Synthesis of the Aminocyclitol Core of Jogyamycin via an Enantioselective Pd-Catalyzed Trimethylenemethane (TMM) Cycloaddition

Article abstract of DOI:10.1021/acs.orglett.8b01518

The use of β-nitroenamines as a new class of acceptors in the enantioselective Pd-catalyzed trimethylenemethane cycloaddition afforded differentiated 1,2-dinitrogen bearing cyclopentanes with three contiguous stereocenters. The utility of these acceptors was demonstrated with the efficient construction of the core of jogyamycin and aminocyclopentitols. Further elaboration of the cycloadducts provided a concise synthetic approach toward joygamycin.

Full text of DOI:10.1021/acs.orglett.8b01518

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of the Aminocyclitol Core of Jogyamycin via an
Enantioselective Pd-Catalyzed Trimethylenemethane (TMM)
Cycloaddition
Barry M. Trost,* Lei Zhang, and Tom M. Lam
Department of Chemistry, Stanford University, Stanford, California 94305-5580, United States
S
* Supporting Information
ABSTRACT: The use of β-nitroenamines as a new class of
acceptors in the enantioselective Pd-catalyzed trimethylene-
methane cycloaddition afforded differentiated 1,2-dinitrogen
bearing cyclopentanes with three contiguous stereocenters.
The utility of these acceptors was demonstrated with the
efficient construction of the core of jogyamycin and
aminocyclopentitols. Further elaboration of the cycloadducts
provided a concise synthetic approach toward joygamycin.
ogyamycin is a metabolite isolated from Streptomyces sp. a-
Our retrosynthetic plan (Scheme 1) toward jogyamycin
involves a late-stage installation of the triol via methylation and
1
JWM-JG-16.2. from soil samples in Jogjakarta, Indonesia. It
is an aminocyclitol derivative that bears close structural
semblance to pactamycin and possesses elevated biological
activity (see Figure 1).2 Members of this class exhibit potent
Scheme 1. Retrosynthetic Analysis
Figure 1. Aminocyclitol natural products jogyamycin and pactamycin.
dihydroxylation, affording cyclopentenone 2. The enone would
be introduced through an alkene ozonolysis with a subsequent
α-methylenation. The urea would be accessed through nitrile
hydration to a primary carboxamide, followed by a Hofmann
rearrangement, leading to intermediate 3. The aryl group of 3
would be introduced through a chemoselective C−N cross
coupling. Careful manipulation of the various nitrogen
oxidation states would allow us to differentiate between the
three core nitrogens in cyclopentane 4. We envisioned that this
core would be furnished by the key palladium-catalyzed TMM
cycloaddition of donor 5 and dinitrogen acceptor 6. Although
these β-nitroenamines have been successfully employed as
Michael acceptors and dienophiles, their utility was largely
limited by access. Consequently, we developed an efficient
method toward these acceptors from the direct nitration of
vinylimines.10 The enantioselective and diastereoselective
addition onto these acceptors affording differentiated 1,2-
anticancer as well as antiprotozoal activities against malaria (P.
Falciparum) and African sleeping sickness (T. Brucei).1−3 The
accepted mechanism of action involves the binding to the small
subunit of ribosomes across all three kingdoms, leading to
cytotoxic properties as well.4 However, studies of analogues
have shown the potential for the modulation of target
selectivity.5 While the synthesis of pactamycin has been
reported by the groups of Hanessian6 and Johnson,7 the
synthesis of jogyamycin remains undisclosed.8
The densely heteroatom substituted cyclopentane core has
remained a major challenge in the efficient and stereoselective
access to this family of compounds. Consequently, we
developed the Pd-catalyzed enantioselective trimethylene-
methane (TMM) cycloaddition9 to address this synthetic
challenge. From readily accessible coupling partners, the TMM
cycloaddition offered an efficient construction of the core,
establishing three stereocenters diastereoselectively and
enantioselectively, providing differentiation of the trans
diamine groups on the target core.
Received: May 14, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01518
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Organic Letters
Letter
a
dinitrogen compounds via the TMM cycloaddition exemplifies
their utility in complex molecule synthesis.
