Concise and Convergent Enantioselective Total Syntheses of (+)-and (-)-Fumimycin

Article abstract of DOI:10.1021/acs.joc.9b02020

The concise and convergent total syntheses of (+)-and (-)-Fumimycin have been achieved by taking advantage of strategies for the asymmetric aza-Friedel-Crafts reaction of a highly substituted hydroquinone and N-fumaryl ketimine generated from the correspo

Full text of DOI:10.1021/acs.joc.9b02020

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Concise and Convergent Enantioselective
Total Syntheses of (+)- and (–)-Fumimycin
Michele Retini, Silvia Bartolucci, Francesca Bartoccini, Michele Mari, and Giovanni Piersanti
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02020 • Publication Date (Web): 03 Sep 2019
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Concise and Convergent Enantioselective Total Syntheses of (+)- and (–)-Fumimycin
Michele Retini, Silvia Bartolucci, Francesca Bartoccini, Michele Mari, and Giovanni Piersanti*
Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, P.zza Rinascimento 6, 61029 Urbino, PU,
Italy
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*giovanni.piersanti@uniurb.it
ABSTRACT: The concise and convergent total syntheses of (+)- and (–)-Fumimycin have been achieved by taking
advantage of strategies for the asymmetric aza-Friedel–Crafts reaction of a highly substituted hydroquinone and N-
fumaryl ketimine generated from the corresponding dehydroalanine. The enantiomerically pure natural product and its
enantiomer were prepared in seven steps and 22% overall yield by employing both enantiomers of a BINOL‐derived
chiral phosphoric acid (CPA) catalyst.
1
The micotoxin (–)-fumimycin (1) was isolated from Aspergillus fumisynnematus in 2007. Soon after its discovery, the
2
syntheses of racemic fumimycin and its immediate precursors were reported in the literature. This natural product continues to
attract considerable interest from the synthetic community due to its strong antibacterial activity against resistant S. aureus
3
strains and its inhibition of peptide deformylases (PDFs) (Scheme 1). However, despite this attention, the asymmetric synthesis
of (+)-fumimycin (ent-1) together with its absolute configuration assignment have only recently been accomplished in 18 steps,
4
90% ee, and 1.6 % overall yield from commercially available material. Herein, we report the concise, highly convergent, and
efficient syntheses of natural (–)-fumimycin (1) and its enantiomer (+)-fumimycin (ent-1). The key step in this synthesis is the
5
asymmetric aza-Friedel–Crafts reaction of a densely functionalized hydroquinone and N-fumaryl ketimine, which is generated
from the corresponding dehydroalanine.
Our approach to (–)-fumimycin (1) and (+)-fumimycin (ent-1) is depicted in Scheme 1. We envisioned that both enantiomers
of fumimycin would be accessed via
a late-stage, chiral phosphoric acid (CPA)-catalyzed, domino aza-
Friedel−Crafts/lactonization process between hydroquinone 6 and dehydroalanine 10 to form the congested benzofuranone 11
bearing an aza-quaternary stereocenter, followed by cleavage of the two methyl groups. The synthesis of hydroquinone 6 would
be accomplished in four steps starting from vanillin (2) and employing Dakin oxidation and Claisen rearrangement.
Dehydroalanine 10, the precursor of N-fumaryl ketimine (A), would in turn be generated from the condensation of serine with
monomethyl fumarate followed by dehydration. In view of the stereochemical and structural complexity of 1, this powerful
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disconnection of the natural product presented an opportunity to highlight the following: i) the utility of functionalized
dehydroalanine 10 as a surrogate for unstable ketimine A, as the electrophilic component, to introduce the quaternary amino
6
acid unit into a natural product, ii) the use of highly substituted vinyl hydroquinone 6 as the nucleophilic component in the
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relatively poorly investigated chemo-, regio-, and enantioselective domino aza-Friedel−Crafts/lactonization reaction, iii) the
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versatility of the CPA organocatalyst in enantioselective transformations of highly dense substrates, iv) the clear advantage for
the availability of CPAs in both enantiomeric forms, and v) merging the structural design and synthetic design for possible
8
natural product analogues and derivatives. It must be stressed that even if the aza-Friedel–Crafts reaction between the π-aryl
nucleophile and simple α,β-dehydroamino acids under stoichiometric and catalytic acidic conditions has been developed by us
9
and others, related catalytic enantioselective transformations are less explored and their application to the synthesis of natural
products has only recently emerged as an environmentally friendly and indispensable tool for the construction of relevant
bioactive molecules.10
Scheme 1. Retrosynthetic Analysis of (–)-Fumimycin (1) and Challenges in the Catalytic Asymmetric Domino
aza-Friedel−Crafts/Lactonization Reaction.
