Enantiospecific total synthesis of the enantiomer of the indole alkaloid affinisine

Article abstract of DOI:10.1016/S0040-4039(00)01061-3

The enantiomer of affinisine has been synthesized (from L-tryptophan) with 100% diastereoselectivity via the asymmetric Pictet-Spengler reaction coupled with a Pd°(enolate mediated) coupling process. This enantiomer has also been converted into a key inte

Full text of DOI:10.1016/S0040-4039(00)01061-3

Tetrahedron Letters 41 (2000) 6299±6303
Enantiospeci®c total synthesis of the enantiomer of the
indole alkaloid anisine
Xiaoxiang Liu, Tao Wang, Qingge Xu, Chunrong Ma and James M. Cook*
Department of Chemistry, University of Wisconsin±Milwaukee, Milwaukee, WI 53201, USA
Received 18 May 2000; revised 20 June 2000; accepted 21 June 2000
Abstract
The enantiomer of anisine has been synthesized (from l-tryptophan) with 100% diastereoselectivity via
the asymmetric Pictet±Spengler reaction coupled with a Pd0 (enolate mediated) coupling process. This
enantiomer has also been converted into a key intermediate which provides a route to the enantiomers of
both macroline and alstonerine following the previous work of LeQuesne. # 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: Pictet±Spengler reaction; enantiomer of anisine; macroline; alstonerine.
During the last few decades over 90 indole alkaloids have been isolated from Alstonia macrophylla
Wall, Alstonia muelleriana Domin, and other Alstonia species.1,2 Interest in the synthesis and
biological activity of these alkaloids as well as their enantiomers continues to grow because of
the antimalarial and antiamoebic activity of some of the bisindoles in the series.3,4 In addition,
the monomeric alkaloids exhibit important activity while the enantiomers have never been
evaluated biologically.
Anisine 1, which has been isolated as one of the minor constituents from Alstonia macrophylla
Wall5 and Peschiera anis Muell. Arg.,6 has been shown to produce delayed intention tremors,
marked CNS depressant activity, ataxia, hypothermia and bradypnea if taken in high doses.6 The
structure determination has been well-documented in the literature;7,8 moreover, 1 serves as the
southern unit in the bisindole alkaloid accedinisine 2 (Fig. 1).9 In an e€ort to provide the enantiomers
of indole alkaloids for study, we wish to report the enantiospeci®c total synthesis of the enantiomer
of anisine 1. In addition, this route (from l-tryptophan) can be employed to prepare the
enantiomers of both macroline and alstonerine.
Previously, the tetracyclic ketone (from d-tryptophan) has been prepared in stereospeci®c
fashion to provide a route for the total synthesis of several alkaloids.10 12 As a consequence,
execution of a similar route via the asymmetric Pictet±Spengler reaction (from l-tryptophan
* Corresponding author. Tel: 414-229-5856; fax: 414-229-5530; e-mail: capncook@csd.uwm.edu
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01061-3

