Enantioselective Formal Synthesis of (+)-Cycloclavine and Total Synthesis of (+)-5- epi-Cycloclavine

Article abstract of DOI:10.1021/acs.orglett.9b02015

Starting from the commercially available 4-bromoindole, a concise and efficient enantioselective formal synthesis of (+)-cycloclavine (1) in 13 steps with 2.0% overall yield and a total synthesis of (+)-5-epi-cycloclavine (2) in 14 steps with 3.3% overall yield were achieved. Key features of the syntheses include the addition of a Grignard reagent to the C-N/Heck reaction sequence to construct the fused 6-5-6 ring systems, cyclopropanation, an ester aminolysis reaction, and the first example of the construction of a 3-azabicyclo[3,1,0]hexane through an intramolecular [3 + 2] cycloaddition/nitrogen extrusion.

Full text of DOI:10.1021/acs.orglett.9b02015

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enantioselective Formal Synthesis of (+)-Cycloclavine and Total
Synthesis of (+)-5-epi-Cycloclavine
Wei Wang, Yang Mi, Xiao-Ping Cao,* and Zi-Fa Shi*
State Key Laboratory of Applied Organic Chemistry and College of Chemistry & Chemical Engineering, Lanzhou University,
Lanzhou 730000, P. R. China
*
S Supporting Information
ABSTRACT: Starting from the commercially available 4-bromoindole, a concise and efficient enantioselective formal synthesis
of (+)-cycloclavine (1) in 13 steps with 2.0% overall yield and a total synthesis of (+)-5-epi-cycloclavine (2) in 14 steps with
3
.3% overall yield were achieved. Key features of the syntheses include the addition of a Grignard reagent to the CN/Heck
reaction sequence to construct the fused 6−5−6 ring systems, cyclopropanation, an ester aminolysis reaction, and the first
example of the construction of a 3-azabicyclo[3,1,0]hexane through an intramolecular [3 + 2] cycloaddition/nitrogen extrusion.
rgot alkaloids comprise one of the largest classes of indole
synthetic community. In 2008, Szantay’s group reported the
́
E
alkaloids, which are a significant and abundant source of
first total synthesis of (±)-cycloclavine, in which intra-
1
pharmaceuticals. Ergot alkaloids possess the characteristics of
molecular aldol condensation and cyclopropanation of the
4b
3
,4-fused tricyclic indole skeletons. Several typical ergot
tetrasubstituted olefin were employed. More reports were
2
4a,c,h
4d
4f
4i
4j
alkaloids are shown in Figure 1. Cycloclavine was isolated
accomplished by Wipf,
and our group.
Brewer, Opatz, Bisai, Dong,
Of particular note is Wipf’s landmark first
enantioselective total synthesis of (−)-cycloclavine and
+)-cycloclavine in eight steps by means of a Rh-catalyzed
asymmetric allene cyclopropanation and intramolecular Diels−
4e,g
in 1969 from the seeds of Ipomea hildebrandtii and was
3
published by Hofmann and coworkers. Cycloclavine is a
(
highly congested polycyclic ring system that contains a
cyclopropane moiety. Because of its inspiring architecture
4a,h
4
a
Alder cycloaddition to assemble the fused cycloclavine.
In
and high potency on the serotonin 5-HT2C receptor,
cycloclavine has attracted significant attention from the
addition, Dong’s group disclosed an asymmetric total synthesis
4j
of (−)-cycloclavine in 2018. The key feature included a Pd-
catalyzed C−N bond coupling, followed by allylic alkylation, a
highly enantioselective Rh-catalyzed C−C activation, and a late
stage cyclopropanation of the disubstituted olefin.
In our previous work, we achieved an efficient formal
synthesis of (±)-cycloclavine via an iron-catalyzed aza-Cope−
Mannich cyclization and a self-terminating 6-exo-trig aryl
4e
radical-alkene cyclization. As an extension of this work, we
published the first asymmetric synthesis of Szantay’s amine
́
utilizing a tandem asymmetrical Barbier-type nucleophilic
addition/intramolecular ester aminolysis reaction and Ru-
4g
catalyzed isomerization. Although numerous cyclopropana-
5
tion strategies in total syntheses have been developed, the
cyclopropanation of Szantay’s amine presents significant
́
challenges. Rh-catalyzed cyclopropanation and the intra-
molecular [3 + 2] cycloaddition of olefinic tosylhydrazone
Received: June 12, 2019
Figure 1. Selected natural ergot alkaloids.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02015
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
have been used as a key step in the construction of
cyclopropane natural product skeletons. With the above
method in mind, the retrosynthetic analyses of (+)-cyclo-
clavine (1) and (+)-5-epi-cycloclavine (2) are outlined in
Scheme 1. We envisioned that (+)-cycloclavine (1) could be
(+)-5-epi-cycloclavine (2) could be realized through the ABC-
tricyclic olefin compound 4 via an intramolecular [3 + 2]
cycloaddition, followed by nitrogen extrusion. The crucial
compound 4 was anticipated to be derived from intermediate 6
by a series of functional group manipulations. Compound 6
could be accessed by an intramolecular Heck reaction of chiral
compound 8, which would be further divided in half via
6
Scheme 1. Retrosynthetic Analyses of (+)-Cycloclavine (1)
and (+)-5-epi-Cycloclavine (2)
asymmetric Grignard addition to deliver the known compound
9
9
and vinylmagnesium bromide.
