Total synthesis of (-)-eburnamonine and (+)-epi-eburnamonine from a chiral non-racemic 4,4-disubstituted γ-lactone

Article abstract of DOI:10.1016/S0040-4039(99)02131-0

The total synthesis of (-)-eburnamonine and (+)-epi-eburnamonine was successfully achieved using a key chiral non-racemic 4,4-disubstituted γ- lactone 4 that was prepared via the Rh(II) carbenoid mediated tertiary C-H insertion reaction of a chiral non-racemic diazomalonate 5. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02131-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 587–590
Total synthesis of (−)-eburnamonine and (+)-epi-eburnamonine
from a chiral non-racemic 4,4-disubstituted γ-lactone
Andrew G. H. Wee ∗ and Qing Yu
Department of Chemistry, University of Regina, Regina, Saskatchewan S4S 0A2, Canada
Received 20 September 1999; revised 10 November 1999; accepted 12 November 1999
Abstract
The total synthesis of (−)-eburnamonine and (+)-epi-eburnamonine was successfully achieved using a key
chiral non-racemic 4,4-disubstituted γ-lactone 4 that was prepared via the Rh(II) carbenoid mediated tertiary C–H
insertion reaction of a chiral non-racemic diazomalonate 5. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: rhodium(II) carbenoid; asymmetric synthesis; tertiary C–H; insertion.
Many natural products, such as alkaloids and terpenes, possess quaternary carbon centers that are part
of the skeletal framework of the molecules. The synthesis of these natural products must invariably
address the challenging task of the enantioselective construction of the quaternary carbon centers.
Many different strategies1 have been developed, but some limitations1c,d,g,h have been noted. We
recently described a strategy2a for the synthesis of (±)-quebrachamine wherein an unsymmetrical
4,4-disubstituted γ-lactone was employed as a key intermediate. The requisite γ-lactone was readily
accessed via our Rh(II) carbenoid mediated intramolecular tertiary C–H insertion reaction.2b This success
prompted us to investigate a similar strategy for the asymmetric synthesis of the pentacyclic indole
alkaloids3 (−)-eburnamonine 1a and (+)-epi-eburnamonine 1b, and we report our findings in this Letter.
The retrosynthetic analysis of 1a,b is shown in Fig. 1. The hydroxy-lactam aldehyde 2 can be derived
from the γ-lactone amide 3, which in turn, is accessible from the chiral non-racemic γ-lactone carboxylic
acid 4. Compound 4 is prepared via Rh(II)-catalyzed tertiary C–H insertion reaction of chiral non-racemic
diazo compound 5.
The diazomalonate 5 was readily prepared starting from the known N-butanoyloxazolidinone4 6 as
summarized in Scheme 1. Alkylation of 6 with allyl bromide followed by hydrolysis5 and reduction
24
gave the volatile primary alcohol (S)-7a {[α] +1.8 (c 1.4, CHCl3)}. The absolute configuration of 7a
D
24
D
was confirmed by conversion to the p-methoxybenzyl ether 7b {[α] −2.8 (c 1.8, CHCl3)}, whose
optical rotation is of the same magnitude but opposite in sign to the optical rotation of the known
∗
Corresponding author. Fax: 306-585-4894; e-mail: andrew.wee@uregina.ca (A. G. H. Wee)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02131-0
tetl 16059

588
Fig. 1.
24
enantiomer,6 (R)-7b {[α] +1.9 (c 2.01, CHCl3)}. Esterification7 of the primary hydroxyl group with
D
α-(carbomethoxy)acetic acid (DCC, DMAP) followed by diazotization afforded 5.
Scheme 1. Reagents and conditions: PMP=p-methoxybenzyl, TBDPS=t-butyldiphenylsilyl: (a) (i) NaN(SiMe3)2, THF, −78°C,
then allyl bromide, −40°C, 89%; (ii) LiOH, H2O2, THF, 99%; (iii) LiAlH4, THF, 0°C, 50%; (b) (i) MeO2CCH2CO2H, DCC,
DMAP, CH2Cl2, 91%; (ii) Sia2BH, THF, 0°C, then H2O2, NaOH, 70%; (iii) TBDPS–Cl, pyridine, 89%; (c) MsN3, Et3N, MeCN,
88%; (d) 2 mol% Rh2OAc4, CH2Cl2, reflux, 90%; (e) 10:1 v/v DMSO:H2O, NaCl, 110°C, 84%; (f) (i) Bu4N F, THF, 93%; (ii)
CrO3, H2SO4, H2O, 95%
With compound 5 in hand, we examined the preparation of the γ-lactone carboxylic acid 4. Rho-
dium(II) carbenoid insertion into the C–H bond of a configurationally defined tertiary carbon stereocenter
has been shown to proceed stereospecifically and with retention of configuration.8 With this fact in mind,
5 was treated with 2 mol% of Rh2(OAc)4 under our previously described2 reaction conditions to furnish
a high yield (90%) of a 1:1 diastereomeric mixture of 9a, which was efficiently decarboxylated9 to yield
23
D
(S)-9b {([α] −3.3 (c 1.5, CHCl3)}. The configuration at the new C-4 stereocenter was confirmed by
the successful transformation of (S)-9b to eburnamonine 1a (and its epimer 1b).
Desilylation of 9b released the primary alcohol unit, which was oxidized using Jones’ reagent to give
24
a high yield of the γ-lactone carboxylic acid (S)-4 {[α] −7.1 (c 1.4, CHCl3)}. Condensation of 4 with
D
24
tryptamine under standard conditions,7 provided a 67% yield of amide 10 {[α] −2.9 (c 0.9, CHCl3)}.
D
Selective reduction of the lactone moiety in 10 (Scheme 2) with LiBH4 produced the corresponding
diol which was selectively protected, at the less hindered, non-neopentylic primary alcohol unit, as the
24
D
t-butyldiphenylsilyl ether 11 {[α] −1.3 (c 2.0, CHCl3)}. Oxidation of the neopentylic alcohol moiety
was best achieved under Parikh–Doering conditions10 to give an excellent yield of a 1.7:1 mixture of the

