General Approach to the Synthesis of Sarpagine and Ajmaline Alkaloids. Enantiospecific Total Synthesis of (+)-Ajmaline and Alkaloid G via the Asymmetric Pictet-Spengler Reaction

Full text of DOI:10.1021/jo980476p

4166
J . Org. Chem. 1998, 63, 4166-4167
Sch em e 1a
Gen er a l Ap p r oa ch to th e Syn th esis of
Sa r p a gin e a n d Ajm a lin e Alk a loid s.
En a n tiosp ecific Tota l Syn th esis of
(+)-Ajm a lin e a n d Alk a loid G via th e
Asym m etr ic P ictet-Sp en gler Rea ction
J in Li and J ames M. Cook*
Department of Chemistry, University of WisconsinsMilwaukee,
Milwaukee, Wisconsin 53201
Received March 12, 1998
(+)-Ajmaline (1), which contains four heteroatoms, six
rings, and nine asymmetric centers, is a clinically important
indole alkaloid1,2 with historical significance3 and is related
to the sarpagine 3 bases. Alkaloid G (2), which was recently
isolated from plant cell cultures of Rauwolfia serpentina
Benth by Sto¨ckigt et al.4 after feeding experiments with
ajmaline, is also related to 3. Both of these bases are
structurally related by the presence of the quinuclidine ring
and the C5-C16 bond linkage. The absolute configurations
of the stereogenic centers at C3, C5, and C15 of members of
both the sarpagine and ajmaline class of indole alkaloids
are identical.
a
Reagents and conditions: (i) PhCHO, CH3OH, rt, 2 h; NaBH4; -30
to -10 °C, 3 h; (CH3O)2CHCH2CH2COOCH3, TFA, CHCl3, ∆, 12 h; (ii)
NaH, CH3OH, PhCH3, ∆, 4 h; HOAc, HCl, ∆ 12 h.
Sch em e 2
Three important reports on the synthesis of ajmaline have
appeared previously.5 The first was published by Masamune
* Ratio of 12a ,b to 12c,d from the anionic oxy-Cope rearrangement
was 3:2.
synthesis of ajmaline that has also resulted in a formal total
synthesis of alkaloid G.
The optically active (-)-Nb-benzyltetracyclic ketone 87 was
prepared in enantiospecific fashion from D-(+)-tryptophan
methyl ester 6 via a stereospecific Pictet-Spengler/Dieck-
mann protocol in an improved two-pot process. Conversion
of the carbonyl function of (-)-8 into the R,â-unsaturated
aldehyde moiety of 9 via the spirooxiranophenylsulfoxide
was accomplished in 90% overall yield8 (Scheme 1). The R,â-
unsaturated aldehyde (-)-9 (>98% ee) serves as the key
intermediate for the total synthesis of alkaloids in both the
sarpagine and ajmaline series, as illustrated above (Scheme
2).
When (-)-9 was stirred with 3-bromo-4-heptene 10 (R )
Et) at 0 °C under the conditions of a Barbier-Grignard
process, the products of 1,2-addition (allylic alcohol 11,
isolated as a mixture of diastereomers) and 1,4-addition
(diastereomers 12a ,b and 12c,d ) were obtained in a com-
bined yield of 90% in a ratio of 51 (11):49 (12).8 The ratio of
desired to undesired isomers from the 1,4-addition was 3:1
(see 12a ,b vs 12c,d ). The allylic alcohol 11 was easily
separated from the mixture by flash chromatography and
underwent the anionic oxy-Cope rearrangement at 150 °C
in 88% yield to provide the same C-15-functionalized tetra-
cyclic systems 12a ,b and 12c,d in a ratio of 3:2. The key
diastereomers could also be obtained by executing the
et al. in 1967 and involved 16 steps; this elegant approach
was not enantiospecific, and the yields were not reported in
some cases. Two years later, Mashimo and Sato converted
tryptophan into an intermediate employed by Masamune in
the earlier synthesis of ajmaline in order to provide a formal
total synthesis of this alkaloid. Van Tamelen in 1970 in his
biogenetic approach synthesized deoxyajmaline, and since
Hobson et al.6 had earlier converted deoxyajmaline to
ajmaline, another synthesis of 1 was completed. This
biogenetic route involved 17 steps, and the overall yield was
quite low. We wish to report the first enantiospecific total
(1) Brugada, J .; Brugada, P. Am. J . Cardiol. 1996, 78(5A), 69-75.
