Diversity oriented synthesis: Concise entry to novel derivatives of Yohimbine and Corynanthe alkaloids

Article abstract of DOI:10.1016/j.tetlet.2011.10.115

A novel MCAP-cycloaddition sequence has been applied to the facile synthesis of β-carboline intermediates to gain rapid access to novel derivatives of Yohimbine-like and Corynanthe-like compounds that may be easily diversified by cross-coupling reactions

Full text of DOI:10.1016/j.tetlet.2011.10.115

Tetrahedron Letters 53 (2012) 477–479
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diversity oriented synthesis: concise entry to novel derivatives
of Yohimbine and Corynanthe alkaloids
⇑
Zhiqian Wang, Kyosuke Kaneda, Zhenglai Fang, Stephen F. Martin
Department of Chemistry and Biochemistry and Texas, Institute for Drug and Diagnostic Development, The University of Texas, Austin, TX 78712, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel MCAP-cycloaddition sequence has been applied to the facile synthesis of b-carboline intermedi-
ates to gain rapid access to novel derivatives of Yohimbine-like and Corynanthe-like compounds that may
be easily diversified by cross-coupling reactions and N-derivatizations to generate small compound
libraries.
Received 27 September 2011
Revised 13 October 2011
Accepted 19 October 2011
Available online 31 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent assembly process
Imine
Dipolar cycloaddition
Suzuki reaction
N-Derivatization
The pentacyclic and tetracyclic ring systems characteristic of the
Yohimbineand Corynanthealkaloids, respectively, areexemplifiedby
yohimbine (1), tetrahydroalstonine (2), and geissoschizine (3), and
alkaloids belonging to these families exhibit a remarkable range of
(BIOS),4 for discovering biologically active compounds. We thus
became interested in preparing 4 and 5, as novel analogs of the
Yohimbine and Corynanthe alkaloids.
1
We have recently been interested in the design and development
of effective strategies for preparing functionalized heterocyclic scaf-
folds that can be easily diversified by cross-coupling and N-derivati-
biological activities. For example, owing to their high affinity for
the a-adrenergic receptor, some of these alkaloids may be used to
2
treat hypertension, depression, and diabetes. Accordingly, deriva-
tives of these alkaloids are promising targets as bioactive com-
pounds in drug discovery, and some analogs having substructures
of these natural products have been found to exhibit useful biologi-
5
zation reactions. Indeed, a three-component reaction of 6 to give 7,
a key step in our concise synthesis of tetrahydroalstonine (2)
6
(
Scheme 1), served as the inspiration for a novel multicomponent
3
assembly process (MCAP) that featured the use of Mannich-type
reactions to give substituted arylaminomethyl derivatives. These
adducts can be subjected to various cyclizationreactions that are en-
abled by selective functional group pairing to construct substituted
cal activities. In this context, it is significant that the synthesis of
functionalized frameworks found in natural products has emerged
as a useful strategy, which is known as biology oriented synthesis
7
heterocyclic ring systems. We have demonstrated the utility of this
generalapproachto diversityorientedsynthesis(DOS)byapplyingit
8
to the preparationof small librariesof substitutedbenzodiazepines,
9
10
11
norbenzomorphans, aryl piperidines, tetrahydroisoquinolines,
as well as several conformationally-constrained benzoxazocines,
1
2
and benzazocines. We now report the extension of this useful
methodology to the facile preparation of compounds derived from
the Yohimbine and Corynanthe scaffolds.
⇑
Corresponding author.
E-mail address: sfmartin@mail.utexas.edu (S.F. Martin).
Scheme 1. Discovery of novel Mannich-type MCAP.
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.115

