Regiospecific, enantiospecific total synthesis of C-19 methyl substituted sarpagine alkaloids dihydroperaksine-17-al and dihydroperaksine

Article abstract of DOI:10.1021/ol202101p

The optically active tetracyclic ketone 8 was converted into the pentacylic core 14 of the C-19 methyl substituted N_a-H sarpagine and ajmaline alkaloids via a critical haloboration reaction. The ketone 14 was then employed in the total synthesi

Full text of DOI:10.1021/ol202101p

ORGANIC
LETTERS
2
011
Vol. 13, No. 19
216–5219
Regiospecific, Enantiospecific Total
Synthesis of C-19 Methyl Substituted
Sarpagine Alkaloids Dihydroperaksine-17-
al and Dihydroperaksine
5
†
Rahul V. Edwankar, Chitra R. Edwankar, Jeffrey Deschamps, and James M. Cook*
†
‡
,†
Department of Chemistry & Biochemistry, University of WisconsinꢀMilwaukee,
Milwaukee, Wisconsin 53201, United States, and Center for Biomolecular Science and
Engineering, Naval Research Laboratory, Code 6930, Washington, D.C. 20375, United
States
capncook@uwm.edu
Received August 2, 2011
ABSTRACT
The optically active tetracyclic ketone 8 was converted into the pentacylic core 14 of the C-19 methyl substituted N -H sarpagine and ajmaline
a
alkaloids via a critical haloboration reaction. The ketone 14 was then employed in the total synthesis of 19(S),20(R)-dihydroperaksine-17-al (1) and
1
9(S),20(R)-dihydroperaksine (2). The key regioselective hydroboration and controlled oxidationꢀepimerization sequence developed in this
approach should provide a general method to functionalize the C(20)ꢀC(21) double bond in the ajmaline-related indole alkaloids.
4
The root of Rauwolfia serpentina Benth (N.O. Apocy-
anaceae) hasbeeninusein Indiaforhundredsofyearsfor a
serpentina by St o€ ckigt et al. along with 16 known alka-
loids. The structuresof these novelC-19methylsubstituted
alkaloids were elucidated via analysis of 1D and 2D NMR
spectroscopy. In addition to the asymmetric centers at
C-3(S), C-5(S), C-15(R), and C-16(R) of the sarpagine
1
host of unrelated ailments. The plant has gained universal
acclamation as a useful therapeutic weapon in the treat-
2
ment of high blood pressure. The presence of high con-
5
a
centrations of alkaloids and other phytochemicals has
provided a basis for the ethnomedical use of this plant in
3
treating various medical conditions. The monoterpenoid
sarpagine indole alkaloids 19(S),20(R)-dihydroperaksine-
17-al (1) and 19(S),20(R)-dihydroperaksine (2) (Figure 1)
were isolated from the hairy root culture of Rauwolfia
framework, the existence of a β-methyl group at C-19
and the R-primary hydroxyl group at C-20 attracted our
attention. A number of alkaloids are known which belong
to the sarpagine-ajmaline series, and share this unique
feature. These include the sarpagine alkaloids 10-hydro-
4 5,6
xy dihydroperaksine (3), O-acetyl preperakine (4), and
5
b
†
University of WisconsinꢀMilwaukee.
(5) (a) Lounasmaa, M.; Hanhinen, P.; Westersund, M. The Alkaloids;
Cordell, G. A., Ed.; Academic Press: San Diego, CA, 1999; Vol. 52,
pp 103ꢀ195 and references cited therein. (b) Lounasmaa, M.; Hanhinen,
P. J. Nat. Prod. 2000, 63, 1456.
(6) (a) Akinloye, B. A.; Court, W. E. Planta Med. 1979, 37, 361.
(b) Stereochemistry at C-20 depicted as per ref 5b.
‡
Naval Research Laboratory.
(
1) Ebadi, M. Pharmacodynamic Basis of Herbal Medicine, 2nd ed.;
CRC Press: Boca Raton, FL, 2006; Chapter 56, pp 515ꢀ519.
2) (a) Vakil, R. J. Brit. Heart J. 1949, 11, 350. (b) Vakil, R. J.
Circulation 1955, 12, 220.
3) Harisaranraj, R.; Suresh, K.; Saravanababu, S. Advan. Biol. Res.