The synthesis ultimately commenced with the preparation of 2,6-disubstituted hydroquinone 6 by quantitative allylation of
vanillin (2) under standard conditions.2a,b Installation of the third oxygen group at the aromatic core was feasible in excellent
yield and with complete chemoselectivity by slight modification of Dakin oxidation (Scheme 2a). Indeed, oxidation of the
aldehyde was accomplished using a catalytic amount (5 mol %) of diphenyl selenide as the activator of H
2
O
2
, according to the
1
1
procedure developed by Syper. Subsequent treatment of the formate intermediate with 5 equiv NH
3
in DCM at 0 °C gave the
desired phenol 4 in a gratifying yield of 92%. Claisen rearrangement of allyl ether 4 in DMF at 180 °C smoothly provided
compound 5.2b Isomerization of the terminal double bond in the conjugated product 6 was achieved in good yield and with
complete E-selectivity under relatively mild conditions by employing 5 mol % RhCl
sequence could be performed routinely on a multigram scale (Scheme 2a). Despite the fact that the synthesis of dehydroalanine
0 from racemic serine methyl ester (7) and monomethyl fumarate (8) in a one-pot amidation/dehydration procedure employing
in refluxing methanol.12 The entire
3
1
thionyl chloride has already been reported,3c in our hands, we were able to detect the product but repeatedly obtained an
unacceptable yield of 10 using these conditions. Therefore, we changed the reagent to the inexpensive and largely used 1-ethyl-
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3-(3′-dimethylaminopropyl)carbodiimide (EDCI) for both dehydration steps.13 Thus, the amide bond formation was carried out
by using EDCI and N-hydroxybenzotriazole (HOBt) under standard basic amide coupling conditions between commercially
available racemic serine methyl ester (7) and monomethyl fumarate (8) to give 9, and the conjugated double bond was obtained
by using a combination of EDCI and catalytic copper (I) chloride. Finally, the water-soluble byproduct urea from EDCI could
be removed by simple aqueous workup, and dehydroalanine 10 was obtained in high yield on a multigram scale. With the
substrates for the key reaction in hand, we explored the organocatalytic enantioselective aza-Friedel−Crafts/lactonization
sequence (Table 1).
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Scheme 2. Syntheses of 2,6-Disubstituted Hydroquinone 6 and Dehydroalanine 10
We started this study by reacting hydroquinone 6ꢀ(1 equiv) with dehydroalanine 10 (1.2 equiv) in the presence of BINOL‐
derived CPA catalyst 12a at 5 mol % loading. Although the first attempt using toluene as the solvent at 85 °C and a reaction
time of 72 h gave only poor conversion to the regioselective desired lactone 11, the enantioselectivity was decent (Table 1, entry
1, er 65:35). Under these conditions, we tested some drying agents, which are standard additives in phosphoric acid-catalyzed
reactions.14 As shown in Table 1 (entries 2–3), the presence of molecular sieves (4 Å or 3 Å) was surprisingly detrimental to
catalyst activity.15 In addition, lower conversion and enantioselectivity, compared to the reaction performed in their absence,
2 4 4
were observed when the drying agent Na SO or MgSO was used as an additive (Table 1, entries 4–5). Also, the use of an
achiral urea as a co-catalyst, which has been reported to provide both a greater reactivity and a higher selectivity,16 failed to
improve the conversion when used with 12a in our reaction; however, a slightly better enantioselectivity (er 82:18) was detected
(Table 1, entry 7). At this point, we envisioned that the addition of an achiral Lewis acid to form a bulky chiral supramolecular
Brønsted acid catalyst, such as the tris(pentafluorophenyl)borane‐assisted CPA catalyst proposed by Ishihara,17 would be a
highly promising and practical catalyst system to achieve both better conversion and enantioselectivity (Table 1, entries 8–13).
6 5 3
Ultimately, complete conversion accompanied by good enantioselectivity (er 70:30) was achieved using the additive B(C F )
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with 20 mol % loading, a reaction temperature of 85ꢀ°C, and a reaction time of 24 h (Table 1, entry 10). Under these conditions,
the negative effect displayed by molecular sieves was confirmed. Low yields and enantioselectivities were observed in DCM
and DCE at 23 °C, respectively (data not shown).
1
Monitoring this reaction by TLC and H NMR spectroscopic analysis in situ revealed excellent conversion of the starting
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materials into the alkylated product. The yield of the isolated lactone 11 (Table 1) was diminished as a result of its partial
sensitivity to chromatography on silica gel and, more likely, minimal polymerization of vinyl hydroquinone 6. In terms of
further catalyst screening with examination of substituents at the 3,3′‐positions of 12a–d with different bulkiness and skeletons
1
9
for asymmetric induction, 13a,b and 14a (Table 1, entries 15–20) were evaluated. No significant improvement in the er value
or yield was observed with these catalysts. Therefore, the use of catalyst 12a (5 molꢀ%) in the presence of the additive B(C
with 20 mol % loading in toluene at 85 °C for 24 h gave the best results. Pleasingly, intermediate 11 could be enantioenriched
by one single recrystallization using 7:1 iPr O:DCM, furnishing 96:4 er in the mother liquor. In modern asymmetric catalysis,
6 5 3
F )
2
chiral Brønsted acid catalysts with (R)- or (S)-binaphthyl skeletons have found widespread applications, and both enantiomers
of 12a are commercially available. Repeating the reaction and crystallization with the catalyst ent-12a, we were able to obtain
11 with the same yield and almost opposite enantioselectivity.
