Toward (-)-Enterocin: An Improved Cuprate Barbier Protocol to Overcome Strain and Sterical Hindrance

Article abstract of DOI:10.1021/acs.orglett.8b00353

An approach toward (-)-enterocin, an antibiotic isolated from Streptomyces hygroscopicus, is described. Its compact, heavily oxidized protoadamantane core represents a daunting challenge for an efficient synthesis. Convergent assembly of its 2-oxabicyclo[3.3.1]nonane core with a cuprate-mediated Barbier reaction is disclosed. Its functionalization to a suitable substrate for a biomimetic aldol to close the final ring of the natural product is evaluated.

Full text of DOI:10.1021/acs.orglett.8b00353

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Toward (−)-Enterocin: An Improved Cuprate Barbier Protocol To
Overcome Strain and Sterical Hindrance
Antonio Rizzo† and Dirk Trauner*,†,‡
†Department of Chemistry and Center for Integrated Protein Science, Ludwig-Maximilians-Universitat Munchen, Butenandtstrasse
̈
5-13, 81377 Munchen, Germany
̈
‡Department of Chemistry, New York University, 100 Washington Square East Room 712, New York, New York 10003, United
States
S
* Supporting Information
ABSTRACT: An approach toward (−)-enterocin, an antibiotic
isolated from Streptomyces hygroscopicus, is described. Its compact,
heavily oxidized protoadamantane core represents a daunting
challenge for an efficient synthesis. Convergent assembly of its 2-
oxabicyclo[3.3.1]nonane core with a cuprate-mediated Barbier
reaction is disclosed. Its functionalization to a suitable substrate for
a biomimetic aldol to close the final ring of the natural product is
evaluated.
(−)-Enterocin (1) (also known as vulgamycin, Figure 1) and its
biosynthetic precursor (−)-deoxyenterocin (2) are metabolites
Scheme 1. Retrosynthetic Analysis of 1 and 2
Figure 1. Structure of (−)-enterocin (1), its biosynthetic precursor (2),
and the crystal structure of m-BrBz-enterocin.6
isolated from Streptomyces hygroscopicus.1 1 behaves as a
bacteriostat against Gram-positive and Gram-negative bacteria,
including Escherichia coli and species of Staphylococcus.2 More-
over, it exhibits a high degree of herbicidal activity. We became
intrigued bythe challengeposedbythepeculiarcaged structure of
1. Enterocin presents a rare oxa-protoadamantane core,3 found
only in a handful of natural products4 which have not yet been
reached by total synthesis, and is decorated with four hydroxyl
groups accounting for four of its seven contiguous stereocenters.
These features and the lack of a prior total synthesis5 of this
unusual polyketide prompted our synthetic endeavors.
The high confluence of oxygenation found in 1 confers
limitations on tactical considerations toward its synthesis (e.g.,
issues of chemoselectivity and stability). Strategic deoxygenation
was our first retrosynthetic simplification (Scheme 1). Sequential
deletion of the secondary alcohol, which is not present in 2, and
the CO oxygen of the lactone led to the identification of an
aldol retron between the C5 tertiary alcohol and the benzylic
ketone. This first C−C bond disconnection is present in the
biosynthesis of15d andwas therefore chosen asthecornerstoneof
our retrosynthesis. Despite the reversibility of aldol reactions, we
envisioned that the proximity derived from the locked
conformation of the 2-oxabicyclo[3.3.1]nonane scaffold would
enable successful ring closure to the tricyclic core of 1 and 2.
Installation of the two ketones was planned by a benzylic
oxidation and a formal anti-Markovnikov hydration of an
endocyclic olefin. A Barbier reaction between a vinyl nucleophile
and a ketone was deemed uniquely suitable to overcome the
Received: January 31, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00353
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
sterical hindrance and strain in forming the C6−C7 bond. The
required α-hydroxylated ketone was then planned to arise via
Sharpless asymmetric dihydroxylation and subsequent oxidation
of the resulting secondary alcohol. Intermediate dihydropyran
was ultimately traced back to building blocks of similar
complexity.
Scheme 3. Cyclization Precursor Assembly
The synthesis commenced with the alkylation of known7
dithiane 3 (97% ee) with allylic bromide 4,8 both prepared in two
steps from commercially available starting materials (Scheme 2).