(2) Slowinski, S.; Rajch, D.; Zabowka, M. Przegl. lek. 1996, 53(3), 196-
8.
(3) Hamaker, L. K.; Cook, J . M. The Synthesis of Macroline-Related
Alkaloids. In Alkaloids: Chemical and Biological Perspectives; Pelletier,
S. W., Ed.; Pergamon Press: London, 1995; pp 23-84 and references cited
therein.
(4) Endreb, S.; Takayama, H.; Suda, S.; Kitajima, M.; Aimi, N.; Sakai,
S.; Sto¨ckigt, J . Phytochemistry 1993, 32, 725-730.
(5) For earlier syntheses of ajmaline see: (a) Masamune, S.; Ang, S. K.;
Egli, C.; Nakatsuka, N.; Sarkar, S. K.; Yasunari, Y. J . Am. Chem. Soc. 1967,
89, 2506-2507. (b) Van Tamelen, E. E.; Oliver, L. K. Bioorg. Chem. 1976,
5 309-326 . (c) Mashimo, K.; Sato, Y. Tetrahedron Lett. 1969, 11, 905-
906. For a synthesis of isoajmaline see: Mashimo, K.; Sato, Y. Tetrahedron
Lett. 1969, 11, 901-904.
(7) Cox, E. D.; Hamaker, L. K.; Li, J in; Yu, Peng; Czerwinski, K. M.; Li,
Deng; Cook, J . M. J . Org. Chem. 1997, 62, 44-61. Yu, Peng; Cook, J . M.
Tetrahedron Lett. 1997, 38, 6819-6822 and references cited therein.
(8) Fu, X.; Cook, J . M. J . Org. Chem. 1993, 58, 661-672.
(6) Hobson, J . D.; McCluskey, J . G. J . Chem. Soc. C 1967, 20, 2015-
2017.
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Published on Web 06/06/1998

Communications
J . Org. Chem., Vol. 63, No. 13, 1998 4167
Sch em e 3
Sch em e 4
and this was followed by oxidative cleavage (OsO4, NaIO4)
of the olefinic bond to provide the two epimeric aldehydes
14a ,b in excellent yield. The desired aldehyde 14a (S
configuration) contains the required chirality for the prepa-
ration of ajmaline 1, as well as alkaloid G (2). For this
reason, the epimeric aldehyde 14b was treated with base
(NaOMe/MeOH) and converted into an equilibrium mixture
of 14a and 14b (1:1), which was subjected to flash chroma-
tography (silica gel, EtOAc/hexane, 2:8). In this manner,
the conversion of 13a ,b into the required 14a could be easily
increased to greater than 80%.
The (-)-(S)-aldehyde 14a was converted into the sarpagine
system present in 15 in 91% yield by catalytic debenzylation
followed by addition of acetic anhydride in a one-pot process.
This acetal 15 was then treated with acetic acid and
concentrated aqueous HCl for 3 h, after which time this
mixture was stirred with acetic anhydride/HCl(g) to effect
smooth cyclization to furnish the 2-hydroxyajmaline deriva-
tive 16 in 85% yield. The structure of this carbinolamine
was determined by NMR spectroscopy and verified by single-
crystal X-ray analysis of a derivative 16 (21-OCbz). The
alcohol 16 was hydrogenated over platinum oxide in dry CH2-
Cl2 in the presence of BF3 etherate to afford 2-epidiacetyl-
ajmaline 17 and diacetylajmaline 18 in a ratio of 3:2 in 89%
yield. Hydrolysis of 18 with aqueous K2CO3 in methanol
furnished (+)-ajmaline (1) in 93% yield. This base was
spectrometrically identical (IR, 1H NMR, 13C NMR, MS, co-
TLC) to that of an authentic sample of ajmaline including
the optical rotation.9 Hydrolysis of the intermediate acetal
15 provided the aldehyde 19. Since aldehyde 19 was
previously converted into alkaloid G in two steps, according
to the method of Sto¨ckigt et al.,4 this also serves as a formal
total synthesis of alkaloid G in enantiospecific fashion
(Scheme 4).