Table 1. Catalyst and Condition Optimization.
entrya CPA (mol %) additive (mol %) T (° C) conv. (%) yield (%)b
er (%)c
1d
2 d
3 d
4 d
5 d
6
12a (5)
12a (5)
12a (5)
12a (5)
12a (5)
12a (5)
12a (5)
12a (5)
12a (5)
/
85
85
85
85
85
85
85
85
85
48
0
0
38
/
/
65:35
/
/
MS, 4 Å
MS, 3 Å
Na
2
SO
4
100
100
100
52
72
52
14
24
15
30
38
48
61:39
61:39
64:36
82:18
75:25
77:23
MgSO
4
2
H O
7
8 d
Urea-(CF
3
)
2
(5)e
(5)
B(C F )
6 5 3
9
B(C
B(C
6
6
F
5
)
)
3
(10)
7
0:30
1
0
12a (5)
F
5
3
(20)
85
100
68
f
(
96:4)
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12a (10)
12a (5)
12a (5)
/
B(C
B(C
B(C
B(C
B(C
B(C
B(C
B(C
B(C
B(C
6
6
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6
6
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F
F
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F
F
F
F
F
F
F
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)
)
)
)
)
)
)
)
)
)
3
3
3
3
3
3
3
3
3
3
(20)
(20)
(20)
(20)
(20)
(20)
(20)
(20)
(20)
(20)
85
65
85
85
85
85
85
85
85
85
100
74
74
40
62
20
20
54
24
34
20
58
71:29
67:33
57:43
/
1
3g
90
1
4
5
68
1
12b (5)
12c (5)
12d (5)
13a (5)
13b (5)
14a (5)
50
38:62
40:60
51:49
55:45
61:39
62:38
16
100
52
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61
51
100
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0:70
2
1
ent 12a (5)
B(C
6
F
5
)
3
(20)
85
100
68
f
(
13:87)
aReaction conditions: 6 (0.25 mmol), 10 (0.3 mmol), CPA (5–10 mol %), additive (5–20 mol %), toluene (0.25 M), 85
°C, 24 h. bIsolated yield. cDetermined by chiral HPLC on a Chiralpack OD-H column. 72 h. 1,3-bis(3,5-
d
e
f
bis(trifluoromethyl)phenyl)urea. In the mother liquor by recrystallization with 7:1 iPr2O/DCM. Crystals were racemic.
g6 (0.3 mmol), 10 (0.25 mmol) were used.
To complete the synthesis of (+)-fumimycin and (–)-fumimycin, only the removal of the two methyl groups of 11 remained.
Initial attempts to remove both of the protecting groups with a single reagent were unsuccessful. Treatment with a large excess
3
of HBr or BBr at 23 °C resulted in cleavage of both the methyl ether and methyl ester as well as multiple other side products.
On the other hand, lithium hydroxide in 2:1 THF/water proved to be a mild and highly effective method for the selective
hydrolysis of the methyl ester to give (+)- and (–)-methoxyfumimicyn 15, itself a target for synthesis (Scheme 3).
As expected,2,3 we encountered many difficulties in the deprotection of the catechol moiety at a late stage. Following a very
recent report describing clean demethylation of various ortho-methoxyphenols to catechol by treatment with a combination of
AlCl
3
and NaI in acetonitrile using N,N′-diisopropylcarbodiimide (DIC) as the acid scavenger, the reaction failed and 11 was
recovered almost quantitatively.20 However, inspired by this work and our previous results, we decided to treat 11 with BBr
(5
3
equiv) in DCM in the presence of DIC (2 equiv) to prevent side reactions probably due to byproducts of the reaction such as
methyl bromide, hydrobromic acid, and boronic acid. Pleasingly, (+)- and (–)-fumimycin methyl ester 16 were obtained cleanly
and in very good yield. The ability to selectively deprotect either functional group provides great flexibility for possible
subsequent synthetic approaches to derivatives. Unfortunately, the one-pot double-deprotection, in either order, resulted in the
formation of a complex mixture. This result indicated that both of the deprotection steps must be carried out under mild and
controlled conditions. For example, when 16 was treated with LiOH under the same conditions used for 11, only a complex
mixture was obtained; whereas when 15 was subjected to the methoxy ether cleavage reaction, only starting material was
recovered. Pleasingly, cleavage of the methyl ester in 16 was achieved with trimethyltin hydroxide, yielding (+)- and (–)-
fumimycin (1) in decent yields, without the decomposition of base-sensitive moieties (Scheme 3).
Scheme 3. Selective Ester/Ether C–O Cleavage of (–)-11.
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In summary, we have developed a concise and convergent route to both enantiomers of fumimycin (1) in 7 steps and 22%
4
overall yield. The synthesis is considerably shorter and higher yielding than the previously reported asymmetric synthesis and
provides rapid access to significant quantities of (–)-fumimycin. The use of a bulky chiral supramolecular Brønsted acid catalyst,
such as the tris(pentafluorophenyl)borane‐assisted CPA catalyst, was crucial to achieve full conversion for the regio- and
enantioselective domino aza-Friedel−Crafts/lactonization reaction. This novel methodology and enantioenrichment by
recrystallization enabled the asymmetric synthesis of (+)-fumimycin and (–)-fumimycin. The chemoselective cleavage of the
ester/ether C–O of methyl anisates in the context of natural product synthesis, under relatively mild conditions, was also
reported. The application of this highly convergent strategy for the synthesis of novel analogues of fumimycin by simply
changing the phenol and/or the dehydroalanine component as well as their full biological evaluation on various bacterial PDFs
are of ongoing interest in our group.
