Semi-synthesis of secologanin analogues

Article abstract of DOI:10.1016/j.tetlet.2006.01.009

Secologanin, a complex iridoid terpene natural product, was derivatized at the vinyl and ester functional groups using cross-metathesis and transesterification methodology, respectively.

Full text of DOI:10.1016/j.tetlet.2006.01.009

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1563–1565
Semi-synthesis of secologanin analogues
M. Carmen Galan and Sarah E. O’Connor*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Received 12 December 2005; accepted 3 January 2006
Abstract—Secologanin, a complex iridoid terpene natural product, was derivatized at the vinyl and ester functional groups using
cross-metathesis and transesterification methodology, respectively.
Ó 2006 Elsevier Ltd. All rights reserved.
Terpene indole alkaloids are derived from the terpene
iridoid glycoside secologanin (1) (Fig. 1). Secologanin
is a densely functionalized molecule containing one free
and two masked aldehyde groups, along with a vinyl
and ester moiety and a glycosidic linkage.1 In the first
step of terpene indole alkaloid biosynthesis, strictosidine
synthase catalyzes a Pictet–Spengler condensation be-
tween secologanin and tryptamine.2,3 The glucose is next
hydrolyzed, and the resulting hemiacetal, previously
masked by the glycosidic linkage, triggers the rearrange-
ment of the molecule.4,5 Secologanin therefore plays a
key role in generating the complex structure of terpene
indole alkaloids and it has been previously used as an
enantiomeric template to chemically synthesize alkaloid
natural products.6,7
biosynthetic pathway, and potentially, will be used in
the enzymatic synthesis of terpene indole alkaloid deriv-
atives. Secologanin was obtained by an optimized multi-
gram-scale isolation protocol from a local source of
Lonicera tatarica.8
Olefin cross metathesis (CM) was used to introduce a
variety of alkyl groups at the vinyl position of secologa-
nin (i.e., compounds 6a–d, Scheme 1). Although we
hoped to use unprotected secologanin directly, attempts
to incorporate alkyl groups onto the vinyl functionality
of the unprotected molecule failed, most likely due to
the insolubility of secologanin in solvents used for olefin
CM. Following reported procedures, the glycan was per-
acetylated and the aldehyde protected as an acetal to
provide the ‘protected’ secologanin, compound 3.9
Reactions of 3 with Grubbs catalyst second generation
(5 mol %) in the presence of a range of alkenes of differ-
ent lengths (a–d) afforded compounds 4a–d in good yield
(4a 90%, 4b 92%, 4c 97%, and 4d 90%; Scheme 1).10 In
every case, we observed (>95%) the E stereoisomer.
After derivatization at the vinyl position, the products
were deprotected in a two-step procedure: the acetal
was first hydrolyzed by treatment with 0.2 M hydrochlo-
ric acid in THF, and the acetates were subsequently re-
moved under mild basic conditions to afford compounds
6a–d11 in yields of approximately 50% (two steps). Alter-
natively, compound 4b was subjected to catalytic hydro-
genation to reduce the alkene (7b), and was then
deprotected to yield a reduced secologanin derivative
8b.12
Here we report in detail the semi-synthesis of a series of
secologanin analogues, in which two of the key func-
tional groups of secologanin have been modified
(Fig. 1). These analogues will be used to evaluate the
substrate requirements of the terpene indole alkaloid
olefin
metathesis
H
O
OH
OH
trans-
esterification
O
O
MeO
O
HO
O
OH
Figure 1. Derivatization of secologanin 1.
A series of ester derivatives were obtained by transeste-
rification13 of secologanin (compounds 9a–f, Scheme 2).
Derivatization of the ester moiety of secologanin is
*
Corresponding author. Tel.: +1 617 324 0180; fax: +1 617 324
0505; e-mail: soc@mit.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.009

1564
M. C. Galan, S. E. O’Connor / Tetrahedron Letters 47 (2006) 1563–1565
R'
R'
O
H
O
O
O
O
O
O
OH
OH
H
OR
OR
OR
OR
OR
OR
O
O
iii
i
O
iv, v
O
O
O
O
O
50%
90%
MeO
O
MeO
O
MeO
O
MeO
HO
RO
RO
RO
1
O
OH
O
OR
O
O
H
OR
OR
5a-d R = Ac
6a-d R = H
v
2 R = H
3 R = Ac
4a-d
ii
vi
a
R'
R'
O
O
O
b
c
OR
OH
R' =
vii, viii
O
O
O
O
d
MeO
O
MeO
O
RO
OR
HO
OH
O
O
OR
OH
7b
8b
Scheme 1. Cross metathesis reaction of secologanin with terminal olefins and subsequent deprotection. Reagents and conditions: (i) HOCH2CH2OH,
Dowex 50WX2 H+; (ii) Ac2O, Pyridine; (iii) Grubbs II (10 mol %), alkene, toluene, 100 °C; (iv) HCl aq (1 M); (v) K2CO3, MeOH; (vi) H2, Pd/C,
MeOH; (vii) HCl aq (1 M); (viii) K2CO3, MeOH.