Barbier-Grignard process at 25 °C (only 1,2-addition)
followed by the anionic oxy-Cope rearrangement. The
desired aldehydes 12a ,b were obtained (from 9) in 63%
overall yield and employed for the preparation of 1 and 2.
The conversion of 9 into aldehydes 12a ,b, although not
stereospecific, constitutes the first effective solution to the
long-standing problem of the stereochemistry at C(16) in the
ajmaline series. In earlier work,5 epimerization of the
aldehyde group at C(16) to the unnatural configuration
complicated the process; the ratio of desired to undesired
diastereomers was reported as 7:43 and 3:7 from different
laboratories.5 In contrast, the presence of the ethyl group
in 12a ,b (from 10, R ) Et) was found to be critical to retard
epimerization of the aldehyde moiety at C(16) to the un-
natural configuration. This ultimately permitted the forma-
tion of the desired ketal 13 in high yield (see below). Support
for the importance of the ethyl group in 10 (R ) Et) derives
from the following experiment. When the anionic oxy-Cope
rearrangement was carried out with the 2-pentenyl deriva-
tive (10, R ) H) rather than the heptene analogue 10 (R )
Et), the diasteroselectivity at C(15) was further improved
(4:1); however, the ease of epimerization at C(16) to the
unnatural diastereomer was increased. The presence of R
) Et in 12a ,b (from 10, R ) Et) from the anionic oxy-Cope
approach retarded isomerization at C(16) to the unnatural
isomer, an epimerization process that had hindered earlier
work.5
Although reduction of 16 gave only 40% of diacetylajma-
line 18, this still constitutes the highest conversion of alcohol
16 to (+)-110,11 reported to date. In this caged molecule 16,
the R-face is much less hindered than the â-face; conse-
quently, 2-epidiacetylajmaline can be formed with 100%
stereoselectivity under certain conditions (Et3SiH, TFA).
This latter reduction process provides a potential route to
alkaloids with the 2-epi configuration, including quebrachi-
dine (4) and vincamajine (5). In addition, the cyclization
reaction of 14 to 15 provides facile entry into the substruc-
ture of a number of sarpagine alkaloids. The steps described
in Schemes 1-3 provide a route (from L-tryptophan) to
prepare the (-) enantiomer of ajmaline via the trans transfer
of chirality in the asymmetric Pictet-Spengler reaction. The
two-pot process for the improved preparation of azabicyclo-
[3.3.1]nonane 8 also streamlines this enantiospecific route
to 1.
As illustrated in Scheme 3, the aldehyde function of 12a ,b
was protected as the ethylene acetal (see 13a ,b) in 90% yield,
(9) (1): [R]27 ) +145.8 (lit.12 [R]20 ) +144).
D
D
(10) More than 20 different reaction conditions and reagents were
employed to convert alcohol 16 into 18; however, most of these gave the epi
configuration at C(2) of 18. In fact, the reduction conditions depicted below
provide a simple entry (from 16) into the epiajmaline (see 17) stereochem-
istry at C(2) for an approach to bases such as 4 and 5 [9-BBN, PtO2, H2
(92%yield); Et3SiH, TFA (90% yield); Pt/H2, TFA (80% yield)].
(11) Bartlett, M. F.; Lambert, B. F.; Werblood, H. M.; Taylor, W. I. J .
Am. Chem. Soc. 1963, 85, 475-477.
Su p p or tin g In for m a tion Ava ila ble: The X-ray crystal-
lographic coordinates for the derivative (21-OCbz) of 16 (16 pages).
(12) Anet, F. A. L.; Chakravarti, D.; Robinson, R.; Schlittler, E. J . Chem.
Soc. 1954, 1242-1259. Siddiqui, S.; Siddiqui, R. H. J . Ind. Chem. Soc. 1931,
8, 667-680.
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