009, 3, 174.
4) Sheludko, Y.; Gerasimenko, I.; Kolshorn, H.; St o€ ckigt, J. J. Nat.
Prod. 2002, 65, 1006.
(
(
(7) Lounasmaa, M.; Hanhinen, P. The Alkaloids; Cordell, G. A., Ed.;
Academic Press: San Diego, CA, 2001; Vol. 55, pp 1ꢀ89.
2
(
(8) Ulshafer, P. R.; Bartlett, M. F.; Dorfman, L.; Gillen, M. A.;
Schlittler, E.; Wenkert, E. Tetrahedron Lett. 1961, 363.
1
0.1021/ol202101p r 2011 American Chemical Society
Published on Web 08/30/2011

5
b,7,8
the ajmaline-related alkaloids perakine (5)
5
and rau-
acetylene in 95% yield. The optically active R-propargylic
alcohol 10 [enantiomeric ratio (er) = 90:10] was synthe-
sized from 9 via a two step oxidation/asymmetric hydro-
genation sequence under the conditions developed by
Marshall et al. for the S-propargylic alcohol. The asym-
metric hydrogenation was performed on a 25 g scale with
little erosion of the er. Treatment of the optically active R-
alcohol 10with2.2 equiv oftosyl chloride in the presence of
b,7,9
caffrinoline (6)
macrosalhine chloride, peraksine, verticillatine, 10-metho-
illustrated in Figure 1, as well as
5
5
5
5
b,7
5b,7
and vincawajine. No enantiospecific total
xyperakine,
1
5
synthesis of this class of sarpagine-ajmaline alkaloids has
appeared to date.
4
3
equiv of triethylamine at ꢀ25 °C in dichloromethane for
.5 h provided the R-tosylate 11. An S 2 alkylation of the
N
N -nitrogen function in 8 with the tosylate 11 took place
b
smoothly in dry acetonitrile/K CO to provide the alky-
2
3
lated ketone which was then treated with tetrabutylammo-
nium fluoride (TBAF xH O) at 0 °C in THF to provide
3
2
the acetylenic ketone 12 in 96% yield (Scheme 1).
Scheme 1. Synthesis of the Acetylenic Ketone 12
Figure 1. Sarpagine-ajmaline alkaloids containing additional
chiral centers at C-19(S) and C-20(R).
An objective of this research effort was to gain entry into
the C-19 methyl substituted sarpagine series which would
permit a study of the potential synthesis of the northern
1
0
hemisphere of the bisindole alkaloid macrospegatrine,
and the basic pentacylic framework 14 would also serve as
the template for the synthesis of the biogenetically impor-
tant ajmaline alkaloids, perakine (5) and raucaffrinoline
The simplest method for converting terminal alkynes to
16
vinyl iodides in a single step is by the use of HI which is
not useful especially for sensitive substrates. Although
1
1
(
6). The fact that a biogenetic link exists between the
sarpagine and ajmaline alkaloids proposed by St o€ ckigt
17
other methods are reported to achieve this important
1
2
et al. can be employed to achieve this interconversion.
Herein we report the first enantiospecific total synthesis of
the C-19 substituted sarpagine indole alkaloids (þ)-dihy-
droperaksine-17-al (1) and (þ)-dihydroperaksine (2).
The synthesis began with the enantiospecific, stereospe-
cific preparation of the (ꢀ)-N -H, N -H tetracyclic ketone
conversion, there are very few reports on the direct synth-
18
esis of R-vinyl iodides from terminal alkynes. In 1983
Suzuki et al. reported the regioselective haloboration of
19
terminal alkynes with B-bromo- or B-iodo-9-BBN [BBN:
borabicyclo(3.3.1)nonane] tofurnish the respectiveR-vinyl
halides in excellent yields and very high regioselectivities.
Initial attempts at haloboration of 12, under these
a
b
8
from D-tryptophan methyl ester 7 on a multihundred
gram scale following the procedure developed in Milwau-
1
3
kee. In order to introduce the desired stereocenter at
C-19 into the sarpagan skeleton, the synthesis of the
optically active R-acetylenic tosylate 11 was carried out as
illustrated in Scheme 1. The racemic TIPS propargylic
alcohol 9 was synthesized according to the procedure of
(15) Marshall, J. A.; Eidam, P.; Eidam, H. S. Org. Synth. 2007, 84,
1
20.
