Asymmetric synthesis of the marine alkaloid (-)-(S)-nakinadine C

Article abstract of DOI:10.1016/j.tetlet.2013.09.043

The first asymmetric synthesis of the marine alkaloid (-)-(S)-nakinadine C is described. This synthesis employs the conjugate addition of lithium dibenzylamide to an N-α-phenylacryloyl SuperQuat derivative followed by diastereoselective protonation of the intermediate enolate using 2-pyridone as the key step to introduce the stereochemistry. (-)-(S)-Nakinadine C was isolated in 13% yield over 9 steps from commercially available atropic acid, 98:2 dr [(Z):(E) ratio] and >99% ee.

Full text of DOI:10.1016/j.tetlet.2013.09.043

Tetrahedron Letters 54 (2013) 6423–6426
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of the marine alkaloid (ꢀ)-(S)-nakinadine C
⇑
Stephen G. Davies , Paul M. Roberts, Rushabh S. Shah, James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2013
Revised 30 August 2013
Accepted 12 September 2013
Available online 21 September 2013
The first asymmetric synthesis of the marine alkaloid (ꢀ)-(S)-nakinadine C is described. This synthesis
employs the conjugate addition of lithium dibenzylamide to an N-a-phenylacryloyl SuperQuat derivative
followed by diastereoselective protonation of the intermediate enolate using 2-pyridone as the key step
to introduce the stereochemistry. (ꢀ)-(S)-Nakinadine C was isolated in 13% yield over 9 steps from com-
mercially available atropic acid, 98:2 dr [(Z):(E) ratio] and >99% ee.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloid
Conjugate addition
Nakinadine
SuperQuat
Sea creatures have proven to be a rich source of structurally di-
verse natural products: the wealth of molecular architectures of
marine origin displaying desirable biological activity continues to
inspire and fascinate chemists and biologists alike.1 A structurally
unique bis-pyridine alkaloid was isolated from the sponge
Amphimedon sp. in 2007 by Kobayashi and co-workers, and was
named nakinadine A.2 Soon after, in 2008, the isolation and charac-
terisation of a further five members of the nakinadine family
(nakinadines B–F) were reported by Kobayashi and co-workers.3
In each case, the atom connectivity (and hence structure) of these
new alkaloids was assigned predominantly on the basis of NMR
spectroscopic and mass spectrometric studies. Nakinadine B and
nakinadine C were determined to comprise a common 2-phenyl-
3-aminopropanoic acid core differentiated by a long N-alkyl side-
chain capped with a pyridin-3-yl substituent. Kobayashi and
co-workers assigned the absolute (S)-configuration to both of these
alkaloids by application of a derivatisation method.3,4 In a biologi-
cal assay, nakinadines A–C demonstrated cytotoxicity against
L1210 murine leukaemia and KB human epidermoid carcinoma
cells2,3 (Fig. 1).
mixture of 4 and 5, which were isolated in 73% and 9% yield,
respectively. Subsequent elaboration of the major product 4 via
reductive N-alkylation and oxidative N-debenzylation gave 6 in
60% yield, and hydrolysis of 6 via a three-step procedure involving
N-Boc protection, hydrolysis with LiOOH and N-Boc deprotection
gave (ꢀ)-(S)-nakinadine B (7) in 55% yield [17% yield over 9 steps
from atropic acid (1)] and >99% ee (Scheme 1).5 Herein we report
the application of this approach to the first asymmetric synthesis
of (ꢀ)-(S)-nakinadine C. A full and detailed comparison of the char-
acterisation data reported for the natural product with that re-
corded for the synthetic material is also undertaken, which
enables confirmation of the reported structure of the natural
product.
The structural similarities of nakinadine B and nakinadine C
suggested that a common route could be employed for their syn-
thesis from 4. The requisite long-chain aldehyde 15 required for
the synthesis of nakinadine C was prepared via initial protection
of 11-bromoundecan-1-ol (8) as the corresponding THP ether 9 fol-
lowed by treatment with PPh3 to give the intermediate phospho-
nium bromide salt 10.10 Addition of KHMDS to 10 followed by
aldehyde 12 (which was prepared via Swern oxidation of commer-
cially available alcohol 11, and used immediately) gave 13 as a
97:3 mixture of (Z):(E) olefin isomers,10,11 which were isolated in
45% combined yield (in 3 steps from 8). Removal of the O-THP pro-
tecting group gave alcohol 14 in 85% yield and 96:4 (Z):(E)
ratio.10,11 IBX oxidation12 of alcohol 14 (as required) gave aldehyde
15, which was used immediately in the next step (Scheme 2).
