Total Synthesis of (R)-Sarkomycin Methyl Ester via Regioselective Intermolecular Pauson-Khand Reaction and Iridium-Catalyzed Asymmetric Isomerization

Article abstract of DOI:10.1021/acs.orglett.8b01525

A new five-step enantioselective synthesis of (R)-sarkomycin methyl ester is described. The cyclopentane scaffold was built by a regioselective intermolecular Pauson-Khand reaction. Enantioselectivity was introduced by a novel Ir-catalyzed isomerization reaction. The last steps involved a catalytic hydrogenation of the exocylic double bond, followed by the deprotection and elimination of the amino group. This route is the shortest enantioselective synthesis of this antibiotic reported to date.

Full text of DOI:10.1021/acs.orglett.8b01525

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Total Synthesis of (R)‑Sarkomycin Methyl Ester via Regioselective
Intermolecular Pauson−Khand Reaction and Iridium-Catalyzed
Asymmetric Isomerization
†
,‡
́ ́
Helea Khaizourane, Martí Garco̧
n,†,‡ Xavier Verdaguer,*,†,‡ and Antoni Riera*,†,‡
†
Albert Cabre,
́
†Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10,
Barcelona E-08028, Spain
‡
̀ ̀ ́ ̀ ̀
Departament de Química Inorganica i Organica, Seccio Organica, Universitat de Barcelona, Martí i Franques 1, Barcelona E-08028,
Spain
*
S Supporting Information
ABSTRACT: A new five-step enantioselective synthesis of (R)-sarkomycin methyl ester is described. The cyclopentane scaffold
was built by a regioselective intermolecular Pauson−Khand reaction. Enantioselectivity was introduced by a novel Ir-catalyzed
isomerization reaction. The last steps involved a catalytic hydrogenation of the exocylic double bond, followed by the
deprotection and elimination of the amino group. This route is the shortest enantioselective synthesis of this antibiotic reported
to date.
1
2
(
R)-Sarkomycin 1, first isolated in 1953 from the soil
workers was the first to use asymmetric catalysis. They
described a five-step sequence based on the Rh-catalyzed
asymmetric conjugate addition of a hexenyl chain to cyclo-
pentenone. However, none of the numerous syntheses of
sarkomycin published so far have exploited the Pauson−Khand
1
microorganism Streptomyces erythrochromogenes, is a cyclo-
pentenone that has rapidly gained relevance not only for its
antibiotic activity, but also for its strong inhibitory effect on
several human tumors and carcinoma cell lines. Because of its
chemical instability, several stable derivatives such as its methyl
2
,3
4
13
reaction (PKR), which is a textbook method for the
construction of cyclopentanic compounds. In most cases,
they used cyclopentanic starting material. We envisioned that
5
6
14
ester (2) or the cyclic lactone (3), so-called cyclosarkomycin,
have been developed. (See Figure 1.)
the cyclopentane ring of (R)-sarkomycin could be rapidly
15
assembled by an intermolecular PKR using an appropriate
internal alkyne and ethylene. The regioselectivity of internal
16
alkynes in the PKR has been widely studied and has proven
useful in the synthesis of natural compounds such as
17
prostaglandins and phytoprostanes B1.
We hypothesized that the PKR of alkyne (4) with ethylene
would afford adduct 5. The underlying challenge was the
regioselective control of the reaction. In the PKR of internal
alkynes with similar steric hindrance for each substituent,
Figure 1. Natural sarkomycin 1 and stable derivatives.
