Asymmetric synthesis of (-)-codonopsinine

Article abstract of DOI:10.1016/j.tetlet.2011.09.114

The asymmetric synthesis of (-)-codonopsinine was achieved in 7 steps (from commercially available tert-butyl crotonate) in 5% overall yield and >99:1 dr. The key step in this synthesis involved ring-closing iodoamination of a functionalised homoallylic a

Full text of DOI:10.1016/j.tetlet.2011.09.114

Tetrahedron Letters 52 (2011) 6477–6480
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of (ꢀ)-codonopsinine
⇑
Stephen G. Davies , James A. Lee, Paul M. Roberts, James E. Thomson, Callum J. West
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:
The asymmetric synthesis of (ꢀ)-codonopsinine was achieved in 7 steps (from commercially available
tert-butyl crotonate) in 5% overall yield and >99:1 dr. The key step in this synthesis involved ring-closing
iodoamination of a functionalised homoallylic amine, which occurred with concomitant N-debenzylation,
to give a 3-iodopyrrolidine that was elaborated to (ꢀ)-codonopsinine.
Received 18 August 2011
Revised 9 September 2011
Accepted 23 September 2011
Available online 29 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
(ꢀ)-Codonopsinine
Lithium amide
Ring-closing iodoamination
Pyrrolidine
Nitrogen-containing heterocycles are widespread in a multi-
tude of natural and unnatural products.1 Pyrrolidines (i.e., 5-mem-
bered azacyclic subunits) are one of the most prevalent core
heterocyclic structures included within these series, and occur
commonly in alkaloids as stand-alone polysubstituted pyrrolidines
and more complex bicyclic systems such as tropanes, pyrrolizi-
dines, and indolizidines.2 Approximately 80 pyrrolidine alkaloids
are known, found across a number of families such as solanaceae,
convolvulaceae, and erythroxylaceae,3 and many display potent
biological activities ranging from antibacterial and neuroexcitatory
agents to potent venoms, glycosidase inhibitors and fungicides.4,5
Polysubstituted pyrrolidines have therefore been the subject of
many total syntheses.6,7 Pyrrolidine alkaloids with aromatic sub-
stituents, for example, (ꢀ)-codonopsinine 1, (ꢀ)-codonopsine 2,
and radicamines A 3 and B 4, occur fairly infrequently in nature
(Fig. 1).8 The dense functionality within these compounds, coupled
with the presence of four contiguous stereogenic centres, makes
them challenging synthetic targets.
Me
N
Me
N
OMe
OMe
OMe
Me
Me
OMe
HO
OH
HO
OH
(−)-codonopsinine 1
(−)-codonopsine 2
HO
HO
OH
H
N
H
N
OH
HO
OH
HO
OH
(+)-radicamine A 3
(+)-radicamine B 4
Figure 1. Examples of C(2)-aryl substituted pyrrolidines.
racemic synthesis19 and one total asymmetric synthesis20 of
codonopsinine 1 are known. A diverse range of synthetic strategies
have been adopted in these syntheses, including the diastereose-
lective addition of Grignard reagents to cyclic nitrones, the decarb-
oxylative cyclisation of allylic carbamates, the Heck reaction of
endocyclic enecarbamates, and intramolecular SN2-type displace-
ment reactions, amongst other approaches.
We have recently reported the total asymmetric syntheses of
pyrrolidine,21 piperidine22, and pyrrolizidine23 scaffolds using a
ring-closing iodoamination protocol (which proceeds with concom-
itant N-debenzylation) as the key step. We envisaged that this strat-
egy would also be applicable to the synthesis of C(2)-aryl substituted
pyrrolidines and selected (ꢀ)-codonopsinine 1 as a target to probe
the scope of this methodology. By analogy to our previous results,
our strategy for the synthesis of a C(2)-aryl substituted pyrrolidine
scaffold involved treatment of homoallylic amine 8 with iodine
(ꢀ)-Codonopsinine 1 was isolated in 1969 from Codonopsis
clematidea, a flowering plant native to East Asia.8a–d Its structure
was unambiguously assigned in 1986 by Kibayashi and co-workers
via single crystal X-ray diffraction analysis of an intermediate in
their total synthesis of the antipode (+)-codonopsinine 1,9 although
a crystal structure of codonopsinine 1 itself is yet to be reported.
