Synthesis of novel geldanamycin derivatives

Article abstract of DOI:10.1016/j.tet.2021.131927

The toxicity associated with the geldanamycin family of benzoquinone ansamycins when used as heat shock protein-90 inhibitor molecular therapeutics is ameliorated by substitution at the 19-position. The resulting 19-substituted derivatives have greater potential for success in oncology clinical trials and for other medicinal purposes such as the treatment of neurodegenerative conditions. Having overcome hurdles associated with the sensitivity and complexity of these molecules, through a variety of synthetic approaches, the synthesis of a series of 19-substituted geldanamycin derivatives is reported herein using optimised Stille and Suzuki coupling reactions. Further compounds were accessible via copper-mediated coupling and nucleophilic addition reactions The new compounds are of significant medicinal interest, in view of their significantly reduced toxicity previously observed for this class of substrate compared to their 19-unsubstituted counterparts that have been evaluated in the clinic.

Full text of DOI:10.1016/j.tet.2021.131927

Tetrahedron 82 (2021) 131927
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of novel geldanamycin derivatives
, b,
Russell R.A. Kitson a *, Christopher J. Moody a
a School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
b Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The toxicity associated with the geldanamycin family of benzoquinone ansamycins when used as heat
shock protein-90 inhibitor molecular therapeutics is ameliorated by substitution at the 19-position. The
resulting 19-substituted derivatives have greater potential for success in oncology clinical trials and for
other medicinal purposes such as the treatment of neurodegenerative conditions. Having overcome
hurdles associated with the sensitivity and complexity of these molecules, through a variety of synthetic
approaches, the synthesis of a series of 19-substituted geldanamycin derivatives is reported herein using
optimised Stille and Suzuki coupling reactions. Further compounds were accessible via copper-mediated
coupling and nucleophilic addition reactions The new compounds are of significant medicinal interest, in
view of their significantly reduced toxicity previously observed for this class of substrate compared to
their 19-unsubstituted counterparts that have been evaluated in the clinic.
Received 29 October 2020
Received in revised form
24 December 2020
Accepted 5 January 2021
Available online 15 January 2021
Keywords:
Hsp90
Geldanamycin
Benzoquinone-ansamycin
Polyketide
© 2021 Elsevier Ltd. All rights reserved.
Cancer neurodegeneration
1. Introduction
family of compounds continues to attract attention in the literature
[14,15].
Since its initial isolation in 1970 [1], geldanamycin 1 (Fig. 1), a
member of the benzoquinone ansamycin polyketide (BQA) family
of natural products, has attracted considerable interest, not only as
a challenging target for synthesis, but also due to its interesting
biological activity. This was sparked by the discovery of geldana-
mycin’s specific and potent inhibition of heat shock protein-90
(Hsp90), which plays a crucial role in various oncogenic pathways
as well as neurodegenerative diseases [2], and has implications in
the treatment of malaria [3e5], and HIV [6e9]. Through improve-
ment of the solubility, stability and hepatotoxicity [10], a series of
compounds have progressed to clinical evaluation (Fig.1), including
Through our research in the area we reported that the intro-
duction of a substituent at the 19-position of geldanamycin de-
rivatives renders the compounds (19-BQAs 5, Fig. 2) essentially
non-toxic through suppression of the addition of biological nucle-
ophiles whilst retaining their potent Hsp90 inhibition [16,17]. In
addition, the introduction of a substituent at C-19 causes a
favourable change in conformation of the macrocyclic ring
involving a trans-cis change in the amide that facilitates binding to
the ATP-site in Hsp90 [16]. We have also reported the preliminary
biological evaluation as therapeutics for cancer [18] and neurode-
generative disease [19].
the
17-amino-derivatives
17-allylamino-17-demethoxygel
[11], 17-(2-dimethyl
We now report the synthesis of a series of new 19-BQAs,
including those using our previously published methodologies, but
also through new approaches that we have found are viable
methods to functionalise these highly sensitive, complex molecules
into less toxic compounds of significant biological interest.
danamycin (17-AAG, tanespimycin)
2
aminoethylamino)-17-demethoxygeldanamycin (17-DMAG, alves-
pimycin) 3 [12] and the 17-AAG hydroquinone hydrochloride salt,
IPI 504 4 [13]. However to the best of our understanding, clinical
evaluations of these compounds were halted, predominantly due to
ongoing issues with formulation and toxicity. Nevertheless, the
2. Results and discussion
2.1. Synthesis
Dedicated with respect and affection to our friend Richard Taylor on the occasion
of his 70th birthday.
Some precedent for derivatisation of geldanamycin 1 at the 19-
position has been reported, using either the conjugate acceptor
properties of the quinone through reaction with nucleophiles
[20e23], or the nucleophilic enamide character of the amido-
* Corresponding author. Department of Chemistry, University of Warwick,
Coventry, CV4 7AL, UK.
E-mail addresses: r.kitson@warwick.ac.uk (R.R.A. Kitson), christopher.moody@
nottingham.ac.uk (C.J. Moody).
https://doi.org/10.1016/j.tet.2021.131927
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

R.R.A. Kitson and C.J. Moody
Tetrahedron 82 (2021) 131927
Fig. 1. Geldanamycin and the clinically-evaluated amino-derivatives 17-AAG, 17-DMAG and 17-AAG hydroquinoneꢁHCl (IPI 504).
quinone functionality for halogenation [20] and Mannich [24,25]
reactions. We were attracted to the latter approach to install a
halogen at C-19, followed by a palladium-catalysed cross-coupling
to install a carbon-carbon bond at C-19 and allow for an array of
commercially available or easily prepared coupling partners to be
employed. Hence our efforts commenced with the preparation of
19-iodogeldanamycin 6 from commercially available geldanamycin
1 in excellent yield (Scheme 1) [20]. This compound was found to
be remarkably stable and was typically prepared in gram quantities
and stored for several months in the freezer. On turning our
attention to the cross-coupling of this iodo derivative, a series of
‘standard’ conditions with a variety of transition-metal catalysts
proved fruitless, with the typically required high temperatures and/
or strong bases leading to degradation of the highly sensitive BQA
substrate 6 or with geldanamycin 1 itself the only recovered
product through a competing reaction pathway. With the Stille
coupling typically regarded as the mildest of the standard cross-
coupling approaches, we adhered to this approach (Scheme 1,
Table 1), employing strategies for increasing the rate of the slow
transmetallation step, which we believed to be the issue leading to
the formation of geldanamycin 1. The’standard’conditions with
triphenylphosphine and dibenzylideneacetone-ligated palladium
catalyst led solely to the recovery of geldanamycin 1 (Entry 1).
However, to our delight, the replacement of the ligand with the
softer, more labile triphenylarsine (known to assist slow trans-
with significant quantities of recovered geldanamycin (29%). We
subsequently carried out an optimisation study for the reaction,
with DMF proving the most effective solvent with 1.2 eq. of the
stannane, 20 mol% of triphenylarsine,
5 mol% of Pd2(dba)3
employed. For the reaction temperature and time, a balance was
struck between a satisfactory reaction rate and the formation of the
undesired geldanamycin 1 side-product, with 35 ꢀC for 16 h proving
optimal. Interestingly, the addition of 5 mol% copper (I) iodide,
proposed to further increase the rate of transmetallation in Stille
couplings, was found to improve the conversion, resulting in an
excellent yield of 19-methylgeldanamycin 7 (86%) (Entry 8).
With the optimal conditions in hand, we proceeded to study the
scope of the methodology with a number of commercially available
or readily prepared stannane coupling partners. These reactions are
discussed in-conjunction with the scope of the corresponding
Suzuki coupling protocol as described below (Table 3).
Clearly residual tin and arsenic (and other metals used) would
be undesirable in potential medicinal compounds. However,
following an aqueous work-up and chromatography employing
Harrowven’s K2CO3/SiO2 protocol [28], low ppm quantities of Pd, Sn
and As and undetectable levels of Cu were observed by ICPMS,
which was further-reduced on formation of the amino-derivatives
(with the exception of copper, likely through traces in the amine
reagents used) [16]. Nonetheless, given that the Suzuki-Miyaura
protocol with boron-based coupling partners is typically amongst
the most attractive cross-coupling approach for the pharmaceutical
industry, particularly on scale-up, our attention turned to
metallations
in
Stille
couplings
[26,27])
gave
19-
methylgeldanamycin 7 in a moderate 56% yield (Entry 2), albeit
2

