Enantiospecific synthesis of (-)-3-iso-19,20-dehydro-β-yohimbine from secologanin: A route to normal and pseudo stereoisomers of yohimbine

Article abstract of DOI:10.1016/S0040-4039(00)00912-6

Hydrolysis of secologanin ethylene acetal at pH 7 resulted in stereoselective aldol cyclisation to a cyclohexene aldehyde, which, on reductive amination and cyclisation with tryptamine afforded (-)-3-iso-19,20- dehydro-β-yohimbine, converted into various normal and pseudo isomers of yohimbine. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00912-6

Tetrahedron Letters 41 (2000) 5627±5630
Enantiospeci®c synthesis of (^)-3-iso-19,20-dehydro-b-
yohimbine from secologanin: a route to normal and pseudo
stereoisomers of yohimbine
Richard T. Brown,* Simon B. Pratt and Paul Richards
Department of Chemistry, The University of Manchester, Manchester M13 9PL, UK
Received 10 May 2000; accepted 1 June 2000
Abstract
Hydrolysis of secologanin ethylene acetal at pH 7 resulted in stereoselective aldol cyclisation to a cyclo-
hexene aldehyde, which, on reductive amination and cyclisation with tryptamine a€orded (^)-3-iso-19,20-
dehydro-b-yohimbine, converted into various normal and pseudo isomers of yohimbine. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: Aldol; alkaloids; biomimetic; indole; stereoselection; terpene.
Â
The pentacyclic series of Corynanthe indole alkaloids, exempli®ed by yohimbine 8, have been
known for well over a century, and, because of their pharmacological properties, have been targets
for many syntheses.1 In nature they occur as various stereoisomers, but all have a common H-15a
(S) con®guration derived from C-7 in the monoterpenoid secologanin 1, which condenses with
tryptamine to form the universal indole alkaloid precursor, strictosidine.2 Our group has carried
out several stereoselective syntheses of alkaloids from secologanin derivatives in which the
asymmetric centre at C-7 played a role in inducing chirality at other centres.3 Thus, conversion of
the C-5 aldehyde in 1 to a methyl ester and hydrolysis with b-glucosidase at pH 5.0 resulted in
rearrangement of the aglucone largely to the known methyl elenolate, from which ajmalicine and
other heteroyohimbine alkaloids could be prepared.4 We found that precise control of the pH was
crucial to optimise the yield of the desired aglucone, and a signi®cant discovery was that at pH
7.0 an alternative rearrangement via a vinylogous aldol reaction predominated to give an epimeric
pair of cyclohexene aldehydes, from which yohimbine and b-yohimbine were obtained.5 However,
although the results were interesting as a biomimetic analogy, the methyl ester did not a€ord a
really satisfactory synthetic route because it gave mixtures at various stages. It was also a rather
cumbersome way of protecting the aldehyde, in that it involved oxidation and reduction of C-5,
so we therefore looked to an alternative.
* Corresponding author. Tel: +44 161 275 4632; fax: +44 161 275 4939; e-mail: r.t.brown@man.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00912-6

5628
An acetal was intrinsically attractive since acid catalysed removal could in principle also promote
Pictet±Spengler cyclisation to the required pentacyclic system. Thus, acetylation of secologanin
followed by ethylene glycol in the presence of acid gave the tetra-acetate of ethylene acetal 2, mp
125ꢀC [ꢀ]D ^100 (CHCl3). Zemplen deacetylation and subsequent hydrolysis with b-glucosidase in
pH 7.0 bu€er at 37ꢀC for 4 days a€orded in 70% yield the cyclohexene aldehyde 3 [ꢀ]D +11.5
(CHCl3) [M+ 270.1109 (C13H18O6); lmax (MeOH): 228 nm; ꢁmax (CHCl3) 3450, 2720, 1725, 1685,
1
1630 cm^1]. Importantly, on the basis of the H NMR spectrum,8 3 consisted of essentially only
one C-9 stereoisomer (unlike the previous analogues) with trans±trans C-7, 8, 9 stereochemistry.
Hence, with the C-5 acetal the vinylogous aldol cyclisation (Scheme 1) has achieved virtually
complete stereoselection with the single chiral centre at C-7 (S) inducing R chirality at both C-8
and C-9 in 3, a result attributable to a chair-like transition state with all the 7, 8 and 9 sub-
stituents equatorial.
