Enantioselective Total Synthesis of Fluvirucinin B1

Article abstract of DOI:10.1021/acs.orglett.6b00513

A convergent synthesis of fluvirucinin B₁ from acid ent-6a and nitrile ent-9, involving an organocopper coupling, a stereoselective allylation, a ring-closing metathesis reaction, and a stereoselective hydrogenation as the key steps, is reported. The starting building blocks have been prepared in a straightforward manner from a common phenylglycinol-derived lactam 1. An unprecedented regioselective oxidation of phenylglycinol-derived secondary amines 5 to carboxylic acids 6 has been developed.

Full text of DOI:10.1021/acs.orglett.6b00513

Letter
pubs.acs.org/OrgLett
Enantioselective Total Synthesis of Fluvirucinin B1
Guillaume Guignard,† Nuria Llor,† Elies Molins,‡ Joan Bosch,*,† and Mercedes Amat*,†
́
†Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine (IBUB), University of Barcelona,
08028 Barcelona, Spain
‡Institut de Cien
̀
cia de Materials (CSIC), Campus UAB, 08193 Cerdanyola, Spain
S
* Supporting Information
ABSTRACT: A convergent synthesis of fluvirucinin B1 from acid ent-6a
and nitrile ent-9, involving an organocopper coupling, a stereoselective
allylation, a ring-closing metathesis reaction, and a stereoselective
hydrogenation as the key steps, is reported. The starting building
blocks have been prepared in a straightforward manner from a common
phenylglycinol-derived lactam 1. An unprecedented regioselective
oxidation of phenylglycinol-derived secondary amines 5 to carboxylic
acids 6 has been developed.
luvirucins are 14-membered macrocyclic lactams isolated1−3
from the fermentation broth of actinomycete strains. They
in B2−5), we envisaged a unified synthetic strategy to these
F
macrolactams in which the C-2 and C-10 ethyl substituents
would come from a common enantiopure amino diol 2, easily
accessible by reductive opening of oxazolopiperidone lactam1.11
Scheme 1 outlines our synthetic plan.
Amino diol 2 would be converted to a 5-hydroxypentanoic
acid derivative A by oxidative removal of the phenylglycinol
moiety and then to the C1−C6 fragment of fluvirucinins B by
are glycosides characterized by the presence of an aminosugar
moiety (L-mycosamine, its 4-epimer, or an N-substituted
derivative) attached at the C-3 or C-9 positions of the core
lactam nucleus through a hydroxy group. They also incorporate
a methyl or ethyl substituent at the C-2 (1S-hydroxyethyl
in fluvirucin A2), C-6 (absent in some members), and C-10
positions (Figure 1). Fluvirucins possess important and varied
Scheme 1. Unified Synthetic Strategy to Fluvirucinins B
Figure 1. Representative fluvirucins.
biological activities, such as antifungal,1 antibiotic,2 antiviral,2 and
anthelmintic.3 In particular, fluvirucin B1 (Sch 38516) exhibits
potent antifungal1a,c and anti-influenza virus2a activities,4 the latter
partially retained in the corresponding aglycon fluvirucinin B1.2b
Although only one total synthesis of a fluvirucin has been
reported,5 the synthesis of the macrolactam aglycons of
fluvirucins, known as fluvirucinins, has received more atten-
tion.6−10 A key point in the synthesis of fluvirucinins is the
stereocontrolled assembly of the stereocenters on the macro-
cyclic ring. Taking into account that all fluvirucinins B possess
the same substitution and stereochemical patterns at the C-2
(R-Et), C-9 (S-OH), and C-10 (R-Et) positions, differing only
in the C-6 substituent (none in fluvirucinin B0, S-Me in B1, S-Et
Received: February 23, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00513
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Organic Letters
Letter
copper-catalyzed coupling of the corresponding iodide with
an appropriately substituted (R = H, Me or Et) alkenyl
Grignard reagent. In turn, the secondary amino group of amino
diol 2 would be oxidized to a cyano group, and the resulting
5-hydroxypentanenitrile B would be converted to the C7−N
fragment of fluvirucinins B after the incorporation of the C-9
stereogenic center by a stereoselective allylation of an aldehyde.
Linkage of the two fragments by an amidation reaction, followed
by a ring-closing metathesis and stereoselective hydrogenation
of the resultant alkene, would complete the synthesis of the
target fluvirucinins B. The success of our synthetic plan would
rely on the development of efficient procedures for the oxidative
removal of the phenylglycinol moiety present in amino diol 2
to afford 5-hydroxypentanoic acid and 5-hydroxypentanenitrile
derivatives.
Scheme 3. Proposed Mechanism for the m-CPBA-Promoted
Oxidation of Secondary Amines 5
The conversion of a secondary amine to a carboxylic acid is a
challenging, unprecedented transformation. Taking into account
that primary amines are oxidized to nitro derivatives by treat-
ment with m-chloroperbenzoic acid,12 we decided to study this
oxidation using a set of phenylglycinol-derived secondary
amines structurally related to 2.
Scheme 4. Oxidation of Secondary Amine 5a to Nitrile 9
To our delight, treatment of the O-protected amino diols
5a−d with an excess of m-CPBA (4.2 equiv) in refluxing
CH2Cl2 directly afforded the corresponding carboxylic acids
