Synthesis of the tetracyclic core of the tetrapetalones through transannular oxidative [4+3] cyclization

Article abstract of DOI:10.1002/anie.200500247

(Chemical Equation Presented) A convergent strategy involving a base-mediated silyl transfer/acylation for fragment coupling and a tandem process consisting of nitro reduction and acyl transfer can be employed to construct strained, bicyclic macrolactams

Full text of DOI:10.1002/anie.200500247

Angewandte
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Natural Product Synthesis
Synthesis of the Tetracyclic Core of the
Tetrapetalones through Transannular Oxidative
[4+3] Cyclization**
Xiang Wang and John A. Porco, Jr.*
A series of novel soybean lipoxygenase (SBL) inhibitors,
tetrapetalones A–D (1–4, Scheme 1), were recently isolated
Scheme 1. Chemical structures of the tetrapetalones A–D (1–4) and
representative ansamycin natural products 5–7.
by Komoda et al.[1] from the culture filtrate of the Strepto-
myces sp. strain USF-4727.[2] These tetrapetalones showed
moderate inhibition of SBL (IC50 = 190–360 mm for 1–4)
comparable to the well-known lipoxygenase inhibitors nordi-
hydroguaiaretic acid (NDGA, IC50 = 290 mm) and kojic acid
(IC50 = 110 mm). The structure of tetrapetalone A (1) was first
1
determined by H NMR NOESY spectroscopic analysis and
modified Mosher analysis,[1a] and then was subsequently
revised by 1H–15N HMBC techniques, detailed NOE analysis,
and chemical derivatization.[1b] The tetrapetalones B–D (2–4)
were structurally characterized shortly thereafter and were
shown to have similar inhibitory activities against SBL. The
tetrapetalones possess an unprecedented tetracyclic skeleton
bearing an appended b-rhodinosyl moiety. The unique
structural feature of the tetracyclic core and its similarity to
[*] X. Wang, Prof. J. A. Porco, Jr.
Department of Chemistry and
Center for Chemical Methodology and Library Development
Boston University, 590 Commonwealth Avenue
Boston, MA 02215 (USA)
Fax: (+1)617-353-6466
E-mail: porco@chem.bu.edu
[**] We thank Dr. J. Lee (Boston University) for assistance with NMR
experiments and the National Institutes of Health (GM-62842) for
research support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200500247
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the ansamycin antibiotics[3,4] attracted our interest and
prompted consideration of synthetic approaches.
The ansamycins are important antibiotics possessing
antibacterial, antifungal, and antitumor activities.[5] For
example, geldanamycin (7) has been shown to inhibit the
chaperone activity of heat shock protein 90 (Hsp90) by
noncovalent binding to its ATP/ADP binding site.[6]
A
synthetic analogue, 17-allylamino-17-demethoxygeldanamy-
cin, has entered phase I clinical trials.[7] The benzylic ansa-
mycin natural products (representative members are shown in
Scheme 1) vary in oxidation level from a monophenol (for
example, reblastatin),[3h] hydroquinone (for example, cyto-
trienin A),[3f] to a benzylquinone (for example, 5–7), each
bearing a highly functionalized polyketide ansa chain. It is
likely that the biosynthesis of the benzylic ansamycins
involves oxidation of the aromatic core after construction of
the macrolactam unit.[8] We considered whether the tetrapet-
alones may be derived from a macrocyclic ansamycin
precursor because of structural similarities between the
tetrapetalones and the ansamycins. During oxidation of
hydroquinone 8, however, the arene-derived oxonium ion 9
may be trapped by the diene fragment, which subsequently
reacts with the amide nitrogen atom to form the tetracyclic
skeleton of 1–4 (Scheme 2).[9] It is also possible that the
desired quinone 10 may undergo excited-state intramolecular
proton transfer (ESIPT)[10] under UV
Scheme 2. Retrosynthetic analysis of tetrapetalone A (1). TBS=tert-
butyldimethylsilyl. MOM=methoxymethyl.
irradiation to afford dipole 11, which
further reacts with the diene fragment
to form the tetracycle. To investigate
these and other possible transannu-
lar[11] [4+3] cyclization processes,[12,13]
we developed a retrosynthetic analysis
for tetrapetalone A to target the prep-
aration of both hydroquinone 8 and
quinone 10. We considered ring-clos-
ing metathesis (RCM)[14] of acyclic
substrate 12, which may be derived
from condensation of the acid 13 and
aniline 14, as a route to develop a
convergent synthetic pathway to these
precursors.