R.R.A. Kitson and C.J. Moody
Tetrahedron 82 (2021) 131927
Table 1
Optimisation of Stille reaction conditions for conversion of 19-iodogeldanamycin 6
into 19-methylgeldanamycin 7.a
Entry Solvent Ligand Additive T/ꢀC
7 Yield/% Recovered 1
/%
1
2
3
4
5
6
7
8
DMF
DMF
DMF
MeCN
CH2Cl2
THF
Ph3P
-
-
50
50
50
50
0
80
29
<10
26
-
-
<5
<5
Ph3As
Ph3As
Ph3As
Ph3As
Ph3As
Ph3As
Ph3As
56
68
34
0
CuI
CuI
CuI
CuI
CuI
CuI
40 (reflux)
50
ca. 20 (rt)
35
0
DMF
DMF
69b
86
aAll reactions were conducted at a concentration of 0.02e0.04 M in the solvent
specified with 1.2 eq. Me4Sn, 20 mol% ligand, 5 mol% Pd2(dba)3ꢁCHCl3 and 5 mol%
Cu(I) iodide (if used) for 16 h bca. 20% recovered starting material 6 after 48 h
[dba ¼ dibenzylideneacetone].
tested resulting in significantly diminished yields (Entries 3e6, 9
and 10). Alcohol solvents proved to be an exception to this trend
with excellent yields of 84% and 87% obtained for methanol and
isopropanol, respectively (Entries 7 and 8) and dioxane/water or
alcoholic/water solvent mixtures (Entries 2, 9, 11e14). The instal-
lation of a phenyl group was also investigated utilising the alter-
native boronate species outlined in Entries 11e14. Reactions
employing the more stable phenyl MIDA boronate [30] and potas-
sium phenyltrifluoroborate [31] coupling partners were found to be
moderately successful, although a switch of palladium catalyst gave
inferior yields. On attempting reactions with the corresponding
pinacol ester however, we were delighted to obtain 19-
phenylgeldanamycin 8 in quantitative yield after simple chroma-
tography (Entry 11).
In terms of substrate scope for the two coupling methodologies,
they were often found to be complementary to one another, and a
comparative summary is outlined in Table 3. For the Stille protocol,
unlike with the coupling of a methyl group (Entry 1), no other alkyl
substituents were able to be successfully installed (e.g. Entry 2) and
the coupling with allyl tri-n-butylstannane gave a meagre z 5%
yield of the desired product 10 (Entry 3). However, for the Suzuki
approach, whilst the coupling of a methyl group resulted in
significantly diminished yields of the product 7 versus the Stille
reaction (with both boronic acid and trifluoro borate coupling
partners: 86% [Stille] vs. 39% [Suzuki], Entry 1), other substituents
were now accessible where little to no product had been isolated
from the Stille procedure including for iso-propyl (19%, Entry 2) and
Fig. 2. 19-Substituted benzoquinone ansamycin derivatives.
developing a Suzuki alternative to our original methodology. As
previously mentioned, early attempts at Suzuki-based couplings
had been unsuccessful, yet hope was offered through an account
describing the synthesis of 17-aryl-geldanamycins in moderate-
good yield from the corresponding triflate, utilising the Neel
modification of the Suzuki-Miyaura procedure (‘ligand-free’ cata-
lytic Pd2(dba)3$CHCl3, CsBr for ligand-exchange with the
palladium-triflate complex, and CsF as the base, in 1,4-dioxane)
[29]. We therefore applied these conditions (minus the CsBr) to 19-
iodogeldanamycin
6 concentrating on the synthesis of 19-
phenylgeldanamycin 8 with benzeneboronic acid for initial in-
vestigations and optimisation of conditions (Scheme 2, Table 2).
Pleasingly the coupling proceeded very efficiently with gentle
heating over 16 h to give the product in excellent yield (Entry 1).
1,4-Dioxane was found to be the optimal solvent, with most others
Scheme 1. Synthesis of 19-methylgeldanamycin through the Stille methodology [16].
3

R.R.A. Kitson and C.J. Moody
Tetrahedron 82 (2021) 131927
Scheme 2. Synthesis of 19-phenylgeldanamycin 8 through the Suzuki methodology [32].
Table 2
of 2-pyridyl stannane, which gave the product 26 in a modest 30%
yield, Entry 19) and 19-hetaryl geldanamycins could also be ob-
tained in very good yield through the corresponding Suzuki
approach (Entry 22).
One important aspect of the Suzuki protocol that was signifi-
cantly superior to the Stille approach was the ease of isolation and
purification of the products. Now straightforward concentration of
the reaction mixture followed by simple silica gel chromatography
was viable rather than repeated washing with saturated aqueous
LiCl solution (to remove the DMF), followed by 10% potassium
carbonate/silica gel chromatography [28] (with subsequent treat-
ment of all glassware for tin contamination).
Although the Stille and Suzuki coupling reactions described
above provided a range of 22 compounds for biological evaluation,
we were keen to extend the range of C-19 substituents, in particular
to include functionalised alkyl groups. One substituent of potential
medicinal interest [34,35] that we were keen to install at the gel-
danamycin 19-position was the trifluoromethyl group. However,
attempts to install this via our Stille approach with tributyltri-
fluoromethylstannane or alternative copper-mediated coupling
methods [36] had been unsuccessful. A 2011 report by Hartwig and
co-workers described a mild approach for coupling trifluoromethyl
groups to aryl halides with greater functional group tolerance and
utility with more hindered substrates than other reported methods,
Optimisation of the Suzuki-Miyaura coupling reaction.a
Entry
Solvent
Boron species
8 Yield/%
Recovered 1/%
1b
2b
3
1,4-dioxane
1,4-dioxane/H2O (9:1)
THF
THF/H2O (9:1)
CH2Cl2
MeCN
MeOH
i-PrOH
i-PrOH/H2O (9:1)
DMF
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(pin)
PhB(MIDA)
PhBFꢂ3 Kþ
PhBFꢂ3 Kþ
91
78
26
57
23
12
84
87
56
4
<5
14
54
29
31
<5
<5
<5
27
<5
<5
8
4
5c
6
7
8
9
10
11
12
13d
14d,e
1,4-dioxane/H2O (9:1)
1,4-dioxane/H2O (9:1)
i-PrOH/H2O (9:1)
i-PrOH/H2O (9:1)
Quant.
20
68
27
<5
71
a
All reactions were conducted at a concentration of 0.02e0.04 M in the solvent
specified with 2.0 eq. of the boron coupling partner, 5 mol% Pd2(dba)3$CHCl3 and 2.0
eq. of caesium fluoride at 40 ꢀC for 16 h.
b
The reaction was heated to 40 ꢀC for 4 h.
The reaction was heated to reflux for 16 h.
The reaction was performed with 3.0 eq. of triethylamine [31].
The reaction was performed with
c
d
e
5
mol% PdCl2(dppf)$CH2Cl2
[dba ¼ dibenzylideneacetone, B(pin) ¼ 4,4,5,5-tetramethyl-1,3,2-dioxaborolane,
MIDA N-methyliminodiacetic acid [30], dppf
1,10-bis(diphenylphosphino)
ferrocene].
¼
¼
using
1,10-phenanthroline-ligated
trifluoromethylcopper(I),
known as Trifluoromethylator™ [37]. With the commercially
available reagent, we tried the coupling under rigorously anhy-
drous and inert (argon) conditions and were delighted to isolate the
19-CF3-geldanamycin 30 in 70% yield after overnight stirring at
room temperature (Scheme 3), somewhat remarkable given the
dense functionality and sensitivity of the substrate and the lack of
previous success, through our otherwise viable approaches. It is
noteworthy that in our hands the yield of 30 dropped significantly
(ca. 30% or lower) without extensive drying of equipment [in
addition to the use of an inert atmosphere], as reported in the
original literature article [37]).
As mentioned previously, the nucleophilic properties of the
geldanamycin enamide moiety has been previously exploited for
other reactions than just halogenation. One such example is a
Mannich-type-oxidation sequence with formaldehyde, t-butyl-
amine and manganese dioxide, initially described by Rinehart et al.
[38] and later by Schnur and co-workers (with intramolecular
cyclisation with lactam observed prior to trapping a range of other
amines to give the corresponding hydrazones) [21]. Given the well-
documented issues with geldanamycin derivatives’ solubility for
allyl (81%, Entry 3) groups. Alkylidene couplings generally pro-
ceeded in good to excellent yield for both coupling methods (En-
tries 4e8) albeit with the vinyl group yield slightly superior for the
product 11 for the Stille coupling (Entry 4). The product from the
coupling with the dihydrofuranylboronic acid was 14 (53%),
resulting from hydrolysis of the 5-membered cyclic enol ether
(Entry 7). Couplings of aromatic groups by both methods proved
particularly fruitful with a range of electron-rich and electron-
deficient coupling partners being successfully utilised (Entries
9e18). However, for electron-rich substrates the Suzuki protocol
gave superior yields and vice versa for electron-deficient coupling
partners. Bulky stannanes were used to investigate whether there
was any effect with the cis/trans amide isomerisation and hence
Hsp90 bonding (Entries 11e12, 18), but the biological results were
no better than for substrates with smaller groups at C-19.
Furthermore, the reduced yields for the Stille couplings with
electron-rich and bulky stannanes is potentially due to the effect
each of these properties has on the transmetallation step [33]. Stille
reactions with hetaryl coupling partners (Entries 19e22) pro-
ceeded extremely smoothly in excellent yield (with the exception
4