O
O
Acknowledgements
H
H
OGlc
OGlc
We gratefully acknowledge financial support from the
Smith Family Medical Foundation, the American
Chemical Society Petroleum Research Fund (41727-
G4), 3M, Amgen Inc., and MIT.
i
Me
R'
O
O
O
O
9
O
1
O
hydrolysis
9a
9b
9c
9d
References and notes
HO
O
OGlc
R' =
O
9e
9f
1. Tietze, L. F. Angew. Chem. 1983, 95, 840–853.
2. Lee, S. L.; Hirata, T.; Scott, A. I. Tetrahedron Lett. 1979,
8, 691–694.
10
BocHN
O
3. Treimer, J. F.; Zenk, M. H. Eur. J. Biochem. 1979, 101,
225–233.
4. Geerlings, A.; Ibanez, M. M.-L.; Memelink, J.; Van der
Heijden, R.; Verpoorte, R. J. Biol. Chem. 2000, 275, 3051–
3056.
Scheme 2. Transesterification on secologanin 1. Reagents and condi-
tions: (i) NaHCO3, R0OH, D. Hydrolysis of the ester under acidic
conditions results in the formation of a hemiacetal 10.
5. Gerasimenko, I.; Sheludko, Y.; Ma, X.; Stockigt, J. Eur. J.
Biochem. 2002, 269, 2204–2213.
6. Brown, R. T.; Curless, D. Tetrahedron Lett. 1986, 27,
6005–6008.
7. Brown, R. T.; Jones, M. F. J. Chem. Soc., Chem. Commun.
1986, 699–700.
8. McCoy, E.; Galan, M. C.; O’Connor, S. E. submitted for
publication.
complicated by the fact that after hydrolysis of the
ester, a cyclic hemiacetal can form (Scheme 2).14
Secologanin was dissolved in a variety of alcohols in
the presence of NaHCO3, and kept at 90 °C or refluxed
for 3 h (Scheme 2). Under these mild conditions, the
ethyl (9a, 65%), allyl (9b, 57%), propargyl (9c, 84%),
butyl (9d, 93%), and isopropyl (9e, 45%) ester deriva-
tives of unprotected secologanin were obtained. In the
same manner, a tert-butyl N-(3-hydroxypropyl)carba-
mate linker was introduced (9f, 62%). This general
trans-esterification method will be used to introduce a
variety of functional groups or chemical tags on
secologanin.15
9. Tietze, L. F.; Henke, S.; Remberg, G. Liebigs Ann. Chem.
1986, 1413–1427.
10. Based on recovered starting material. Typical yields of
recovered starting material for these reactions was 50%.
11. Characterization of compounds 6a–d (hydrated aldehyde
1
observed in 1D NMR spectra): Compound 6a: H NMR
(CD3OD, 500 MHz): 7.43 (d, 1H, J = 2 Hz), 5.77–5.66 (m,
1H), 5.49–5.42 (m, 1H), 5.29 (dd, 1H, J = 9.5, 15.3 Hz),
4.93 (m, 1H), 4.67 (dd, 1H, J =< 1, 8.0 Hz), 4.51 (dd, 1H,
J = 4.3, 7.3 Hz), 3.98–3.86 (m, 2H), 3.84–3.78 (m, 1H),
3.70 (s, 3H), 3.74–3.64 (m, 1H), 3.21 (t, 1H, J = 7.9 Hz),
3.04–2.85 (m, 1H), 2.76–2.61 (m, 1H), 2.20–2.03 (m, 2H),
1.80–1.74 (m, 1H), 1.64–1.56 (m, 1H), 1.46–1.24 (m, 8H),
0.97–0.84 (m, 3H). ESI (C23H36NaO10): m/z 495.4
[M+Na]+. Compound 6b: 1H NMR (CD3OD,
500 MHz): 7.43 (d, 1H, J = 2 Hz), 5.77–5.65 (m, 1H),
5.50–5.43 (m, 1H), 5.30 (dd, 1H, J = 9.2, 15.3 Hz), 4.95
(m, 1H), 4.67 (dd, 1H, J =< 1, 8.0 Hz), 4.51 (dd, 1H,
J = 4.3, 7.3 Hz), 3.98–3.86 (m, 2H), 3.85–3.78 (m, 1H),
3.70 (s, 3H), 3.74–3.64 (m, 1H), 3.20 (t, 1H, J = 8.0 Hz),
Qualitative studies evaluated the enzymatic activity of a
few of these unnatural secologanin derivatives with
strictosidine synthase and strictosidine glucosidase.8
Briefly, while bulkier groups at the vinyl position com-
pletely prevented turnover (compounds 6b,d), transeste-
rification at the methyl ester with larger alkyl groups
(compounds 9a,b) yielded substrates that were turned
over by the enzyme to yield the corresponding stricto-
sidine analogues, suggesting that this is a promising
position for derivatization for enzymatic biosynthesis
studies.