Several syntheses of codonopsinine 1 have been reported: most
of these approaches are enantiospecific, starting from either
L
-xylose,4,10
D
-alanine,11,12
L
-threonine,13
D L-tartaric
-tartaric acid,14
acid,15
L
-pyroglutamic acid16,17 or
D
-ribose.18 In addition, one total
⇑
Corresponding author.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.114

6478
S. G. Davies et al. / Tetrahedron Letters 52 (2011) 6477–6480
Me
N
Me
Me
PMP
N
Li
(R)-6
Me
PMP
N
PMP
N
Me
PMP
(i)
5
4
2
PMP
CO2tBu
CO2tBu
3
Me
Me
Me
then (−)-CSO
OMOM
RO
I
OH
7
14
16, R = MOM, 54%, >99:1 dr
17•HCl, R = H, 52%, >99:1 dr
5
(ii)
Scheme 3. Reagents and conditions: (i) NaHCO3, I2, MeCN, rt, 20 h; (ii) HCl, MeOH,
rt, 48 h.
Me
PMP
Me
PMP
PMP
N
PMP
N
I2
I
NaHCO3
Me
Me
MeCN
OR
OR
8
9
Me
PMP
Me
Me
N
N
PMP
Me
PMP
I
RO
I
RO
10
11
Scheme 1. Proposed synthetic strategy towards polysubstituted pyrrolidine
scaffolds.
Figure 2. X-ray crystal structure of 17ꢂHCl (selected H-atoms are omitted for
clarity).
leading to the formation of iodonium species 9, which may undergo
cyclisation to form ammonium ion 10, followed by in situ SN1-type
loss of the N-a-methyl-p-methoxybenzyl protecting group (with
Reduction of the ester functionality within 12 with DIBAL-H, fol-
lowed by Wittig olefination of the resultant aldehyde 13 gave a
ꢁ2:1 mixture of homoallylic amines (E)-14 and (Z)-15, which were
isolated in 57% and 9% yield (over 2 steps), respectively, and in
>99:1 dr in each case (Scheme 2). The configurations of the newly
formed double bonds within (E)-14 and (Z)-15 were assigned by 1H
NMR 3J coupling constant analyses, with diagnostic trans
[J1,2 = 16.0 Hz for (E)-14] and cis [J1,2 = 12.0 Hz for (Z)-15] olefinic
coupling constants being observed.
ensuing Ritter reaction) to give 3-iodopyrrolidine 11. Manipulation
of the C(3)-iodide functionality within 11, followed by deprotection
would then give access to (ꢀ)-codonopsinine 1. It was anticipated
that homoallylic amine 8 could be easily synthesised from tert-butyl
crotonate 5 using our asymmetric aminohydroxylation protocol24,25
whereby conjugate addition of enantiopure lithium amide (R)-6 to 5,
followed by in situ oxidation of the intermediate lithium b-amino
enolate with (ꢀ)-camphorsulfonyloxaziridine [(ꢀ)-CSO], gives
Following our previously optimised procedure,21a,24e treatment
of 14 with I2 and NaHCO3 in MeCN gave 3-iodopyrrolidine 16 as a
single diastereoisomer (>99:1 dr), which was isolated in 54% yield
and >99:1 dr after chromatographic purification. The relative con-
figuration within 16 was unambiguously established by derivatisa-
tion to the corresponding alcohol 17 (which was achieved upon
treatment with HCl in MeOH), followed by single crystal X-ray dif-
fraction analysis of the corresponding hydrochloride salt 17ꢂHCl
(Scheme 3).26 These crystallographic data allowed the relative con-
figuration within 17ꢂHCl to be unambiguously assigned, with the
anti-a-hydroxy-b-amino ester 7 with high diastereoselectivity.
Subsequent protection of the hydroxyl group within 7, reduction
of the tert-butyl ester moiety, and Wittig olefination of the resultant
aldehyde was expected to give access to homoallylic amine 8
(Scheme 1).
Thus, the conjugate addition of enantiopure lithium amide 6 to
tert-butyl crotonate 5 gave 7 as a single diastereoisomer (>99:1 dr)
which was isolated in 71% yield after chromatographic purification.