Although its structure is relatively simple, with only one
7
stereogenic center, a large number of synthetic approaches
16
regioselectivity is influenced mostly by electronic factors.
toward sarkomycin (or sarkomycin derivatives) have been
reported, often being used as a benchmark for new synthetic
methodologies. Some of the syntheses addressed the racemic
According to previous studies, the most electron-withdrawing
group (the methoxycarbonyl, in this case) should go to the β-
position. Therefore, we assumed that, using 4 as an alkyne, the
major isomer would be enone (5). We hypothesized that the
8
mixture and involve a relatively large number of steps. In other
cases, the desired enantiopurity was obtained via (a) kinetic
9
10
resolution, (b) the chiral auxiliary approach, or (c) classical
1
1
racemic resolution. However, most of these processes gave
low overall yields. A recent report by Von Zezschwitz and co-
Received: May 15, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01525
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
asymmetric hydrogenation would lead to cyclopentanone (6),
which after hydrolysis and elimination, would afford (R)-
sarkomycin methyl ester 2 (see Scheme 1).
crude material was cleaner and the workup much easier. We
believe that the ethylene glycol behaves as a chelating agent
reducing the activating effect of NMO and allowing
coordination of the alkene before decomposition of the
complex.
Scheme 1. Retrosynthetic Analysis of Sarkomycin Methyl
Ester 2
With the Pauson−Khand adduct (5) in hand, we then
studied its hydrogenation into the corresponding cyclo-
pentanone 6. Catalytic hydrogenation using Pd/C afforded
the racemic methyl ester (6) (see Table 2, entry 1). Somewhat
surprisingly for a tetrasubstituted olefin, the hydrogenation
took place in quantitative yield at 3 barG or even with a
hydrogen balloon. The stereochemistry of the hydrogenated
product was determined to be trans by two-dimensional (2D)
nuclear magnetic resonance (NMR) spectroscopy. In some
occasions, we have observed the presence of a mixture of cis
and trans stereoisomers. However, the former equilibrates to
the more stable trans under acid catalysis and even on standing
in chloroform solution.
Here, we report a total five-step synthesis of (R)-sarkomycin
methyl ester from acyclic precursors, using a regioselective
intermolecular PKR. During our search for appropriate
asymmetric hydrogenation conditions, we uncovered an
unprecedented iridium-catalyzed asymmetric isomerization of
allylcarbamate 5 that allowed us to obtain (R)-sarkomycin
methyl ester in excellent enantiomeric excess. The iridium-
With pure 5 in hand, we performed a catalyst screening for
the corresponding asymmetric hydrogenation. We chose the
following as standard conditions: 50 barG of hydrogen, 5 mol %
catalyst loading, and stirring overnight at room temperature.
18
catalyzed isomerization of allyl amides has received very little
attention, in comparison to other substrates, such as allyl
19−22
alcohols and allyl amines.
Moreover, to the best of our
Rh[(R,R)EtDuPhos (COD)]CF SO (8), which is the standard
knowledge, this is the first example of an asymmetric
isomerization of allyl carbamates to date.
The starting material 4, according to our retrosynthetic
analysis, was prepared in a straightforward manner in multigram
scale by carboxylation of N-Boc-propargyl amine with CO2,
followed by esterification in 74% overall yield (Scheme 2).
3
3
Rh catalyst for asymmetric hydrogenation, afforded poor
conversion (53%) with moderate enantiomeric excess (49%
ee) (see Table 2, entry 2). Using [Rh(COD)(R-MaxPHOS)]-
24
BF (9), full conversion was achieved, but with moderate
4
enantiomeric excess (51% ee) (Table 2, entry 3). We then
selected the iridium complexes of the P,N-ligands MaxPHOX
developed by our group (see Scheme 3), which are highly
active for the asymmetric hydrogenation of cyclic enamides and
Scheme 2. Synthesis of Internal Alkyne 4 from N-Boc-
Propargyl Amine
25
imines, giving excellent yields and enantioselectivities. These
modular P,N-ligands have three stereogenic centers, thus
allowing the optimization of the stereoselectivity by playing
with the four possible diastereoisomers. We started our
hydrogenation study with the four diastereomers 10−13a
with isopropyl substituents as catalysts. Two of them (10a and
11a) showed very low (15%−21%) conversion. However,
unexpectedly, the hydrogenation of 5 using 12a and 13a
afforded substantial conversion (70%−55%) into exocyclic
enamine 7 with no traces of the hydrogenation product 6. This
observation indicates that an unprecedented isomerization
process had occurred. Enamine 7 was hydrogenated using
Pd/C to the desired cyclopentanone 6, which showed
remarkable enantiomeric excess. Comparing the two best
catalysts, 12a (Table 2, entry 6) outperformed 13a (Table 2,
entry 7), both in terms of conversion and enantioselectivity .