R.R.A. Kitson and C.J. Moody
Tetrahedron 82 (2021) 131927
Table 3
Scope of the Stille and Suzuki-Miyaura coupling reactions; synthesis of 19-substituted geldanamycins [16,33].
a,16
Entry
R
Product
Stille Yield/%
Suzuki Yield/%b,32
1
Me
i-Pr
7
9
10
86
0
<5
39 (29c)
19
81
2
3d
4d
5d
11
12
76
-
59 (54e)
Quant
6d
13
-
90
7,f
8d
14
15
-
-
53
46
9
8
85
-
91 (Quantd)
Quant
10
16
11
12
14
17
18
19
34
39
56
-
-
95
(continued on next page)
5

R.R.A. Kitson and C.J. Moody
Tetrahedron 82 (2021) 131927
Table 3 (continued)
a,16
Entry
13
R
Product
Stille Yield/%
-
Suzuki Yield/%b,32
81
20
14
21
67
-
15
16
22
23
80
-
-
64
17
24
-
65
18
19
20
21
25
26
27
28
47
30
90
55
-
-
-
-
22
29
94
73
a
Stille reactions were performed using Me4Sn for methyl couplings and RSnBu3 for all other couplings at a concentration of 0.02e0.04 M in DMF with 1.2 eq. stannane,
20 mol% Ph3As, 5 mol% Pd2(dba)3.CHCl3 and 5 mol% Cu(I) iodide at 35 ꢀC.
b
Suzuki reactions were performed at 0.02e0.04 M in 1,4-dioxane with 2.0 eq. boronic acid, 5 mol% Pd2(dba)3·CHCl3 and 2.0 eq. of CsF at 40 ꢀC for 16 h.
c
Performed with 2.0 eq. MeBFꢂ3 Kþ in i-PrOH/H2O (9:1) with 3.0 eq. of Et3N [31].
d
Performed with 2.0 eq. RB(pin) in 1,4-dioxane/H2O (9:1). Performed with 2.0 eq. vinylboronic acid MIDA boronate. fPerformed with 2.0 eq. 2,3-dihydro-5-furylboronic acid
pinacol ester. [dba ¼ dibenzylideneacetone], B(pin) ¼ 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, MIDA ¼ N-methyliminodiacetic acid [30]].
formulation leading to the amino derivatives being developed for
clinical evaluation [2], we envisaged an opportunity to modify this
literature approach, exploiting the chemistry to introduce hydro-
philic moieties such as amines and alcohols. We started by utilising
a similar approach to that previously reported, but with Eschen-
moser’s salt rather than forming the iminium intermediate in situ
and without the oxidation in order to access the amine derivatives.
We were pleased to observe the quantitative conversion to 19-
(dimethylamino)methylgeldanamycin 31 with the expected in-
crease in polarity (as observed for the 17-amino derivatives, re-
ported below) observed by TLC analysis (Scheme 4). Buoyed by this
success we applied the principle to another simple electrophile,
formaldehyde, in order to access 19-hydroxymethylgeldanamycin.
Even with the high reactivity of formaldehyde derivatives, the re-
action required Lewis-acid mediation in order to proceed effi-
ciently, with the product 32 being obtained in a good yield of 62%
(Scheme 4) along with some double addition of formaldehyde
observed (product not isolated).
In the geldanamycin family, the 17-amino derivatives (17-
allylamino [17-AAG] and -dimethylaminoethylamino [17-DMAG])
have shown the most clinical promise to date. We therefore un-
dertook the synthesis of the 19-substituted 17-AAG and 17-DMAG
analogues readily achieved through heating the compounds with
excess allylamine or N.N-dimethylethylenediamine (for 17-AAG
and 17-DMAG, respectively) in THF (Scheme 5, Table 4). The
amino derivatives were almost always obtained in excellent yield,
albeit the 19-vinyl derivative 11 gave no product, likely due to
competing conjugate addition processes. Some incorporation of a
second equivalent of the amine was often observed (indicated by an
extra purple spot by TLC analysis with Rf z 0.55 [ethyl acetate] for
17-AAG derivatives and Rf z 0.02e0.05 [9:1 ethyl acetate/meth-
anol] for 17-DMAG derivatives-crude mixture analysis [19-Ph de-
rivative] suggestive of a conjugate addition), particularly with
hetaryl substrates whereby the reactions needed to be performed
at room temperature in order to minimise formation of this un-
desired side-product (Entries 11e14, 18e19). The same issue was
encountered in reactions with 19-hydroxymethylgeldanamycin 32,
although decreasing the reaction temperature made no difference
to the product distribution. Nevertheless, modest-excellent yields
of the desired compounds 33e51 were still obtained.
3. Conclusion
In summary, both Stille and Suzuki-Miyaura coupling reactions
have been optimised to allow access to a range of 19-substituted
geldanamycin (19-BQAs) Hsp90 inhibitors, compounds that we
have previously shown to be significantly less toxic to normal
endothelial and epithelial cell systems than their parent quinones
[16]. Additional new 19-BQAs, including the trifluoromethyl de-
rivative, by copper-mediated coupling, and the dimethylamino-
and hydroxy-methyl derivatives, by addition of the corresponding
electrophiles, have also been prepared. The work reported herein
6

R.R.A. Kitson and C.J. Moody
Tetrahedron 82 (2021) 131927
Scheme 3. Synthesis of 19-CF3-geldanamycin using Hartwig’s Trifluoromethylator™ [37].
Scheme 4. Synthesis of 19-BQAs using the nucleophilic properties of geldanamycin at the 19-position [21,38]
7

R.R.A. Kitson and C.J. Moody
Tetrahedron 82 (2021) 131927
adds to the suite of 19-subsituted geldanamycins available for
biological evaluation.
spectroscopic data were acquired at 295 K. Chemical shifts are
quoted in parts per million (ppm), using the residual solvent peak
as an internal standard (2.50 ppm [1H NMR] for DMSO-H6 and
39.52 ppm [13C NMR] for DMSO-d6). Coupling constants (J) are
reported in Hz. Multiplicity abbreviations used: s singlet, d doublet,
t triplet, q quartet, m multiplet. Signal assignment was accom-
plished by analysis of DEPT, COSY, NOESY, HMBC and HSQC exper-
iments where necessary. Low and high-resolution mass spectra
were obtained for all novel compounds. Electrospray ionisation
(ESI) and high-resolution mass spectrometric (HRMS) analyses
were measured on a Bruker MicroTOF spectrometer. Melting points
were determined using a Riechert-Kofler hot stage apparatus and
are uncorrected.
4. Experimental section
4.1. General experimental details
Except where specified, all reagents were purchased from
commercial sources and were used without further purification.
Tetrahydrofuran was distilled from sodium-benzophenone ketyl
immediately before use. Anhydrous dimethylformamide was ob-
tained from commercial sources. Water refers to deionised water.
Thin layer chromatography (TLC) was performed using Merck
Kieselgel 60GF254 pre-coated aluminum-backed plates. The com-
pounds were visualised by visible colour, UV light (254 nm) and
basic aqueous potassium permanganate. Flash chromatography
was performed at medium pressure using slurry packed Davisil
The numbering and naming of geldanamycin derivatives does
not conform to IUPAC rules, instead conforming to the traditional
numbering system for the ansamycins.
silica gel 35e70
m
m, 60 Å with the eluant specified. Light petroleum
4.2. Starting materials
is the fraction with bp 40e60 ꢀC. 1H NMR, 13C NMR and 19F NMR
spectra were recorded on a Bruker Avance III-500 spectrometer,
operating at 500 MHz, 125 Hz and 470.6 MHz, respectively. All
Biphenyltributylstannane was prepared via a modified proced-
ure (aryl iodide used instead of the bromide) of that described by
Scheme 5. Synthesis of 17-amino-19-BQAs.
8

