A new asymmetric synthesis of (+)-12b-epidevinylantirhine

Article abstract of DOI:10.1016/j.tetlet.2006.06.033

We report a new asymmetric synthesis of the indole alkaloid derivative (+)-12b-epidevinylantirhine through stereoselective cyclization of a tethered indole nucleus onto an N-acyliminium ion intermediate, generated from a readily available non-racemic bicy

Full text of DOI:10.1016/j.tetlet.2006.06.033

Tetrahedron Letters 47 (2006) 5737–5739
A new asymmetric synthesis of (+)-12b-epidevinylantirhine
Steven M. Allin,a,* Jagjit S. Khera,a Jason Witheringtonb and Mark R. J. Elsegooda
aDepartment of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
bDepartment of Medicinal Chemistry, Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline
Research Limited, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
Received 13 February 2006; revised 23 May 2006; accepted 2 June 2006
Available online 27 June 2006
Abstract—We report a new asymmetric synthesis of the indole alkaloid derivative (+)-12b-epidevinylantirhine through stereoselec-
tive cyclization of a tethered indole nucleus onto an N-acyliminium ion intermediate, generated from a readily available non-racemic
bicyclic lactam building block, and subsequent template modification through a highly diastereoselective conjugate addition proto-
col. In addition, we present the first X-ray crystal structure of this indole target.
Ó 2006 Elsevier Ltd. All rights reserved.
The indole alkaloids and their synthetic analogues re-
main a major topic of synthetic endeavour due to their
important structural and pharmacological properties.
The indolo[2,3-a]quinolizine ring system is found within
a plethora of alkaloids and related compounds including
geissoschizine 1,1 geissoschizol 22 and (+)-12b-epide-
vinylantirhine 3.2 Recent approaches to the construction
of this heterocyclic target system by other groups have
included the diastereoselective vinylogous Mannich
reaction,3 Bischler–Napieralski reaction,4 Fischer indole
synthesis,5 an asymmetric Pictet–Spengler reaction,6 and
more recently our own contribution to the area: the ste-
reoselective cyclization of a pendent indole substituent
onto an N-acyliminium intermediate generated from
bicyclic lactam templates such as 4.7 An alternative,
but related, approach by Bosch, Amat and co-workers
allows the construction of more highly functionalized
substrates prior to a similar N-acyliminium-mediated
cyclization.8 In this letter we describe the application
of our own methodology in target synthesis, and report
a new asymmetric synthesis of (+)-12b-epidevinylanti-
rhine, 3. This target was originally isolated by Wenkert2
during studies towards the synthesis of geissoschizine 1
and geissoschizol 2, and has, to the best of our knowl-
edge, only been prepared in an asymmetric fashion by
Ihara and co-workers.9
Our new approach for the asymmetric synthesis of (+)-
12b-epidevinylantirhine, 3, began with the preparation
of the enantiomerically pure key building block 11 from
indolizino[2,3-a]quinolizidine derivative 5, obtained as a
single diastereoisomer on activation and cyclization of
bicyclic lactam template 4 (Ar = 30-indole), as previ-
ously reported (Scheme 1).7
On addition of 2 equiv of lithiated methyl 1,3-dithio-
lane-2-carboxylate to substrate 11, we were pleased to
observe the exclusive formation of the addition product
N
N
N
Ar
N
N
H
N
H
H
H
H
H
O
N
O
H
H
H
H
MeO2C
OH
OH
OH
1
2
3
4
*
Corresponding author. Tel.: +44 1509 222559; fax: +44 1509 223925; e-mail: S.M.Allin@lboro.ac.uk
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.033