Experimental Section
General methods. All reagents were purchased from best-known commercial suppliers and used without further
purification. All reactions were run in air unless otherwise noted. Column chromatography purifications were performed
in flash conditions using 230-400 Mesh silica gel. H NMR and 13C NMR were recorded on a 400 spectrometer, using
1
3 3
CDCl and CD OD as solvents. Chemical shifts (δ scale) are reported in parts per million (ppm) relative to the central
peak of the solvent. Coupling constants (J values) are given in Hertz (Hz). Enantiomeric excesses were determined on an
−1
HPLC instrument (chiral column OD-H; mobile phase n-hexane/i-PrOH 85:15, flow 1.0 mL min , λ = 220 nm). Optical
20
rotation analysis was performed with a polarimeter using a sodium lamp (λ 589 nm, D-line); [α]
D
values are reported in
10−1 deg cm g ; concentration (c) is in g for 100 mL. HRMS analysis was performed using a Q-TOF micro TM mass
2
−1
spectrometer.
4-(Allyloxy)-3-methoxybenzaldehyde (3): To a suspension of vanillin 2 (3.04 g, 20 mmol, 1 equiv) and K
2 3
CO (3.86 g,
2
8 mmol, 1.4 equiv) in acetone (30.0 mL) allyl bromide (2.38 mL, 4.37 g, 26 mmol, 1.3 equiv) was added. The mixture
was heated to reflux in oil bath for 2 h. After filtration, the filtrate was concentrated under reduced pressure and purified
by flash chromatography (cyclohexane/EtOAc 9:1) to afford the allylether 3 as a colorless oil (3.80 g, 19.8 mmol, 99%).
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1H NMR (CDCl
, 400 MHz) δ 3.94 (s, 3H), 4.69-4.71 (m, 2H), 5.32-5.35 (m, 1H), 5.41-5.46 (m, 1H) 6.04-6.11 (m, 1H),
3
6.97 (d, J = 8.5 Hz, 1H), 7.40-7.44 (m, 2H), 9.84 (s, 1H). The chemical-physical data are according to those published
the literature.2a
4
-(Allyloxy)-3-methoxyphenol (4): To a 0.5 M solution of 3 (3.80 g, 19.8 mmol) in CH
of diphenylselenide (231 mg, 0.99 mmol, 0.05 equiv) followed by the addition of 5 mL of 30% H
was stirred at 23 °C for 60 h. Water was added and the aqueous layer was extracted with CH Cl . The solvent was removed
under reduced pressure and the residue was dissolved in CH Cl (198 mL) and cooled to 0 °C. 47.4 mL of NH (2N in
EtOH) were added and the reaction was stirred for 1 h at 0 °C. The reaction mixture was concentrated, dissolved in
CH Cl (50 ml), washed with a saturated solution of NaHCO aqueous (50 ml) and water (50 ml). The organic phase was
dried over Na SO , concentrated and the residue purified by flash chromatography (cyclohexane/EtOAc 8:2) to give the
phenol 4 as a brown oil (3.28 g, 18.2 mmol, 92%). H NMR (CDCl
2
Cl
2
was added a catalytic amount
9
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2 2
O
. The reaction mixture
2
2
2
2
3
2
2
3
2
4
1
3
, 400 MHz) 3.84 (s, 3H), 4.52-4.55 (m, 2H), 4.61 (br
s, 1H), 5.25-5.27 (m, 1H), 5.39-5.40 (m, 1H), 6.03-6.06 (m, 1H), 6.31 (dd, J = 8.5, 3.0 Hz, 1 H), 6.47 (d, J = 3.0 Hz, 1H),
+
6.76 (d, J = 8.5 Hz, 1H); HRMS (ESI-TOF) m/z: [M+H] calcd for C10
H
13
O
3
181.0859; found 181.0866. The chemical-
physical data are according to those published the literature.2a
2
b
2-Allyl-6-methoxybenzene-1,4-diol (5) : A solution of 4 (3.28 g, 18.2 mmol) in DMF (300 mL) was heated in oil bath
at 180 °C for 18 h. The solvent was removed under reduced pressure; water (800 mL) was added to residue and the
2 4
mixture was extracted with EtOAc (3 x 800 mL). The organic phase was washed with brine, dried over Na SO and
concentrated under reduced pressure. The residue was purified by flash chromatography (gradient from
1
cyclohexane/EtOAc 9:1 to 7:3) to give 5 as a white solid (2.79 g, 15.5 mmol, 85%). H NMR (CDCl
3
, 400 MHz) δ 3.35-
3
.37 (m, 2H), 3.86 (s, 3H), 4.44 (br s, 1H), 5.06–5.11 (m, 2H), 5.28 (br s, 1H) 5.94 -6.01(m, 1H) 6.22 (d, J = 3.0 Hz, 1
H), 6.35 (d, J = 3.0 Hz, 1H); 13C H NMR (CDCl
1
, 100 MHz) δ 33.8, 56.0, 97.6, 107.8, 115.7, 126.0, 136.3, 137.3,
181.0859; found 181.0876.