Reductive N-alkylation of secondary amine 4 with a freshly pre-
pared sample of aldehyde 15 gave tertiary amine 16 in 80% yield
and 97:3 (Z):(E) ratio,11 with subsequent oxidative N-debenzyla-
tion with CAN9 giving secondary amine 18 in 70% isolated yield
and 96:4 (Z):(E) ratio.11 In order to establish that competing
To date, the only reported synthesis of any of the nakinadine
alkaloids is our asymmetric synthesis of (ꢀ)-(S)-nakinadine B from
atropic acid (1).5 Atropic acid (1) was converted into the corre-
sponding anhydride, which was reacted with the lithium anion of
D
-valine derived SuperQuat 26,7 to give 3 in 72% yield. The key step,
conjugate addition of lithium dibenzylamide to 3 with in situ dia-
stereoselective enolate protonation with 2-pyridone, gave an 87:13
mixture of the corresponding N-b-aminoacryloyl SuperQuats.8
After chemoselective mono-N-debenzylation,9 this gave an 87:13
⇑
Corresponding author.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.043

6424
S. G. Davies et al. / Tetrahedron Letters 54 (2013) 6423–6426
O
O
( )7
(i), (ii)
CO2H
CO2H
N
O
( )11
N
H
N
Ph
Ph
Ph
N
nakinadine A
assigned relative configuration: (RS,SR)
atropic acid 1
3, 72%
(iii), (iv)
CO2H
( )11
N
H
Ph
N
nakinadine B
assigned absolute configuration: (S)
O
O
O
O
O
HN
O
CO2H
BnHN
N
O
BnHN
N
O
+
( )9
N
H
Ph
Ph
Ph
N
nakinadine C
2
assigned absolute configuration: (S)
4, 73%, >99:1 dr
5, 9%, >99:1 dr
( )9
(v), (iv)
CO2H
O
O
( )10
N
H
N
Ph
N
H
N
O
N
nakinadine D
Ph
assigned relative configuration: (RS,SR)
6, 60%, >99:1 dr
N
N
( )9
(vi)-(viii)
CO2H
( )11
N
H
N
CO2H
N
H
Ph
N
nakinadine E
Ph
(−)-(S)-nakinadine B 7, 55%, >99% ee
assigned relative configuration: (RS,SR)
( )7
Scheme 1. Reagents and conditions: (i) pivaloyl chloride, Et3N, THF, 0 °C, 1 h; (ii) 2,
BuLi, THF, ꢀ78 °C to rt, 2 h; (iii) LiNBn2, THF, ꢀ78 °C, 4 h, then 2-pyridone, ꢀ78 °C to
rt, 16 h; (iv) CAN, MeCN, H2O, rt, 16 h; (v) 13-(pyridin-30-yl)tridecanal, NaB(OAc)3H,
AcOH, DCE, rt, 16 h; (vi) Boc2O, NaHCO3, EtOH, 0 °C to rt, 16 h; (vii) LiOH, aq H2O2,
THF, 0 °C to rt, 16 h; (viii) HCl (2 M in Et2O), rt, 30 min.
CO2H
( )9
N
H
N
Ph
N
nakinadine F
assigned relative configuration: (RS,SR)
Figure 1. Assigned structures, relative and absolute configurations of nakinadines
A–F.