Subsequent protection of the C(2)-hydroxyl group within 7 as the
corresponding O-MOM ether gave 12 in 70% yield and >99:1 dr.
Me
Me
Me
PMP
N
Li
PMP
N
PMP
N
(i)
(ii)
6
CO2tBu
CO2tBu
Me
Me
CO2tBu
Me
OH
OMOM
12, 70%, >99:1 dr
5
7, 71%, >99:1 dr
(iii)
Me
Me
N
Me
PMP
N
PMP
PMP
N
(iv)
PMP
Me
Me
MOMO
15, 9% (2 steps), >99:1 dr
Me
O
PMP
OMOM
14, 57% (2 steps), >99:1 dr
MOMO
13
Scheme 2. Reagents and conditions: (i) THF, ꢀ78 °C, 2 h, then (ꢀ)-CSO, ꢀ78 °C to rt, 12 h; (ii) NaH, DMF, 0 °C, 30 min, then MOMCl, rt, 12 h; (iii) DIBAL-H, CH2Cl2, ꢀ78 °C,
30 min; (iv) BuLi, [4-MeOC6H4CH2PPh3]+ [Cl]ꢀ, THF, ꢀ78 °C, 30 min, then rt, 12 h.

S. G. Davies et al. / Tetrahedron Letters 52 (2011) 6477–6480
6479
R1
R2
Me
N
Me
PMP
I
R1
PMP
N
I
N
Me
PMP
Me
PMP
OMOM
Me
N
R2
PMP
Me
Me
MOMO
I
MOMO
I
OMOM
18
19 FAVOURED
16, 54%, >99:1 dr
20
I2
Me
3
PMP
R1/R2 = Me or
PMP
PMP
N
4
1
2
(R)-α-methyl-p-methoxybenzyl
OMOM
14, >99:1 dr
I2
R1
R2
Me
N
MOMO
Me
Me
N
PMP
I
R1
I
N
Me
PMP
Me
PMP
N
PMP
Me
R2
MOMO
I
MOMO
I
OMOM
21
22 DISFAVOURED
24, not observed
23
Figure 3. The origin of diastereoselectivity in the ring-closing iodoamination of 14.
aryl group oriented away from the site of reaction; this is not pos-
sible within disfavoured transition state 22 as, regardless of the
Me
N
Me
N
conformation of the N-a-methyl-p-methoxybenzyl group (residing
Me
PMP
PMP
Me
(i)
at either position R1 or R2), unfavourable steric interactions will be
encountered (Fig. 3).
OMe
MOMO
I
MOMO
As (ꢀ)-codonopsinine 1 possesses the same ‘all-trans’ configura-
tion as 3-iodopyrrolidine 16, elaboration of 16 to enable the total
synthesis of (ꢀ)-codonopsinine 1 required substitution of the io-
dide substituent at C(3) with retention of configuration. A double
inversion strategy [e.g., SN2 displacement with acetate, hydrolysis
of the resultant 3-acetoxypyrrolidine then Mitsunobu reaction]
was considered, but a strategy reliant on neighbouring group par-
ticipation by the C(2)-p-methoxyphenyl group (i.e., an SN1-type
process) was envisaged to be more efficient in installing the oxy-
gen functionality at C(3) with the correct configuration, with sub-
sequent deprotection then providing access to (ꢀ)-codonopsinine
1. In order to promote an SN1-type reaction, 16 was treated with
AgOAc in AcOH. Under these reaction conditions a mixture of 26
(>99:1 dr) and regioisomeric product 27 (>99:1 dr) was produced
which, despite exhaustive efforts, proved to be inseparable by flash
column chromatography and was therefore isolated as a 75:25
mixture; there was sufficient resonance dispersion in the 1H
NMR spectrum of this mixture (in CDCl3) to allow the relative
configurations within both 26 and 27 to be determined by 1H
16
25
75:25
[26:27]
Me
N
Me
N
Me
N
Me
HO
Me
PMP Me
+
OAc
(ii)
OH
MOMO
OAc
MOMO
PMP
(−)-codonopsinine 1
26, >99:1 dr
27, >99:1 dr
30% (2 steps), >99:1 dr
Scheme 4. Reagents and conditions: (i) AgOAc, AcOH, 40 °C, 24 h; (ii) HCl, MeOH,
50 °C, 48 h.
absolute (R,R,R,R)-configuration within 17 being assigned relative
to the known configurations of the C(4) and C(5) stereocentres.