6a−d, bearing a variety of substituents (ethyl, benzyl,
isopropylidenedioxy) in good yields (Scheme 2). Considering
Scheme 2. Oxidative Removal of the Chiral Inductor: Access
to Enantiopure O-Protected 5-Hydroxypentanoic Acids
In this way, secondary amine 5a was converted to nitrile 9 in
71% yield (Scheme 4).
This transformation involves the initial generation of an
imine and its reaction with ammonia to form an aminal, which
decomposes to a primary amine and an imine. Subsequent
oxidation and hydrolytic steps lead to the nitrile and (tert-
butyldiphenylsilyloxy)methyl phenyl ketone, regardless of the
regioselectivity of the initial oxidation.
Having developed straightforward procedures for the
conversion of secondary amines 5 to functionalized carboxylic
acids 6 and nitrile 9, to evaluate the feasibility of the unified
strategy outlined in Scheme 1, we undertook the synthesis of
fluvirucinin B1. To achieve the required 2R and 10R con-
figuration characteristic of fluvirucinins B, we started from the
(S)-phenylglycinol-derived secondary amine ent-4a (= 2),
which was converted, as in the above (R)-phenylglycinol series,
to hydroxy acid ent-6a (A; Prot = TBDPS) and hydroxy nitrile
ent-9 (B; Prot = TBDPS).
Scheme 5 outlines the synthesis of fluvirucinin B1. The
C1−C6 fragment (compound 12) was prepared from carboxylic
acid ent-6a, which was converted, via an alcohol, to iodide 10.
A subsequent cross-coupling with 2-propenylmagnesium
bromide in the presence of a catalytic amount of CuI16 (bond
formed C5−C6) provided the protected alcohol 11, which was
desilylated and oxidized to carboxylic acid 12 (23% overall yield
from 1).
On the other hand, after the protected hydroxy nitrile ent-9
was converted to aldehyde 13, a stereoselective allylation using
the (S,S)-Leighton reagent17 installed the C-9 stereogenic center
to give homoallylic syn alcohol 1418 (bond formed C8−C9).
Protection of the hydroxy group of 14, followed by reduction
of the cyano group, afforded amine 15 (the C7−N fragment of
fluvirucinins B) in 21% overall yield from 1.
Coupling of the two fragments, carboxylic acid 12 and amine
15, took place in excellent yield to give amide 16. A sub-
sequent ring-closing metathesis reaction (bond formed C6−C7),
that amino diols 4 are available with virtually any type of
substitution pattern,11 the above oxidative procedure opens a
general synthetic entry to enantiopure 5-hydroxypentanoic acid
derivatives.
The formation of carboxylic acids 6 can be accounted for by
considering the generation of the nonconjugated nitrones 713
and their m-CPBA-promoted oxidative cleavage14 with sub-
sequent oxidation of the resulting aldehyde. The oxidative
cleavage also produces a nitroso derivative, which was isolated
as the corresponding nitroso dimer 8 (Scheme 3).
In support of this mechanism, nitrone 7e, prepared by
Na2WO4/hydrogen peroxide−urea oxidation13b of the simple
secondary amine 5e, was converted to hydroxypentanoic acid
derivative 6e (45% from 5e) and dimer 8 by treatment with
m-CPBA (2.5 equiv).
On the other hand, the generation of a 5-hydroxypentaneni-
trile by oxidative cleavage of the phenylglycinol moiety of the
starting O-protected amino diol was successfully accomplished
in a single step using molecular iodine in aqueous ammonia.15
B
DOI: 10.1021/acs.orglett.6b00513
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Letter
a
Scheme 5. Total Synthesis of Fluvirucinin B1
a
The carbon numbering of the intermediates corresponds to that of fluvirucinin B1.
followed by stereoselective catalytic hydrogenation of the result-
ing 1.2:1 mixture of trisubstituted olefins 17, generated the C-6
stereocenter of the macrocycle,19 leading to the O-protected
fluvirucinin derivative 18. The NMR data of our silyl derivative
18 matched those reported in the literature,5b,9b and its mp
and absolute rotation were consistent with those previously
reported.9b Additionally, the absolute configuration of 18 was
unambiguously established by X-ray crystallographyic analysis20
(Figure 2). A final removal of the silyl protecting group
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00513.
■
S
Experimental procedures, product characterizations, and
1H and 13C NMR spectra (PDF)
Crystallographic data for compound 18 (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: joanbosch@ub.edu.
*E-mail: amat@ub.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Spanish Ministry of Economy and
Competitiveness/FEDER (Projects CTQ2012-35250 and
CTQ2015-65384-R) and the Generalitat de Catalunya (Grant
No. 2014-SGR-155) is gratefully acknowledged. We also
acknowledge the networking contribution from the COST
Action CM1407.
Figure 2. X-ray crystal structure of the fluvirucinin B1 precursor 18.
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Supporting Information).
■
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herein reported consists of 12 linear synthetic steps from
phenylglycinol-derived lactam 121 in the longest linear sequence.
The overall yield was 11%, which compares advantageously with
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Org. Lett. XXXX, XXX, XXX−XXX