Asymmetric route to the hydroindolone core of the Amaryllidaceae alkaloids employing chiral bicyclic lactams

Article abstract of DOI:10.1016/S0040-4039(99)02328-X

The asymmetric synthesis of the hydroindolone core (5) of the Amaryllidaceae alkaloids employing chiral bicyclic lactams is described. The vicinal quaternary and tertiary stereocenters were assembled via an addition of lactam 14 enolate to acrolein. (C) 2

Full text of DOI:10.1016/S0040-4039(99)02328-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1519–1522
Asymmetric route to the hydroindolone core of the
Amaryllidaceae alkaloids employing chiral bicyclic lactams
Daniel J. Watson and A. I. Meyers ∗
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA
Received 17 November 1999; accepted 14 December 1999
Abstract
The asymmetric synthesis of the hydroindolone core (5) of the Amaryllidaceae alkaloids employing chiral
bicyclic lactams is described. The vicinal quaternary and tertiary stereocenters were assembled via an addition
of lactam 14 enolate to acrolein. © 2000 Elsevier Science Ltd. All rights reserved.
The alkaloids of the Amaryllidaceae family are composed of over 100 architecturally interesting natu-
ral bases and may be classified into several principal skeletally homogeneous subgroups.1 In particular
the 2-benzopyrano-(3,4-c)-hydroindole derived members, exemplified by tazettine (1), pretazettine (2)
and 6a-epipretazettine (3) have captured the interest among a number of synthetic groups as targets for
total synthesis due to their biological properties.
Tazettine (1) exhibits mild activity against certain tumor cell lines.2 However there is more interest in
the chemically labile pretazettine (2) owing to its antiviral and anticancer activity particularly in Rauscher
leukemia, Lewis lung carcinoma and spontaneous AKR lymphocytic leukemia.3 Pretazettine (2) has
also been found to inhibit protein synthesis in eukaryotic cells by a mechanism which does not affect
DNA and RNA synthesis.3a Racemic total syntheses of the 2-benzopyrano-(3,4-c)-hydroindole subunit
of the Amaryllidaceae alkaloids have been reported by groups of Hendrickson,4 Tsuda,5 Danishefsky,6
White,7 Martin,8 Overman9 and Rigby.10 Formal synthesis and partial synthesis of pretazettine and
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02328-X
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related compounds have also been reported.11 More recently the first asymmetric total synthesis of (−)-
haemanthidine (4) and (+)-pretazettine (2) has been reported by Mori et al.12
Our retrosynthetic analysis was based on our earlier report describing the first asymmetric synthesis of
mesembrine.13 The desired core 5 was envisioned to arise from lactam 7 and the amine appendage on the
intermediate bicyclic lactam which in turn may be derived from aminoalcohol 8 and keto acid 9 (Scheme
1).
Scheme 1.
Synthesis of the requisite keto acid 9 was accomplished by basic hydrolysis (25% NaOH, MeOH) of
commercially available phenylacetonitrile to provide the corresponding phenylacetic acid in quantitative
yield. Following metalation (2.1 equiv. n-BuLi, THF) and treatment with 2-methyl-2-(2-iodoethyl)-1,3-
dioxolane14 cleavage of the ketal functionality (PPTS, EtOH, 60°C) furnished 9 in 74% overall yield
after recrystallization from hexanes/ether. Condensation of 9 with (1S,2S)-(+)-2-amino-1-phenyl-1,3-
propanediol (8) (toluene, reflux, 16 h, 73%) provided bicyclic lactams 10, 11, as a three component
mixture of diastereomers with aryl substituents epimeric at both the α-C and angular methyl group (endo
aryl 10:exo aryl 10 and 11, 57:23:20). Thus, 80% of the mixture (exo–endo 10) is useful for the synthesis
(Scheme 2).
Scheme 2. Reagents and conditions: (a) toluene, reflux, 16 h, 73%; (b) TBSCl, imid., DMAP, CH2Cl2, 12, 74%, 13, 21%; (c)
LDA, (2.0 equiv.), THF, −78°C, 20 min, acrolein, 3 h, 80%; (d) Dess–Martin periodinane, CH2Cl2, 90%
Silylation of the 3-component mixture of primary alcohols 10, 11 (TBDMSCl, imid. DMAP, CH2Cl2)
furnished lactam 12 in 74% yield as a 2:1 mixture of α-C aryl diastereomers along with recovered
alcohol 11 in 20–21% yield. Addition of the lithio-enolate of lactam 12 to amino aldehyde 158a (R=Boc,
Bn) proved to be fruitless. However, addition of 12 (LDA, −78°C) to acrolein provided lactam 13 in 98%