OTHP
OH
Br
OTHP
Br
(ii)
(i)
9( )
9( )
9( )
PPh3Br
epimerisation had not occurred during conversion of 4 into 18,
authentic samples of the epimeric compounds 17 and 19 were pre-
pared from 5 via an analogous sequence of reactions. Hydrolysis of
18 via the optimised three-step procedure gave a sample of (S)-20
8
9
10
(iv)
{½a 2D0
ꢁ
ꢀ5.9 (c 1.0 in CHCl3)},13 the reported structure of nakinadine
OH
( )9
OTHP
C,3 in 45% yield over the 3 steps [representing 13% overall yield in 9
11
12
13, 45% from 8, 97:3 (Z):(E)
steps from atropic acid (1)] and 98:2 (Z):(E) ratio,11 with SuperQuat
N
N
2 {½a 2D0
ꢁ
ꢀ23.6 (c 1.0 in CHCl3); lit.14
½
a 2D3
ꢁ
ꢀ24.2 (c 1.0 in CHCl3)}
(v)
(iii)
being recovered in 73% isolated yield over the 3 steps. Similarly,
hydrolysis of 19 (in 3 steps) gave (R)-20 {½a D20
ꢁ
+5.8 (c 1.0 in
( )9
OH
CHCl3)}13 in 48% yield over the 3 steps and 95:5 (Z):(E) ratio;11
O
SuperQuat 2 {½a 2D0
ꢀ24.1 (c 1.0 in CHCl3)} was recovered in 63% iso-
ꢁ
14, 85%, 96:4 (Z):(E)
N
N
N
lated yield over the 3 steps. The samples of (S)-20 and (R)-20 were
each determined to be >99% ee by conversion into the correspond-
ing methyl ester upon treatment with SOCl2 in MeOH, subsequent
conversion into the corresponding Mosher’s amides, and analysis
by 1H and 19F NMR spectroscopy.15 This demonstrates that neither
hydrolysis reaction (of 18 or 19) nor the esterification of 20 are
(vi)
( )9
O
15
Scheme 2. Reagents and conditions: (i) DHP, PPTS, CH2Cl2, rt, 16 h; (ii) PPh3, MeCN,
reflux, 48 h; (iii) (ClCO)2, DMSO, CH2Cl2, ꢀ78 °C, 40 min, then Et3N, ꢀ78 °C to rt,
90 min; (iv) KHMDS, 12, THF, ꢀ78 °C to rt, 3 h; (v) HCl (3 M aq), MeOH, rt, 16 h; (vi)
IBX, EtOAc, 80 °C, 3 h.
accompanied
(Scheme 3).
by
competing
epimerisation/racemization
A detailed comparison of the characterisation data obtained for
(S)-20 with those for the material derived from the natural source,
reported by Kobayashi and co-workers,3 was undertaken next.13
Both the UV trace and the ESI MS/MS fragmentation pattern for
(S)-20 proved to be essentially identical to those reported for the
natural product, with the exception that the ESI MS/MS fragmenta-
tion pattern for the natural product was reported to include an ion
ArC14H26NHþ where Ar = pyridin-3-yl). The IR spectroscopic data
3
reported for natural nakinadine C included absorption bands at
1733 cmꢀ1 and 2900–3400 cmꢀ1, although these absorptions are
not characteristic of a zwitterionic amino acid.16 Analysis of (S)-
20 by IR spectroscopy produced no significant absorptions around
at m/z 287, which was attributed to C19H31Nþ (i.e., ArC14H26NHþ
1730 cmꢀ1 but strong absorption bands at 1564 and 1653 cmꢀ1
,
2
where Ar = pyridin-3-yl), but the synthetic material (S)-20 gave
which are characteristic of a bending vibration of the ammonium
functionality and stretching vibration of the carboxylate
an ion at m/z 289, consistent with the fragment C19H33Nþ (i.e.,
a
2

S. G. Davies et al. / Tetrahedron Letters 54 (2013) 6423–6426
6425
O
O
O
O
BnHN
N
O
BnHN
N
O
Ph
Ph
4, >99:1 dr
5, >99:1 dr
(i)
(i)
O
O
O
O
(
)
N
N
O
(
)
N
N
O
9
9
Bn
Bn
Ph
Ph
N
N
17, 67%, 96:4 (Z):(E)
16, 80%, 97:3 (Z):(E)
(ii)
(ii)
O
O
O
O
( )9
N
H
N
O
( )9
N
H
N
O
Ph
Ph
N
N
19, 68%, 96:4 ( ):( )
E
18, 70%, 96:4 (Z):(E)
Z
(iii)-(v)
(iii)-(v)
CO2H
CO2H
(
)
N
H
(
)
N
H
9
9
Ph
Ph
N
N
(
)-( )-nakinadine C 20, 45%
98:2 (Z):(E), >99% ee
−
S
(+)-(R)-nakinadine C 20, 48%
95:5 (Z):(E), >99% ee
Scheme 3. Reagents and conditions: (i) 15, NaB(OAc)3H, AcOH, DCE, rt, 16 h; (ii) CAN, MeCN, H2O, rt, 16 h; (iii) Boc2O, NaHCO3, EtOH, 0 °C to rt, 16 h; (iv) LiOH, aq H2O2, THF,
0 °C to rt, 16 h; (v) HCl (2 M in Et2O), rt, 30 min.