Scheme 1. Reagents and conditions: (i) Ac2O/py, 12 h; (ii) (CH2OH)2/THF/TFA, Á, 1 h; (iii) NaOMe/MeOH, 12 h;
(iv) b-glucosidase/pH 7.0 aq. bu€er, 37ꢀC, 4 days; (v) tryptamine, MeOH/NaCNBH3, 2 days; (vi) 10% aq.
HCl:Me2CO 1:1, Á, 2 h; (vii) H2/Pd/MeOH, 12 h; (viii) DMSO/Ac2O, 16 h; (ix) NaBH4, iPrOH, 20 h; (x) AcOH, Á, 2±
4 days; (xi) H2/PtO2/Et OH, 24 h
The next step was reductive amination of the aldehyde with tryptamine, a reaction which had
previously been problematic due to mixtures formed by competing conjugate reduction under a
variety of conditions and reducing agents. However, in this case over-reduction was essentially
avoided by the use of sodium cyanoborohydride in methanol to a€ord in ca. 85% yield the

5629
desired amine 4 [M+ 414.2170 (C23H30N2O5); lmax: 226, 283, 292 nm; ꢁmax: 3470, 1730 cm^1]
together with a probable boron complex. The structure 4 was corroborated by the H NMR
1
spectrum (300 MHz, CDCl3) with signals for both indole [ꢂ 8.29 (s, HN-1), 7.7±7.1 (m, 4 arH),
7.10 (bs, H-2)] and monoterpene [ꢂ 5.59 (bd, H-19), 4.79 (t, H-3), 4.83 (s, CO2Me)] moieties.
Heating the above crude product in a 1:1 mixture of acetone and 10% aq. hydrochloric acid
under re¯ux for 2 hours gave, in 75% yield on crystallisation from acetone, a single compound,
mp 140^142ꢀC [ꢀ]D ^73 (MeOH); [lmax (MeOH): 227, 283, 291 nm; ꢁmax (CHCl3): 3470, 1730
cm^1]. That hydrolysis of the acetal and subsequent cyclisation to a 19,20-dehydroyohimbine had
occurred was indicated inter alia by the mass spectrum with M+ 352.1777 (C21H24N2O3) and
several characteristic peaks, including an ion at m/z 156 that was much more intense than that at
m/z 184,6 and by the loss of the NMR signal for the indolic H-2 in 4. The structure and relative
stereochemistry was established as 3-iso-19,20-dehydro-b-yohimbine 5 from a complete analysis
1
of the the H NMR spectra9 of the product and its 17-O-acetate. Diaxial couplings of 10 Hz
con®rmed that the H-15, 16, 17 trans±trans stereochemistry had been retained, whereas the small
ae and ee couplings of 5 and 2.5 Hz to the C-14 methylene protons showed that H-3 was equa-
torial, establishing a 3±15 trans orientation. From the known absolute stereochemistry of C-7 in
secologanin, this would correspond in 5 to a 3-b(R) con®guration, which was con®rmed by a ^ve
Cotton e€ect (^2.7Â104 cm^2 dmol^1) at 280 nm in the CD spectrum.7 Exclusive generation of
this stereochemistry in the Pictet±Spengler cyclisation can be attributed to kinetic axial attack by
the indole at a C-3/N-4 iminium in a chair-like intermediate with equatorial C-15, 16 and 17
substituents to give a cis-quinolizidine (Scheme 2). Because this was a kinetic product, in addition
to the 3b(R) series, it a€orded routes to the thermodynamically preferred trans-quinolizidine
alkaloids with 3a(S) con®guration.
Scheme 2.