An increase of hydrogen pressure to 50 barG produced only
traces of hydrogenated product; enamine 7 was still the major
product without erosion of the enantioselectivity (Table 2,
entry 8). We concluded that the cis configuration of the two
With alkyne 4 in hand, its cobalt hexacarbonyl complex was
quantitatively prepared by treatment with Co (CO)8 in
2
toluene. After concentration in vacuo, the complex was
submitted to several PKR conditions (Table 1). Although the
standard thermal conditions under 6 barG pressure of ethylene
gave only trace amounts of the product, we were pleased to see
that, by using N-methylmorpholine N-oxide (NMO) as a
promoter, it was obtained in 60%−75% yields with complete
18
15b
regioselectivity (Table 1, entry 1). Inspired by Baran’s work,
we recently reported a new synthetic protocol for intermo-
23
lecular PKR using ethylene glycol (MEG) as an additive.
Adding 15% (v/v) of ethylene glycol to the reaction mixture,
the yield increased up to 85% (Table 1, entry 2). Moreover, the
Table 1. Synthesis of Cyclopentenone 5 Using Pauson−Khand Reaction with Ethylene
entry
conditions
additives
isolated yield (%)
1
2
NMO (10 equiv), room temperature, 4 h
NMO (6 equiv), room temperature, 4 h
60−75
85
4 Å MS, MEG
B
DOI: 10.1021/acs.orglett.8b01525
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Hydrogenation/Isomerization of 6
b
entry
1
catalyst
mol %
solvent
CH Cl
conversion (%)
isolated yield
enantiomeric excess, ee (%)
Pd/C
8
20
5
100
53
6, 100
6, nd
6, nd
nd
2
2
[
a
]
2
3
CH Cl
(R)-49
(R)-51
nd
2
2
[
a
]
9
5
CH Cl
100
15
2
2
4
5
6
7
10a
11a
12a
13a
12a
12b
12c
12b
12b
7
THF
THF
THF
THF
THF
THF
THF
THF
7
21
nd
nd
7
70
7, 56
7, 45
7, 50
7, 64
(R)-93
(R)-71
(R)-93
(R)-95
7
55
8[
a
]
7
68
9
0
1
2
7
75
1
7
1
1
12
12
88
93
7, 70
7, 73
(R)-95
(R)-99
CH Cl
2
2
a
b
5
0 barG of H were used. Measured by HPLC Chiralpak IA on compound 6.
2
Scheme 3. Catalysts Used in the Hydrogenation Screening:
a) R = iPr; (b) R = Ph; (c) R = t-Bu
(
bulky groups (in the oxazoline and the P atom) was necessary
for the isomerization to occur. Of the two catalysts with such a
requirement, 12a, gave the best enantioselectivity; therefore its
configuration was considered optimum. We then modified the
substituent in the oxazoline ring. An increase in steric hindrance
by placing a tert-butyl group at the oxazoline fragment (catalyst
Figure 2. (a) Structures of the products before and after isomerization.
The planar conjugated systems are depicted in blue. Hydrogen bonds
are shown in magenta. (b) Schematic representation of the conjugated
π-system of product 7. (c) HOMO and LUMO of product 7 and
major atomic contributions to the molecular orbitals.