4
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Z. Wang et al. / Tetrahedron Letters 53 (2012) 477–479
Scheme 2. Corynanthe-like compounds via N-derivatizations.
We envisioned that compounds generally related to 4 could be
accessed by a sequential MCAP of a dihydro-b-carboline such as 6
followed by a dipolar cycloaddition of a nitrone derived from the
adduct.7 Toward this end, treatment of 6 with crotonyl chloride
2 2
and tert-butyldimethyl(vinyloxy)silane in CH Cl afforded the
amide 8 in 85% yield (Scheme 2). Heating 8 with N-methylhydr-
oxylamine hydrochloride and triethylamine in refluxing toluene
then provided an intermediate nitrone that underwent a [3+2]
dipolar cycloaddition to give 9 as a single diastereoisomer. When
9
was treated with LiAlH
quantitative yield. Subsequent reductive scission of the N–O bond
in 10 using Ni
B, which was generated in situ,13 delivered the ami-
4
, the amine 10 was obtained in nearly
2
no alcohol 11 in 64% yield. The amino group in 11 could then be
derivatized by a number of selective N-functionalizations. For
example, N-acylation provided amides such as 12, whereas reac-
tion with sulfonyl chlorides gave sulfonamides like 13.
In order to establish the versatility of our approach to Yohimbine
analogs as 9 and 10 and Corynanthe derivatives like 11–13, we que-
ried whether representative bromo substituted carbolines might
be employed as starting materials. We reasoned that a bromo
group would be a convenient functional handle for performing a
variety of cross-coupling reactions to introduce other substituents.
Scheme 3. 4-Arylated Yohimbine- and Corynanthe-like compounds.
and 15 in the presence of 5 mol % [Pd(dppf)Cl
in refluxing toluene for 17 h. Use of other catalysts including
Pd(OAc) , Pd(PPh , and Pd(t-Bu P) gave lower yields. Reduction
2 2 2 2 3
]ÁCH Cl and Cs CO
2
3
)
4
3
2
14
Accordingly, the known 5-bromo-b-carboline (14), which was
prepared in four steps from 4-bromoindole was treated with tert-
butyldimethyl(vinyloxy)silane and crotonyl chloride to provide
an intermediate adduct that was then heated with N-methylhydr-
oxylamine hydrochloride in the presence of triethylamine to afford
the isoxazolidine 15 in 43% overall yield (Scheme 3). The intramo-
lecular dipolar cycloaddition reaction was highly stereoselective as
of the lactam moiety in 16 with alane gave amine 17 in 85% yield.
Subsequent reductive cleavage of the N,O–bond in 17 using nickel
boride as before produced the desired amino alcohol 18 in excel-
lent yield. Selective N-functionalization of 18 was then achieved
in several ways. For example, reaction of 18 with cyclohexanecarb-
oxaldehyde provided a relatively stable N,O-acetal that was subse-
quently reduced upon treatment with NaCNBH
3
under mildly
1
5 was the only isomer detected. After exploring a number of con-
acidic conditions to furnish 19 in 53% yield. Similarly, the cycload-
duct 15 was converted into the amino alcohol 22 in good overall
yield via sequential Suzuki cross-coupling, lactam reduction, and,
ditions for performing a Suzuki cross-coupling reaction, we found
the best yield of 16 was obtained by heating phenylboronic acid

Z. Wang et al. / Tetrahedron Letters 53 (2012) 477–479
479
the lower solubility of 9 in ethyl acetate or by column chromatog-
raphy. Reduction of the lactam moiety of 26 and 30 with LiAlH
4
,
followed by cleavage of the N–O bond with nickel boride provided
the amino alcohols 28 and 32; alane could also be used to reduce
the lactam. The amino alcohol 28 was then converted into the urea
2
9 upon reaction with phenylisocyanate, whereas 32 was
transformed into the amide 33 with p-toluoyl chloride.
In summary, we have extended our general approach for diver-
7
sity oriented synthesis and applied a MCAP/cyclization sequence
to various dihydro-b-carbolines to gain facile access to novel com-
pounds having scaffolds related to the Yohimbine and Corynanthe
alkaloids. Intermediates are functionalized to enable a number of
different derivatization reactions, including Suzuki cross-coupling
reactions and N-functionalization by reductive alkylation, acyla-
tion, urea and thiourea formation, and sulfonylation. The applica-
tion of this general plan for DOS to the synthesis of small
libraries of biaryl compounds for biological screening is in
progress, and the results of these and related investigations will
be reported in due course.
Acknowledgments
We thank the National Institutes of Health (GM 25439 and
GM 86192) and the Robert A. Welch Foundation (F-0652) for their
generous support of this work.
Supplementary data
Supplementary data (representative experimental procedures
and characterization data of compounds 14, 16, 20–24, 26, 27,
3
3, and 36) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2011.10.115.
References and notes
1.
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Scheme 4. 7-Arylated Yohimbine- and Corynanthe-like compounds.
N–O bond scission. Reaction of the secondary amine in 22 with
ethylisocyanate gave urea 23 in 72% yield.
We then extended this chemistry in a straightforward fashion
4
.
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Wetzel, S.; Casaulta, M.; Odermatt, A.; Ertl, P.; Waldmann, H. Proc. Natl. Acad.
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Ertl, P.; Waldmann, H. Chimia 2007, 61, 355–360.
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5
6
.
.
For a review of such strategies, see: Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J.
2009, 15, 1300–1308.
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a multicomponent assembly
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process to provide an intermediate adduct, heating of which with
N-methylhydroxylamine generated isoxazolidine 25 in 50% yield.
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7. (a) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org. Lett. 2007, 9, 4223–
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8
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6% yields, respectively. The products of these Suzuki cross-
2
2 2
]ÁCH Cl and
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2
3
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8
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