(
16) Smith, M. B.; March, J. March’s Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 6th ed.; Wiley-Interscience: Hobo-
ken, NJ, 2007; Chapter 15, pp 999ꢀ1250.
1
4
(17) (a) Katagiri, T.; Fujiwara, K.; Kawai, H.; Suzuki, T. Tetrahe-
dron Lett. 2008, 49, 3242. (b) Va, P.; Roush, W. R. Tetrahedron 2007, 63,
Jones et al. from commercially available triisopropylsilyl
5
1
768. (c) Nielsen, T. E.; Le Quement, S.; Tanner, D. Synthesis 2004,
381. (d) Kazmaier, U.; Pohlman, M.; Schauss, D. Eur. J. Org. Chem.
(
(
(
9) Libot, F.; Kunesch, N.; Poisson, J. Phytochemistry 1980, 19, 989.
10) Lin, X.; Zheng, Q.; Zhang, Y. J. Struct. Chem. 1987, 6, 89.
11) Takayama, H.; Phisalaphong, C.; Kitajima, M.; Aimi, N.; Sakai,
2000, 2761. (e) Kikukawa, K.; Umekawa, H.; Wada, F.; Matsuda, T.
Chem. Lett. 1988, 881.
(18) (a) Gao, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10961.
(b) Kawaguchi, S.; Ogawa, A. Org. Lett. 2010, 12, 1893. (c) Campos,
S.; St o€ ckigt, J. Chem. Pharm. Bull. 1991, 39, 266.
12) (a) Pfitzner, A.; St o€ ckigt, J. Tetrahedron Lett. 1983, 24, 5197.
b) Ruppert, M.; Ma, X.; St o€ ckigt, J. Curr. Org. Chem. 2005, 9, 1431.
13) Yu, P.; Wang, T.; Li, J.; Cook, J. M. J. Org. Chem. 2000, 65,
173.
14) Jones, G. B.; Wright, J. M.; Plourde, G. W., II; Hynd, G.; Huber,
(
P. J.; Garcıa, B.; Rodrıguez, M. A. Tetrahedron Lett. 2002, 43, 6111.
´ ´
(
(d) Reddy, C. K.; Periasamy, M. Tetrahedron Lett. 1990, 31, 1919.
(e) Kamiya, N.; Chikami, Y.; Ishii, Y. Synlett 1990, 675. (f) Gras, J.-L.;
Kong Win Chang, Y. Y.; Bertrand, M. Tetrahedron Lett. 1982, 23, 3571.
(19) (a) Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron
Lett. 1983, 24, 731. (b) Suzuki, A. Rev. Heteroatom. Chem. 1997, 17, 271.
(
3
(
R. S.; Mathews, J. E. J. Am. Chem. Soc. 2000, 122, 1937.
Org. Lett., Vol. 13, No. 19, 2011
5217

conditions, were accompanied by inconsistent reproduci-
bility, purification problems, and very low yields. At best,
up to 30% yield of the vinyl iodide 13 could be achieved by
this method after varying many parameters. It was felt that
the first few equivalents of the borane reagent resulted in
complexation of the boron reagent to the ketone in 12 and
created a steric cloud, which prevented/slowed further
reaction of B-I-9-BBN from approaching the acetylenic
function. With such low yields obtained in this critical step,
attention turned to the use of other reagents that could be
employed to achieve this conversion. The order of
a
Scheme 2. Synthesis of the Pentacyclic Ketone 14
2
0
reactivity of the haloborating reagents commonly used
is: B-I-9-BBN, BBr > BCl > B-Br-9-BBN . B-Cl-9-
3
3
BBN. Although BBr is equivalent in reactivity to B-I-9-
3
BBN the propensity of the N -nitrogen in 12, to form
b
a
stable borane complexes with smaller boranes as observed
Sarpagine numbering not followed.
2
1
earlier in a similar sarpagine framework and possibly
altering the course of the reaction at the terminal alkyne,
rendered it unsuitable.
The haloboranes, B-I-9-BBN, and dicyclohexyliodobor-
ane [I-B(Cy) ] have been employed for the synthesis of (Z)-
thermodynamically stable C-17 R-aldehyde even with the
presence of the C-19 methyl group in the β-position, via a
Wittigꢀhydrolysisꢀepimerization sequence (Scheme 3).
