBM-SEGPHOS which gave the best
results in intermolecular reaction, was not effective in the intramo-
lecular reaction with 1a (12% yield, 0% ee).
11. Similar stereoselective a-mono-alkylation with racemic atropisomeric
N-(ortho-tert-butylphenyl)-5,6-dehydropiperidin-2-one has been
reported by Simpkins and co-workers (Ref. 8c).
12. Stereochemistries of lactams 5a and 5a0 were determined by NOESY
experiment. In 5a0, NOE between the ortho-tert-butyl group and
alkenyl hydrogen was observed, while in 5a, NOE between these
groups was not observed.
5.10 (1H, qd, J = 1.0, 10.0 Hz), 4.99 (1H, qd, J = 1.0, 17.0 Hz), 2.96
(1H, d, J = 15.8 Hz), 2.86 (1H, d, J = 15.8 Hz), 2.29 (1H, dd, J = 7.1,
14.6 Hz), 2.21 (1H, dd, J = 7.8, 14.6 Hz), 1.32 (3H, s), 1.22 (9H, s);
13C NMR (CDCl3): d 174.8, 147.7, 142.0, 136.6, 133.0, 132.3, 129.4,
128.5, 128.3, 127.6, 126.9, 123.7, 122.7, 118.7, 116.5, 40.8, 40.0, 37.2,
35.8, 31.5, 22.3; MS (m/z) 334 (MH+); Anal. Calcd for C23H27NO: C,
82.84; H, 8.16; N, 4.20. Found: C, 82.53; H, 8.10; N, 3.98. Compound
6b (93% ee): white solid; [a]D ꢀ44.0 (c 1.0, CHCl3); mp 91–92 ꢁC; IR
(KBr) 3420, 1681 cmꢀ1 1H NMR (CDCl3): d 7.63 (1H, dd, J = 1.5,
;
8.1 Hz), 7.39 (1H, dt, J = 1.5, 7.6 Hz), 7.31 (1H, dt, J = 1.5, 7.6 Hz),
7.20 (1H, d, J = 7.0 Hz), 7.04 (1H, dt, J = 1.5, 7.6 Hz), 6.98 (1H, dt,
J = 1.2, 7.3 Hz), 6.87 (1H, dd, J = 1.5, 7.6 Hz), 6.19 (1H, d,
J = 7.6 Hz), 3.60–3.70 (2H, m), 3.21 (1H, dd, J = 5.1, 15.3 Hz), 2.88
(1H, dd, J = 6.8, 15.3 Hz), 2.82 (1H, m), 2.01 (1H, br s), 1.88 (1H, m),
1.55–1.82 (3H, m), 1.25 (9H, s); 13C NMR (CDCl3): d 173.3, 147.9,
141.7, 136.0, 131.8, 129.7, 128.7, 128.4, 127.8, 127.1, 123.8, 122.9,
117.0, 62.4, 40.8, 35.9, 31.6, 30.9, 30.1, 26.1; MS (m/z) 338 (MH+);
Anal. Calcd for C22H27NO2: C, 78.30; H, 8.06; N, 4.15. Found: C,
78.16; H, 7.90; N, 3.98. Compound 6a (93% ee): colourless oil; [a]D
ꢀ145.7 (c 0.2, CHCl3); IR (neat) 3443, 1668 cmꢀ1; 1H NMR (CDCl3):
d 7.60 (1H, dd, J = 1.5, 8.1 Hz), 7.37 (1H, dt, J = 1.5, 7.6 Hz), 7.30
(1H, dt, J = 1.5, 7.6 Hz), 7.17 (1H, d, J = 7.1 Hz), 7.03 (1H, t,
J = 7.6 Hz), 6.96 (1H, dt, J = 1.0, 7.3 Hz), 6.85 (1H, dd, J = 1.5,
7.6 Hz), 6.15 (1H, d, J = 8.0 Hz), 3.55 (2H, t, J = 5.8 Hz), 3.01 (1H, d,
J = 15.8 Hz), 2.86 (1H, d, J = 15.8 Hz), 1.50–1.67 (5H, m), 1.33 (3H,
s), 1.21 (9H, s); 13C NMR (CDCl3): d 175.0, 147.8, 141.8, 136.6, 132.2,
129.4, 128.5, 128.3, 127.7, 127.0, 123.7, 122.7, 116.5, 63.0, 40.6, 38.1,
35.9, 32.2, 31.5, 27.3, 22.5; MS (m/z) 352 (MH+); HRMS: (MH+)
calcd for C23H30NO2, 352.2277; found, 352.2288. Compound 7b (93%
ee): white solid; [a]D +15.6 (c 0.4, CHCl3); mp 106–108 ꢁC; IR (KBr)
13. General procedure of catalytic asymmetric intramolecularN-arylation:
Under Ar atmosphere, to 1a (407 mg, 1.0 mmol) in toluene (3.0 mL)
was added Cs2CO3 (651 mg, 2.0 mmol). After being stirred for 5 min
at rt, the suspension of Pd(OAc)2 (11.2 mg, 0.05 mmol) and (R)-
SEGPHOS (45.8 mg, 0.075 mmol) in toluene (2.0 mL) was added to
the mixture, and then the reaction mixture was vigorously stirred for
24 h at 80 ꢁC (When the reaction mixture was heated for several
hours, some solids adhered to the flask’s walls above the solution. The