R.R.A. Kitson and C.J. Moody
Tetrahedron 82 (2021) 131927
Table 4
described by Pinhey and Roche [42].
Scope of the 17-amino substitution reactions;a synthesis of 17-allylamino- and 17-
(2-dimethylaminoethylamino)-19-substituted geldanamycins.
4.3. Prepared compounds
Entry
1
R
Amino group
Product
Yield/%
Quant.
Me
33
The characterisation of the following 19-BQA compounds has
been described previously [16,32]: 7e16, 19e24, 26, 27, 29, 33e46.
2
3
Me
Ph
34
35
Quant.
Quant.
4.3.1. (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-21-(4-(tert-butyl)phenyl)-
13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-
trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl
carbamate
4
5
Ph
36
37
Quant.
Quant.
[19-4-t-Bu-phenyl-geldanamycin]
6
7
8
9
38
39
40
41
Quant.
77
75
Quant.
17.
10
42
Quant.
11
12
13
14
15
16
17
43
44
45
46
47
48
49
96b
92b
48b
92b
66
A stirred solution of 19-iodogeldanamycin 6 [20] (56 mg,
0.056 mmol, 1.0 eq.), tris-(dibenzylideneacetone)dipalladium(0)
chloroform complex (4 mg, 0.004 mmol, 5 mol%), triphenylarsine
(5 mg, 0.016 mmol, 20 mol%) and copper(I) iodide (1 mg,
0.004 mmol, 5 mol%) in DMF (3 mL) was sparged with argon for
20 min (4-tert-butylphenyl)tributylstannane (41 mg, 0.098 mmol,
1.2 eq.) was added and the mixture was heated to 35 ꢀC for 16 h.
Ethyl acetate (20 mL) was added and the mixture was washed with
5% aqueous lithium chloride solution (3 ꢃ 20 mL), before being
dried (MgSO4), filtered and concentrated in vacuo, pre-adsorbing
onto silica gel. The residue was purified by flash chromatography
on 10% K2CO3/silica gel, eluting with 1:1 light petroleum/ethyl ac-
etate / ethyl acetate to give the title compound 17 (19 mg, 34%) as
an orange glass; TLC Rf ¼ 0.24 (1:2 light petroleum/ethyl acetate,
71
38
18
19
50
51
39c
73d
det: KMnO4/
D
); (Found: M þ Naþ, 715.3557. C39H52N2O9þNaþ, re-
quires 715.3565); dH (500 MHz; DMSO-D6) 9.47 (1H, s, NH),
7.57e7.53 (2H, m, H-30), 7.33e7.29 (2H, m, H-31), 6.50 (1H, d, J 11.9,
H-3), 6.48e6.21 (2H, m, NH2), 6.41 (1H, dd, J 11.9, 10.7, H-4), 5.29
(1H, t, J 10.7, H-5), 5.17 (1H, d, J 10.3, H-9), 4.90 (1H, d, J 8.7, H-7),
4.40 (1H, d, J 4.4, OH), 4.00e3.97 (1H, m, H-6), 3.96 (3H, s, OMe-26),
3.47 (1H, ddd, J 8.7, 4.4, 2.8, H-11), 3.20 (3H, s, OMe-28), 3.09 (3H, s,
OMe-27), 2.84e2.78 (1H, m, H-12), 2.54 (1H, dd, J 12.3, 5.9, H-15),
2.41 (1H, dd, J 12.3, 4.4, H-15), 2.14e2.04 (2H, m, H-10 þ 14), 1.86
(3H, s, Me-22), 1.44 (1H, ddd, J 13.9, 9.5, 4.8, H-13), 1.35 (9H, s, Me-
34), 1.22 (3H, s, Me-23), 0.86 (3H, d, J 6.7, Me-24), 0.73e0.65 (1H, m,
H-13), 0.64 (3H, d, J 6.3, Me-25); dC (125 MHz; DMSO-D6) 184.2 (C]
O-21), 181.6 (C]O-18), 172.9 (C]O-1), 156.8 (C-17), 155.8 (OC]
ONH2), 151.0 (C-32), 139.6 (C-20), 138.1 (C-2), 134.4 (CH-9), 130.1
(CH-5), 129.6 (CH-31), 128.8 (C-16), 128.5 (C-8), 128.5 (CH-4), 128.2
aReactions with allylamine were performed at reflux for 16 h at a concentration of
0.01 M in THF with 5.0 eq. amine. Reactions with N,N-dimethylethylenediamine
were performed at 60 ꢀC for 2 h at a concentration of 0.01 M in THF with 5.0 eq.
amine. bThe reaction was performed at room temperature for 16 h cThe reaction was
performed at room temperature for 2 h dThe reaction was performed at room
temperature for 1 h.
Ritter and co-workers [39]. (4-tert-Butylphenyl)tributylstannane
was prepared according to the procedure described by Zalubovskis
and co-workers [40]. 2-(Tributylstannyl)naphthalene was prepared
according to the procedure described by Patil and co-workers [41].
3-(Tributylstannyl)furan was prepared according to the procedure
ꢀ
9

R.R.A. Kitson and C.J. Moody
Tetrahedron 82 (2021) 131927
(C-29), 125.1 (CH-30), 122.8 (CH-3), 118.6 (C-19), 79.9 (CH-7), 79.7
(CH-12), 74.7 (CH-6), 71.4 (CH-11), 61.0 (Me-26), 55.7 (Me-27), 55.7
(Me-28), 34.9 (CH-10), 34.6 (C-33), 31.1 (Me-34), 30.7 (CH2-13),
29.7 (CH2-15), 28.7 (CH-14), 18.9 (Me-25), 18.7 (Me-24), 14.0 (Me-
22), 11.7 (Me-23); m/z (ESI) 715 ([MþNa]þ, 10%).
139.0 (C-2), 134.5 (CH-9), 130.5 (CH-30), 130.2 (CH-5), 129.1 (CH-
35), 128.8 (C-8), 128.4 (CH-4), 127.9 (C-16), 127.4 (CH-36), 126.8
(CH-34), 126.4 (CH-31), 123.3 (CH-3), 118.0 (C-19), 79.9 (CH-7), 79.7
(CH-12), 75.8 (CH-6), 71.4 (CH-11), 61.1 (Me-26), 55.9 (Me-27), 55.7
(Me-28), 35.0 (CH-10), 30.8 (CH2-13), 30.0 (CH2-15), 28.7 (CH-14),
20.1 (Me-25), 18.9 (Me-24), 14.0 (Me-22), 11.7 (Me-23); m/z (ESI)
735 ([MþNa]þ, 17%).
4.3.2. (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-21-([1,10-biphenyl]-4-yl)-
13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-
trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl
carbamate
4.3.3. (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-
trimethoxy-4,10,12,16-tetramethyl-21-(naphthalen-2-yl)-3,20,22-
trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl
carbamate
[19-biphenyl-geldanamycin]
[19-(naphthalen-2-yl)-geldanamycin]
18.
25
A stirred solution of 19-iodogeldanamycin [20] 6 (50 mg,
0.073 mmol, 1.0 eq.), tris-(dibenzylideneacetone)dipalladium(0)
chloroform complex (4 mg, 0.004 mmol, 5 mol%), triphenylarsine
(5 mg, 0.015 mmol, 20 mol%) and copper(I) iodide (1 mg,
0.004 mmol, 5 mol%) in DMF (3 mL) was sparged with argon for
20 min. 4-Biphenyltributylstannane (39 mg, 0.087 mmol, 1.2 eq.)
was added and the mixture was heated to 35 ꢀC for 16 h. Ethyl
acetate (20 mL) was added and the mixture was washed with 5%
aqueous lithium chloride solution (3 ꢃ 20 mL), before being dried
(MgSO4), filtered and concentrated in vacuo, pre-adsorbing onto
silica gel. The residue was purified by flash chromatography on 10%
K2CO3/silica gel, eluting with 1:1 light petroleum/ethyl acetate /
ethyl acetate to give the title compound 18 (20 mg, 39%) as an orange
glass; TLC Rf ¼ 0.31 (1:2 light petroleum/ethyl acetate, det: KMnO4/
A stirred solution of 19-iodogeldanamycin [20] 6 (60 mg,
0.087 mmol, 1.0 eq.), tris-(dibenzylideneacetone)dipalladium(0)
chloroform complex (5 mg, 0.004 mmol, 5 mol%), triphenylarsine
(5 mg, 0.017 mmol, 20 mol%) and copper(I) iodide (1 mg,
0.004 mmol, 5 mol%) in DMF (3 mL) was sparged with argon for
20 min. 2-(Tributylstannyl)naphthalene (44 mg, 0.105 mmol, 1.2
eq.) was added and the mixture was heated to 35 ꢀC for 16 h. Ethyl
acetate (20 mL) was added and the mixture was washed with 5%
aqueous lithium chloride solution (3 ꢃ 20 mL), before being dried
(MgSO4), filtered and concentrated in vacuo, pre-adsorbing onto
silica gel. The residue was purified by flash chromatography on 10%
K2CO3/silica gel, eluting with 1:1 light petroleum/ethyl acetate /
ethyl acetate to give the title compound 25 (28 mg, 47%) as an or-
ange glass; TLC Rf ¼ 0.34 (ethyl acetate, det: KMnO4/
D); (Found:
D
); (Found:
M
þ
Naþ, 735.3256. C41H48N2O9þNaþ, requires
M þ Naþ, 709.3093. C39H46N2O9þNaþ, requires 709.3096); dH
(500 MHz; DMSO-D6) 9.67 (1H, s, NH), 8.06 (1H, d, J 8.4, H-31),
8.01e7.98 (1H, m, H-33), 7.98e7.92 (2H, m, H-36 þ 38), 7.63e7.57
(2H, m, H-34 þ 35), 7.50 (1H, dd, J 8.4, 2.0, H-30), 6.65 (1H, d, J 11.4,
H-3), 6.54e6.11 (2H, m, NH2), 6.45 (1H, dd, J 11.4, 10.4, H-4), 5.34
(1H, t, J 10.4, H-5), 5.19 (1H, d, J 9.8, H-9), 4.92 (1H, d, J 8.8, H-7), 4.41
(1H, d, J 3.7, OH), 4.07e4.02 (1H, m, H-6), 4.00 (3H, s, OMe-26), 3.48
(1H, dt, J 9.1, 3.7, H-11), 3.21 (3H, s, OMe-28), 3.17 (3H, s, OMe-27),
2.85e2.80 (1H, m, H-12), 2.57 (1H, dd, J 12.5, 5.7, H-15), 2.44 (1H,
dd, J 12.5, 4.0, H-15), 2.17e2.05 (2H, m, H-10 þ 14), 1.87 (3H, s, Me-
22), 1.47 (1H, ddd, J 13.8, 9.4, 4.4, H-13), 1.25 (3H, s, Me-23), 0.86
(3H, d, J 5.7, Me-24), 0.76e0.68 (1H, m, H-13), 0.66 (3H, d, J 6.7, Me-
25); dC (125 MHz; DMSO-D6) 184.2 (C]O-21), 181.5 (C]O-18),
172.9 (C]O-1), 156.8 (C-17), 155.8 (OC]ONH2), 140.1 (C-20), 138.7
735.3252); dH (500 MHz; DMSO-D6) 9.66 (1H, s, NH), 7.85 (2H, d, J
8.4, H-31), 7.80e7.76 (2H, m, H-34), 7.56e7.45 (4H, m, H-30 þ 35),
7.45e7.38 (1H, m, H-36), 6.58 (1H, d, J 11.8, H-3), 6.43 (1H, t, J 11.8,
H-4), 6.51e6.18 (2H, m, NH2), 5.31 (1H, t, J 11.8, H-5), 5.17 (1H, d, J
10.2, H-9), 4.90 (1H, d, J 9.2, H-7), 4.41 (1H, d, J 4.8, OH), 4.05e4.00
(1H, m, H-6), 3.99 (3H, s, Me-26), 3.48 (1H, ddd, J 9.4, 4.8, 2.9, H-11),
3.20 (3H, s, OMe-28), 3.13 (3H, s, OMe-27), 2.84e2.79 (1H, m, H-12),
2.55 (1H, dd, J 12.4, 5.9, H-15), 2.43 (1H, dd, J 12.4, 4.3, H-15),
2.15e2.05 (2H, m, H-10 þ 14), 1.87 (3H, s, Me-22), 1.49e1.40 (1H, m,
H-13), 1.23 (3H, s, Me-23), 0.86 (3H, d, J 6.5, Me-24), 0.75e0.67 (1H,
m, H-13), 0.65 (3H, d, J 6.5, Me-25); dC (125 MHz; DMSO-D6) 184.2
(C]O-21), 181.4 (C]O-18), 173.0 (C]O-1), 156.8 (C-17), 155.8
(OC]ONH2), 143.5 (C-20), 140.2 (C-32), 139.8 (C-29), 139.5 (C-33),
10

