Synthesis of Chiral Tryptamines via a Regioselective Indole Alkylation

Article abstract of DOI:10.1021/acs.orglett.8b02335

A practical synthesis of chiral tryptamines from simple, unprotected indoles has been developed. Indole nucleophiles prepared with MeMgCl in the presence of CuCl reacted with chiral cyclic sulfamidates almost exclusively at the C³-position of i

Full text of DOI:10.1021/acs.orglett.8b02335

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Chiral Tryptamines via a Regioselective Indole
Alkylation
Jens Wolfard, Jie Xu,* Haiming Zhang, and Cheol K. Chung*
Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United
States
S
* Supporting Information
ABSTRACT: A practical synthesis of chiral tryptamines from simple, unprotected indoles has been developed. Indole
nucleophiles prepared with MeMgCl in the presence of CuCl reacted with chiral cyclic sulfamidates almost exclusively at the C3-
position of indole to form a variety of α- and/or β-substituted chiral tryptamines in good yield with excellent regioselectivity.
The utility of this simple alkylation process has been demonstrated with the practical synthesis of two biologically active targets,
cipargamin and TIK-301, which were completed in three steps, starting from the corresponding indole starting materials.
and chiral amine-derived electrophiles, such as chiral aziridines
and cyclic sulfamidates, would provide convenient access to
these valuable chiral scaffolds. Indeed, the C3-selective indole
alkylation had been the subject of extensive studies in order to
overcome the unwanted alkylation at the C2 or N1 positions.5
However, there are only limited examples where these
approaches were used in a stereocontrolled manner. For
instance, it is reported that the use of chiral aziridines or cyclic
sulfamidates as reaction partners preferentially provided N1-
alkylation (see Scheme 1a).6 Aziridine electrophiles have been
applied to provide C3-selective alkylation under Lewis acidic
hiral tryptamines are frequently encountered in pharma-
Ccology, because of their significant biological activities in
the central nervous system.1 In addition, the chiral tryptamine
moiety serves as the synthetic precursor of many medicinally
important indole alkaloids and is found in numerous
biologically active natural products and pharmaceuticals (see
Figure 1).2
Scheme 1. Regioselective Indole Alkylation
Figure 1. Chiral tryptamine-containing pharmaceuticals.
In particular, stereocontrolled synthesis of tetrahydro-β-
carboline-containing compounds such as cipargamin often
relies on the diastereoselective Pictet−Spengler reaction,
which, in turn, requires enantiomerically pure tryptamines as
starting material.3 The latter is typically prepared in a
nonstereoselective manner via a multistep sequence involving
hazardous nitroalkane reagents or prepared by Larock
indolization via a three-step sequence requiring the use of
palladium and additional silyl deprotection.4 Therefore, the
development of a simple regioselective alkylation approach that
involves readily available nonprotected indoles as nucleophiles
Received: July 24, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02335
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
conditions; however, this method is only applicable to the
synthesis of β-substituted tryptamines, because the displace-
ment occurs preferentially at the more-substituted carbon (see
Scheme 1b).7 Here, we report that low-order cuprate of
indoles, in combination with chiral cyclic sulfamidates,
successfully provide practical access to both α- and β-
substituted chiral tryptamines with high regioselectivity (see
Scheme 1c).
was observed, presumably due to the incomplete cuprate
formation (see Table 1, entries 11−13).11
With the optimized conditions in hand, the generality of this
reaction was examined next, and the results are summarized in
Tables 2 and 3. Encouragingly, the Cu-mediated indole
a
Table 2. Indole Substrate Scope
At the outset, and while avoiding the protective group on the
indole, we considered the use of either chiral aziridines or
cyclic sulfamidates as the electrophile. It was found that the
reaction with the former always led to a mixture of α-and β-
substituted tryptamines, while the latter unambiguously
reacted to displace the C−O bond.8 Therefore, we chose the
cyclic sulfamidates as the reaction partner for our optimization
studies (see Table 1).
a
Table 1. Optimization of Sulfamidate Alkylation
b
entry
base/additive (temperature)
isolated yield (%)
C3/N1
1
2
3
4
5
6
7
MeMgCl/none (−10 °C)
MeMgCl/CuCl (−10 °C)
MeMgCl/CuBr (−10 °C)
MeMgCl/Cul (−10 °C)
MeMgCl/CuCl (−10 °C)
MeMgCl/ZnCl2 (−10 °C)
MeMgCl/ZnBr2 (−10 °C)
MeMgBr/CuCl (−10 °C)
PhMgCl/CuCl (−10 °C)
MeLi/CuCl (−10 °C)
14
66
37
26
38
38
28
26
66
N.D.
N.D.