3
+
1
46.9, 148.4; HRMS (ESI-TOF) m/z: [M+H] calcd for C10
H
13
O
3
(
3 2
E)-2-Methoxy-6-(prop-1-enyl)benzene-1,4-diol (6): A mixture of 5 (2.78 g, 15.5 mmol, 1 equiv) and RhCl ·3H O (176
mg, 0.77 mmol, 0.05 equiv) in methanol (282 mL) was heated to reflux in oil bath for 24 h. The reaction mixture was
allowed to cool to 23 °C and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and
purified by flash chromatography (gradient from cyclohexane/EtOAc 9:1 to 7:3) to give 6 as a white solid (2.51 g, 14.0
1
mmol, 90%). H NMR (CD
3
OD, 400 MHz) δ 1.85 (dd, J = 6.5, 1.5 Hz, 3H), 3.79 (s, 3H), 6.15 (dq, J = 16.0, 6.5 Hz, 1H),
6.30 (d, J = 2.5 Hz, 1H), 6.40 (d, J = 2.5 Hz, 1H), 6.65 (ddd, J = 16.0, 3.5, 1.5 Hz, 1H); 13C H NMR (CD
1
3
OD, 100
+
MHz) δ 18.5, 56.0, 99.2, 103.8, 125.6, 125.8, 126.5, 137.2, 149.3, 150.6; HRMS (ESI-TOF) m/z: [M+H] calcd for
10 13 3
C H O 181.0859; found 181.0871.
(
E)-Methyl 4-(3-hydroxy-1-methoxy-1-oxopropan-2-ylamino)-4-oxobut-2-enoate (9): DIPEA (6.97 mL, 40 mmol, 2
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5
5
6
2 2
equiv) was added to a 0.25 M stirred solution of serine methyl ester hydrochloride 7 (3.11 g, 20 mmol, 1 equiv) in CH Cl
2
at 0°C under N . After 10 minutes were added (E)-4-methoxy-4-oxobut-2-enoic acid 8 (2.86 g, 22 mmol, 1.1 equiv),
EDCI (4.22 g, 22 mmol, 1.1 equiv) and HOBt (2.7 g, 20 mmol, 1 equiv). The reaction mixture was stirred at 23 °C for 16
h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (gradient from
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
cyclohexane/EtOAc 1:1 to EtOAc 100%) to afford 10 (3.65 g, 15.8 mmol, 79%) as white solid. H NMR (CDCl
3
, 400
MHz) δ 2.94 (br s, 1H), 3.75 (s, 3H), 3.76 (s, 3H), 3.88 (dd, J = 11.5, 3.0 Hz, 1H), 4.0 (dd, J = 11.5, 3.5 Hz, 1H), 4.71-
13
1
4
3
.74 (m, 1H), 6.79 (d, J = 15.5 Hz, 1H), 7.09 (d, J = 15.5 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H); C H NMR (CDCl , 100
+
MHz) δ 52.3, 52.9, 54.9, 63.0, 130.8, 135.8, 163.8, 166.0, 170.7; HRMS (ESI-TOF) m/z: [M+H] calcd for C
9
H
14NO
6
2
32.0816; found 232.0823.
E)-methyl 4-(3-methoxy-3-oxoprop-1-en-2-ylamino)-4-oxobut-2-enoate (10): To a solution of 9 (3.65, 15.8 mmol, 1
equiv) in CH Cl dry (105 mL) under N , were added CuCl (469 mg, 4.74 mmol, 0.3 equiv) and EDCI (3.33 g, 17.38
mmol, 1.1 equiv). After 2 h of stirring at 23 °C, the reaction mixture was filtered through a pad of Celite. The filtrate
(
2
2
2
washed with brine, dried over Na
2
SO
4
, concentrated under reduced pressure and purified by flash chromatography
1
(gradient from cyclohexane/EtOAc 9:1 to 7:3) to yield 10 (3.23 g, 15.2 mmol, 96%) as a white solid. H NMR (CDCl
3
,
400 MHz) δ 3.82 (s, 3H), 3.88 (s, 3H), 6.01 (d, J = 1.5 Hz, 1H), 6.76 (s, 1H), 6.89 (d, J = 15.5 Hz, 1H), 7.02 (d, J = 15.5
1
3
1
Hz, 1H), 8.11 (br s, 1H); C H NMR (CDCl
3
, 100 MHz) δ 52.3, 53.2, 110.5, 130.7, 131.3, 136.1, 162.0, 164.2, 165.6;
+
HRMS (ESI-TOF) m/z: [M+H] calcd for C
according to those published the literature.2c
9 5
H12NO 214.0710; found 214.0731. The chemical-physical data are
General procedure for Aza-Friedel-Craft Alkylation/lactonization cascade reaction. A vial was charged with 6 (45
mg, 0.25 mmol, 1 equiv), 10 (64 mg, 0.3 mmol, 1.2 equiv), the appropriate CPA (0.0125 mmol, 0.05 equiv), B(C
26 mg, 0.05 mmol, 0.2 equiv) and toluene (1 mL). The vial was sealed and immersed in a preheated (85 °C) oil bath and
6 5 3
F )
(
stirred at this temperature for 24 h. The solvent was evaporated under reduced pressure, and the residue obtained was
purified by flash chromatography.