1
2c) did not lead to conversion (Table 2, entry 10). However,
In contrast with product 5, in which the nitrogen atom had a
slightly pyramidalized geometry, the N atom in product 7 was
completely planar. This implies that the N p-orbital can overlap
with the π-orbitals of the double bond. Therefore, there is no
actual loss of conjugation upon isomerization, since the
fragment that goes from the carbonyl of the cyclopentanone
ring to the carbonyl of the Boc group is a completely planar,
conjugated π-system. Inspection of the frontier molecular
orbitals clearly illustrates this point, with the HOMO and
LUMO being a combination of all the aforementioned p-
orbitals forming an extended, conjugated π-system.
when a phenyl group was placed at the oxazoline (catalyst 12b),
the conversion increased and, after conversion to 6, the
enantiomeric excess rose to 95% ee (Table 2, entry 9). Since
the reaction was not complete, we increased the catalyst loading
to 12 mol % (Table 2, entry 11). Finally, when performing the
reaction in dichloromethane (Table 2, entry 12), 6 was
obtained in an enantiopure form after hydrogenation of 7 with
Pd/C (ee >99).
At first sight, there was no evident driving force for the
reaction to occur, since the isomerization led to a seemingly
less-conjugated product. In order to gain insight into the
isomerization process, DFT calculations were performed (see
Intramolecular hydrogen bonds are also responsible for the
stabilization of product 7. The strong hydrogen bond explains
the experimental observation of the Z-isomer of the enamide as
the only product (see the SI). Although product 5 also has an
intramolecular hydrogen bond, NBO calculations and NCI
(noncovalent interactions) analysis showed that it is signifi-
cantly weaker than the hydrogen bond in product 7. This could
26
the Supporting Information (SI) for details). We found that
the isomerization is, in fact, an exergonic process, ΔG = −5.4
−1
kcal mol . The counterintuitive formation of product 7 can be
rationalized by considering two key factors, namely, (i)
conjugation and (ii) formation of a strong intramolecular
hydrogen bond (see Figure 2).
−1
also be observed by IR: the NH frequency of 7 (3301 cm )
C
DOI: 10.1021/acs.orglett.8b01525
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
appears at a shorter wavelength than 5 (3401 cm ) and 6
Letter
−1
ORCID
−1
(
3439 cm ) (see the SI).
With the enantiopure compound 6 in hand, we then
Martí Garc o̧ n: 0000-0002-3214-0150
Xavier Verdaguer: 0000-0002-9229-969X
Antoni Riera: 0000-0001-7142-7675
proceeded to perform the last steps (see Scheme 4). Boc-
Author Contributions
Scheme 4. Final Steps To Afford (R)-sarkomycin Methyl
Ester
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(
We thank the Spanish Ministerio de Economia y Competividad
MINECO) (Nos. CTQ2014-56361-P and CTQ2017-87840-
deprotection was first attempted using TFA or HCl in MeOH.
However, a considerable amount of base was then required to
neutralize the solution. We realized that the chiral position was
easily racemized in basic media and that neutral conditions
were required. After much experimentation, we found that
TMSCl in MeOH were the best reaction conditions for the
cleavage of the Boc protecting group. After evaporation of the
solvent, the crude product was dissolved in DMF, and
P) and IRB Barcelona for financial support. IRB Barcelona is
the recipient of a Severo Ochoa Award of Excellence from
MINECO (Government of Spain). H.K. thanks LaCaixa for a
predoctoral fellowship. A.C. thanks MINECO for a predoctoral
FPU fellowship.
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NaHCO (4.0 equiv) and MeI (4.0 equiv) were added to
■
3
form the quaternary ammonium salt, which was eliminated
spontaneously. When the reaction was completed by TLC, it
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of the volatility of 2, great care had to be taken to evaporate the
solvent. The desired (R)-sarkomycin methyl ester (2) was
obtained in 45% yield. An enantiomeric excess of 98% was
determined by HPLC analysis.
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DOI: 10.1021/acs.orglett.8b01525
Org. Lett. XXXX, XXX, XXX−XXX