Table 1. TMM Optimization
Our synthesis began with the development of a highly
scalable route to the TMM donor 5,9k synthesized from
commercially available phosphonoacetate 7 (Scheme 2). A
Scheme 2. Synthesis of TMM Donor
equiv
5:6
yield
(%)
entry
additive (equiv)
dr
1
2
3
4
5
6
7
8
9
1:1
40
1:1
1:1
1:1
1:1
1:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
1.5:1
BSA (1)
In(acac)3 (1)
Me3SnOAc (1)
B(OEt)3 (1)
B(OEt)3 (1)
B(OEt)3 (0.5)
B(OiPr)2Me (1)
Et2BOMe (1)
BEt3 (1)
B(OEt)3 (0.15), Et2BOMe (0.15)
B(OEt)3 (0.15), Et2BOMe (0.15)
B(OEt)3 (0.15), Et2BOMe (0.15)
b
c
60
3:1
1.6:1
5:1
2:1
6:1
57
47
67
c
50
sequential acylation/decarboxylation step provided access to
the ketophosphonate 8.11 Subsequent alkylation of the
ketophosphonate to install the methylene trimethylsilane was
realized with the use of ICH2TMS in dimethoxyethane (DME)
with Cs2CO3.12 These conditions favorably promoted C-
instead of O-alkylation, along with minimal desilylation. In
addition, the alkylation conditions were compatible for the
addition of the reagents for the subsequent Horner−Wads-
worth−Emmons reaction to furnish the enone 9 in a
convenient one-pot fashion. Finally, cyanohydrin formation
was achieved using TMSCN in the presence of ZnI2, and the
TMM donor 5 was formed after silyl group exchange with
Ac2O in the presence of TMSOTf in good yields.
c
78
c
1.9:1
11:1
46
10
11
b
85
89
5.3:1
10:1
13:1
de
,
12
13
def
,
,
95
a
b
c
d
ee = 89% unless indicated. Decomposition. Conversion. [Pd-
e
(cinnamyl)Cp] was used instead of [Pd(allyl)Cp]. ee = 88%.
f
[Pd(cinnamyl)Cp] (2 mol %), (S,S,R,R,S,S)-TL (3 mol %), dioxane
(1.33 M), 1.5 h.
The synthesis of the nitroenamine TMM acceptor 6 started
with the condensation of benzophenone with ethanolamine
(Scheme 3). Mesylation and elimination afforded the stable
In(acac)3 and Me3SnOAc led to marginal improvement in
conversion and selectivity (Table 1, entries 3 and 4). However,
the borate additives proved to be notably beneficial. At 50%
conversion, B(OEt)3 afforded a 6:1 diastereomeric ratio (dr)
for the desired product (Table 1, entry 6). Although Et2BOMe
did not improve the conversion, it significantly enhanced the
diastereoselectivity (Table 1, entry 9). Thus, the combination
of both B(OEt)3 and Et2BOMe conferred both the respective
conversion and selectivity of the reaction, affording the
cycloadduct with an 85% yield, 89% ee, and 5:1 dr (Table 1,
entry 11).
Scheme 3. Synthesis of TMM Acceptor
vinylimine 10 in high yields with no need for purification.
Nitration of the vinylimine using the procedure reported by
Maiti and co-workers10 provided 6. Nitroenamines bearing
other protecting groups were synthesized in a similar fashion.
The efficient access to the coupling partners allowed the
development of the palladium-catalyzed TMM cycloaddition
to furnish the highly functionalized cyclopentane core 11 of
jogyamycin with three defined contiguous stereocenters (see
Table 1). Employing a Pd(0) precursor, [Pd(allyl)Cp], and a
diamidophosphite ligand,9i preliminary investigation of the
amino protecting group on the acceptor including phthalimide
and carbamates indicated that the benzophenone imine
conferred the most optimal enantioselectivities and diaster-
eoselectivities.13
Further refinement with the use of [Pd(cinnamyl)Cp] as a
more stable Pd(0) precursor allowed reduction of the catalyst/
ligand loading. In addition, decreasing the donor equivalence
and increasing reaction concentration were beneficial practi-
cally, but also were important for improving the diaster-
eoselectivity upward to 13:1 (Table 1, entry 13). The relative
stereochemical assignment of the cycloadduct was determined
using NOE experiments (Figure 2).15 Based on the ligand
chirality, the stereoconfiguration of the cycloadduct is
predicted to be the enantiomer of the natural product.9k The
natural enantiomer can be accessed by employment of readily
prepared (R,R,S,S,R,R)-TL.