R.R.A. Kitson and C.J. Moody
Tetrahedron 82 (2021) 131927
(C-2), 134.2 (CH-9), 132.7 (C-29), 132.6 (C-37), 132.5 (C-32), 130.6
(CH-5), 129.7 (C-36), 128.8 (C-16), 128.5 (C-8), 128.3 (C-4), 128.2
(CH-38), 127.6 (C-33), 127.5 (CH-31), 127.0 (CH-30), 126.6 (CH-35),
126.6 (CH-34), 123.2 (CH-3), 119.0 (C-19), 79.9 (CH-7), 79.7 (CH-12),
75.0 (CH-6), 71.4 (CH-11), 61.1 (Me-26), 56.1 (Me-27), 55.7 (Me-28),
34.9 (CH-10), 30.7 (CH2-13), 29.7 (CH2-15), 28.7 (CH-14), 18.9 (Me-
25), 18.6 (CH-24), 14.0 (Me-22), 11.7 (Me-23); m/z (ESI) 709
([MþNa]þ, 20%).
79.9 (CH-7), 79.6 (CH-12), 74.4 (CH-6), 71.5 (CH-11), 61.0 (Me-26),
55.7 (Me-28), 55.6 (Me-27), 34.9 (CH-10), 30.6 (CH2-13), 29.6 (CH2-
15), 28.6 (CH-14), 18.8 (Me-25), 18.7 (Me-24), 14.0 (Me-22), 11.4
(Me-23); m/z (ESI) 649 ([MþNa]þ, 37%).
4.3.5. (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-Hydroxy-8,14,19-
trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-21-
(trifluoromethyl)-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-
pentaen-9-yl carbamate
4.3.4. (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-21-(furan-3-yl)-13-
hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-
2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate
[19-(3-furyl)-geldanamycin]
[19-trifluoromethyl-geldanamycin]
30.
28.
A stirred solution of 19-iodogeldanamycin [20] 6 (54 mg,
0.079 mmol, 1.0 eq.), tris-(dibenzylideneacetone)dipalladium(0)
chloroform complex (4 mg, 0.004 mmol, 5 mol%), triphenylarsine
(5 mg, 0.016 mmol, 20 mol%) and copper(I) iodide (1 mg,
0.004 mmol, 5 mol%) in DMF (3 mL) was sparged with argon for
20 min. 3-(Tributylstannyl)furan (34 mg, 0.094 mmol, 1.2 eq.) was
added and the mixture was heated to 35 ꢀC for 16 h. Ethyl acetate
(20 mL) was added and the mixture was washed with 5% aqueous
lithium chloride solution (3 ꢃ 20 mL), before being dried (MgSO4),
filtered and concentrated in vacuo, pre-adsorbing onto silica gel.
The residue was purified by flash chromatography on 10% K2CO3/
silica gel, eluting with 1:1 light petroleum/ethyl acetate / ethyl
acetate to give the title compound 28 (34 mg, 86%) as a yellow solid;
Trifluoromethylator™,37 (185 mg, 0.590 mmol, 3.0 eq.) was
added to a stirred solution of 19-iodogeldanamycin [20] 6 (135 mg,
0.197 mmol, 1.0 eq.) in anhydrous DMF (5 mL) in a flame-dried flask
under argon at room temperature and the resulting solution was
stirred for 18 h. An extra 10 mol% of Trifluoromethylator™ was
added and stirring was continued for a further 3 h before the
mixture was concentrated in vacuo to give a red oil. The residue was
purified by flash chromatography on silica gel, eluting with 1:2
light petroleum/ethyl acetate / ethyl acetate to give the title
compound 30 (87 mg, 70%) as a dark yellow glass; TLC Rf ¼ 0.54
(ethyl acetate, det: KMnO4/D
); mp 137e138 ꢀC (CHCl3); (Found:
M þ Naþ, 651.2508. C30H39F3N2O9þNaþ, requires 651.2500); dH
(500 MHz; DMSO-D6) 10.70 (1H, s, NH), 6.67e6.20 (2H, m, NH2),
6.40 (1H, t, J 11.7, H-4), 6.35 (1H, d, J 11.9, H-3), 5.34 (1H, t, J 10.6, H-
5), 5.19 (1H, d, J 10.3, H-9), 4.90 (1H, d, J 9.1, H-7), 4.45 (1H, br. s, J
4.3, OH), 4.01 (3H, s, OMe-26), 3.89 (1H, t, J 9.9, H-6), 3.47 (1H, dd, J
9.6, 2.0, H-11), 3.19 (3H, s, OMe-28), 3.02 (3H, s, OMe-27), 2.78 (1H,
dt, J 9.1, 2.8, H-12), 2.44 (1H, dd, J 12.7, 6.0, H-15), 2.38 (1H, dd, J
12.8, 4.4, H-15), 2.15e2.03 (2H, m, H-10 þ 14), 1.86 (3H, s, Me-22),
1.39 (1H, ddd, J 13.6, 9.3, 3.8, H-13), 1.29 (3H, s, Me-23), 0.88 (3H, d, J
6.5, Me-24), 0.63e0.59 (1H, m, H-13), 0.60 (3H, d, J 6.8, Me-25); dC
(125 MHz; DMSO-D6) 182.4 (C]O-21), 177.8 (q, JC-F 3, C]O-18),
173.0 (C]O-1), 156.7 (C-17), 155.9 (OC]ONH2), 143.5 (q, JC-F 4, C-
20), 139.8 (C-2), 134.4 (CH-9), 132.1 (q, JC-F 34, C-19), 131.6 (CH-5),
128.8 (C-16), 128.3 (CH-4), 128.2 (C-8), 124.5 (CH-3), 119.3 (q, JC-F
130, C-29), 79.8 (CH-7), 79.6 (CH-12), 74.6 (CH-6), 71.5 (CH-11), 61.4
(Me-26), 55.7 (Me-28), 55.7 (Me-27), 35.1 (CH-10), 30.5 (CH2-13),
29.8 (CH2-15), 28.4 (CH-14), 18.9 (Me-25), 18.5 (Me-24), 14.1 (Me-
22), 11.5 (Me-23); m/z (ESI) 651 ([MþNa]þ, 100%).
TLC Rf ¼ 0.37 (1:2 light petroleum/ethyl acetate, det: KMnO4/
D);
(Found: M þ Naþ, 649.2725. C33H42N2O10þNaþ, requires 649.2732);
dH (500 MHz; DMSO-D6) 9.68 (1H, br. s, NH), 8.29 (1H, dd, J 1.7, 0.8,
H-30), 7.89 (1H, t, J 1.7, H-31), 6.93 (1H, dd, J 1.7, 0.8, H-32),
6.59e6.13 (2H, m, NH2), 6.38 (1H, dd, J 13.0, 10.1, H-4), 6.34 (1H, d, J
13.0, H-3), 5.23 (1H, t, J 10.1, H-5), 5.14 (1H, d, J 10.8, H-9), 4.85 (1H,
d, J 9.4, H-7), 4.42 (1H, d, J 4.3, OH), 3.97 (3H, s, Me-26), 3.79 (1H, dd,
J 10.1, 9.4, H-6), 3.46 (1H, ddd, J 9.7, 4.3, 2.6, H-11), 3.18 (3H, s, OMe-
28), 3.01 (3H, s, OMe-27), 2.81e2.75 (1H, m, H-12), 2.54e2.47 (1H,
m, H-15-obscured by solvent peak), 2.38 (1H, dd, J 12.2, 4.3, H-15),
2.15e2.01 (2H, m, H-10 þ 14), 1.86 (3H, s, Me-22), 1.43 (1H, ddd, J
14.4, 9.7, 4.7, H-13), 1.13 (3H, s, Me-23), 0.86 (3H, d, J 6.1, Me-24),
0.69e0.62 (1H, m, H-13), 0.60 (3H, d, J 6.8, Me-25); dC (125 MHz;
DMSO-D6) 183.8 (C]O-21), 181.4 (C]O-18), 173.4 (C]O-1), 156.5
(C-17), 155.8 (OC]ONH2), 145.2 (CH-30), 143.3 (CH-31), 140.7 (C-
20),137.7 (C-2), 134.4 (CH-9),130.3 (CH-5),129.0 (C-16),128.4 (C-8),
128.4 (CH-4), 122.8 (CH-3), 118.6 (C-19), 115.3 (C-29), 110.6 (C-32),
11