(
E)-Methyl 4-((S)-5-hydroxy-6-methoxy-3-methyl-2-oxo-4-((E)-prop-1-enyl)-2,3-dihydrobenzofuran-3-ylamino)-
-oxobut-2-enoate ((–)-11): the title compound was synthesized according to the general procedure above from
4
commercially available BINOL‐derived chiral phosphoric acid catalysts (S)-12a. The product was purified by flash
chromatography (gradient from cyclohexane/EtOAc 9:1 to 7:3) to give (-)-11 as a pale-yellow solid (61 mg, 0.17 mmol,
1
68%). H NMR (CDCl
3
, 400 MHz) δ 1.77 (s, 3H), 1.93 (dd, J = 6.5, 1.5 Hz, 3H) 3.80 (s, 3H), 3.92 (s, 3H), 5.82 (s, 1H),
13
1
6.31 (dd, J = 16.0, 1.5 Hz, 1H), 6.66 (s, 1H), 6.78 (d, J = 15.5 Hz, 1H), 6.82 (brs, 1H), 6.96 (d, J = 15.5 Hz, 1H); C H
NMR (CDCl
3
, 100 MHz) δ 19.9, 23.4, 52.4, 56.5, 58.3, 93.7, 116.2, 120.3, 121.0, 131.9, 134.0, 134.5, 140.7, 146.2,
+
1
47.4, 162.5, 165.8, 175.8; HRMS (ESI-TOF) m/z: [M+H] calcd for C18
H
20NO
7
362.1213; found 362.1223; Chiral
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HPLC analysis: t
in the mother liquor after recrystallization with iPr
(E)-Methyl 4-((R)-5-hydroxy-6-methoxy-3-methyl-2-oxo-4-((E)-prop-1-enyl)-2,3-dihydrobenzofuran-3-ylamino)-
R
(major) = 19.6 min, t
R
(minor) = 25.2 min, er = 87:13; [α] 20
D
= -26.6 (c = 0.67, MeOH) (determinated
O/DCM 7:1), corresponds to [α] 20
= -35.6 (optically pure).
2
D
4
-oxobut-2-enoate ((+)-11): the title compound was synthesized according to the general procedure above from
commercially available BINOL‐derived chiral phosphoric acid catalysts (R)-12a. The product was purified by flash
chromatography (gradient from cyclohexane/EtOAc 9:1 to 7:3) to give (+)-11 as a pale-yellow solid (61 mg, 0.17 mmol,
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
8%). The spectroscopic data are identical with those of (–)-11. Chiral HPLC analysis: t
R
(minor) = 19.6 min, t
R
(major)
2
0
=
25.1 min, er = 96:4; [α]
O/DCM 7:1), corresponds to [α]
E)-4-((S)-5-Hydroxy-6-methoxy-3-methyl-2-oxo-4-((E)-prop-1-enyl)-2,3-dihydrobenzofuran-3-ylamino)-4-
oxobut-2-enoic acid ((–)-15): To a 0.1 M solution of (–)-11 (90 mg, 0.25 mmol, 1 equiv.) in THF/H O (2:1, 2.5 mL) was
added LiOH (30 mg, 1.25 mmol, 5 equiv.) and the mixture was stirred at 23 °C for 30 minutes. After completion, the
organic solvent was removed in vacuo and the resulting mixture was diluted with H O, acidifed with 2N HCl, then
and concentrated to provide (–)-15 as
D
= +36.8 (c = 1.27, MeOH) (determinated in the mother liquor after recrystallization with
2
0
iPr
2
D
= +40 (optically pure).
(
2
2
2 4
extracted 3 times with EtOAc. The organic layer was separated, dried over Na SO
1
a pale-yellow solid (72 mg, 0.21 mmol, 83%). H NMR (CD
3
OD, 400 MHz) δ 1.67 (s, 3H), 1.91 (dd, J = 6.5, 1.5 Hz,
3
H), 3.88 (s, 3H), 6.40 (dd, J = 16.0, 1.5 Hz, 1H), 6.61 (d, J = 15.5 Hz, 1H), 6.69-6.78 (m, 2H), 6.95 (d, J = 15.5 Hz, 1H);
1
3
1
C H NMR (CD
3
OD, 100 MHz) δ 19.8, 23.4, 57.0, 59.5, 94.9, 118.1, 122.0, 123.0, 134.0, 134.6, 134.7, 142.9, 147.2,
1
49.7, 165.3, 169.0, 178.1. Chiral HPLC analysis: compound ((–)-15) proved to be too polar for the determination of the
enantiomeric excess. Since racemization of the quaternary stereocenter, under mild deprotection conditions can be
excluded, the title compound should also possess er = 87:13; [α] 20
= -40.8 (c = 0.44, MeOH), corresponds to [α]
20
= -
D
D
+
5
4 (optically pure); HRMS (ESI-TOF) m/z: [M+H] calcd for C17
7
H18NO 348.1078; found 348.1075. The chemical-
physical data are according to those published the literature.2b
(
E)-4-((R)-5-Hydroxy-6-methoxy-3-methyl-2-oxo-4-((E)-prop-1-enyl)-2,3-dihydrobenzofuran-3-ylamino)-4-
oxobut-2-enoic acid (ent-15): Compound ent-15 was synthesized from (+)-11 by following similar procedure for the
synthesis of compound ((–)-15). The spectroscopic data are identical with those of ((–)-15). Chiral HPLC analysis:
compound (ent-15) proved to be too polar for the determination of the enantiomeric excess. Since racemization of the
quaternary stereocenter, under mild deprotection conditions can be excluded, the title compound should also possess er
= 96:4; [α] 20
(E)-Methyl
oxobut-2-enoate ((–)-16): To a cooled (0°C) solution of (-)-11 (90 mg, 0.25 mmol, 1 equiv) and 1,3-
diisopropylcarbodiimide (77 µL, 0.5 mmol, 2 equiv) in CH Cl (4 mL) was added BBr (1M in DCM; 1.25 mL, 5 equiv).