In the initial results, the cycloadduct 11 was isolated in a
40% yield as a mixture of diastereomers about the carbon
bearing the nitro group (Table 1, entry 1). The other
stereocenters created remained cis. Interestingly, the enantio-
meric excess (ee) was maintained at 89% throughout the
optimization. To further improve the reactivity and selectivity,
the use of Lewis acids14 to activate the acceptor/donor was
examined. The precedented use of BSA in TMM did not lead
to reactivity in this case (Table 1, entry 2). The use of
Figure 2. NOE of TMM cycloaddition product.
B
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The TMM cycloaddition effectively accessed the densely
substituted cyclopentane core of the natural product.
Subsequent efforts in functionalizing the core steered toward
the reduction of the nitro group (see Scheme 4). As the carbon
the rearrangement smoothly to form the isocyanate in situ,
which was trapped with the addition of dimethylamine to
furnish the urea. Ozonolysis of the exocyclic alkene afforded
the cyclopentanone 16.
Subsequent efforts to install an α-methylene group proved to
be difficult. Although α-deprotonation using lithium amide
bases to form the enolate could be observed indirectly via D2O
quench and 95% deuterium incorporation, efforts to trap the
enolate with a one-carbon electrophile proved to be
unsuccessful. Screening bases such as LDA, Li-, Na-, and
KHMDS against a variety of electrophiles including
Eschermoser’s salt, paraformaldehyde, methyl formate,
MOMCl, and chlorosilanes invariably led to decomposition.
Methods to access silyl enol ethers using amine bases and silyl
chlorides and triflates did not achieve the desired reactivity.
Upon exploration of alternative strategies for the functionaliza-
tion of the α-position, the treatment of 17 with MCPBA led to
the elimination of the dimethylamine, forming the isocyanate
17′ (see Scheme 5). This peculiar transformation of the urea
Scheme 4. Accessing Cyclopentanone Intermediate
Scheme 5. Accessing Cyclopentanone Intermediate
has been reported by Johnson7 in the synthesis of pactamycin
and was proposed to occur through nucleophilic attack of the
dimethylamine on the peracid to generate an N-oxide, which
eliminated to form the isocyanate. The nucleophilic character
of the urea could account for the lack of compatibility of the
enolate for electrophiles. Thus, α-methylenation was inves-
tigated prior to the formation of the urea.
Rerouting the synthetic path, the exocyclic methylene of 14
was cleaved with ozonolysis after oxalamide protection to
introduce the ketonitrile 18 (see Scheme 6). Extended time
under ozone saturation was required to cleave the electron-
poor exocyclic methylene. α-Methylenation methods were
bearing the nitro group was prone to epimerization and the
benzophenone imine was prone to hydrolysis, acidic and basic
conditions were not well-tolerated. For example, various
Clemenson reductions and metal hydrides caused epimeriza-
tion, led to decomposition, or lacked reactivity. Metal-
catalyzed reductions such as metal borides, metal silanes, and
hydrogenation, were also ineffective. Invariably, the use of
SmI2,16 which is a highly effective reducing agent in pH neutral
conditions and at ambient temperatures, proved to be key. The
excellent reducing power of SmI2 led to the concomitant
reduction of the nitro and imine groups, furnishing diamine 12.
Several methods for N-arylation were investigated sub-
sequently. Although both Chan-Lam and Ullman cross
couplings provided reactivity affording the desired product
with selective arylation of the primary amine, the lack of
desirable yields along with significant amounts of overoxidation
of the product to the benzophenone imine were observed.
Consequently, the Buchwald-Hartwig coupling was inves-
tigated. Ligand/catalyst screening identified XPhos pallada-
cycle G217 as the catalyst of choice and afforded the arylated
product 13 with high yields with minimal overoxidation and
scalability.
Scheme 6. Accessing the Frontier Intermediate
In preparation for the conversion of the nitrile to the urea,
the protection of the diamine was examined. Surprisingly,
various methods to form carbamates lacked reactivity.