6300
Figure 1.
methyl ester) would provide a route to the enantiomers. In order to demonstrate this possibility a
modi®cation of the previous route (Na-methylation) has been developed and employed in the ®rst
total synthesis of the enantiomer of anisine 1. As shown in Scheme 1, l-tryptophan methyl ester
3 was stirred with benzaldehyde and this was followed by reduction with sodium borohydride at
low temperature to a€ord the Nb-benzyl derivative 4. The Pictet±Spengler reaction was then
executed with the acetal11,12 to furnish the trans-isomer 5 with 100% diastereoselectivity. This
was subsequently transformed into its Na-methyl derivative 6 via a facile modi®cation of previous
work (95% yield). This is faster and safer than the previous route requiring the preparation of
Na-methyltryptophan with Na/liquid NH3. Dieckmann cyclization of the Na-methyl trans-diester
derivative 6 which resulted was followed by acid-mediated hydrolysis and decarboxylation to
a€ord the key tetracyclic ketone 7a in 80% yield. The carbon NMR spectrum was identical to
that derived from d-tryptophan;11,12 however, the optical rotation was equal and opposite in
sign. The template for the synthesis of the enantiomers of the macroline alkaloids has been
constructed with 100% diastereoselectivity.
Scheme 1. (1) PhCHO, MeOH, rt, 2 h; NaBH4, ^10ꢀC, 85%; (2) (MeO)2CHCH2CH2COOMe, TFA, CH2Cl2, rt, 7
days, 90%; (3) NaH, MeI, DMF, 0ꢀC to rt, 95%; (4) NaH/MeOH/toluene, 110ꢀC, 3 h; HOAc, HCl, re¯ux 8 h, 80%
Incorporation of the E-ethylidene function into the sarpagine skeleton with Z-1-bromo-2-iodo-
2-butene 8, a unit prepared earlier by Enseley et al.13 and employed by Bosch,14 Rawal,15 as well
as Kuehne,16 was achieved in our laboratory recently via a Pd0-catalyzed (enolate driven)
intramolecular cyclization.17 Miura et al.18 had previously observed a similar cyclization in a
di€erent system. As shown in Scheme 2, the tetracyclic ketone 7a was debenzylated via catalytic
hydrogenation to a€ord the Nb-H ketone 7b in 85% yield. This base was then stirred with the

6301
Scheme 2. (1) Pd/C, EtOH/HCl, 85%; Z-1-bromo-2-iodo-2-butene 8, THF, K2CO3, 83%; (2) 5% Pd(OAc)2, 20%
Ph3P, 1 equiv. Bu4NBr, 4 equiv. K2CO3, DMF:H2O (9:1), 65ꢀC, 8 h, 80%
Z-1-bromo-2-iodo-2-butene 8 in the presence of K2CO3 to give ketone 9 in 83% yield. When
ketone 9 was heated to 65ꢀC in DMF:H2O (9:1) in the presence of palladium(II) acetate, triphenyl
phosphine, Bu4NBr and K2CO3, the intramolecular cyclization took place to a€ord the desired
ketone 10 in stereospeci®c fashion (80% yield).
To obtain a better understanding of this palladium (enolate mediated)17,18 cyclization, several
additional experiments have been carried out. As shown in Table 1, the cyclization did not take
place when pure DMF (entries 2±4) was employed; however, when the solvent was altered to
DMF:H2O (9:1), the cyclization did take place when triphenyl phosphine (entry 5) was used as
the ligand. This process furnished 60% of the desired ole®n 10, accompanied by 30% of the
deallylated material (Nb-H ketone) 7b. When the sequence was carried out in the presence of
tri-o-tolyl phosphine (entry 6) as the ligand, the outcome reversed to provide 30% of the desired
ole®n 10, accompanied by 60% of the Nb-H ketone 7b. However, if the cyclization was carried
out in the presence of the phase transfer catalyst (Bu4NBr) but without the ligand (entry 7), the
process still underwent cyclization but several byproducts in addition to 7b were produced. From
the limited amount of data gathered to date, it appears that enolate formation (as expected) is key
to the success of this cyclization. In the absence of water none of the ole®n 10 was observed; it
was felt this was due to the low concentration of enolate present. The ligand choice was also
found to be important in order to depress the deallylation pathway (to 7b). Further work in this
area is underway to better understand the ligand e€ect in this process.
Table 1
With the cyclized ketone 10 in hand, the synthesis was completed in simple fashion (Scheme 3).
Wittig reaction of 10 was followed by acidic hydrolysis of the enol ether so generated to a€ord
the enantiomer of Na-methylvellosimine 11. In fact, Na-methylvellosimine is also a natural
product (but in the natural series).19 Reduction of the aldehyde 11 with NaBH4 then gave the
enantiomer of anisine 1 with 100% diastereoselectivity. The spectral data for the enantiomer of