5738
S. M. Allin et al. / Tetrahedron Letters 47 (2006) 5737–5739
R'
R'
(iii)
(vi)
O
O
O
N
N
N
N
R
N
N
H
H
H
Boc
Boc
(i)
11
5, R = H, R' = CH2OH
6, R = H, R' = CHO
7, R = Boc, R' = CHO
8, R = Boc, R' = CO2H
9, R = Boc, R' = COSePh
10, R = Boc, R' = H
(iv)
(v)
(ii)
Scheme 1. Reagents and conditions: (i) IBX, DMSO, rt, 24 h (70%); (ii) Et3N, (Boc)2O, DMAP, THF, rt, 4 h (98%); (iii) NaClO2, NaH2PO4, 1-
methyl-1-cyclohexene, CH3CN, t-BuOH, H2O, 0 °C to rt, 18 h (83%); (iv) (PhSe)2, PBu3, CH2Cl2, 0 °C to rt, 18 h (83%); (v) n-Bu3SnH, AIBN,
toluene, 80 °C, 2 h (73%); (vi) LDA, PhSeBr, THF, ꢀ78 °C to rt, 24 h; then NaIO4, NaHCO3, MeOH, H2O, rt, 18 h (85% for two steps).
O
O
N
N
O
(i)
(ii)
N
N
N
H
H
N
CO2Me
Boc
Boc
H
S
Boc
11
H
H
S
13
MeO2C
12
(iii)
N
H
N
O
N
(iv)
H
H
N
H
H
3
H
OH
14
MeO2C
[α]D = + 34.4 (c = 0.5, MeOH)
Scheme 2. Reagents and conditions: (i) methyl 1,3-dithiolane-2-carboxylate (2 equiv), n-BuLi (2 equiv), THF, ꢀ78 °C to rt, 24 h (47%); (ii)
NiCl2Æ6H2O (10 equiv), NaBH4 (30 equiv), THF–MeOH (1:3), 0 °C to rt, 4 h (73%); (iii) HCOOH (neat), rt, 28 h (71%); (iv) LiAlH4 (8 equiv), THF,
D 3 h, then rt 12 h (50%).
12 as a single diastereoisomer in 47% yield (Scheme 2).
Analysis of compound 12 by X-ray crystallography10
confirmed that the protons at positions 2 and 12b had
cis relative stereochemistry, as required for the current
target, (+)-12b-epidevinylantirhine 3,2,9 and also found
in the natural products geissoschizine 11 and geisso-
schizol 2.2
2. With 13 in hand we then achieved the deprotection
of the indole nitrogen through removal of the N-Boc
protecting group on treatment of 13 with neat formic
acid to generate 14 in 71% yield. Completion of the syn-
thesis involved reduction of both the lactam carbonyl
and the methyl ester moieties, and this global reduction
was achieved with excess lithium aluminium hydride to
furnish the desired target 3 in 50% yield.
The stereocontrol observed in the addition reaction is
presumably under thermodynamic control, with the
addition of the stabilized nucleophile being ultimately
reversible in nature. However, other studies by our
group have shown that one cannot discount the possibil-
ity of a conformational change in the template caused by
appropriate choice of N-protection on the indole ring.11
The conjugate addition of carbon nucleophiles to a,b-
unsaturated lactams is known to be challenging, and
although in our case the addition of the lithiated methyl
1,3-dithiolane-2-carboxylate to compound 11 proceeded
well, previous work on similar templates, including
Overman’s derivatization of racemic and enantiomeri-
cally pure indolo[2,3-a]quinolizine derivatives, has re-
quired the presence of an activating group on the
substrate.12
Whilst the spectroscopic data of our compound 3
matched that reported in the literature,9 the optical rota-
tion, found to be +34.4 (c 0.5, CH3OH), did not corre-
spond to the value of +12.3 (c 0.5, CH3OH) that was
previously reported.9
We were able to obtain an X-ray crystal structure14 of
target 3, both to confirm the final structure and also
to determine that the protons at the chiral centres were
present with cis relative stereochemistry as required
(Fig. 1).
In summary, we report a new, facile and highly stereo-
selective approach for the synthesis of the indole alkaloid
derivative (+)-12b-epidevinylantirhine.15 Our method
combines two highly diastereoselective protocols: rapid
construction of the core indolo[2,3-a]quinolizine ring
system, with efficient template manipulation through
stereoselective conjugate addition to an a,b-unsaturated
Our transformation of 12 to target 3 involved the desul-
furization13 of the dithioacetal moiety with nickel bor-
ide, furnishing 13 in 73% yield, as detailed in Scheme