Furthermore, the determination of a Flack x parameter27,28 of
ꢀ0.03(3) for the structure allowed the absolute (R,R,R,R)-configura-
tion within 17, and therefore also the absolute configurations with-
in 7 and 12–16, to be confirmed unambiguously (Fig. 2).
The formation of 16 as a single diastereoisomer in the ring-clos-
ing iodoamination step suggests that cyclisation occurs via the at-
tack of an iodonium species (which is presumably formed
reversibly from 14), as cyclisation via the corresponding carbo-
nium ion at C(1) would be expected to give rise to a mixture of dia-
stereoisomeric pyrrolidines. The diastereoselectivity of this
transformation can be rationalised by considering the two possible
diastereoisomeric intermediate iodonium ions 18 and 21: within
transition state 22 for the cyclisation of iodonium 21, both the
C(3)-alkoxy and C(4)-methyl groups occupy pseudo-axial positions
and experience unfavourable steric interactions with the nitrogen
protecting groups (i.e., R1 and R2, one of which is
a-branched).
For cyclisation of iodonium 18, however, the C(3)-alkoxy and
C(4)-methyl groups occupy pseudo-equatorial positions and do
not suffer unfavourable steric interactions with the nitrogen pro-
tecting groups in transition state 19. If the N-a-methyl-p-methoxy-
benzyl group was to reside at position R2 within the favoured
transition state 19 it can minimise 1,2-strain with the C(1)-p-
methoxyphenyl substituent by adopting a conformation with the
Figure 4. X-ray crystal structure of (ꢀ)-codonopsinine 1 (selected H-atoms are
omitted for clarity).

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S. G. Davies et al. / Tetrahedron Letters 52 (2011) 6477–6480
8. (a) Matkhalikova, S. F.; Malikov, V. M.; Yunusov, S. Yu. Khim. Prir. Soedin. 1969,
5, 30; (b) Matkhalikova, C. F.; Malikov, V. M.; Yunusov, S. Y. Khim. Prir. Soedin.
1969, 5, 606; (c) Matkhalikova, S. F.; Malikov, V. M.; Yunusov, S. Yu. Khim. Prir.
Soedin. 1969, 5, 607; (d) Yagudaev, M. R.; Matkhalikova, S. F.; Malikov, V. M.;
Yusunov, S. Y. Khim. Prir. Soedin. 1972, 495; (e) Shibano, M.; Tsukamoto, D.;
Masuda, A.; Tanaka, Y.; Kusano, G. Chem. Pharm. Bull. 2001, 49, 1362.
9. Iida, H.; Yamazaki, N.; Kibayashi, C.; Nagase, H. Tetrahedron Lett. 1986, 27, 5393.
10. Chandrasekhar, S.; Saritha, B.; Jagadeshwar, V.; Prakash, S. J. Tetrahedron:
Asymmetry 2006, 17, 1380.
11. Reddy, J. S.; Rao, B. V. J. Org. Chem. 2007, 72, 2224.
12. Wang, C. J.; Calabrese, J. C. J. Org. Chem. 1991, 56, 4341.
13. Haddad, M.; Larcheveque, M. Synlett 2003, 274.
14. Yoda, H.; Nakajima, T.; Takabe, K. Tetrahedron Lett. 1996, 37, 5531.
15. Goti, A.; Cicchi, S.; Mannucci, V.; Cardona, F.; Guarna, F.; Merino, P.; Tejero, T.
Org. Lett. 2003, 5, 4235.
16. Oliveira, D. F.; Severino, E. A.; Correia, C. R. D. Tetrahedron Lett. 1999, 40, 2083.
17. Severino, E. A.; Correia, C. R. D. Org. Lett. 2000, 2, 3039.
NMR nOe analysis. The appearance of regioisomeric product 27
lends support to the original hypothesis that a mechanism involv-
ing neighbouring group participation via a phenonium ion inter-
mediate 25 was occurring and also giving rise to retention of
configuration upon attack of the acetate anion at C(3) to give 26.