R.R.A. Kitson and C.J. Moody
Tetrahedron 82 (2021) 131927
4.3.6. (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-21-((Dimethylamino)
methyl)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-
3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-
9-yl carbamate
4.3.7. (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-Hydroxy-21-
(hydroxymethyl)-8,14,19-trimethoxy-4,10,12,16-tetramethyl-
3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-
9-yl carbamate
[19-(dimethylamino)methyl
-geldanamycin]
[19-hydroxymethyl-geldanamycin]
32.
31.
Paraformaldehyde (7 mg, 0.232 mmol, 5.0 eq.) was added to a
stirred solution of geldanamycin 1 (26 mg, 0.046 mmol, 1.0 eq.) in
THF (2 mL) at room temperature under argon. After stirring for 2 h,
boron trifluoride diethyl etherate complex (1 drop) was added and
the mixture was stirred for further 1 h before being concentrated in
vacuo, to give an orange oil. Some double addition of formaldehyde
was observed by TLC [Rf ¼ 0.38 (ethyl acetate)] and NMR spec-
troscopy. The residue was purified by flash chromatography on
silica gel, eluting with 1:2 light petroleum/ethyl acetate / 9:1
ethyl acetate/MeOH to give the title compound 32 (17 mg, 62%) as a
Eschenmoser’s salt (22 mg, 0.118 mmol, 1.05 eq.) was added to a
stirred solution of geldanamycin 1 (63 mg, 0.112 mmol, 1.0 eq.) in
THF (2 mL) under argon at room temperature. Triethylamine (19 L,
m
0.135 mmol,1.2 eq.) was added and the mixture was stirred for 16 h.
After concentrating in vacuo, the residue was purified by flash
chromatography on silica gel, eluting with ethyl acetate / 9:1
ethyl acetate/MeOH to give the title compound 31 (72 mg, quanti-
tative yield) as a purple glass; TLC Rf ¼ 0.33 (9:1 ethyl acetate/
MeOH, det: KMnO4/
C
D
); (Found:
M
þ
Hþ, 618.3379.
32H48N3O9þHþ, requires 618.3385); dH (500 MHz; DMSO-D6) 6.45
yellow glass; TLC Rf ¼ 0.46 (ethyl acetate, det: KMnO4/
D); (Found:
(1H, d, J 11.8, H-3), 6.38e6.23 (2H, m, NH2), 6.33 (1H, t, J 11.4, H-4),
5.21 (1H, t, J 10.8, H-5), 5.13 (1H, dd, J 10.5, 0.9, H-9), 4.86 (1H, d, J
9.4, H-7), 4.09 (1H, t, J 10.0, H-6), 3.97 (3H, s, OMe-26), 3.70e3.27
(1H, br. m, OH), 3.65 (1H, d, J 13.0, H-29), 3.46 (1H, dd, J 9.8, 2.4, H-
11), 3.45 (1H, d, J 13.0, H-29), 3.18 (3H, s, OMe-28), 3.05 (3H, s, OMe-
27), 2.79 (1H, dt, J 9.1, 2.8, H-12), 2.44 (1H, dd, J 12.5, 6.1, H-15), 2.34
(1H, dd, J 12.5, 4.3, H-15), 2.29 (6H, s, Me-30), 2.14e2.02 (2H, m, H-
10 þ 14), 1.86 (3H, s, Me-22), 1.39 (1H, ddd, J 13.8, 9.5, 3.8, H-13),
1.23 (3H, d, J 0.9, Me-23), 0.87 (3H, d, J 6.4, Me-24), 0.65 (1H, td, J
14.7, 3.1, H-13), 0.61 (3H, d, J 6.8, Me-25); dC (125 MHz; DMSO-D6)
183.1 (C]O-21), 180.5 (C]O-18), 174.0 (C]O-1), 157.0 (C-17), 155.8
(OC]ONH2), 144.3 (C-20), 139.1 (C-2), 134.4 (CH-9) 130.3 (CH-5),
128.5 (CH-4), 128.5 (C-8), 127.7 (C-16), 124.0 (CH-3), 118.7 (C-19),
80.2 (CH-7), 79.6 (CH-12), 74.4 (CH-6), 71.6 (CH-11), 61.0 (Me-26),
55.6 (Me-28), 55.3 (Me-27), 51.6 (CH2-29), 44.5 (Me-30), 34.9 (CH-
10), 30.6 (CH2-13), 29.5 (CH2-15), 28.5 (CH-14), 19.0 (Me-25), 18.6
(Me-24), 14.0 (Me-22), 11.3 (Me-23); m/z (ESI) 618 ([MþH]þ, 100%).
M þ Naþ, 613.2726. C30H42N2O10þNaþ, requires 613.2732); dH
(500 MHz; DMSO-D6) 9.19 (1H, br. s, NH), 7.91 (1H, br. s, CH2OH),
7.20e6.86 (2H, m, NH2), 6.99e6.86 (1H, m, H-3), 6.58 (1H, t, J 10.8,
H-4), 5.87e5.70 (1H, m, H-5), 5.59e5.44 (1H, m, H-9), 4.97e4.89
(1H, m, H-7), 4.38e4.36 (3H, m, H-6þ29), 4.04e3.98 (1H, m,
CHOH), 3.96 (3H, s, OMe-26), 3.24 (3H, s, OMe-27), 3.23 (3H, s,
OMe-28), 3.14e2.99 (2H, m, H-11 þ 12), 2.63e2.52 (1H, m, H-10),
2.42 (1H, dd, J 12.7, 10.0, H-15), 2.18 (1H, dd, J 12.7, 4.5, H-15),
1.99e1.86 (1H, m, H-14), 1.93 (3H, s, Me-22), 1.62 (3H, s, Me-23),
1.51e1.41 (1H, m, H-13), 1.03e0.92 (3H, m, Me-25), 0.90e0.79
(1H, m, H-13), 0.75 (3H, d, J 6.7, Me-24); dC (125 MHz; DMSO-D6)
183.8 (C]O-18),183.2 (C]O-21),170.3 (C]O-1),156.5 (C-17),155.5
(OC]ONH2), 144.1 (C-20), 139.1 (CH-5), 133.4 (C-2), 132.3 (CH-9),
128.9 (C-16), 128.5 (C-8), 128.2 (CH-3), 126.0 (CH-4), 124.1 (C-19),
81.9 (CH-6), 81.0 (CH-7), 80.2 (CH-12), 71.9 (CH-11), 64.4 (CH2-29),
61.2 (Me-26), 56.6 (Me-27), 56.1 (Me-28), 32.0 (CH-10), 31.1 (CH2-
15), 30.4 (CH2-13), 26.5 (CH-14), 23.6 (Me-25), 12.5 (Me-24), 12.4
(Me-23), 12.3 (Me-22); m/z (ESI) 613 ([MþNa]þ, 100%).
12

