Enantioselective Total Synthesis of (+)-Lysergol: A Formal anti-Carbopalladation/Heck Cascade as the Key Step

Article abstract of DOI:10.1021/acs.orglett.7b00675

The enantioselective synthesis of (+)-lysergol was completed in 12 steps and an overall yield of 13% starting from a known literature precursor. The key step relies on a domino reaction containing a formal anti-carbopalladation, which is terminated by a β-silyl-directed Heck reaction. During this transformation, the two six-membered rings of the ergot scaffold are formed in a completely stereospecific manner.

Full text of DOI:10.1021/acs.orglett.7b00675

Letter
pubs.acs.org/OrgLett
Enantioselective Total Synthesis of (+)-Lysergol: A Formal
anti‑Carbopalladation/Heck Cascade as the Key Step
Bastian Milde,† Martin Pawliczek,† Peter G. Jones,‡ and Daniel B. Werz*,†
‡
†Institut fur Organische Chemie and Institut fur Anorganische und Analytische Chemie, Technische Universitat Braunschweig,
̈
̈
̈
Hagenring 30, 38106 Braunschweig, Germany
S
* Supporting Information
ABSTRACT: The enantioselective synthesis of (+)-lysergol was completed in 12 steps and an overall yield of 13% starting from
a known literature precursor. The key step relies on a domino reaction containing a formal anti-carbopalladation, which is
terminated by a β-silyl-directed Heck reaction. During this transformation, the two six-membered rings of the ergot scaffold are
formed in a completely stereospecific manner.
hree of the most famous indole alkaloids belonging to the
ergot family are (+)-lysergol, 1, (+)-isolysergol, 2, and
(+)-lysergic acid, 3, the parent compound of LSD (Figure 1).
Scheme 1. Two Examples of the Synthesis of Indole Alkaloids
of the Ergot Family
T
Figure 1. Indole alkaloids of the ergot family.
They have attracted much attention in the past few decades,
especially because of their biological activity,1 and therefore,
numerous synthetic routes have been developed.2 In 2011, the
Ohno group presented a Pd-catalyzed domino cyclization
starting from allene-substituted bromoindole 4 to access these
prominent alkaloids (Scheme 1, top).2p This method allowed the
assembly of the C and D rings in one step. In contrast, Luo et al.
recently reported the construction of the ergot alkaloid scaffold
using a Rh-catalyzed [3 + 2]-annulation, whereas the indole
moiety was formed at a late stage (Scheme 1, bottom).2v
Latterly, we focused our research on the development of a
novel type of a Pd-catalyzed domino reaction, in which an alkyne
moiety is forced to undergo a formal anti-carbopalladation to
obtain tetrasubstituted olefins.3,4 A normal syn-carbopalladation
usually proceeds via a syn-attack of an organometallic R-[Pd]
species on the π-system of an alkyne, and therefore, the two
residues [Pd] and R are located on the same side of the emerging
double bond. Since such an intermediate is still a highly reactive
species, additional transformations, such as further carbopalla-
dations or a terminating cross-coupling reaction, are possible and
have been extensively used to build up complex scaffolds in only
one step.4,5 Under certain conditions (i.e., the absence of any β-
hydrogen atoms at the alkyne terminus, monodentate phosphine
ligands at the Pd center, and polar aprotic solvents), the system is
forced to isomerize after the initial syn-attack in the coordination
sphere of the metal. Residues [Pd] and R are now located in an
anti-fashion across the emerging double bond. Since such a motif
available via an anti-carbopalladation is also found in certain
classes of natural products, we focused our efforts on a novel
Received: March 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00675
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Organic Letters
Letter
approach to synthesize (+)-lysergol, 1. Our retrosynthetic
analysis revealed that the alkaloid scaffold can be traced back
to the TMS-substituted tetrasubstituted double bond in tosyl-
protected amine 8 (Scheme 2). Previous studies showed that the
Scheme 3. Synthesis of the Domino Precursor
Scheme 2. Retrosynthetic Analysis
silyl group can be easily removed either under acidic conditions
or in the presence of a fluoride source.3d The ester moiety in 8
arises from an oxidation sequence of the exocyclic double bond in
9. As a key step, a cascade involving a formal anti-
carbopalladation reaction and a terminating β-silyl-directed
Heck reaction is envisioned. The allylic TMS group at the side
chain of the domino precursor 10 seems to be crucial because we
expect a fully conjugated system to be formed in its absence.