Thus, catalytic hydrogenation of the 19,20 double bond in 5 with Pd/C occurred only from the
top face to give a quantitative yield of pseudo-b-yohimbine 6, mp 135±138ꢀC [ꢀ]D +68 (MeOH),
as indicated by M+ 354.1939 (C21H26N2O3) and the NMR spectrum9 with three large trans-di-
axial couplings to H-20 from protons on C-15, 19 and 21; small couplings to H-3 showed retention
of an equatorial b-con®guration which was corroborated by a ^ve Cotton e€ect at 280 nm in the
CD spectrum. Mot oxidation of 6 gave the 17-ketone, mp 220±223ꢀC [M+ 352.1787
(C21H24N2O3)] which was reduced stereoselectively with sodium borohydride in isopropanol to
only pseudoyohimbine 7, mp 250±253ꢀC [M+ 354.1927 (C21H26N2O3)]. Its NMR spectrum9 was
similar to that of 6, except for small couplings to H-17 in accord with inversion to an axial OH
group. Subsequent heating in glacial acetic acid epimerised C-3 to give the trans-quinolizidine
yohimbine 8 [M+ 354.1943 (C21H26N2O3)], characterised by a broadened doublet for H-3 with a
trans diaxial coupling of 11 Hz in the NMR spectrum,9 and a +ve Cotton e€ect at 280 nm in the
CD spectrum,7 and identi®ed by comparison with an authentic sample. A similar epimerisation of
6 a€orded b-yohimbine 9 [M+ 354.1924 (C21H26N2O3)], which was also produced directly by

5630
hydrogenation of 5 with Adams' catalyst. Again, oxidation of 9 to yohimbone, mp 245±248ꢀC
[M+ 352.1783 (C21H24N2O3)] and subsequent reduction gave yohimbine.
Hence, we have synthesised, in ca. 40% overall yield from secologanin, (^)-3-iso-19,20-dehydro-
b-yohimbine 5, an example (as yet unknown in nature) of a rare type of indole alkaloid, and used
it to prepare selectively four of the normal and pseudo stereoisomers of yohimbine. Its further
conversion into epiallo and allo isomers is discussed in the following paper.10
Acknowledgements
We thank the EPSRC for Studentships (S.B.P., P.R.).
References
1. For reviews, see: (a) Szantay, C.; Honty, K. In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; John Wiley:
Chichester, 1994; chapter 4. (b) Szantay, C.; Blasko, G.; Honty, K.; Dornyei, G. In The Alkaloids; Brossi, A., Ed.;
Academic Press: Chicago, 1986; Vol. 27, chapter 2, and references cited therein.
2. Nagakura, N.; Ru€er, M.; Zenk, M. H. J. Chem. Soc., Perkin Trans. 1 1979, 2308±2312.
3. (a) Brown, R. T. In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; John Wiley: New York, 1983; pp. 135±139,
192±194. (b) Brown, R. T.; Dauda, B. E. N.; Santos, C. A. M. Chem. Commun. 1991, 825±826. (c) Brown, R. T.;
Kandasamy, M. Tetrahedron Lett. 2000, 41, 3547±3550.
4. Brown, R. T.; Chapple, C. L.; Duckworth, D. M.; Platt, R. J. Chem. Soc., Perkin Trans. 1 1976, 160±163.
5. Brown, R. T.; Pratt, S. B. Chem. Commun. 1980, 165±166.
6. Arndt, R. R.; Djerassi, C. Experientia 1965, 21, 566±568.
7. (a) Klyne, W.; Swan, R. J.; Dastoor, N. J.; Gorman, A. A.; Schmid, H. Helv. Chim. Acta 1967, 50, 115±119. (b)
Lee, C. M.; Trager, W. F.; Beckett, A. H. Tetrahedron 1967, 23, 375±379.
8. 1H NMR spectrum (300 MHz, d6-Me2CO) (numbering based on secologanin). Compound 3: ꢂ 9.50 (s, H-1), 6.91
(ddd, J=5, 3, 1 Hz, H-3), 4.92 (dd, J=5.5, 5 Hz, H-5), 4.12 (ddd, J=8, 7.5, 5 Hz, H-9), 4.0±3.8 (m, OCH2CH2O),
3.71 (s, OMe), 3.15 (m, J=8, 7.5, 3.5, 1 Hz, H-7), 3.08 (dd, J=8, 7.5 Hz, H-8), 2.44 (ddt, J=19.5, 7.5, 3 Hz, H-4b),
2.69 (dtd, J=19.5, 5, 1.5 Hz, H-4a), 2.29 (ddd, J=14, 8, 5 Hz, H-6a), 1.80 (ddd, J=14, 5.5, 3.5 Hz, H-6b).