We planned to explore the enantioselective synthesis of
+)-cycloclavine (1) by utilizing known Ellman (S)-N-tert-
(
butanesulfinyl imine 9, which was prepared from the
commercially available 4-bromoindole 10 in five steps and
4g,10
57% overall yield by us.
Thus chiral imine 9 (>99% ee was
determined by chiral HPLC; see the SI, p S39) was prepared
by C3-selective allylation, N-protection, oxidative cleavage of
the double bond, and condensation with (S)-2-methylpropane-
2-sulfinamide. Then, as outlined in Scheme 2, the treatment of
Scheme 2. Asymmetric Synthesis of Compounds 7 and 8
chiral imine 9 on a 20 g scale with 2 equiv of vinylmagnesium
bromide in CH Cl for 8 h at −78 °C afforded olefinic
2
2
sulfenamines 7 and 8 in 40 and 50% yields, respectively. The
reaction on a 0.5 g scale gave compounds 8 and 7 with a
diastereomeric ratio (dr) of 1.5:1 (see the SI, p S38).
Compound 7 (Scheme 3) was treated with potassium
bis(trimethylsilyl)amide (KHMDS), followed by reaction with
MeI to afford compound 11 in 80% yield. The desired product
5
by Heck reaction was found in 32% yield, together with the
7-endo-trig cyclization product in 64% yield (see the SI, p S26),
which could be separated by flash column chromatogra-
4e−g,i,11
phy.
To the best of our knowledge, a Rh-catalyzed
cyclopropanation of an alkene with an α-alkyl-α-diazoester has
7
been previously described. Therefore, compound 3 could be
constructed by the Rh-catalyzed protocol for the cyclo-
propanation of compound 5 with ethyl 2-diazopropanoate in
CH Cl at room temperature in 55% yield with recovered
starting material in 27% yield. According to the nuclear
Overhauser effect (NOE) experiments (see the SI, p S25), the
hydrogen of position five and the hydrogen of the t-
butanesulfinyl group are a little correlative, and they are far
away. Meanwhile the t-butanesulfinyl group is in close
proximity to the double bond of compound 5 from the back.
As shown in ChemBio 3D (see the SI, p S38), cyclo-
2
2
synthesized through ester aminolysis and the reduction of
4a
tetracyclic compound 3. The ABCE-tetracyclic compound 3
was accomplished from intermediate 5 via Rh-catalyzd
7
cyclopropanation. The fused A−B−C skeleton of disubsti-
tuted olefin compound 5 could be built by an intramolecular
Heck reaction of 7. The precursor 7 could be generated by
8
Grignard addition and the methylation of 9. On the contrary,
B
DOI: 10.1021/acs.orglett.9b02015
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Asymmetric Synthesis of Compound 13
Scheme 4. Attempted Heck Reaction of Compounds 8 and 7
11
reaction. To our delight, Heck reaction of the olefin using
Pd(OAc) /PPh and K CO in refluxing MeCN gave the
2
3
2
3
products 6 and 14 in a proportion of 3:5, which could not be
separated by flash column chromatography (see the SI, p S15).
As with the preparation of compound 5 from compound 11,
we hypothesized that the reaction was likely due to its sterically
hindered environment, as a bulky tert-butylsulfinamide was in
close proximity to the olefin, thus favoring the undesired 7-
endo-trig cyclization product over the 6-exo-trig cyclization
product, whether the nitrogen was methylated or not. A m-
CPBA-mediated oxidation reaction of compound 7 yielded a
sulfonamide intermediate. Then, the Heck reaction of the
sulfonamide intermediate, which used Pd(OAc) and (o-tol) P
propanation occurred from the front, less sterically hindered,
double bond of compound 5, leading to good selectivity. Other
diastereomers were not detected. Compared with the cyclo-
propanation strategies that have been previously used in
2
3
in Et N at 100 °C, gave the undesired 7-endo-trig cyclization
3
product 15 in 69% yield, whose structure was confirmed by
single-crystal X-ray diffraction. The C-5 stereochemistry of
compound 7 is the same as that of compound 15. This result
indicated that the C-5 stereocenter of compound 8 was in the
S configuration because of the opposite configuration at the C-
5 position.