6302
anisine 1 were in good agreement with that of the natural product and the optical rotation was
equal and opposite in sign.20
Scheme 3. (1) MeOCH2PPh3Cl, KOt-Bu, benzene, rt, 24 h; 2N aq. HCl/THF, 55ꢀC, 5 h, 75%; (2) NaBH4/MeOH,
0ꢀC, 90%
Encouraged by the earlier work of LeQuesne,21,22 the enantiomer of anisine was transformed
into the key intermediate 14 which completes a formal total synthesis of the enantiomers of both
macroline 15 and alstonerine 16. As shown in Scheme 4, the enantiomer of anisine 1 was
protected as its TBDMS ether 12 using KHMDS as the base (95% yield). The ole®n was then
oxidized via hydroboration/H2O2 to a€ord the alcohols 13a and b in 70% yield. The major
isomer was subjected to a Swern oxidation to provide the ketone 14 in greater than 80% yield.
The ketone 14 can be converted into the enantiomers of both macroline and alstonerine directly
following the previous work of LeQuesne et al.21,22 Further work is underway to improve this
approach to the enantiomers 15 and 16.
Scheme 4. (1) 3 equiv. KHMDS, 3 equiv. TBDMSCl, THF, 0ꢀC to rt, 90%; (2) BH3±THF, THF, 0ꢀC, 24 h; NaOH/
H2O2, rt, 2 h, then 60ꢀC, 1 h, 70%; (3) (COCl)2/DMSO, ^78ꢀC; Et3N, ^78ꢀC to rt, 80%
In summary, the enantiospeci®c total synthesis of the enantiomer of anisine 1 was completed
(from l-tryptophan methyl ester) in seven reaction vessels in 22% overall yield via the asymmetric
Pictet±Spengler reaction (100% diasteroselectivity). This process provides a synthetic route to the
21
enantiomers of macroline 15 and alstonerine 16,22 as well as other Alstonia alkaloids. The Pd0
(enolate mediated)17,18 incorporation of the E-ethylidene unit into 1 is stereospeci®c and
important for the synthesis of the enantiomers of other sarpagine/macroline alkaloids.

6303
Acknowledgements
The authors wish to thank the NIMH (in part) and the Graduate School (UW-Milwaukee) for
®nancial support.
References
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20. The 13C NMR data8 for the synthetic material is reported in parentheses. 1H NMR (CDCl3, 300 MHz) of
synthetic compound (enantiomer of anisine 1): 1.67 (4H, m), 1.82 (1H, dd, J=13.8 and 6.3 Hz), 2.10 (1H, dt,
J=12.2 and 2.0 Hz), 2.65 (1H, d, J=15.4 Hz), 2.82 (2H, m), 3.09 (1H, dd, J=15.4 and 5.1 Hz), 3.54 (7H, m), 4.24
(1H, d, J= 9.8 Hz), 5.42 (1H, q, J=6.7 Hz), 7.09 (1H, dt, J=7.9 and 1.0 Hz), 7.20 (1H, dt, J=7.8 and 1.1 Hz),
7.31 (1H, d, J=8.1 Hz), 7.47 (1H, d, J=7.7 Hz). 13C NMR (CDCl3, 75.5 MHz): 12.6 (12.5), 27.0 (26.7), 27.2
(27.2), 29.1 (29.0), 32.5 (32.5), 44.0 (43.9), 49.2 (49.2), 54.5 (54.0), 55.9 (56.0), 64.6 (64.7), 103.4 (103.3), 108.5
(108.4), 116.2 (116.5), 118.0 (117.8), 118.6 (118.6), 120.6 (120.6), 127.2 (127.0), 135.6 (135.4), 137.1 (137.0), 139.4
(139.0). [ꢀ]D=^31.5ꢀ (chloroform, c 0.78), lit. value: [ꢀ]D=30ꢀ, 27ꢀ (chloroform, see Ref. 5). EIMS: 308 (M+, 19),
307 (18), 183 (100), 182 (83), 168 (48).
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