R.R.A. Kitson and C.J. Moody
Tetrahedron 82 (2021) 131927
4.3.8. (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-(allylamino)-13-
hydroxy-21-(hydroxymethyl)-8,14-dimethoxy-4,10,12,16-
tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-
1(21),4,6,10,18-pentaen-9-yl carbamate
4.3.9. (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-((2-(dimethylamino)
ethyl)amino)-13-hydroxy-21-(hydroxymethyl)-8,14-dimethoxy-
4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-
1(21),4,6,10,18-pentaen-9-yl carbamate
[19-hydroxymethyl-AAG]
[19-hydroxymethyl-DMAG]
48.
47.
Dimethylethylenediamine (17 mL, 0.152 mmol, 5 eq.) was added
to a stirred solution of 19-hydroxymethylgeldanamycin 32 (13 mg,
0.030 mmol,1.0 eq.) in THF (2 mL) under argon and the mixture was
heated to reflux for 30 min. After cooling, the mixture was
concentrated in vacuo and the residue was purified by flash chro-
matography on silica gel, eluting with 9:1 ethyl acetate/methanol
/ 4:1 ethyl acetate/methanol, to give the title compound 48 (14 mg,
71%) as a purple glass; TLC Rf ¼ 0.16 (9:1 ethyl acetate/methanol,
Allylamine (12 mL, 0.161 mmol, 5 eq.) was added to a stirred
solution of 19-hydroxymethylgeldanamycin 32 (19 mg,
0.032 mmol,1.0 eq.) in THF (2 mL) under argon and the mixture was
heated to reflux for 30 min. After cooling, the mixture was
concentrated in vacuo and the residue was purified by flash chro-
matography on silica gel, eluting with 1:2 light petroleum/ethyl
acetate / ethyl acetate to give the title compound 47 (13 mg, 66%)
as a purple glass; TLC Rf ¼ 0.54 (ethyl acetate, det: purple by eye and
det: purple by eye, KMnO4/
D
); (Found: M þ Naþ, 669.3452.
33H50N4O9þNaþ, requires 669.3470); dH (500 MHz; DMSO-d6)
KMnO4/
D
); (Found: M þ Naþ, 638.3021. C32H45N3O9þNaþ, requires
C
9.38 (1H, s, O]CeNH), 7.10e7.00 (1H, m, H-3), 6.98e6.87 (3H, m,
CH2NH þ NH2), 6.60 (1H, t, J 10.8, H-4), 5.83e5.71 (1H, m, H-9),
5.61e5.53 (1H, m, H-5), 5.51 (1H, t, J 6.7, CH2OH), 5.03 (1H, br. s, H-
7), 4.45e4.34 (3H, m, H-6þ26), 4.23e4.14 (1H, m, CHOH),
3.61e3.49 (2H, m, H-29), 3.35e3.28 (1H, m, H-11), 3.23 (3H, s, OMe-
28), 3.21 (3H, s, OMe-27), 3.19e3.15 (1H, m, H-12), 2.55 (1H, dd, J
13.4, 6.4, H-15), 2.53e2.47 (2H, m, H-30-obscured by solvent peak),
2.32 (1H, dd, J 13.4, 7.0, H-15), 2.20 (6H, br. s, Me-31), 1.93 (3H, s,
Me-22), 1.92e1.83 (1H, m, H-14), 1.64 (3H, s, Me-23), 1.58e1.45 (1H,
m, H-10), 1.26e1.21 (1H, m, H-13), 0.94 (3H, d, J 7.0, Me-25),
0.87e0.82 (1H, m, H-13), 0.81 (3H, d, J 7.0, Me-24); dC (125 MHz;
DMSO-d6) 184.3 (C]O-18), 178.9 (C]O-21), 169.2 (C]O-1), 155.5
(OC]ONH2), 145.4 (C-17), 143.9 (C-20), 135.3 (CH-9), 134.5 (C-2),
133.5 (C-8), 132.1 (CH-5), 129.5 (CH-3), 126.1 (CH-4), 123.8 (C-19),
115.7 (C-16), 80.7 (CH-12), 80.7 (CH-6), 80.3 (CH-7), 71.9 (CH-11),
64.4 (CH2-26), 56.5 (Me-27), 56.0 (Me-28), 46.3 (CH2-30), 44.7 (Me-
31), 40.3 (CH2-29), 32.4 (CH-10), 32.3 (CH2-15), 29.0 (CH2-13), 28.1
(CH-14), 22.6 (Me-25), 13.6 (Me-24), 12.9 (Me-23), 12.3 (Me-22); m/
z (ESI) 647 ([MþH]þ, 100%), 669 ([MþNa]þ, 19%).
638.3048); dH (500 MHz; DMSO-d6) 9.36 (1H, br. s, O]CeNH),
8.00e7.90 (1H, m, CH2NH), 7.26e7.16 (1H, m, CH2OH), 7.11e6.92
(2H, m, NH2), 6.62 (1H, t, J 10.8, H-4), 5.94 (1H, ddt, J 17.3, 10.3, 4.7,
H-30), 5.84e5.73 (1H, m, H-3), 5.63e5.55 (1H, m, H-9), 5.52 (1H,
dd, J 10.8, 6.6, H-5), 5.17 (1H, dd, J 10.3, 1.5, H-31-cis), 5.11 (1H, dd, J
17.3, 1.5, H-31-trans), 5.05e4.99 (1H, m, H-7), 4.39 (3H, m, H-
26 þ 6), 4.19e4.09 (3H, m, H-29þCHOH), 3.31e3.27 (1H, m, H-11),
3.23 (3H, s, Me-27), 3.22 (3H, s, Me-28), 3.20e3.15 (1H, m, H-12),
2.44 (1H, dd, J 13.7, 7.9, H-15), 2.24 (1H, dd, J 13.7, 7.2, H-15), 1.94
(3H, s, Me-23), 1.93e1.88 (1H, m, H-14), 1.64 (3H, s, Me-22),
1.58e1.44 (1H, m, H-10), 1.28e1.22 (1H, m, H-13), 0.95 (3H, d, J
6.7, Me-25), 0.89e0.84 (1H, m, H-13), 0.80 (3H, d, J 6.7, Me-24); dC
(125 MHz; DMSO-d6) 184.3 (C]O-18), 178.9 (C]O-21), 169.2 (C]
O-1), 155.6 (OC]ONH2), 145.4 (C-17), 141.9 (C-20), 139.6 (C-2),
135.3 (CH-30), 133.6 (CH-9), 130.2 (CH-5), 128.4 (C-8), 126.1 (CH-4),
123.7 (C-19), 121.9 (CH-3), 115.7 (CH2-31), 108.1 (C-16), 80.7 (CH-6),
80.3 (CH-12), 79.2 (CH-7), 72.5 (CH-11), 64.4 (CH2-26), 56.5 (Me-
28), 56.0 (Me-27), 46.3 (CH2-29), 33.1 (CH2-15), 32.3 (CH-10), 30.3
(CH2-13), 29.0 (CH-14), 22.6 (Me-25), 13.6 (Me-24), 12.9 (Me-22),
12.3 (Me-23); m/z (ESI) 638 ([MþNa]þ, 100%).
13