To test our notion, we started with 4-bromoindole (11);
aldehyde 12 was obtained in 72% yield using a known four-step
protocol (Scheme 3).2m The procedure consists of a C3-selective
allylation followed by N-protection and finally the oxidation of
the double bond to the corresponding aldehyde using an OsO4/
NaIO4-mediated cleavage. In the next step, the alkyne moiety was
installed using trimethylsilylacetylene, and secondary alcohol 13
was obtained in 71% yield as a racemic mixture. To generate the
desired enantiomer, a redox manipulation was applied using
Dess-Martin periodinane to oxidize the alcohol. The resulting
ketone 14 was reduced enantioselectively by employing Noyori’s
catalyst 15.6 After the formation of Mosher’s ester, an
enantiomeric excess of ∼99% was observed using 19F NMR
integration. The synthesis of the domino precursor was finalized
in 74% yield by applying a Mitsunobu reaction with sulfonamide
17. The latter compound was easily prepared in 68% yield using
the second generation Hoveyda−Grubbs catalyst and the
corresponding terminal olefins.
To elucidate the stereochemistry of chiral alcohol 16, X-ray
crystallography seemed to be the method of choice. Unfortu-
nately, the secondary alcohol did not yield any single crystals.
Therefore, ester 18, bearing a camphanoyl moiety, was
synthesized.7 The bicyclic scaffold facilitates crystallization, and
suitable single crystals were obtained. After X-ray analysis, the
absolute configuration was unequivocally established (Figure 2).
With domino precursor 10 in hand, we next investigated its
transformation to the desired ergot scaffold 9, containing a
terminal double bond arising from a β-silyl-directed Heck
reaction. Based on our previous results, we first chose a catalytic
system consisting of [PdCl2(PhCN)2], Fu’s salt,9 to liberate the
highly sterically encumbered tris(t-butyl)phosphine as the ligand
Figure 2. Molecular structure (50% ellipsoid probability) of 18 in the
solid state. Oxygen atoms are shown in red, sulfur atom in yellow,
bromine atom in dull yellow, nitrogen atom in blue, and silicon atom in
turquoise. Some hydrogen atoms are omitted for clarity.8
and Et3N in DMF at 70 °C (Table 1, entry 1). After 15.5 h, a
mixture of the desired product 9 and the silyl-containing side
product 19, which is formed by β-hydrogen elimination, was
obtained in a ratio of almost 1:1. The ratio slightly increased by
heating the reaction to 100 °C, but a major improvement was first
effected by switching to XPhos10 instead of tris(t-butyl)-
B
DOI: 10.1021/acs.orglett.7b00675
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Domino Reaction
Scheme 4. Finalization of the (+)-Lysergol Synthesis
entry
1
ligand
solvent temp (°C) time (h) yields (%)
[t-Bu3PH][BF4]
DMF
DMF
DMF
DMF
DMF
DMA
70
100
100
100
120
120
15.5
1.5
2.5
7.5
2.0
2.0
9, 29
19, 37
9, 41
2
3
4
5
6
[t-Bu3PH][BF4]
XPhos
19, 34
9, 59
19, 13
9, 56
BrettPhos
XPhos
19, 13
9, 68
19, 17
9, 80
XPhos
19, 17
b
7
XPhos
XPhos
XPhos
DMF
DMF
DMA
120
120
140
decomposition
many side reactions
c
8
9
2.0
9, 72
19, 12
a
Reaction conditions: 10 (1.0 equiv), [PdCl2(PhCN)2] (10 mol %),
b
ligand (20 mol %), Et3N (5.0 equiv), solvent (25 mM), temp, time. n-
Bu4NOAc (5.0 equiv) was used instead of Et3N. [Pd(OAc)2] (10 mol
c
%) was used instead of [PdCl2(PhCN)2].