M. C. Galan, S. E. O’Connor / Tetrahedron Letters 47 (2006) 1563–1565
1565
3.03–2.85 (m, 1H), 2.76–2.61 (m, 1H), 2.17–2.03 (m, 2H),
1.80–1.72 (m, 1H), 1.64–1.56 (m, 1H), 1.46–1.28 (m, 4H),
0.98–0.85 (m, 3H). ESI (C21H32NaO10): m/z 467.5
[M+Na]+. Compound 6c: 1H NMR (CD3OD,
500 MHz): 7.42 (d, 1H, J = 2 Hz), 5.77–5.65 (m, 1H),
5.45 (dd, 1H, J = 4.9, 9.5 Hz), 5.30 (dd, 1H, J = 8.9,
15.3 Hz), 4.94 (dd, 1H, J = 4.3, 10.1 Hz), 4.67 (dd, 1H,
J = 1.22, 7.3 Hz), 4.51 (dd, 1H, J = 4.3, 7.3 Hz), 3.98–3.86
(m, 2H), 3.84–3.78 (m, 1H), 3.70 (s, 3H), 3.73–3.64 (m,
1H), 3.20 (m, 1H), 3.03–2.84 (m, 1H), 2.76–2.62 (m, 1H),
2.18–2.01 (m, 2H), 1.80–1.71 (m, 1H), 1.64–1.56 (m, 1H),
1.48–1.38 (m, 2H), 1.0–0.88 (m, 3H). ESI (C20H30NaO10):
2.8 Hz), 1.98 (dd, 1H, J = 4.0, 2.5 Hz), 1.50 (dd, 2H,
J = 9.8, 13.4 Hz), 1.34–1.20 (m, 3H). ESI (C18H26NaO10):
1
m/z 425.5 [M+Na]+. Compound 9b: H NMR (CD3OD,
500 MHz): 9.66 (s, 1H), 7.46 (s, 1H), 6.01–5.80 (m, 1H),
5.78–5.67 (m, 1H), 5.63–5.44 (m, 2H), 5.38–5.14 (m, 3H),
4.67 (d, 1H, J = 7.8 Hz), 4.74–4.53 (m, 2H), 4.39–4.28 (m,
1H), 4.24–4.13 (m, 2H), 3.89 (d, 1H, J = 9.9 Hz), 3.71–
3.61 (m, 1H), 3.20–3.10 (m, 2H), 2.76–2.60 (m, 1H), 1.98–
1.83 (m, 1H), 1.80–1.65 (m, 1H). ESI (C19H26NaO10): m/z
437.1 [M+Na]+. Compound 9c: 1H NMR (CD3OD,
500 MHz): 9.60 (s, 1H), 7.62 (s, 1H), 5.70–5.62 (m, 1H),
5.61–5.48 (m, 1H), 5.38–5.27 (m, 1H), 4.69 (t, 2H,
J = 7.9 Hz), 4.47 (t, 1H, J = 2.44 Hz), 4.40 (d, 1H,
J =< 2 Hz), 3.91 (dd, 1H, J =< 2, 11.9 Hz), 3.71–3.63
(m, 1H), 3.44–3.24 (m, 2H), 3.24–3.16 (m, 1H), 2.98–2.94
(m, 1H), 2.68 (dd, 1H, J = 5.8, 9.8 Hz), 2.06–1.98 (m, 1H),
1.93–1.85 (m, 1H), 1.83–1.74 (m, 1H), 1.58–1.46 (ddd, 1H,
J = 10.1, 9.8, 13.43 Hz). ESI (C19H24NaO10): m/z 435.1
[M+Na]+. Compound 9d: 1H NMR (CD3OD, 500 MHz):
9.59 (s, 1H), 7.60 (s, 1H), 5.80–5.70 (m, 1H), 5.61–5.48
(m, 1H), 5.37–5.22 (m, 1H), 4.69 (t, 2H, J = 7.9 Hz), 4.67–
4.58 (m, 1H), 4.16–4.08 (m, 1H), 4.01–3.94 (m, 1H), 3.91
(dd, 1H, J =< 2, 11.9 Hz), 3.71–3.64 (m, 1H), 3.64–3.58
(m, 1H), 3.45–3.24 (m, 2H), 3.24–3.15 (m, 1H), 3.02–2.94
(m, 1H), 2.68 (m, 1H), 2.10–1.92 (m, 1H), 1.78–1.56 (m,
2H), 1.52–1.38 (m, 2H), 1.02–0.90 (m, 3H). ESI
(C20H30NaO10): m/z 453.1 [M+Na]+. Compound 9e: 1H
NMR (CD3OD, 500 MHz): 9.67 (s, 1H), 7.43 (s, 1H),
5.80–5.68 (m, 1H), 5.63–5.46 (m, 1H), 5.38–5.20 (m, 3H),
4.66 (dd, 1H, J = 2.3, 7.9 Hz), 4.72–4.58 (m, 1H), 3.90 (d,
1H, J = 11.9 Hz), 3.71–3.61 (m, 2H), 3.24–3.10 (m, 3H),
2.76–2.60 (m, 1H), 2.20–1.88 (m, 1H), 1.78–1.58 (m, 1H),
1.29 (s, 6H). ESI (C19H28NaO10): m/z 439.2 [M+Na]+.