Scheme 2. Preparation of the HWE Partners
additions, the challenge of metalating vinyl bromides in the
presence of ketones with subsequent 1,2-addition is well-
documented. Execution of these two concomitant processes
was hampered duetotworeasons: thelowchemoselectivity ofthe
harsh conditions required to metalate these bromides, and the
lack of reactivity of both softer, more chemoselective organo-
metallics and ketones. Intramolecular applications to prepare
congested cyclohexenes are scarce.16 We started our cyclization
studies by generating zincated species in an intramolecular
Reformatsky reaction (entry 1, Table 1).17 Application of
Table 1. Exploration and Optimization Studies for Cyclization
The obtained ether was subjected to standard metathesis
conditions using Hoveyda−Grubbs II, followed by alkylative
removal of the dithiane. This short sequence delivered multigram
quantities of aldehyde 5, which possesses a handle to introduce
the pyrone fragment. Regarding the HWE (Horner−Wads-
worth−Emmons) partner, an ad hoc preparation was developed
as the difficulty of controlling regioselectivities in radical benzylic
brominations of pyrones is well-documented.9 Our approach
encompassed the use of aldehyde 610 in an Abramov−Pudovik
reaction with cyclic phosphite 7.11 The choice of the latter
permitted the facile isolation of solid 8 by simple filtration of the
reaction mixture and, more importantly, use of this type of
oxaphosphorinane delivers higher Z-selectivities in subsequent
olefinations.12 The planned bromination of 8 proved nontrivial13
but could be achieved by subjection to hexabromoacetone and
dppe.14 Use of dppe in place of triphenylphosphine greatly
simplified purification of 10.
NaH-mediated HWE reaction quantitatively delivered the
expected vinyl bromide as a 3.5:1 E/Z mixture of isomers
(Scheme 3).15 Despite the low isomeric ratio, the inseparable
mixture was carried forward to the next reaction. Sharpless
asymmetric dihydroxylation installed the first of the tertiary
alcohols present in the natural product, delivering diol 11 in good
yield. It was observed during the subsequent oxidation−
protection sequence (which advanced us to cyclization precursor
12) that the configuration of the vinyl bromide was subject to
thermodynamic control. Under Lewis acidic conditions, as with
silylium ions, and under Swern conditions, we noticed that the
isomeric ratio was shifted in favor of the desired Z-isomer. It
appeared that the pyrone could be activated as an extended
Michael system. Indeed, use of excess TMSOTf buffered by
pyridine and prolonged reaction times delivered desired
cyclization precursor 12 as a single isomer.
entry
reagents
solvent, t °C
THF, 23
result
reduction
1
2
3
4
5
6
7
Rh(PPh3)3Cl, Et2Zn
t-BuLi, TMEDA
t-BuLi
Et2O, −78
decomp.
decomp.
reduction
a
Trapp, −90
SmI2
THF, −78
CrCl2, NiCl2
DMSO or DMF, 23 reduction + dimer
CrCl2, NiCl2 4-t-Bu-pyr DMF, 70/90/125
reduction
reduction
traces
TMSSnBu3
DMF, 60
b
8
b
n-Bu2CuLi·LiI
n-Bu2CuLi·LiI
Np2CuLi·LiI
n-Bu2CuLi·LiI
n-Bu2CuLi·LiI
n-Bu2CuLi·LiCN
n-Bu2CuCN·LiCN
Et2O/n-hex, −78
Et2O/n-hex, −50
Et2O/n-hex, −50
THF, −50
Et2O, −50
Et2O, −50
9
15%
b
10
reduction
reduction
44%
b
11
b
12
c
13
89%
14
Et2O, −50
70%, 1.4 g
a
b
Trapp16a 4/4/1 THF/Et2O/pentane. Conditions: R2CuX·LiX (12
c
equiv), 0.01 M, 30 mg scale. Scale: 100 mg. 13/13I = 1/1.
Wilkinson’s catalyst provided partial metalation, but the resulting
organozinc species lacked the reactivity to close the ring.
Therefore, generation of more nucleophilic organolithium
species was examined.18 These processes delivered complex
mixtures or decomposition (entries 2 and 3). Employment of
SmI2 providedmainlyreducedcompounds19 (entry4), andunder
Nozaki−Hiyama−Kishi conditions, dimer formation was ob-
served (entry 5). Although addition of 4-t-Bu-pyridine sup-
pressed dimer formation,20 cyclization to produce the cyclo-
After gaining access to compound 12, the stage was set for the
key cyclization to construct the 2-oxabicyclo[3.3.1]nonane core.