= +50.9 (c = 0.66, MeOH), corresponds to [α]
20
= +55 (optically pure).
D
D
4-((S)-5,6-dihydroxy-3-methyl-2-oxo-4-((E)-prop-1-enyl)-2,3-dihydrobenzofuran-3-ylamino)-4-
2
2
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6
After 30 minutes the resulting mixture was diluted with CH
phases were separated. The aqueous layer was acidified with 2N HCl (pH 2-3) and extracted with EtOAc (3 x 10 mL).
The combined organic extracts were dried over Na SO and concentrated under reduced pressure. The residue was
Cl :MeOH 10:0 to 9:1) to afford ((–)-16) (61 mg, 0.175 mmol, 70%)
2 2 3
Cl , basified by the addition of sat. NaHCO solution and the
2
4
purified by flash chromatography (gradient from CH
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
as a pale-yellow solid. H NMR (CD
3
OD, 400 MHz) δ 1.66 (s, 3H), 1.91 (dd, J = 6.5, 1.5 Hz, 3H), 3.77 (s, 3H), 6.38 (dd,
13
1
J = 16.0, 1.5 Hz, 1H), 6.49 (s, 1H), 6.63 (d, J = 15.5 Hz, 1H), 6.63-6.72 (m, 1H), 7.02 (d, J = 15.5 Hz, 1H); C H NMR
CD OD, 100 MHz) δ 19.7, 23.5, 52.7, 59.5, 97.6, 117.0, 122.6, 123.2, 131.7, 134.3, 135.8, 141.9, 147.2, 147.4, 164.7,
67.0, 178.1. Chiral HPLC analysis: compound ((–)-16) proved to be too polar for the determination of the enantiomeric
excess. Since racemization of the quaternary stereocenter, under mild deprotection conditions can be excluded, the title
(
3
1
2
0
20
compound should also possess er = 87:13 [α]
D
= -53.8 (c = 0.65, MeOH), corresponds to [α]
348.1078; found 348.1082.
D
= -72.7 (optically pure),
+
HRMS (ESI-TOF) m/z: [M+H] calcd for C17
H
18NO
7
(
E)-Methyl
4-((R)-5,6-dihydroxy-3-methyl-2-oxo-4-((E)-prop-1-enyl)-2,3-dihydrobenzofuran-3-ylamino)-4-
oxobut-2-enoate (ent-16):
Compound ent-16 was synthesized from (+)-11 by following similar procedure for the synthesis of compound ((–)-16).
The spectroscopic data are identical with those of ((–)-16). Chiral HPLC analysis: compound (ent-16) proved to be too
polar for the determination of the enantiomeric excess. Since racemization of the quaternary stereocenter, under mild
deprotection conditions can be excluded, the title compound should also possess er = 96:4 [α] 20
= +62.7 (c = 0.76,
D
2
0
MeOH), corresponds to [α]
D
= +71 (optically pure).
(
-)-Fumimycin (1): ((–)-16) (61 mg, 0.175 mmol, 1 equiv) was dissolved in 1,2-dichloroethane (4 mL) and after addition
of trimethyltinhydroxide (158 mg, 0.875 mmol, 5 equiv), the mixture was heated in oil bath at 80 °C until TLC analysis
indicated a complete reaction. After completion of the reaction, the mixture was concentrated in vacuo, and the residue
was taken up in EtOAc and basified by the addition of sat. solution of NaHCO
3
. The phases were separated and the
SO
Cl
aqueous layer was acidified with 2N HCl (pH 2-3) and extracted with EtOAc. The organic layer was dried over Na
2
4
and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient from CH
2
2
:
1
MeOH 10:0 to CH
2
Cl
2
: MeOH 9:1+ 0.1% acetic acid) to afford (–)-1 (35 mg, 0.10 mmol, 60%). H NMR (CD
3
OD /CDCl
3
1:1, 400 MHz) δ 1.38 (s, 3H), 1.61 (dd, J = 6.6, 1.6 Hz, 3H), 6.08 (dq, J = 15.7, 1.7 Hz, 1H), 6.23 (s, 1H), 6.33 (d, J =
13
1
3 3
15.6 Hz, 1H), 6.36 (dq, J = 15.8, 6.6 Hz, 1H), 6,56 (d, J = 15.5 Hz, 1H); C H NMR (CD OD /CDCl 1:1, 100 MHz)
δ 19.0, 22.5, 58.1, 96.7, 115.8, 121.1, 121.7, 132.9, 133.3, 133.7, 140.2, 145.6, 145.9, 164.1, 169.7, 177.3. Chiral HPLC
analysis: compound (–)-1 proved to be too polar for the determination of the enantiomeric excess. Since racemization of
the quaternary stereocenter, under mild deprotection conditions can be excluded, the title compound should also possess
er = 87:13 [α] 20
= -91 (c = 0.31, MeOH), corresponds to [α]
20
= -123 (optically pure). The spectroscopic data are
D
D
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1
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1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
according to those published the literature. HRMS (ESI-TOF) m/z: [M+H] calcd for C16
7
H16NO 334.0921; found
334.0943.