The aldehydic group was then protected as the cyclic acetal
15 with ethylene glycol in the presence of p-toluene sulfonic
2
2
2
enolborinates exclusively from various ethyl ketones.
I-B(Cy) is also a highly stereoselective reagent for the
2
2
3
24
enolboration of esters and tertiary amides. If all other
parametersarekept thesame, theinability ofB-I-9-BBN to
drive the haloboration reaction to completion was felt to
be due to the rigid skeleton of the bicyclo ring of B-I-9-
BBN as a major factor. In contrast, the two cyclohexyl
acid monohydrate (pTSA H O) in refluxing benzene.
2
3
With the acetal olefin 15 readily available, the hydrobor-
ationꢀoxidation sequence was employed to functionalize
C-20. As illustrated in Scheme 3, the desired primary
alcohol 16, accompanied by the tertiary alcohol, was
rings of I-B(Cy) are conformationally more flexible and
2
should be able to adjust to the neighboring environment.
As anticipated, the alkyne 12 on stirring with 2.5 equiv of
I-B(Cy) (added in two portions) furnished the desired
2
obtained in the ratio 25:1 (both obtained as N
-borane
b
2
6
complexes as observed in other sarpagine systems).
Clearly hydroboration of the C(20)ꢀC(21) terminal ole-
finic bond had taken place from the R-face and supported
boron adduct with complete consumption of the starting
material 12 (Scheme 2). Subsequent protonlysis with acetic
acid generated the vinyl iodide 13. A modified workup was
employed to ensure complete decomposition of excess
borane, excess iodine, baseline impurities, and other boron
impurities which were previously observed in the aliphatic
region of the NMR spectrum with B-I-9BBN. With this
improved procedure 74% of pure iodo-olefin 13 was
achieved. To our knowledge, this is the first example of
its hindered nature from the β-face. The mixture of N -
b
borane complexes of the primary alcohol 16 and tertiary
alcohol was stirred in the presence of 5 equiv of sodium
carbonate in refluxing methanol for 5 h, after which the
desired β-primary alcohol 16 along with tertiary alcohol
was obtained with the free N
yield.
nitrogen function in 88%
b
I-B(Cy) as the haloboration reagent for terminal alkynes.
2
The iodo-olefin 13 was then subjected to the conditions of
2
a
5
Scheme 3. Regioselective Hydroboration
the recently developed palladium catalyzed R-vinylation
to generate the key pentacyclic system 14 in 60% isolated
yield (Scheme 2). The S-configuration at C-19 was con-
firmed by X-ray analysis of 14.
With the critical formation of the E ring in place, the
pentacyclic ketone 14 was subjected to a one carbon
atom homologation process at C-16 to provide the
(
20) Suzuki, A.; Brown, H. C. Organic Synthesis Via Boranes; Aldrich
Chemical Company, Inc.: Milwaukee, WI, 2003; Vol. 3, Chapter 2,
pp 5ꢀ36.
(
(
21) Liu, X.; Cook, J. M. Org. Lett. 2002, 3, 4023.
22) Brown, H. C.; Ganesan, K.; Dhar, R. K. J. Org. Chem. 1993, 58,
147.
(
(
(
23) Ganesan, K.; Brown, H. C. J. Org. Chem. 1994, 59, 2336.
24) Ganesan, K.; Brown, H. C. J. Org. Chem. 1994, 59, 7346.
25) Liao, X.; Zhou, H.; Yu, J.; Cook, J. M. J. Org. Chem. 2006, 71,
a
DST = DeanꢀStark trap.
8884.