In the context of C−C bond formation by organometallic
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DOI: 10.1021/acs.orglett.8b00353
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hexene failed, even at elevated temperatures (entry 6). Use of
Shibasaki’sconditions (TMSSnBu3, BnEt3NCl)alsoproved futile
(entry 7).21 The commonly available toolbox of reactions for this
type of transformation did not provide the required chemo-
selectivity and reactivity to forge strained bicycle 13.
Scheme 4. Selective Functionalization Studies
After extensive screening, metalation using dialkylcuprates, as
studied by Corey in the 1970s for the synthesis of cyclopentanols,
provided trace amounts of 13 for the first time (entry 8).22
Despite the few successful applications of this method,23 this
procedure proved to be capricious with respect to almost all
reaction parameters. Temperature control was necessary to avoid
decomposition or transfer of the alkyl ligand onto the alkene
(entry 9), and use of nontransferable ligands was deleterious
(entry 10).24 In contrast to the literature precedence,23a THF
completely abolished reactivity (entry 11). Although Et2O was
able to provide 13 in moderate yield (entry 12), its reproduction
was highly variable and, at times, failed.13
A major improvement resulted from the realization that CuI as
a copper source forms metastable dibutylcuprate salts subject to
nonproductive pathways. This realization came upon the
empirical observation of particles in solution. Employment of
CuCN delivered colorless, homogeneous solutions of dibutyl-
cupratecapableofprovidingcyclizedbicycle13withreproducibly
high yields on gram scale (entries 13 and 14).25 Crystals obtained
by vapor diffusion permitted determination of absolute and
relative stereochemistry (Figure 2).
Figure 2. Determination of the absolute configuration of 13I by X-ray
analysis.
A protection/deprotection sequence on substrate 13 + 13I
afforded cyclic carbonate 14, providing material to probe the
reactivity of the endocyclic alkene (Scheme 4, BTC =
bis(trichloromethyl)carbonate). Functionalization attempts by
epoxidations and various anti-Markovnikov hydrofunctionaliza-
tions to install the tertiary hydroxyl at C5 failed.13 Use of
unprotected diol bore the same results, as well as oxidative
cleavage by VO(acac)2. Allylic oxidation of 14 could be achieved
using Fuchs’ conditions to provide corresponding enone 15.26
Despite our inability to functionalize this olefin, it permitted us to
regioseletively oxidize the carbon bearing 1’s secondary hydroxyl
group. Notably, this same protocol could be efficiently applied to
model substrate 16 to oxidize the ether bridge directly to lactone
17, thereby encouraging our late-stage functionalization strat-
egy.27
After considerable experimentation, dihydroxylation with
OsO4 and citric acid28 was found to be the only method to
generate 18. Diol 18 was then treated with TCDI (1,1′-
thiocarbonyldiimidazole), and subsequent radical reduction
provided monodeoxygenated alcohol 19 in high yield, albeit
with epimeric stereochemistry with respect to enterocin (Scheme
4). The stereochemistry was unequivocally confirmed by X-ray
analysis. Efforts to control the diastereoselectivity of hydrogen
delivery with different donors or initiators were fruitless.
Significantly, attempts to epimerize this center following
oxidation of the adjacent hydroxyl were thwarted by the inherent
instability of the resulting ketone.
In conclusion, a convergent enantioselective synthesis of the
heterocyclic core of (−)-enterocin was developed that comprises
the complete carbon skeleton of the natural product, with the
complete pyrone and two of the three tertiary alcohols in place.
Notably, we have systematically investigated and developed a
potentially broadly useful intramolecular Barbier reaction. This
improved method permitted us to reliably gain access to bicycle
13, which allowed us to probe the assembly of a suitable substrate
for the planned biomimetic aldol. The results indicate that our
proposed cyclization precursor is inherently unstable or difficult
to muster in a non-enzymatic environment. Efforts toward this
last ring closure using minor structural variants of 13 are currently
under investigation and will be reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.8b00353.
Detailed experimental procedures, spectral data, and X-ray
crystallography (PDF)
C
DOI: 10.1021/acs.orglett.8b00353
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dirktrauner@nyu.edu.
ORCID
Dirk Trauner: 0000-0002-6782-6056
Author Contributions
A.R. and D.T. conceived the project. A.R. carried out the
experimental work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Deutsche Forschungsgemeinschaft (SFB 749) for
financial support. Dr. Peter Mayer is acknowledged for X-ray
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Julius R. Reyes (LMU Munchen) for helpful discussions during
the preparation of this paper.
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