S. M. Allin et al. / Tetrahedron Letters 47 (2006) 5737–5739
5739
I.; Allard, J. E.; Doyle, K.; Elsegood, M. R. J. Eur. J. Org.
Chem. 2005, 4179–4186.
8. Bassas, O.; Llor, N.; Santos, M. M. M.; Griera, R.;
Molins, E.; Amat, M.; Bosch, J. Org. Lett. 2005, 7, 2817–
2820.
9. Katsumata, A.; Iwaki, T.; Fukumoto, K.; Ihara, M.
Heterocycles 1997, 46, 605–616; Ihara, M.; Katsumata, A.;
Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1997, 991–
992.
10. Crystallography for 12: C25H30N2O5S2, M = 502.63,
monoclinic, P21, a = 10.5505(7), b = 9.3807(6), c =
3
˚
˚
12.4921(8) A,
b = 100.281(2)°,
V = 1216.51(14) A ,
Z = 2, 10,789 data measured, Rint = 0.0192, wR2 =
0.0905 for all 5594 unique data, R1 = 0.0379 for 5007
data with F2 P 2r(F2). Absolute structure para-
meter = ꢀ0.03(6)—thus reliably determined. CCDC
286786 contains supplementary crystallographic data in
cif format. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK. Fax:
+44 1223 336033, e-mail: deposit@ccdc.cam.ac.uk).
11. Allin, S. M.; Khera, J. S.; Thomas, C. I.; Witherington, J.;
Doyle, K.; Elsegood, M. R. J.; Edgar, M. Tetrahedron
Lett. 2006, 47, 1961–1964.
Figure 1. Crystal structure of (+)-12b-epidevinylantirhine.
lactam. Current work is focused on extending the meth-
odology described in this letter to other, more complex
indole alkaloid targets. Our progress will be reported in
due course.
12. Overman, L. E.; Robichaud, A. J. J. Am. Chem. Soc. 1989,
111, 300–308, and references cited therein.
Acknowledgements
13. Amat, M.; Perez, M.; Llor, N.; Bosch, J. Org. Lett. 2002,
4, 2787–2790.
14. Crystallography for 3: C17H22N2O, M = 270.37, ortho-
The authors thank Loughborough University and GSK
Pharmaceuticals for a joint studentship to J.S.K., and
also thank Dr. Sandeep Handa of the University of
Leicester for providing access to facilities for
polarimetry.
rhombic, P212121, a = 6.6981(9), b = 10.1667(14), c =
3
˚
˚
22.163(3) A, V = 1509.2(4) A , Z = 4, 8832 data mea-
sured, Rint = 0.0543, wR2 = 0.1472 for all 1958 unique
data, R1 = 0.0622 for 1351 data with F2 P 2r(F2). Abso-
lute structure parameter = 0(5)—thus not reliably deter-
mined. Two unique H-bonds: N(12)–H(12)ꢁ ꢁ ꢁO(10) and
O(1)–H(1)ꢁ ꢁ ꢁN(500) {Symmetry operations for equivalent
References and notes
0
00
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ꢀz + 1/2}, with each molecule making four H-bonds to its
neighbours in a thick-sheet structure. CCDC 296935.
15. Selected data for compound 3; colourless needles, mp 239–
240 °C; [a]D 34.4 (c 0.5, MeOH); dH (400 MHz; MeOH)
1.16–1.24 (1H, m), 1.38–1.48 (1H, m), 1.50–1.63 (2H, m),
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3.29–3.34 (1H, m) 3.67–3.70 (2H, m), 6.94–6.98 (1H, m),
7.01–7.05 (1H, m), 7.27–7.29 (1H, m), 7.36–7.38 (1H, m),
[OH, NH not visible]; dC (100 MHz; CDCl3) 22.4, 32.9,
33.8, 36.7, 40.5, 54.4, 56.5, 60.4, 61.7, 107.7, 111.9, 118.6,
119.8, 121.9, 128.4, 135.9, 138.1; MS (EI) m/z 270 [M+,
14.1%] (Found: M+, 270.17290. C17H22N2O requires
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