Synthesis of the requisite diene
acid 13 commenced with the Evans
syn-aldol condensation[15] of dienal
15[16] and chiral oxazolidinone 16 to
afford chiral alcohol 17 as a single
diastereomer (Scheme 3). Methoxy-
methyl (MOM) protection of the
alcohol and hydrolysis of the chiral
auxilary afforded 13 (85% yield, three
steps). Asymmetric crotylation[17] of
Scheme 3. RCM approach to macrolactam 22. a) 16, Bu2BOTf, Et3N, CH2Cl2, ꢀ78!08C;
b) 1. MOMCl, DIPEA; 2. LiOH, H2O2, THF, H2O (85% yield over 3 steps); c) 19, CH2Cl2, ꢀ78!
258C (100% yield); d) 1. TBSOTf, Et3N, ꢀ788C; 2. NaBH4, S8, THF, 658C (62% yield over
2 steps); e) 13, (COCl)2, cat. DMF, CH2Cl2, 0!258C; then 14, Et3N, 82% yield. MOMCl=chloro-
methyl methyl ether, DIPEA=diisopropylethylamine, TBSOTf=tert-butyldimethylsilyl triflate,
DMF=N,N-dimethylformamide, Mes=mesitylene, Cy=cyclohexyl, Bn=benzyl.
aldehyde 18[4a] using the chiral cis-crotylboronate 19 derived
from l-diisopropyltartrate (l-dipt) afforded chiral alcohol 20
(100% yield, single diastereomer). Silylation followed by
reduction of the nitro group[18] afforded the desired aniline 14
(62% yield, two steps). Coupling of fragments 13 and 14 using
chloride proved to be feasible in the preparation of 12 (82%)
without epimerization. However, treatment of acyclic triene
12 with the Grubbs second generation catalyst 21 did not
1
produce the desired cyclic diene 22. H NMR spectroscopic
analysis of the crude reaction mixture indicated that the
ruthenium catalyst had reacted with the monosubstituted
olefin, with no evidence of metathesis of the 1,1-disubstituted
olefin. We believe that the 1,1-disubstituted olefin was
N,N-bis(2-oxo-3-oxazolidinyl)phosphorodiamidic
chloride
(BOPCl)[19] led to epimerization of the a chiral center (C2,
Scheme 3) of the amide product 12. The use of an acid
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unreactive in this case and that the two meta-substituted side
chains are likely to be positioned away from each other
because of “meta bridging” of the aromatic substituents.
Therefore, the macrocyclic RCM was prohibited by both the
reactivity of the olefin and the conformational strain within
the substrate 12.[4f] A conformational search on model A by
molecular mechanics force field (MMFF) studies[20]
(Scheme 4) suggested a possible rationale: the smallest
Scheme 5. Revised retrosynthetic analysis for macrolactam 23.
Scheme 4. Conformers of the “meta-bridged” acyclic model.
distance between the C6’ and C7’ atoms is
6.2 ꢀ among the low-energy conformers (Erel
=
0–5.2 kcalmolꢀ1) of model A. Therefore, the
conformational strain of the “meta-bridged”
framework may provide a significant barrier for
macrocyclization of substrate 12.
Since the direct macrocyclic RCM approach
did not afford the desired macrocycle, we next
considered that macrolactam 23 (Scheme 5) may
be derived from an “ortho-bridged” macrolac-
tone 24 through intramolecular acyl transfer[21]
(ring expansion). Lactone 24 may be prepared
from selective reduction of the nitro group of 25,
which may be obtained from nitrophenol 26 and
acyl chloride 27. A TBS group was chosen to
protect the phenol of 26, to facilitate removal at
a later stage.