76
65
31/69
95/5
95/5
90/10
67/33
22/78
37/63
45/54
96/4
11/89
42/58
97/3
c
8
9
d
a
10
11
12
Standard conditions: MeMgCl (130 mol %, 3 M in THF), indole
d
MeMgCl/CuCl (−40 °C)
MeMgCl/CuCl (−20 °C)
MeMgCl/CuCl (−0 °C)
(150 mol %), CuCl (130 mol %) in DCM, 0 °C, followed by 5a (100
mol %) in DCM (0.2−0.5 mol/L), −20 °C. bAs determined by HPLC
analysis of the crude products.
e
13
95/5
a
Base (130 mol %) was added to a mixture of 1a (150 mol %) and
additive (130 mol %) in DCM followed by 5a (100 mol %) in DCM
b
c
(0.2−0.5 mol/L). Determined by HPLC analysis. A catalytic
amount of CuCl (20 mol %) was used. Not determined. The
cuprate was prepared at 0 °C, and 5a was added at −20 °C.
alkylation tolerated a variety of substituents both on the
indole nucleophile, as well as on the cyclic sulfamidate,
providing the C3-alkylated indole products in moderate to
good yield and excellent regioselectivity. For instance, indoles
with either electron-donating or electron-withdrawing sub-
stituents participated in the reaction well (Table 2, 6b−6g),
and sterically demanding substrates also worked reasonably
well (6h and 6i).
On the other hand, azaindoles generally are poor substrates.
Under standard reaction conditions, 6-azaindole provided only
8% of the alkylation product, albeit with comparable
regioselectivity (6j). Other azaindoles, such as indazole and
7-azaindole, failed to produce any of the desired alkylated
products.
Gratifyingly, a variety of sulfamidates were tested in the
reaction successfully. Both aryl- and alkyl-substituted sulfami-
dates, prepared in a two-step sequence from the corresponding
amino alcohols, were converted smoothly to the respective α-
substituted chiral tryptamines (6k−6q).12 Similarly, six-
membered cyclic sulfamidate also participated in the alkylation
well, producing a homologated tryptamine in good yield and
regioselectivity (6r). Note that this alkylation process can be
also applied to gain access to β-substituted, and α,β-
disubstituted tryptamines (6s, 6t).13 In these cases, the indole
nucleophile added to the corresponding cyclic sulfamidate with
the inversion of stereochemistry at the carbon-bearing oxygen
with complete stereospecificity.14 For instance, the reaction
with the cis-aminoindanol-derived cyclic sulfamidate led to
d
e
Contrary to the literature precedents, which suggest
preferential alkylation at the C3-position when Grignard
reagents were used as a base, our initial attempts were met
with low yields and poor site selectivity (see Table 1, entry
1).5a Postulating that the softer indole nucleophile would
prefer to react as a carbon-centered nucleophile, various
additives, including Cu and Zn salts, were surveyed.
Interestingly, a mixed halide system such as MeMgCl, in
combination with CuBr or CuI, or MeMgBr in combination
with CuCl was much less efficient than the chloride-only
system (see Table 1, entries 2, 3, 4, and 8).9 In our hands,
other copper salts, such as CuCl2, CuCN, CuTC, or Cu(SCN),
were also inferior to CuCl.10 A catalytic amount of CuCl was
not tolerated, resulting in significant decreases in yield and
selectivity (see Table 1, entry 5). Notably, a reversal of
regioselectivity was observed when zinc halides were used
instead of CuCl (see Table 1, entries 6 and 7). The same was
true when MeLi was used as base instead of MeMgCl (see
Table 1, entry 10), while the use of another Grignard reagent
was well-tolerated (see Table 1, entry 9). Finally, we evaluated
the effect of reaction temperature, and established that the
displacement reaction performed optimally at approximately
−20 °C. At below −30 °C, a significant drop in regioselectivity
B
DOI: 10.1021/acs.orglett.8b02335
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Spengler reaction completed the synthesis in 91% yield
(Scheme 2, eq 1). The versatility of this process was further
Table 3. Cyclic Sulfamidate Substrate Scope
Scheme 2. Synthesis of Cipargamin and TIK-301
exemplified in a practical synthesis of a β-substituted
tryptamine-based investigational melatonin agonist, TIK-
301.18 This time, the alkylation product 11 was smoothly
converted to the target product after a simple N-acyl group
swap. This three-step sequence compares favorably with
previous syntheses (see Scheme 2, eq 2).19
a
Standard conditions: MeMgCl (130 mol %, 3 M in THF), indole
(150 mol %), CuCl (130 mol %) in DCM, 0 °C, followed by 5a (100
mol %) in DCM (0.2−0.5 mol/L), −20 °C. bAs determined by HPLC
analysis of the crude products.