Treatment with TFAA also resulted in the monoprotection
of the aniline, indicating the significant steric bulk of the
benzhydryl (Dpm) amine. Conveniently, the diamine reacted
with oxalyl chloride to form the cyclic oxalamide 14.18
Treatment of the protected diamine with the Parkins−
Ghaffar catalyst19 under neutral aqueous conditions led to
nitrile hydration to the carboxamide 15, setting the stage for a
Hofmann rearrangement. The mild and pH neutral conditions
afforded by Zhdankin’s hypervalent iodine reagent20 effected
C
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Letter
investigated again. Although deprotonation/electrophilic trap-
ping remained unsuccessful, the use of Ac2O/(Me2N)2CH2 as
a mild and acidic methylenation method proved to be
pivotal.21 The methylenation readily occurred at 4 °C.
Comparatively, under the same conditions, the substrate
bearing the urea did not afford reactivity and decomposed
upon heating.
Diligent isolation, handling, and storage under argon in a
freezer were important in attenuating the decomposition and
polymerization of the exocyclic enone 19. Because of its
sensitivity, the enone did not tolerate subsequent nucleophilic
epoxidation and many metal-catalyzed epoxidation/dihydrox-
ylation methods. Stoichiometric use of OsO4 proved to be
essential. In addition, the use of the chiral ligand
(DHQ)2PHAL was important in affording optimal yield and
diastereoselectivity of diol 20. The use of the pseudo
enantiomer of the ligand, (DHQD)2PHAL, afforded sluggish
conversion with mismatched diastereoselectivity. While the
diastereoselectvity could be attained with achiral amine ligands,
the osmate ester hydrolysis under acidic conditions also led to
the deprotection of the ketal. NOE analysis provided the
assignment of the relative stereoconfiguration of the diol and
further corroborated with the stereochemical assignment of the
TMM adduct 11.22
class of acceptors in the development of the TMM method-
ology.
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.8b01518.
Experiment details, compound characterization data, and
spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bmtrost@stanford.edu.
ORCID
Barry M. Trost: 0000-0001-7369-9121
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIH (No. GM-033049) and the NSF (No.
CHE-1360634) for their generous support of our programs.
L.Z. thanks NSERC for a postdoctoral fellowship award.
The stereoselective installation of the diol provided a
pathway for the formation of the urea. Again, the nitrile was
hydrated to carboxamide 21 with the Parkins−Ghaffar catalyst.
The protection of the diol into a cyclic ketal was unsuccessful,
which led to the alternative regioselective TBDPS protection of
the primary hydroxyl. While the Hofmann rearrangement of
this α-ketoamide 22 was a concern due to the inherent
decreased migratory aptitude of the α-carbon, the rearrange-
ment did occur. However, the isocyanate that was formed in
situ was unstable and readily hydrolyzed to the tertiary amine
23, and trapping with dimethylamine was unsuccessful. Several
attempts to form the isocyanate from the amine and trap in
situ for example, with triphosgene or diphosgene in NEt3, then
dimethylamine, only led to recovery of the starting amine.
Importantly, switching the base to pyridine led to the
formation of the carbamoyl chloride,23 which is a more stable
species, instead of the isocyanate. Quenching the carbamoyl
chloride with dimethylamine led to the desired urea 24.
With the urea in hand, the installation of the last piece of the
natural product, the methylation of the ketone, was attempted.
Both the Hanessian6 and Johnson7 groups utilized this 1,2-
addition strategy to stereoselectively install the C5 methyl
group with the use of MeMgBr. However, a variety of attempts
to install the methyl group, including halide counterions of the
methyl Grignard, MeLi, MeCuLiI, AlMe3, Me2Zn alone or in
combination with CeCl3, remained unsuccessful. As a plausible
side product, the ring opening of the oxalamide was observed.
In summary, the densely functionalized cyclopentane core of
joygamycin was constructed expediently through a palladium-
catalyzed enantioselective TMM cycloaddition. The establish-
ment of three contiguous stereocenters with control of
diastereoselectivity, along with the differentiation of three
amino moieties, provided an efficient approach toward the
installation of the heteroatom-rich functional groups. This
synthetic strategy demonstrated the effectiveness of the use of
β-nitroenamines as TMM acceptors. The efficient access via
direct nitration, coupled with the high enantioselectivity and
diastereoselectivity to access differentially substituted dinitro-
gen compounds, demonstrate their utility as a powerful new
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