(+)-Fumimycin (ent-1): Compound ent-1 was synthesized from ent-16 by following similar procedure for the synthesis
of compound 1. The spectroscopic data are identical with those of (–)-1. Chiral HPLC analysis: compound (ent-1) proved
to be too polar for the determination of the enantiomeric excess. Since racemization of the quaternary stereocenter, under
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mild deprotection conditions can be excluded, the title compound should also possess er = 96:4 [α] 20
= +112 (c = 0.31,
D
2
0
= +121.7 (optically pure), according to data reported by Brase et al.4
MeOH), corresponds to [α]
D
Supporting Information
1
13
Copies of H, C NMR spectra for all new compounds and HPLC traces of 11.
Acknowledgments
We would like to thank Prof. Gilberto Spadoni and Prof. Annalida Bedini, University of Urbino “Carlo Bo”, for useful
discussions. MR thanks GLUOS for a research fellowship.
References
(
1) Kwon, Y.-J.; Sohn, M.-J.; Zheng, C.-J.; Kim, W.-G. Fumimycin:ꢀ A Peptide Deformylase Inhibitor with an Unusual
Skeleton Produced by Aspergillus fumisynnematus. Org. Lett. 2007, 9, 2449-2451.
2) (a) Gross, P. J.; Bräse, S. The Total Synthesis of (±) Fumimycin. Chem. Eur. J. 2010, 16, 12660-12667. (b) Gross,
(
P. J.; Hartmann, C. E.; Nieger, M.; Bräse, S. Synthesis of (±)-Methoxyfumimycin with 1,2-Addition to Ketimines. J. Org.
Chem. 2010, 75, 229-232. (c) Zhou, Z.; Hu, Y.; Wang, B.; He, X.; Ren, G.; Feng, L. A Concise Synthesis of (±)-
Methoxyfumimycin Ethyl Ester. J. Chem. Res. 2014, 38, 378-380. (d) Zhou, Z.-W.; Li, W.-C.; Hu, Y.; Wang, B.; Ren, G.;
Feng, L.-H. Synthesis of the Intermediate for Fumimycin: a Natural Peptide Deformylase Inhibitor. Res. Chem.
Intermediat. 2013, 39, 3049-3054.
(
3) Zaghouani, M.; Bögeholz, L. A.K.; Mercier, E.; Wintermeyer, W.; Roche, S. P. Total Synthesis of (±)-Fumimycin
and Analogues for Biological Evaluation as Peptide Deformylase Inhibitors. Tetrahedron 2019, 75, 3216-3230.
4) Gross, P. J.; Furche, F.; Nieger, M.; Bräse, S. Asymmetric Total Synthesis of (+)-Fumimycin via 1,2-Addition to
Ketimines. Chem.Commun. 2010, 46, 9215-9217.
5) For selected reviews enantioselective aza-Friedel–Crafts reactions, see: (a) Kobayashi, S.; Mori, Y.; Fossey, J. S.;
(
(
Salter, M. M.; Catalytic Enantioselective Formation of C−C Bonds by Addition to Imines and Hydrazones: A Ten-Year
Update Chem. Rev. 2011, 111, 2626-2704. (b) Kataja, A. O.; Masson, G. Imine and Iminium Precursors as Versatile
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15) Molecular sieves contain alkaline and alkaline earth metals. It can be speculated that molecular sieves convert the
4
(
acidic catalyst to metal phosphate species, which are not able to promote enamine/imine tautomerization. We have also
verified that the magnesium salt of catalyst 12a is not efficient in the promotion of these reactions, although we could not
reach a decisive conclusion.
(
16) Maskeri, M. A.; O'Connor, M. J.; Jaworski, A. A.; Davies, A. V.; Scheidt, K. A. A Cooperative Hydrogen Bond
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(
18) Interestingly, BBr
traces.
19) (a) Melikian, M.; Gramüller, J.; Hioe, J.; Greindla, J.; Gschwind, R.M. Brønsted Acid Catalysis – the Effect of
3
-(R)-12a did not effectively promote the reaction of 6 with 10, and 11 was obtained only in
(
3
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,3′-Substituents on the Structural Space and the Stabilization of Imine/Phosphoric acid Complexes. Chem. Sci. 2019, 10,
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