1
9. Selected H NMR spectra (300 MHz, CDCl3) (numbering based on yohimbine). Compound 5: ꢂ 8.14 (bs, NH),
7.49±7.13 (m, ar-H4), 5.47 (d, J=5.5 Hz, H-19), 4.42 (ddd, J=5, 2.5, 2 Hz, H-3), 3.86 (ddd, J=10.5, 10, 5 Hz, H-17),
3.81 (s, OMe), 3.34 (d, J=13 Hz, H-21eq), 3.27 (m, H2-5), 3.07 (d, J=13 Hz, H-21ax), 3.01 (dm, J=17 Hz, H-6eq),
2.59 (ddd, J=17, 4.5, 2.5 Hz, H-6ax), 2.35±2.40 (m, H-14eq, H-15, H-16, H-18eq), 2.10 (ddd, J=17.5, 10.5, 3 Hz, H-
18ax), 1.81 (ddd, H-14ax). Compound 5 O-acetate: ꢂ 5.50 (d, J=4.5 Hz, H-19), 4.98 (ddd, J=10.5, 10, 5 Hz, H-17),
4.54 (ddd, J=5, 2.5, 2 Hz, H-3), 3.76 (s, OMe), 3.40 (dm, J=13, ꢁ3, ꢁ1 Hz, H-21eq), 3.3 (m, H2-5), 3.14 (d, J=13
Hz, H-21ax), 3.02 (dm, J=17 Hz, H-6eq), 2.63 (ddd, J=17, 4.5, 2.5 Hz, H-6ax), 2.50 (dm, J=17.5, 10, ꢁ3, ꢁ1 Hz,
H-18eq), 2.54 (t, J=10 Hz, H-16), 2.48 (ddd, J=11.5, 10, 4.5 Hz, H-15), 2.32 (ddd, J=13.5, 4.5, 2.5 Hz, H-14eq),
2.12 (ddm, J=17.5, 10.5, ꢁ3 Hz, H-18ax), 1.87 (ddd, J=13.5, 11.5, 5 Hz, H-14ax). Compound 6: ꢂ 4.47 (dd, J=4,
1.5 Hz, H-3), 3.84 (s, OMe), 3.58 (td, J=11, 4 Hz, H-17), 4.41 (m, H2-5), 3.02 (tdd, J=12, 6, 2.5 Hz, H-6a), 3.74
(dm, J=12 Hz, H-6b), 2.76 (dd, J=12, 5 Hz, H-21eq), 2.53 (t, J=12 Hz, H-21ax), 2.16 (t, J=11 Hz, H-16), 2.10
(dtd, J=11, 9, 2.5 Hz, H-15), 2.1±2.0 (m, H2-14, H-18eq), 2.12 (dtd, J=16, 12, 2.5 Hz, H-18ax), ca. 1.6 (m, H-19eq, H-
20), 1.39 (dtd, J=16, 12, 2.5 Hz, H-18a), 0.92 (dtd, J=16, 12, 2.5 Hz, H-19a). Compound 7: ꢂ 4.75 (ddd, J=5, 2.5,
1.5 Hz, H-3), 4.29 (bs, J=3, 2.5, 2 Hz, H-17), 3.92 (s, OMe), 3.44 (m, H2-5), 3.07 (dm, J=16 Hz, H-6a), ca. 2.8
(dm, J=16 Hz, H-6b; dd, J=12, 3.5 Hz, H-21eq), 2.68 (t, J=12 Hz, H-21ax), 2.34 (dd, J=12, 3 Hz, H-16), 2.30
(dm, J=12, 3, 2.5 Hz, H-14eq), 2.00 (td, J=12, 5 Hz, H-14ax), 1.87 (dm, J=12, ꢁ3 Hz, H-18eq), 1.78±1.55 (tm, J=12
Hz, H-15; tm, J=12 Hz, H-18ax; td, J=12, 3.5 Hz, H-20), 1.30 (bq, J=12 Hz, H-19ax), 0.92 (dbd, J=12, 3 Hz, H-
19eq). Compound 8: ꢂ 4.35 (dm, J=ꢁ3 Hz, H-17), 3.72 (s, OMe), 3.43 (bd, J=11 Hz, H-3), 3.01 (dd, J=11, 3 Hz, H-
21ex), 2.65 (t, J=11 Hz, H-21aq), 2.38 (dd, J=11, 3 Hz, H-16), 1.45 (tm, J=11 Hz, H-15), 1.26 (q, J=11 Hz, H-
14ax). Compound 9: ꢂ 3.81 (ddd, J=5, 2.5, 1 Hz, H-17), 3.78 (s, OMe), 3.22 (dd, J=11, 2.5 Hz, H-3).
10. Binns, F.; Brown, R. T.; Dauda, B. E. N. Tetrahedron Lett. 2000, 41, 5631±5635.