29
Natural Nakinadine C
Appearance colourless oil
[α]D not report ed
Synthetic (S)-20
30
28
27
white solid (mp 124-125 °C)
4
20
3
8
11
13
15
17
19
21
N
H
23
[α]D −5.9 (c 1.0 in CHCl3)
5
6
7
9
10
12
14
16
18
20
22
24
25
26
λmax (10−2 ε) 258 (32), 263 (33), 269 (30) 258 (35), 263 (40), 269 (29)
2
CO2H
N
vmax
3350, 3200, 2920, 1733
3030, 2923, 2852, 1653, 1564
1
Figure 2A. Selected physical and spectroscopic data for natural nakinadine C and
synthetic (S)-20. UV absorption data for (S)-20 were recorded in MeOH (kmax in nm,
Nakinadine C
600 MHz
(S)-20
in L molꢀ1 cmꢀ1); IR absorption data for (S)-20 were recorded using an ATR
500 MHz
e
Proton #
2-H, 6-H
4-H
δH (ppm)
δH (ppm)
8.44 (2H, m)
7.50 (1H, app dt)
7.19 (1H, dd)
module (mmax in cmꢀ1).
8.44 (2H, m)
7.49 (1H, m)
7.18 (1H, m)
pyridin-3-yl
moiety
5-H
Natural nakinadine C: parent ion at m/ z 437 (C28H41N2O2+, [M+H]+)
7-H2
8-H2
9-H, 10-H
11-H2
12-18-H2
19-H2
20-H2
2.65 (2H, t)
2.66 (2H, t)
Ph
CO2H
m/ z 93(+H)
132
160
188
216
244
272
2.35 (2H, dt)
5.37 (2H, m)
1.92 (2H, dt)
1.2 (14H, m)
1.61 (2H, br s)
2.84 (3H, m)*
2.36 (2H, app q)
5.39 (2H, m)
1.93 (2H, app q)
1.26 (14H, m)
1.66 (2H, m)
2.99 (2H, m)
N
H
alkyl chain
106
m/ z
146
174
202
230
258
287
301
N
Synthetic (S)-20: parent ion at m/ z 437 (C28H41N2O2+, [M+H]+)
Ph
CO2H
m/ z 93(+H)
132
160
188
216
272
22-HA
22-HB
23-H
2.84 (3H, m)*
3.49 (1H, br s)
4.11 (1H, br s)
2.85 (1H, dd)
3.42 (1H, app t)
4.04 (1H, dd)
β-amino
acid moiety
N
H
26-H, 30-H
27-H, 29-H
28-H
7.33 (2H, m)
7.25 (2H, m)
7.20 (1H, m)
7.38 (2H, app d)
7.30 (2H, app t)
7.23 (1H, app t)
106
m/ z
146
174
202
258
289
301
N
phenyl ring
Figure 2B. ESI MS/MS fragmentation pattern for natural nakinadine C and synthetic
(S)-20.
Figure 3. 1H NMR spectroscopic data for natural nakinadine C (unknown concen-
tration in CDCl3) and synthetic (S)-20 (127 mM in CDCl3). For purposes of
comparison, the numbering convention adopted by Kobayashi and co-workers.
(see Ref. 3) has also been adopted here. ⁄The (unassigned) 1H NMR data for the
natural product includes resonances at 2.82 (2H, br s) and 2.86 (1H, br s); the mid-
point of these has been quoted here for purposes of comparison.
functionality, respectively, within a zwitterionic amino acid16
(Figs. 2A and 2B). Addition of HCl to the sample of (S)-20 and
acquisition of an IR spectrum did show an absorption band at
1721 cmꢀ1, however. The IR absorption values of (S)-20 and the
corresponding HCl salt are entirely in accord with those for over
200 examples of zwitterionic b-amino acids and the corresponding
ammonium salts that have been synthesised within our labora-
tory.17 Analogous differences were noted in comparison of the
ESI MS/MS fragmentation and IR spectroscopic data for (S)-7 (our
synthetic sample of nakinadine B) with those reported for the nat-
ural product.5

6426
S. G. Davies et al. / Tetrahedron Letters 54 (2013) 6423–6426
29
McCullagh for the acquisition of the ESI MS/MS fragmentation pat-
tern of nakinadine C.