Subsequently, treating the 75:25 mixture of 26 and 27 with meth-
anolic HCl at 50 °C for 48 h was found to give (ꢀ)-codonopsinine 1
in 30% isolated yield (2 steps) and >99:1 dr, thus completing the to-
tal asymmetric synthesis of this pyrrolidine natural product
(Scheme 4).
The spectroscopic data for the synthetic sample of (ꢀ)-codon-
opsinine 129 were found to be in excellent agreement with those
corresponding to the sample isolated from the natural source
{½a 2D0
ꢃ
ꢀ9.1 (c 0.1 in MeOH); Lit.8b
½
a 2D0
ꢃ
ꢀ8.8 (c 0.1 in MeOH)} and
18. Kotland, A.; Accadbled, F.; Robeyns, K.; Behr, J. J. Org. Chem. 2011, 76, 4094.
19. Chowdhury, M. A.; Reissig, H.-U. Synlett 2006, 2383.
other samples obtained by total synthesis.30 Furthermore, recrys-
tallisation of (ꢀ)-codonopsinine 1 from pyridine produced colour-
less plates which were subjected to X-ray diffraction analysis,26
unambiguously confirming the relative configuration within
codonopsinine (Fig. 4).
20. Uraguchi, D.; Nakamura, S.; Ooi, T. Angew. Chem., Int. Ed. 2010, 49, 7562.
21. (a) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Smith, A. D. Synlett
2004, 901; (b) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Savory,
E. D.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2009, 20, 756.
22. (a) Davies, S. G.; Hughes, D. G.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Smith,
A. D.; Thomson, J. E.; Williams, O. M. H. Synlett 2010, 567; (b) Davies, S. G.;
Fletcher, A. M.; Hughes, D. G.; Lee, J. A.; Price, P. D.; Roberts, P. M.; Russell, A. J.;
Smith, A. D.; Thomson, J. E.; Williams, O. M. H. Tetrahedron, 2011. doi:10.1016/
j.tet.2011.09.038.
In summary, ring-closing iodoamination of a homoallylic amine,
with concomitant N-debenzylation, was used to generate a 3-
iodopyrrolidine in >99:1 dr. Subsequent elaboration upon
treatment with AgOAc in AcOH, followed by global deprotection
gave (ꢀ)-codonopsinine (in >99:1 dr) in 7 steps from commercially
available tert-butyl crotonate in 5% overall yield. Furthermore, the
single crystal X-ray diffraction structure of (ꢀ)-codonopsinine is,
for the first time, disclosed herein.
23. Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2011,
13, 1594.
24. For selected examples, see: (a) Bunnage, M. E.; Burke, A. J.; Davies, S. G.;
Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem.
2003, 1, 3708; (b) Abraham, E.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.;
Nicholson, R. L.; Roberts, P. M.; Russell, A. J.; Sánchez-Fernández, E. M.; Smith,
A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2007, 18, 2510; (c) Abraham, E.;
Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org.
Biomol. Chem. 2008, 6, 1655; (d) Abraham, E.; Brock, E. A.; Candela-Lena, J. I.;
Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.;
Russell, A. J.; Sánchez-Fernández, E. M.; Scott, P. M.; Smith, A. D.; Thomson, J. E.
Org. Biomol. Chem. 2008, 6, 1665; (e) Davies, S. G.; Nicholson, R. L.; Price, P. D.;
Roberts, P. M.; Russell, A. J.; Savory, E. D.; Smith, A. D.; Thomson, J. E.
Tetrahedron: Asymmetry 2009, 20, 758.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.114.
25. For a review, see: Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry
2005, 16, 2833.
References and notes
26. Crystallographic data (excluding structure factors) for compounds 17ꢂHCl and
1 have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 840035 and 840036, respectively.
Copies of these data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif
27. Flack, H. D. Acta Crystallogr. A 1983, 39, 876.
1. (a) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679; (b) Johnson, T. A.;
Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2001, 123, 1004.
2. (a) Pinder, A. R. Nat. Prod. Rep. 1989, 6, 67; (b) Pinder, A. R. Nat. Prod. Rep. 1989,
6, 515; (c) Pinder, A. R. Nat. Prod. Rep. 1990, 7, 447; (d) Pinder, A. R. Nat. Prod.
Rep. 1992, 9, 491; (e) Plunkett, A. O. Nat. Prod. Rep. 1992, 11, 581.