4a−d,h,j
cycloclavine synthesis,
not only did we use an achiral Rh
catalyst but also we obtained compound 3 as a single
diastereomer. Its stereochemistry was supported by the NOE
experiments (see the SI, p S28 and S29). The removal of the
tert-butylsulfinyl group with 2 N HCl (in MeOH) in CH Cl
Next, the removal of the tert-butylsulfinyl group of the
inseparable mixture of compounds 6 and 14 with 4 N HCl
resulted in the corresponding primary amine products, which
were converted without further purification to the correspond-
ing other inseparable sulfamide compounds by treatment with
TsCl in the presence of Et N in CH Cl (Scheme 5). The
2
2
and the subsequent intramolecular ester aminolysis cyclization
in MeOH at room temperature led to the formation of lactam
1
2 in 72% yield by a two-step process without the isolation of
any intermediates. The cleavage of the tosyl groups from
compound 12 by the treatment with sodium naphthalenide in
THF at −78 °C led to compound 13 in 98% yield, which was
converted to (+)-cycloclavine (1) by reduction by Wipf and
3
2
2
mixture was allowed to react with bromoacetone in acetone to
give the separable product 16. At this time, we focused our
efforts on constructing the critical DE rings. The treatment of
ketone 16 with H NNHTs and HCl in MeOH/CH Cl
4
a
1
13
coworkers. The spectroscopic data ( H and C NMR) of
(
+)-cycloclavine (1) were in agreement with the compound
2
2
2
4a,c
reported by Wipf and coworkers (see the SI, p S2).
afforded tosylhydrazone 4. The stage was set for the key
installation of the DE rings by an intramolecular [3 + 2]
cycloaddition of olefinic tosylhydrazone, along with nitrogen
extrusion in a cascading manner. To our delight, the
intramolecular formal [3 + 2] cycloaddition reaction of
The intramolecular [3 + 2] cycloaddition reaction could be
regarded as a powerful tool for the formation of the
6
cycloclavine core. On the basis of this, we developed a
route for the synthesis of (+)-5-epi-cycloclavine (2) from
monosubstituted olefin 8 (Scheme 4). The Heck reaction was
6
compound 4 went smoothly, and the ABCDE pentacyclic
4e−g,i
previously employed in the cycloclavine synthesis.
A
product 17 was achieved as a single isomer in an overall yield
of 60% with a trace amount of pyrazoline 18 detected. We
think that it is favorable to form a cis configuration for the 6−5
highly congested ring system. Thus the cyclopropane is in a cis
configuration. This is the first example of constructing 3-
azabicyclo[3,1,0]hexane by means of an intramolecular [3 + 2]
variety of catalysts (Pd(OAc) , Pd(PPh ) , Pd (dba) )
2
3
4
2
3
combined with various ligands (PPh , Ph PCH CH PPh )
3
2
2
2
2
and bases (K CO , Cs CO ) in the presence of different
2
3
2
3
solvents (MeCN, DMF, THF) were screened for the assembly
of the tricyclic skeleton by means of an intramolecular Heck
C
DOI: 10.1021/acs.orglett.9b02015
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Asymmetric Synthesis of (+)-5-epi-Cycloclavine
ASSOCIATED CONTENT
Supporting Information
■
(
2)
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02015.
1H and 13C NMR spectra for compounds (7, 8, 11, 5,
NOE spectra of 5, 7-endo-trigcyclization product, 3,
NOE spectra of 3, 12, 13, 1, 15, 16, 18, and 2) along
with X-ray crystallographic data for 15 and HPLC
spectra of 2 and 9 (PDF)
Accession Codes
CCDC 1882003 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*
*
E-mail: caoxplzu@163.com (X.-P. C.).
E-mail: shizf@lzu.edu.cn (Z.-F. S.).
ORCID
Wei Wang: 0000-0002-0142-5612
Yang Mi: 0000-0002-0297-6782
Xiao-Ping Cao: 0000-0001-8340-1122
Zi-Fa Shi: 0000-0001-9231-5963
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to Lanzhou University on the occasion
of its 110th anniversary. We are grateful for financial support
from the National Natural Science Foundation of China
(
21572085, 21272098, and 21572086); the Program for
Changjiang Scholars and Innovative Research Team in
University (PCSIRT: IRT_15R28), the Fundamental Research
Funds for the Central Universities (FRFCU: lzujbky-2016-
ct02), and the 111 Project of MOE (111-2-17). We thank
Yong-Liang Shao of Lanzhou University for X-ray crystallo-
graphic analyses.
cycloaddition reaction. The subsequent cleavage of two tosyl
groups of 17 by treatment with sodium naphthalenide in THF
at −78 °C and N-methylation afforded (+)-5-epi-cycloclavine
(
2) in 71% yield (97% ee was determined by chiral HPLC; see
1
13
the SI, p S40). The spectroscopic data ( H and C NMR) of
(
+)-5-epi-cycloclavine (2) were consistent with those of (±)-5-
4c
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