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yield as a 1:1 mixture of diastereomers epimeric at the newly formed hydroxy stereocenter. Dess–Martin
oxidation15 of the crude allylic alcohol 13 furnished enone 14 in 90% yield (Scheme 2). The 1H NMR
spectrum of 14 indicated a 12:1 diastereomeric mixture corresponding to endo:exo aryl-allylic ketone
and therefore allylic alcohol 13 was also assumed to be a 12:1 mixture at the α-carbon. Interestingly,
generation of the zinc enolate of 12 followed by addition of acrolein provided alcohol 13 as a 2:1
mixture of diastereomers at the hydroxyl center. Silylation16 of the allylic alcohol 13 (SEMCl, iPr2NEt,
CH2Cl2; 80%) then gave 2-(trimethylsilyl) ethoxymethyl acetal 17 (Scheme 3). Treatment of 17 with a
catalytic amount of OsO4 using N-methylmorpholine N-oxide as reoxidant, followed by sodium periodate
cleavage17 and reductive amination18 (MeNH2·HCl, NaCNBH3, MeOH) of the resulting aldehyde gave
amine 7 in 91% overall yield. Fluoride induced removal of the tert-butyldimethylsilyl ether (TBAF, THF,
3 h; 50%) furnished the primary alcohol 18.
Scheme 3. Reagents and conditions: (a) SEMCl, iPr2NEt, CH2Cl2, 80%; (b) (i) OsO4 (0.05 equiv.), NMO (2.0 equiv.), THF/H2O
(3:1), tBuOH, rt, 14 h, (ii) NaIO4, THF/H2O (3:1), 1 h, (iii) CH3NH2·HCl, NaCNBH3, MeOH, 3 d, 91%; (c) TBAF, THF, 0°C,
30 min, rt, 3 h, 50%; (d) RedAl (2.4 equiv.), 24 h, (ii) Bu2NH2PO4, EtOH, reflux, 21 h, (e) 4 M NaOH, 30 min, rt
It has previously been reported that reduction of the lactam carbonyl of 5,6-bicyclic lactams is often
accompanied by reductive cleavage at the angular methyl position.19 However, the presence of the
primary alcohol moiety in the amino diol derived bicyclic lactam 18 allows intramolecular delivery of
hydride providing after hydrolysis, 4,4-disubstituted cyclohexenones. Hence, reduction of 18 (RedAl,
toluene, 24 h) followed by hydrolysis (Bu4NH2PO4, H2O, EtOH, reflux, 21 h) gave keto-aldehyde 19.
Treatment of 19 with 4 M NaOH for 30 min furnished the cyclohexenone 6 which spontaneously gave
the hydroindolone 5 as a single diastereomer in 27% yield over three steps. Thus, the mixture at the
OSEM center appeared to have been separated during the three step sequence and flash chromatography
(Scheme 3). At this point we have not confirmed the stereochemistry of the SEM ether.
In summary, a general route to the hydroindolone core of the Amaryllidaceae alkaloids has been
developed from chiral non-racemic bicyclic lactams which after some routine synthetic steps should
be in a position to reach the four members (1–4) of the Amarylidaceae alkaloids. Further studies are in
progress to enhance the stereoselectivity of acrolein addition to 12, as well as completion of the synthetic
routes depicted to reach these alkaloids.
Acknowledgements
The authors are grateful to the National Institutes of Health for financial support.

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