30
28
27
4
3
8
11
13
15
17
19
21
N
H
23
5
6
7
9
10
12
14
16
18
20
22
24
25
26
Supplementary data
2
CO2H
N
1
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
09.043.
Nakinadine C
150 MHz
(S)-20
125 MHz
Carbon #
2 (CH)
3 (C)
4 (CH)
5 (CH)
6 (CH)
δC (ppm)
δC (ppm)
149.9
137.3
135.8
123.2
147.2
150.0
137.2
135.9
123.2
147.3
References and notes
pyridin-3-yl
moiety
1. (a) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461; (b) Saleem, M.; Ali, M.
S.; Hussain, S.; Jabbar, A.; Ashraf, M.; Lee, Y. S. Nat. Prod. Rep. 2007, 24, 1142; (c)
Jimenez, J. T.; Šturdíková, M.; Šturdíka, E. Acta Chim. Slov. 2009, 2, 63; (d)
Gademann, K.; Kobylinska, J. Chem. Rec. 2009, 9, 187.
2. Kubota, T.; Nishi, T.; Fukushi, E.; Kawabata, J.; Fromont, J.; Kobayashi, J.
Tetrahedron Lett. 2007, 48, 4983.
3. Nishi, T.; Kubota, T.; Fromont, J.; Sasaki, T.; Kobayashi, J. Tetrahedron 2008, 64,
3127.
4. Nagai, Y.; Kusumi, T. Tetrahedron Lett. 1995, 36, 1853.
5. Davies, S. G.; Lee, J. A.; Roberts, P. M.; Shah, R. S.; Thomson, J. E. Chem. Commun.
2012, 9236.
7 (CH2)
8 (CH2)
9 (CH)
10 (CH)
11 (CH2)
12-18 (CH2)
19 (CH2)
20 (CH2)
33.0
28.7
127.7
131.4
27.2
26.7, 29-30
29-30
47.9
33.0
28.7
127.7
131.4
27.2
alkyl chain
26.9, 29-30
25.4
6. SuperQuat 2 was prepared according to the procedure outlined by: Bull, S. D.;
Davies, S. G.; Jones, S.; Polywka, M. E. C.; Prasad, R. S.; Sanganee, H. J. Synlett
1998, 519.
7. For selected applications of SuperQuat chiral auxiliaries in asymmetric
synthesis, see: (a) Davies, S. G.; Sanganee, H.; Szolcsanyi, P. Tetrahedron 1999,
55, 3337; (b) Bull, S. D.; Davies, S. G.; Garner, A. C.; Kruchinin, D.; Key, M.-S.;
Roberts, P. M.; Savory, E. D.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem.
2006, 4, 2945.
8. (a) Beddow, J. E.; Davies, S. G.; Smith, A. D.; Russell, A. J. Chem. Commun. 2004,
2778; (b) Beddow, J. E.; Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.;
Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2007, 5, 2812.
9. (a) Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, R. S.; Smith, A.
D. Chem. Commun. 2000, 337; (b) Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney,
A. W.; Prasad, R. S.; Smith, A. D. J. Chem. Soc., Perkin Trans. 1 2000, 3765.
10. Baldwin, J. E.; Spring, D. R.; Atkinson, C. E.; Lee, V. Tetrahedron 1998, 54, 13655.
11. The (Z):(E) ratio was assigned from integration of the resonances associated
with the allylic protons [C(10)H2 or C(100)H2, as relevant] in the 700 MHz 1H
NMR spectrum recorded in C6D6. Independent homonuclear decoupling of each
of the allylic C(10)H2 and C(13)H2 groups within 13 enabled determination of
the olefinic 3J coupling constant as 10.3 Hz, consistent with the formation of a
(Z)-olefin.