In summary, we successfully developed a practical synthesis
of chiral tryptamines using unprotected indole and chiral cyclic
sulfamidates as starting materials. Careful optimization of base
and Cu additive led to a simple protocol allowing the desired
alkylation at the C3-position of indole with high regioselectivity
and good yield with a range of substrates. Considering the
significance of its product structural class, and simplicity of the
reaction conditions, we believe this method will find broader
application in drug discovery and development.
trans-1-amino-2-indolylindane (6t), which was confirmed by
X-ray crystallographic analysis (see Figure 2).15
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02335.
Full experimental details and characterization data,
including X-ray crystallography data (PDF)
X-ray crystal structure of compound 6t (Figure S1);
crystal data and structure refinement for 6t (Table S1);
atomic coordinates (× 104) and equivalent isotropic
displacement parameters (× 103 Å2) for 6t (Table S2);
bond lengths (Å) and angles (°) for 6t (Table S3);
anisotropic displacement parameters (× 103 Å2) for 6t
(Table S4); and hydrogen coordinates (× 104) and
isotropic displacement parameters (× 103 Å2) for 6t
(Table S5) (PDF)
Figure 2. X-ray structure of 6t.
The utility of this alkylation process was next demonstrated
by converting the chiral tryptamine product to tetrahydro-β-
carbolines by using the Pictet−Spengler reaction.16 For
instance, the chiral tryptamine 9, derived from 5-fluoro-6-
chloroindole, could be readily converted to cipargamin, which
is a potent inhibitor of a parasite plasma membrane Na+-
ATPase that regulates sodium and osmotic homeostasis.17 The
alkylation was achieved to provide the intermediate 9 in 65%
yield with 99:1 regioselectivity, and Boc removal/Pictet−
Accession Codes
CCDC 1857975 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
C
DOI: 10.1021/acs.orglett.8b02335
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) (a) Hebeisen, P.; Weiss, U.; Alker, A.; Staempfli, A. Tetrahedron
Lett. 2011, 52, 5229−5233. (b) White, G. J.; Garst, M. E. J. Org.
Chem. 1991, 56, 3177−3178.
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
(9) For a related chloride ion effect in cyclic sulfamidate alkylation,
see: Arigala, P.; Sadu, V. S.; Hwang, I.-T.; Hwang, J.-S.; Kim, C.-U.;
Lee, K.-I. Adv. Synth. Catal. 2015, 357, 2027−2032.
AUTHOR INFORMATION
(10) For a recent review on nucleophilic organocopper (I) reaction,
see: Yoshikai, N.; Nakamura, E. Chem. Rev. 2012, 112, 2339−2372.
(11) We found that chlorinated solvents such as DCM or DCE
worked best in the reaction, although many other solvents were also
usable including THF, 1,4-dioxane, and DME. In later solvents,
however, the reaction mixture tended to form thick slurries, making
proper agitation difficult.
■
Corresponding Authors
*E-mail: xu.jie@gene.com (J. Xu).
*E-mail: chungc4@gene.com (C. K. Chung).
ORCID
Jie Xu: 0000-0001-6424-1055
Haiming Zhang: 0000-0002-2139-2598
Cheol K. Chung: 0000-0001-5658-4306
(12) For the preparation of cyclic sulfamidates and their synthetic
application, see: (a) Lohray, B. B.; Bhushan, V. Adv. Heterocycl. Chem.
1997, 68, 89−180. (b) Posakony, J. J.; Grierson, J. R.; Tewson, T. J. J.
́
Org. Chem. 2002, 67, 5164−5169. (c) Melendez, R. E.; Lubell, W. D.
Notes
Tetrahedron 2003, 59, 2581−2616. (d) Hebeisen, P.; Weiss, U.; Alker,
A.; Staempfli, A. Tetrahedron Lett. 2011, 52, 5229−5233. (e) Moss, T.
A.; Hayter, B. R.; Hollingsworth, I. A.; Nowak, T. Synlett 2012, 23,
2408−2412. (f) Arigala, P.; Sadu, V. S.; Hwang, I.-T.; Hwang, J.-S.;
Kim, C.-U.; Lee, K.-I. Adv. Synth. Catal. 2015, 357, 2027−2032.
(g) Mata, L.; Avenoza, A.; Busto, J. H.; Peregrina, J. M. Chem. - Eur. J.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Francis Gosselin (Genentech, Inc.) for helpful
discussions, and Dr. Antonio DiPasquale, Dr. Kenji Kurita, and
Tina Nguyen (Genentech, Inc.) for analytical support.
(13) In the formation of 6t, it was noted that the reaction was
accompanied by the formation of a few unidentifiable side products
judged by LCMS analysis, which presumably led to lower yield.
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DOI: 10.1021/acs.orglett.8b02335
Org. Lett. XXXX, XXX, XXX−XXX