phosphine as the ligand (Table 1, entries 2 and 3). Using a more
polar ligand, namely, BrettPhos,10 did not further increase the
yield, but when the reaction was carried out at 120 °C, the desired
product was obtained in 68% yield (Table 1, entries 4 and 5). As
much as 80% of the desired domino product 9 was formed when
the solvent was changed to DMA, representing the best
conditions (Table 1, entry 6). Further attempts to optimize
this reaction by using n-Bu4NOAc, [Pd(OAc)2], or the use of
even higher temperatures were not successful (entries 7−9). It is
noteworthy that the cyclization cascade proceeds in a completely
stereoselective manner: only one diastereoisomer was formed,
and the enantiomeric excess remains at 99%, as analyzed by chiral
HPLC.
With optimized conditions in hand, we proceeded to finish the
total synthesis of (+)-lysergol, 1 (Scheme 4). Again, an OsO4/
NaIO4-mediated oxidative cleavage of the exocyclic double bond
was applied to obtain the corresponding aldehyde 20. Attempts
to achieve the desired cleavage by ozonolysis proved to be
unsuccessful and led to decomposition of the complete skeleton.
Next, the generated aldehyde 20 was reduced to the
corresponding alcohol, but unfortunately, all attempts to cleave
the TMS group at this stage either under acidic conditions or by
using a fluoride source have been in vain. Therefore, the aldehyde
was converted into methyl ester 8 in 90% yield via a two-step
protocol comprising Pinnick oxidation and subsequent ester-
ification using trimethylsilyldiazomethane. The enantiomeric
excess remains at 99% as determined by chiral HPLC. The
trisubstituted olefin in 21 was now obtained by silyl deprotection
using TFA. Finally, DIBAL-H was used to reduce the ester to the
known primary alcohol 22. A following two-step sequence,
containing tosyl deprotection and selective N-methylation,
would yield (+)-lysergol in 60% yield.
In summary, we have shown that the formal anti-
carbopalladation reaction developed in our lab is a powerful
and reliable synthetic tool for constructing tetrasubstituted
olefins, even in more complex scaffolds. A novel enantioselective
route to access the ergot alkaloid (+)-lysergol was achieved in 12
steps and an overall yield of 13% starting from the known racemic
alcohol 13. During the key step, the formal anti-carbopalladation
which is terminated by a silyl-directed Heck reaction, two rings
are formed in a completely stereospecific way.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00675.
Detailed experimental procedures, analytical data for all
new compounds (PDF)
Crystal data for 18 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: d.werz@tu-braunschweig.de.
ORCID
Daniel B. Werz: 0000-0002-3973-2212
C
DOI: 10.1021/acs.orglett.7b00675
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Angew. Chem., Int. Ed. 2013, 52, 13243−13246. (o) Gu, S.; Luo, L.; Liu,
J.; Bai, L.; Zheng, H.; Wang, Y.; Luan, X. Org. Lett. 2014, 16, 6132−6135.
(p) Milde, B.; Leibeling, M.; Pawliczek, M.; Grunenberg, J.; Jones, P. G.;
Werz, D. B. Angew. Chem., Int. Ed. 2015, 54, 1331−1335. (q) Goh, S. S.;
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(s) Blouin, S.; Gandon, V.; Blond, G.; Suffert, J. Angew. Chem., Int. Ed.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the German Research Foundation (DFG, WE
2932/7-1) for funding.
■
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