Synthesis of the revised C7–C15 fragment
began with nitration of phenol 28[22] followed by
silylation to afford bis(silyl) ether 29 (70%, two
steps; Scheme 6). Asymmetric crotylation of 29
using cis-crotyl boronate 19[17] produced chiral
alcohol 30 as a single diastereomer in quantita-
tive yield. Deprotonation of the secondary
alcohol of 30 using sodium hexamethyldisilazane
Scheme 6. Synthesis of ansamycin 34. a) 1. Cu(NO3)2·3H2O, Ac2O, 0!258C; 2. TBSCl, Et3N,
DMF, 70% yield over 2 steps; b) 19, CH2Cl2, ꢀ78!258C, 99% yield; c) NaHMDS, THF,
ꢀ788C; then 27, Et3N, DMAP, ꢀ78!258C, 85% yield; d) 21, benzene, 808C; e) TBAF/HOAc,
THF, 08C, 85% yield over 2 steps; f) Pd/CaCO3, Et3N, THF, 1 atm H2; then silica gel, EtOAc.
DMAP=4-N,N-dimethylaminopyridine, DMF=N,N-dimethylformamide; HMDS=1,1,1,3,3,3-
hexamethyldisilazane; TBAF=tetrabutylammonium fluoride.
[25]
(NaHMDS; THF, ꢀ788C) generated a sodium phenoxide
species 31 in situ through intramolecular transfer of a silyl
group.[23,24] Subsequent addition of acyl chloride 27, Et3N, and
DMAP afforded phenol ester 32. To our delight, triene 32
underwent smooth RCM macrocyclization to afford cyclic
diene 33 after treatment with the Grubbs second generation
catalyst 21 (808C, 30 min). NOE analysis showed that the
newly formed olefin possessed a Z configuration. Selective
desilylation of 33 (TBAF/AcOH) afforded nitrophenol 25
(85%, two steps).
tions for reduction of the nitro group, such as SnCl2 and
NaBH4/S8,[18] to substrate 25 not only reduced the nitro group
but also hydrolyzed the ester, and no desired macrolactam 34
was formed. The use of Pd/C[26] or Pd/CaCO3[27] in a hydrogen
atmosphere was found to reduce both the diene and nitro
groups. However, Pd/CaCO3 chemoselectively reduced the
nitro group of 25 when 10% triethylamine was employed as a
cosolvent. Filtration of the reaction mixture through silica gel
followed by elution with EtOAc cleanly afforded the desired
acyl migration product 34. It is interesting to note that use of
the Lindlar catalyst[4b] resulted in formation of trace amounts
of the desired product, presumably because of the catalyst
poison PbO2 and the sensitivity of aniline 24 to the oxidant.
We next evaluated conditions for the selective reduction
of the aryl nitro group in the presence of the diene
functionality. We found that application of standard condi-
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With hydroquinone 34 in hand, we next evaluated the
oped that involves a one-pot, base-mediated silyl transfer/
acylation process for fragment coupling and a tandem
reduction of the nitro group/acyl transfer process for con-
struction of the highly strained, bicyclic system. This novel
strategy provides an alternative approach to the construction
of macrolactams as precursors to the ansamycin antibiotics
and analogues. Synthetic studies toward the total synthesis of
tetrapetalone A (1) and development of related oxidative
[4+3] cyclization processes are currently being investigated
and will be reported in due course.
crucial biomimetic transannular oxidative [4+3] cycliza-
tion.[28] Out of the possible oxidants to effect the trans-
formation of hydroquinones to quinones, we first chose
[29]
PhI(OAc)2
for the activation of hydroquinone. After
considerable experimentation, we found that hydroquinone
34 was readily oxidized, with oxidative oligomerization as a
major side reaction. Addition of a dilute solution of 34 in
CH2Cl2 to a solution of PhI(OAc)2 in CH2Cl2 at 08C over
15 minutes provided tetracycle 35 (42%, two steps;
Scheme 7). The structure of 35 was determined by NOESY
spectroscopic analysis as shown in Scheme 7. Three stereo-
centers were formed (see inset, Scheme 7), and out of these,
the configurations at the C4 and C7 atoms are the same as
those of the natural products 1–4 but the configuration at C15
is reversed (S).
A conformational search of substrate 34 was performed
by using MMFF studies to investigate the stereochemical
outcome of this highly diastereoselective transannular
[4+3] cyclization.[20] The macrocycle is positioned underneath
the aromatic ring in the ground-state conformer (see inset,
Scheme 7), thus establishing an Sconfiguration for the C15
Received: January 21, 2005
Published online: April 14, 2005
Keywords: acylation · antibiotics · cyclization · iodine
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Scheme 7. IIII-promoted transannular oxidative [4+3] cyclization. a) PhI(OAc)2, CH2Cl2, 08C (42% yield over 2 steps).
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