589
lactam alcohol 12 and the aldehyde 13. Separation of the two products was not essential as treatment
of the mixture of 12 and 13 in toluene (rt) with 50 mol% Nafion-H afforded a 95% yield of the readily
24
24
separable lactams 14a {[α] −50 (c 0.2, CHCl3)} and 14b {[α] +85 (c 0.5, CHCl3)}, and in a
D
D
ratio of 1:2.11 Treatment of 14a and 14b with Me3SiCl in dry methanol proceeded efficiently to furnish
24
D
the known crystalline alcohols 15a12a {[α] −192.3 (c 0.13, MeOH), lit.3b [α] −195.5 (c 0.16,
D
24
24
D
MeOH)} and 15b12b {[α] +111 (c 0.54, MeOH, lit.3b [α] +88.3 (c 0.13, MeOH)}, respectively.
D
The conversion of 15a to (−)-eburnamonine 1a proved to be non-trivial. Brief treatment of 15a with
LiAlH4 gave a moderate yield of the corresponding amino alcohol 16a; it was found that prolonged
reaction times resulted only in decomposition products. Attempted direct oxidation of 16a to 1a using
TPAP13 in the presence of N-methylmorpholine oxide (NMMO) only gave an intractable mixture of
products. However, oxidation of 16a under Parikh–Doering conditions10 to obtain the corresponding
24
aldehyde followed immediately by TPAP/NMMO oxidation furnished (−)-eburnamonine 1a14a {[α]
D
24
D
−77 (c 0.13, CHCl3), lit.3b [α] −88 (c 0.09, CHCl3)}. Unlike 15a, LiAlH4 reduction of 15b proceeded
to give a high yield of 16b, which upon oxidation with TPAP/NMMO afforded (+)-epi-eburnamonine
24
1b14b {[α] +158 (c 0.19, CHCl3), lit.3f [α] +168 (c 1, CHCl3)} in good yield.
D
D
Scheme 2. Reagents and conditions: (a) (i) LiBH4, THF, 0°C to rt, 92%; (ii) TBDPS–Cl, imidazole, DMF, rt, 98%; (b)
pyridine–SO3, DMSO, Et3N, rt, 95%; (c) 50 mol% Nafion-H, PhMe, rt, 18 h, 95%; (d) 4 equiv. Me3SiCl, MeOH: 15a, 97%;
15b: 95%; (e) For 1a: (i) LiAlH4, THF, reflux, 30 min, 30%; (ii) pyridine–SO3, DMSO, Et3N, rt; then TPAP, NMMO, 4A MS,
CH2Cl2, 37% (two steps); (f) for 1b: (i) LiAlH4, THF, reflux, 84%; (ii) TPAP, NMMO, 4A MS, CH2Cl2, 55%
In summary, we have demonstrated a strategy based on the use of the readily accessible chiral non-
racemic 4,4-disubstituted γ-lactone 4, for the synthesis of (−)-eburnamonine and (+)-epi-eburnamonine.
The use of 4,4-disubstituted γ-lactones as intermediates in synthesis has received only limited attention
and our investigations in this area are continuing.

590
Acknowledgements
Support for this work from the Natural Sciences and Engineering Research Council, Canada, and the
University of Regina is gratefully acknowledged. We thank Dr. K. Marat, Prairie Regional High Field
NMR, Manitoba for 500 MHz NMR experiments, and Mr. K. Thoms, University of Saskatchewan, for
elemental and HRMS analyses. We also thank Professor A. G. Schultz, Rensselaer Polythechnic Institute,
NY, for providing the 1H NMR spectrum of 15a for comparison.
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1
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