5
218
Org. Lett., Vol. 13, No. 19, 2011

Because of the basicity of the N -nitrogen function in the
b
sarpagine framework and the electron-rich character of the
indole nucleus (especially with the indole N -H function),
Scheme 4. Completion of the Total Synthesis of Dihydroper-
aksine-17-al (1) and Dihydroperaksine (2)
a
the oxidation of the primary alcohol 16 was a much bigger
problem than earlier anticipated. Oxidation of 16 under
27
various conditions always led to the formation of trace
amounts of the aldehyde accompanied by the aldehyde Nb-
oxide and some overoxidized byproduct. A modified Coreyꢀ
Kim oxidation (with lesser equivalents of the reagent and
lower temperature) completely eliminated the formation of
any overoxidized byproducts with sole formation of the
epimeric R,β-aldehydes. Complete epimerization to the R-
aldehyde 17 (67% yield) was achieved in the same reaction
vessel by addition of a large excess of triethylamine (up to 16
equiv) and stirring the reaction mixture at room tempera-
ture (up to 3 h) (Scheme 4). The R-aldehyde 17 was then
reduced with sodium borohydride in ethanol for
3
h at room temperature to furnish the R-alcohol 18 in
4% yield. The acetal group in 18 was cleaved under acidic
9
conditions (1.38 N aqueous HCl) in refluxing acetone.
Advantage was taken of the basicity of the N -nitrogen
b
function to remove all the nonalkaloidal impurities by
washing the aqueous layer containing the HCl salt of the
alkaloid with ether, followed by regeneration of the free
amine by treatment with 10% aqueous ammonium hydro-
xide. This completed the first regiospecific, enantiospecific
total synthesis of (þ)-dihydroperaksine-17-al (1) in 96%
yield. Reduction of 1 with sodium borohydride completed
the first total synthesis of (þ)-dihydroperaksine (2) as well
In summary, the first enantiospecific, stereospecific total
synthesis of 19(S),20(R)-dihydroperaksine-17-al (1) and
19(S),20(R)-dihydroperaksine (2) has been accomplished
in overall yields of 10.2% (14 reaction vessels) and 9.6%
(15 reaction vessels), respectively, from commercially
available D-(þ)-tryptophan methyl ester 7. The critical
haloboration of terminal alkyne 12 was achieved by em-
ploying dicylcohexyliodoborane as the haloborating agent
for the first time. The stereospecific synthesis of the core
pentacyclic ketone 14 contained in the C-19 methyl sub-
stituted sarpagine alkaloids thus provides a potentially
general entry into a whole series of biosynthetically im-
portant monterpene C-19 substituted indole alkaloids.
(
Scheme 4). The synthetic alkaloids 1 and 2 were identical
on TLC (including a mixed TLC sample) to the sample of
natural (þ)-dihydroperaksine-17-al (1) and natural (þ)-
dihydroperaksine (2) kindly supplied by Professor Joachim
2
8
St o€ ckigt at Johannes Gutenberg-University (Germany).
1
The spectral data of 1 ( H and C NMR) are in complete
13
agreement with those of the natural product. For com-
1
pound 2, some ambiguity was observed in the H NMR
1
3
(
difference in chemical shifts), and a C NMR comparison
between it and the natural product indicated that C-15 and
C-6 carbon atoms were interchanged. A detailed NMR
Acknowledgment. We thank Professor J. St o€ ckigt
28
Johannes Gutenberg-University) for providing samples
(
13
anlaysis of the synthetic alkaloid 2 including C DEPT 135
as well as 2D COSY, HSQC, NOESY, and 1D NOE
experiments (see Supporting Information) unequivocally
support the structure as indicated in Scheme 4, in agreement
with that of natural (þ)-dihydroperaksine (2).
of 1 and 2 for TLC comparison. We wish to acknowledge
NIMH (in part) and the Lynde and Harry Bradley Foun-
dation for support of this work. X-ray crystallographic
studies were supported by NIDA-NRL Interagency
Agreement Number Y1-DA1101.
(
26) Edwankar, C. R.; Edwankar, R. V.; Rallapalli, S. K.; Cook,
J. M. Nat. Prod. Commun. 2008, 3, 1389.
27) (a) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978,
Supporting Information Available. Experimental proce-
dures and spectral data for all new compounds including
X-ray data for 14 and H and C comparison tables
between natural and synthetic 1 and 2. This material is
available free of charge via the Internet at http://pubs.acs.
org.
(
43, 2480. (b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
1
13
7277. (c) Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586.
(
28) Currently Dr. J. St o€ ckigt is Professor at the College of Pharma-
ceutical Sciences, Zhejiang University (Hangzhou, China) and retired
from the Institute of Pharmacy, Johannes Gutenberg-University,
Mainz, Germany.
Org. Lett., Vol. 13, No. 19, 2011
5219