3. Seigler, D. S. Plant Secondary Metabolism, 1st ed.; Springer, 2001.
4. (a) Toyao, A.; Tamura, O.; Takagi, H.; Ishibashi, H. Synlett 2003, 35; (b)
Chandrasekhar, S.; Jagadeshwar, V.; Prakash, S. J. Tetrahedron Lett. 2005, 46,
3127.
5. El Ashry, E. S. H.; Rashed, N.; Shobier, A. H. S. Pharmazie 2000, 55, 331.
6. (a) Denmark, S. E.; Marcin, L. R. J. Org. Chem. 1995, 60, 3221; (b) Enders, D.;
Thiebes, T. Pure Appl. Chem. 2001, 73, 573; (c) Robins, D. J.; Sainsbury, M. Rodd’s
Chemistry of Carbon Compounds, 2nd ed.; 1997; 4 (Part B), pp 1–19; (d) Pandey,
G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484; (e) Huang, P.-Q. Synlett
2006, 1133; (f) Husineca, S.; Savic, V. Tetrahedron: Asymmetry 2005, 16, 2047;
(g) Pyne, S. G.; Davis, A. S.; Gates, N. J.; Hartley, J. P.; Lindsay, K. B.; Machan, T.;
Tang, M. Synlett 2004, 2670; (h) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003,
3693; (i) Brasholz, M.; Reissig, H.-U.; Zimmer, R. Acc. Chem. Res. 2009, 42, 45.
7. The synthesis of C2-symmetric 2,5-disubstituted pyrrolidine derivatives is a
popular area of research for organic chemists as these compounds are also
especially useful as chiral auxiliaries for asymmetric synthesis, for instance,
see: (a) Shi, M.; Satoh, Y.; Masaki, Y. J. Chem. Soc., Perkin Trans. 1 1998, 2547; (b)
Blum, A.; Diederich, W. E. Curr. Org. Synth. 2009, 6, 38.
28. Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143.
29. Data for (R,R,R,R)-N(1)-methyl-2-(40-methoxyphenyl)-3-hydroxy-4-hydroxy-
5-methylpyrrolidine [(ꢀ)-codonopsinine] 1: mp 147–150 °C; ½a D20
ꢀ9.1 (c 0.1
ꢃ
in MeOH); dH (400 MHz, pyridine-d5) 1.34 (3H, d, J 6.8, C(5)Me), 2.23 (3H, s,
NMe), 3.64 (3H, s, OMe), 3.67–3.72 (1H, m, C(5)H), 4.09 (1H, d, J 6.7, C(2)H), 4.39
(1H, dd, J 4.4, 3.8, C(4)H), 4.65 (1H, dd, J 6.7, 4.4, C(3)H), 5.25 (2H, br s, OH), 6.95
(2H, d, J 8.6, C(30)H, C(50)H), 7.31 (2H, d, J 8.6, C(20)H, C(60)H); dC (100 MHz,
pyridine-d5) 14.3 (C(5)Me), 35.2 (NMe), 55.5 (OMe), 65.7 (C(5)), 74.6 (C(2)), 85.6
(C(4)), 88.0 (C(3)), 114.7 (C(30), C(50)), 130.2 (C(20), C(60)), 135.4 (C(10)), 160.1
(C(40)); m/z (ESI+) 238 ([M+H]+, 100%); HRMS (ESI+) C13H20NOþ3 ([M+H]+)
requires 238.1438; found 238.1437.
30. Ref. 4a: ½a 2D8
ꢃ
ꢀ13.2 (c 0.3 in MeOH); Ref. 4b: ½a D20
ꢀ8.8 (c 0.1 in MeOH); Ref. 10:
ꢃ
½
a 2D5
ꢃ
ꢀ12.4 (c 0.4 in MeOH); Ref. 11: ½a D34
ꢃ
ꢀ8.7 (c 0.3 in MeOH); Ref. 13: ½a D20
ꢃ
ꢀ10.5 (c 1.1 in MeOH); Ref. 15: ½a D20
ꢀ7.2 (c 0.1 in MeOH); Ref. 17: mp 153–
ꢃ
155 °C; ½a 2D0
ꢃ
ꢀ7.3 (c 0.2 in MeOH); Ref. 20: ½a D20
ꢀ13.1 (c 1.3 in MeOH).
ꢃ