47.6
22 (CH2)
23 (CH)
24 (C)
50.8
51.1
176.7
51.1
51.8
176.4
β-amino
acid moiety
25 (C)
135.8
128.2
128.7
127.3
139.0
128.2
128.8
127.2
26, 30 (CH)
27, 29 (CH)
28 (CH)
phenyl ring
Figure 4. 13C NMR spectroscopic data for natural nakinadine C (unknown concen-
tration in CDCl3) and synthetic (S)-20 (127 mM in CDCl3). For purposes of
comparison, the numbering convention adopted by Kobayashi and co-workers.
(see Ref. 3) has also been adopted here.
Comparison of the 1H NMR spectroscopic data of (S)-20
(127 mM in CDCl3) with those reported for natural nakinadine C
(unknown concentration in CDCl3)18 gave excellent agreement
(Fig. 3),19 whilst similar comparison of the 13C NMR data showed
generally excellent agreement,18 with most values having
12. More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
13. Although the absolute configuration assignments of our samples of both (S)-20
and (R)-20 are secure, unfortunately no value for the specific rotation of the
natural product was reported by Kobayashi and co-workers for comparison.
14. Bull, S. D.; Davies, S. G.; Jones, S.; Sanganee, H. J. J. Chem. Soc., Perkin Trans. 1
1999, 387.
15. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
16. Pretsch, E.; Bühlmann, P.; Affolter, C. Structure Determination of Organic
Compounds: Tables of Spectral Data, 2000.
|D
d| 6 0.3 ppm20 (Fig. 4). Larger differences were observed for
C(19) [|
D
d| ꢂ 4 ppm],20 C(23) [|
D Dd|
d| 0.7 ppm]20 and C(25) [|
3.2 ppm].20,21 Although the origin of these differences is unclear,
the structural assignment of 20 is secure.
17. (a) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16,
2833; (b) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E.
Tetrahedron: Asymmetry 2012, 23, 1111.
In conclusion, an efficient asymmetric synthesis of the marine
alkaloid (ꢀ)-(S)-nakinadine C has been developed, using a strategy
reliant upon conjugate addition of lithium dibenzylamide to an
18. Resonances in the 1H and 13C NMR spectra of the natural product were not fully
assigned by Kobayashi and co-workers; they are assigned here by closest
comparison. The resonance at dC 26.7 ppm for the natural product was,
however, assigned as being due to C(11); this assignment has been revised here
on the basis of the extensive NMR spectroscopic data obtained for (S)-20.
19. In contrast, the hydrochloride salt (S)-2ꢃHCl proved to be only sparingly soluble
in CDCl3 and produced a broad 1H NMR spectrum; the chemical shift values did
not correspond well with those reported for the natural product.
N-a-phenylacryloyl SuperQuat derivative followed by diastereose-
lective protonation of the intermediate enolate using 2-pyridone as
the key step to introduce the stereochemistry. This synthesis pro-
ceeds over 9 steps from commercially available atropic acid in 13%
overall yield, delivering the natural product as a 98:2 mixture of
(Z):(E) diastereoisomers in >99% ee. Further investigations into
the development of efficient asymmetric syntheses of the remain-
ing members of the nakinadine family of alkaloids are ongoing
within our laboratory.
20.
|
D
d| Refers to the absolute value of (dnatural) ꢀ (dsynthetic).
21. A similar phenomenon was observed when the 13C NMR data for (S)-7 (our
synthetic sample of nakinadine B) were compared with those reported for
natural nakinadine B (see Ref. 5): values showed generally excellent agreement
[|Dd| 6 0.5 ppm], although larger differences were noted for C(18), C(22) and
C(24). Thus, in both nakinadine B and nakinadine C, these correspond to
NCH2CH2 [C(18), nakinadine B; C(19), nakinadine C], NCH2CHPh [C(22),
nakinadine B; C(23), nakinadine C] and i-Ph [C(24), nakinadine B; C(25),
nakinadine C]. Note also, |Dd| >0.5 ppm for C(8) of nakinadine B; however the
equivalent carbon atom in nakinadine C is in an allylic position so their
environments (and hence chemical shift values) are not directly comparable.
Acknowledgements
The authors would like to thank Dr. Tim Claridge and Dr.
Barbara Odell for the acquisition of NMR spectra, and Dr. James