solids, including active catalyst, had to be resuspended in the reaction
solution by shaking the flask). The mixture was poured into 2% HCl
solution and extracted with AcOEt. The AcOEt extracts were washed
with brine, dried over MgSO4 and evaporated to dryness. Purification
of the residue by column chromatography (hexane/AcOEt = 10) gave
2a (267 mg, 95%). The ee (93% ee) of 2a was determined by HPLC
analysis using a CHIRALPACK AD-H column [25 cm · 0.46 cm i.d.;
3% i-PrOH in hexane; flow rate, 1.0 mL/min; (ꢀ)-2a (major);
tR = 11.3 min, (+)-2a (minor); tR = 12.6 min]. Compound 2a: [a]D
ꢀ77.1 (c 1.0, CHCl3); 1H NMR of lactam 2a coincided with that
reported in our previous paper.4
14. Spectral data of key compounds 3b, 5a, 6b, 6a, 7b and 7a. Compound
3b (93% ee): white solid; [a]D ꢀ58.4 (c 1.0, CHCl3); mp 78–82 ꢁC; IR
(KBr) 1683 cmꢀ1; 1H NMR (CDCl3): d 7.63 (1H, dd, J = 1.5, 8.1 Hz),
7.39 (1H, dt, J = 1.5, 8.1 Hz), 7.30 (1H, dt, J = 1.5, 7.6 Hz), 7.19 (1H,
d, J = 7.0 Hz), 7.04 (1H, dt, J = 1.5, 7.6 Hz), 6.97 (1H, dt, J = 1.2,
7.6 Hz), 6.88 (1H, dd, J = 1.5, 7.6 Hz), 6.19 (1H, dd, J = 1.0, 8.0 Hz),
5.84 (1H, dddd, J = 6.1, 8.1, 10.2, 17.0 Hz), 5.10 (1H, d, J = 10.2 Hz),
5.06 (1H, qd, J = 1.6, 17.0 Hz), 3.15 (1H, dd, J = 5.4, 15.6 Hz), 2.89
(1H, dd, J = 6.7, 15.6 Hz), 2.81 (1H, m), 2.61 (1H, m), 2.23 (1H, td,
J = 8.1, 14.0 Hz), 1.25 (9H, s); 13C NMR (CDCl3): d 172.6, 147.9,
141.9, 136.1, 135.3, 132.0, 129.6, 128.6, 128.4, 127.7, 127.0, 123.6,
122.8, 117.5, 116.9, 40.8, 35.9, 33.8, 31.6, 29.6; MS (m/z) 320 (MH+);
Anal. Calcd for C22H25NO: C, 82.72; H, 7.89; N, 4.38. Found: C,
82.75; H, 7.94; N, 4.47. Compound 5a (93% ee): colourless oil; [a]D
3420, 1682 cmꢀ1 1H NMR (CDCl3): d 7.50 (2H, t, J = 7.6 Hz), 7.41
;
(1H, tt, J = 1.2, 7.6 Hz), 7.18–7.22 (3H, m), 7.04 (1H, dt, J = 1.5,
7.6 Hz), 6.99 (1H, dt, J = 1.2, 7.6 Hz), 6.34 (1H, dd, J = 1.2, 7.8 Hz),
3.62–3.72 (2H, m), 3.13 (1H, dd, J = 5.4, 15.4 Hz), 2.92 (1H, dd,
J = 9.8, 15.4 Hz), 2.80 (1H, m), 1.98 (1H, m), 1.58–1.82 (4H, m); 13C
NMR (CDCl3): d 172.7, 141.1, 138.6, 129.8, 129.0, 128.1, 128.1, 127.1,
124.9, 123.0, 116.8, 62.4, 40.7, 31.3, 30.2, 25.9; MS (m/z) 304 (MNa+);
HRMS: (MNa+) calcd for C18H19NO2Na, 304.1313; found, 304.1305.
Compound 7a (93% ee): white solid; [a]D ꢀ12.8 (c 1.0, CHCl3); mp
82–85 ꢁC; IR (KBr) 3435, 1680 cmꢀ1; 1H NMR (CDCl3): d 7.50 (2H,
t, J = 7.5 Hz), 7.40 (1H, t, J = 7.5 Hz), 7.16–7.20 (3H, m), 7.03 (1H,
dt, J = 1.5, 7.5 Hz), 6.98 (1H, dt, J = 1.0, 7.5 Hz), 6.28 (1H, dd,
J = 1.0, 8.0 Hz), 3.59 (2H, t, J = 5.7 Hz), 3.02 (1H, d, J = 15.7 Hz),
2.88 (1H, d, J = 15.7 Hz), 1.63–1.78 (5H, m), 1.27 (3H, s); 13C NMR
(CDCl3): d 174.7, 140.8, 138.8, 129.8, 129.0, 128.4, 128.0, 127.0,
124.0, 122.9, 116.2, 62.8, 40.6, 37.8, 32.6, 27.5, 22.5; MS (m/z) 296
(MH+); HRMS: (MH+) calcd for C19H22NO2, 296.1651; found,
296.1678.
ꢀ122.6 (c 1.0, CHCl3); IR (neat) 1682 cmꢀ1
;
1H NMR (CDCl3): d
7.60 (1H, dd, J = 1.6, 8.0 Hz), 7.38 (1H, dt, J = 1.6, 7.3 Hz), 7.31 (1H,
dt, J = 1.6, 7.3 Hz), 7.16 (1H, d, J = 7.1 Hz), 7.03 (1H, dt, J = 1.2,
7.5 Hz), 6.97 (1H, dt, J = 1.2, 7.3 Hz), 6.87 (1H, dd, J = 1.6, 7.5 Hz),
6.15 (1H, dd, J = 1.0, 8.0 Hz), 5.80 (1H, tdd, J = 7.4, 10.0, 17.0 Hz),