Compound 9f: 1H NMR (CD3OD, 500 MHz): 9.72 (s,
1H), 7.64 (s, 1H), 5.80–5.70 (m, 1H), 5.69–5.48 (m, 1H),
5.42 (dd, 1H, J = 2.1, 9.8 Hz),5.38–5.12 (m, 3H), 4.72–4.60
(m, 1H), 4.68 (d, 1H, J = 7.6 Hz), 4.13 (m, 1H), 4 (m, 1H),
3.91 (d, 1H, J = 11.9 Hz), 3.72–3.60 (m, 1H), 3.24 (m, 2H),
3.41–3.26 (m, 4H), 2.71 (m, 2H), 2.02 (d, 1H, J = 12.5 Hz),
0.99 (t, 9H, J = 6.7 Hz). ESI (C24H37NaO12): m/z 554.2
[M+Na]+.
1
m/z 453.1 [M+Na]+. Compound 6d: H NMR (CD3OD,
500 MHz): 7.43 (d, 1H, J = 2 Hz), 5.77–5.65 (m, 1H),
5.49–5.41 (m, 1H), 5.36–5.18 (m, 1H), 4.97 (m, 1H), 4.68
(m, 1H), 4.51 (dd, 1H, J = 4.3, 7.3 Hz), 3.98–3.86 (m, 2H),
3.85–3.78 (m, 1H), 3.70 (s, 3H), 3.76–3.63 (m, 1H), 3.20 (t,
1H, J = 7.5 Hz), 3.03–2.85 (m, 1H), 2.76–2.60 (m, 1H),
2.17–2.03 (m, 2H), 1.04 (s, 9H). ESI (C21H32NaO10): m/z
467.5 [M+Na]+.
12. Characterization of compound 8b (hydrated aldehyde
observed in 1D NMR spectra): 1H NMR (CD3OD,
500 MHz): 7.46 (d, 1H, J = 2 Hz), 5.48–5.39 (m, 1H),
4.86 (m, 1H), 4.72 (dd, 1H, J = 3.1, 7.8 Hz), 4.54 (d, 1H,
J = 7.9 Hz), 4.42 (t, 1H, J = 5.4 Hz), 4.13–4.04 (m, 1H),
3.98–3.86 (m, 2H), 3.84–3.76 (m, 1H), 3.70 (s, 3H), 3.74–
3.62 (m, 1H), 3.20 (t, 1H, J = 9.2 Hz), 2.90–2.85 (m, 1H),
2.76–2.62 (m, 1H), 1.90–1.72 (m, 2H), 1.66–1.52 (m, 2H),
1.46–1.22 (m, 6H), 0.98–0.85 (m, 3H). ESI
(C21H34NaO10): m/z [M+Na]+ 469.3.
13. For a review on transesterification see: Otera, J. Chem.
Rev. 1993, 93, 1449–1470.
14. Tomassini, L.; Cometa, M. F.; Serafini, M.; Nicoletti, M.
J. Nat. Prod. 1995, 11, 1756–1758.
1
15. Characterization of Compounds 9a–f: Compound 9a: H
NMR (CD3OD, 500 MHz): 9.74 (s, 1H), 7.43 (s, 1H),
5.79–5.70 (m, 1H), 5.60–5.48 (m, 1H), 5.44 (dd, 1H,
J = 2.5, 9.8 Hz), 5.36–5.22 (m, 1H), 4.68 (d, 1H,
J = 7.9 Hz), 4.68–4.58 (m, 1H), 4.20–4.12 (m, 1H), 4.06–
3.98 (m, 1H), 3.92–3.86 (m, 2H), 3.74–3.63 (m, 1H), 3.40–
3.10 (m, 1H), 2.74–2.64 (m, 1H), 2.10 (dd, 1H, J = 6.7,