R.R.A. Kitson and C.J. Moody
Tetrahedron 82 (2021) 131927
4.3.10. (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-(allylamino)-21-
((dimethylamino)methyl)-13-hydroxy-8,14-dimethoxy-4,10,12,16-
tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-
1(21),4,6,10,18-pentaen-9-yl carbamate
4.3.11. (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-((2-(dimethylamino)
ethyl)amino)-21-((dimethylamino)methyl)-13-hydroxy-8,14-
dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo
[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate
[19-(dimethylamino)methyl-DMAG]
[19-(dimethylamino)methyl-AAG]
50.
49.
Dimethylethylenediamine (25 mL, 0.028 mmol, 5 eq.) was added
to a stirred solution of 19-(dimethylamino)methylgeldanamycin 31
(28 mg, 0.045 mmol, 1.0 eq.) in THF (2 mL) under argon and the
mixture was heated to 60 ꢀC for 3 h. After cooling, the mixture was
concentrated in vacuo and the residue was purified by flash chro-
matography on silica gel, eluting with ethyl acetate / 4:1 ethyl
acetate/methanol, to give the title compound 50 (12 mg, 39%) as a
purple glass; TLC Rf ¼ 0.08 (9:1 ethyl acetate/methanol, det: purple
Allylamine (17 mL, 0.227 mmol, 5 eq.) was added to a stirred
solution of 19-(dimethylamino)methylgeldanamycin 31 (28 mg,
0.045 mmol,1.0 eq.) in THF (2 mL) under argon and the mixture was
heated to reflux for 16 h. After cooling, the mixture was concen-
trated in vacuo and the residue was purified by flash chromatog-
raphy on silica gel, eluting with 1:1 light petroleum/ethyl acetate
/ ethyl acetate to give the title compound 49 (11 mg, 38%) as a
purple glass; TLC Rf ¼ 0.74 (9:1 ethyl acetate/methanol, det: purple
by eye, KMnO4/D); dH (500 MHz; DMSO-d6) 7.48e7.38 (1H, m, O]
CeNH), 7.25e7.18 (1H, m, NH), 6.78e6.21 (3H, m, H-4þNH2),
6.04e5.94 (1H, m, H-3), 5.58e5.44 (1H, m, H-5), 5.34e5.23 (1H, m,
H-9), 4.79e4.60 (1H, m, H-7), 4.27e3.97 (2H, m, 6þOH), 3.62e3.52
(2H, m, H-29), 3.14 (3H, br. s, OMe-28), 3.05 (3H, br. s, OMe-27),
by eye and KMnO4/D); dH (500 MHz; DMSO-d6) 7.46e7.31 (1H, m,
O]CeNH), 7.25e7.18 (1H, m, NH), 6.71e6.54 (2H, m, NH2),
6.54e6.43 (1H, m, H-4), 6.10e6.02 (1H, m, H-3), 5.89 (1H, ddt, J 17.2,
10.3, 4.6, H-30), 5.53e5.42 (1H, m, H-5), 5.35e5.26 (1H, m, H-9),
5.19e5.01 (2H, m, H-31-cis, H-31-trans), 4.73e4.62 (1H, m, H-7),
4.40e4.31 (1H, m, HeOH), 4.19e3.93 (3H, m, H-6þ29), 3.18e3.01
(8H, m, H-26þMe-27þMe-28), 3.00e2.92 (1H, m, H-12), 2.90e2.83
(1H, m, H-11), 2.55e2.47 (7H, m, H-15þMe-32), 2.37e2.35 (1H, m,
H-15), 1.90 (3H, s, Me-23), 1.85e1.75 (1H, m, H-14), 1.60 (3H, s, Me-
22), 1.40e1.31 (1H, m, H-10), 1.25e1.21 (1H, m, H-13), 0.97e0.87
(3H, m, Me-25), 0.87e0.83 (1H, m, H-13), 0.78 (3H, d, J 6.9, Me-24);
dC (125 MHz; DMSO-d6) 179.2 (C]O-18), 178.8 (C]O-21), 173.5
(C]O-1), 156.1 (OC]ONH2), 147.6 (C-17), 141.9 (C-20), 140.5 (C-2),
135.0 (CH-30), 132.8 (CH-9), 131.8 (CH-5), 130.4 (C-8), 126.5 (CH-4),
124.1 (C-19), 122.2 (CH-3), 115.3 (CH2-31), 106.9 (C-16), 83.0 (CH-
11), 79.4 (CH-6), 79.2 (CH-7), 75.9 (CH-12), 58.0 (CH2-26), 55.8 (Me-
28), 51.6 (Me-27), 46.6 (CH2-29), 40.3 (Me-32), 37.9 (CH-10), 37.3
(CH2-15), 29.8 (CH2-13), 28.5 (CH-14), 22.1 (Me-25), 16.6 (Me-24),
14.1 (Me-23), 13.8 (Me-22); m/z (ESI) 665 ([MþNa]þ, 5%). High
resolution mass spectrometry within the required error limit could
not be obtained for this compound.
2.98e2.85 (2H, m, H-11
þ
12), 2.83e2.69 (1H, m, H-15),
2.56e2.46 (2H, m, H-26-obscured by solvent peak), 2.44e2.37 (1H,
m, H-15), 2.21 (8H, br. s, Me-32þH-30), 2.13 (6H, br. s, Me-31), 1.91
(3H, m, Me-23), 1.79e1.68 (1H, m, H-14), 1.64e1.54 (3H, m, Me-22),
1.49e1.38 (1H, m, H-10), 1.23 (3H, m, Me-25), 1.00e0.91 (1H, m, H-
13), 0.88e0.81 (1H, m, H-13), 0.78 (3H, d, J 6.6, Me-24); dC
(125 MHz; DMSO-d6) 184.2 (C]O-18), 178.7 (C]O-21), 172.0 (C]
O-1), 156.1 (OC]ONH2), 151.2 (C-17), 146.8 (C-2), 137.7 (C-20), 132.0
(CH-9), 131.6 (CH-5), 130.4 (C-8), 125.7 (CH-4), 124.3 (C-19), 121.7
(CH-3), 116.5 (C-16), 82.5 (CH-11), 79.2 (2 ꢃ CH-6 and 7), 74.4 (CH-
12), 57.3 (CH2-26), 56.2 (2 ꢃ CH2-27 and 28), 49.7 (CH2-30), 45.2
(Me-31), 44.6 (Me-32), 40.3 (CH2-29), 35.4 (CH-10), 35.3 (CH-15),
30.4 (CH2-13), 29.0 (CH-14), 22.1 (Me-25), 16.2 (Me-24), 14.3 (Me-
23), 14.0 (Me-22); m/z (ESI) 696 ([MþNa]þ, 100%). High resolution
mass spectrometry within the required error limit could not be
obtained for this compound.
14

R.R.A. Kitson and C.J. Moody
Tetrahedron 82 (2021) 131927
4.3.12. (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-((2-(dimethylamino)
ethyl)amino)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-
3,20,22-trioxo-21-(trifluoromethyl)-2-azabicyclo[16.3.1]docosa-
1(21),4,6,10,18-pentaen-9-yl carbamate
https://doi.org/10.1016/j.tet.2021.131927.
References
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[2] R.R.A. Kitson, C.J. Moody, J. Org. Chem. 78 (2013) 5117.
[3] P. Acharya, R. Kumar, U. Tatu, Mol. Biochem. Parasitol. 153 (2007) 85.
[4] Y.D. Sharma, Comp. Biochem. Physiol. B: Biochem. Mol. Biol. 102 (1992) 437.
[5] D. Wider, M.P. Peli-Gulli, P.A. Briand, U. Tatu, D. Picard, Mol. Biochem. Para-
sitol. 164 (2009) 147.
[19-trifluoromethyl-DMAG]
[6] I. Anderson, J.S. Low, S. Weston, M. Weinberger, A. Zhyvoloup, A.A. Labokha,
G. Corazza, R.A. Kitson, C.J. Moody, A. Marcello, A. Fassati, Proc. Natl. Acad. Sci.
111 (2014) E1528.
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A. Fassati, A. Marcello, M. Benkirane, O. Schwartz, PLoS Pathog. 8 (2012),
e1002792.
51.
[9] L. Vozzolo, B. Loh, P.J. Gane, M. Tribak, L.H. Zhou, I. Anderson, E. Nyakatura,
R.G. Jenner, D. Selwood, A. Fassati, J. Biol. Chem. 285 (2010) 39314.
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36 (1995) 305.
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G. D’Andrea, M. Dickler, M.E. Moynahan, S. Sugarman, W.N. Ma, S. Patil,
L. Norton, A.L. Hannah, C. Hudis, Clin. Cancer Res. 17 (2011) 5132.
[12] S. Pacey, R.H. Wilson, M. Walton, M.M. Eatock, A. Hardcastle, A. Zetterlund,
H.T. Arkenau, J. Moreno-Farre, U. Banerji, B. Roels, H. Peachey, W. Aherne,
J.S. de Bono, F. Raynaud, P. Workman, I. Judson, Clin. Cancer Res. 17 (2011)
1561.
[13] D. Siegel, S. Jagannath, D.H. Vesole, I. Borello, A. Mazumder, C. Mitsiades,
J. Goddard, J. Dunbar, E. Normant, J. Adams, D. Grayzel, K.C. Anderson,
P. Richardson, Leukemia Lymphoma 52 (2011) 2308.
[14] L. Li, L. Wang, Q.-D. You, X.-L. Xu, J. Med. Chem. 63 (2020) 1798.
[15] S. Talaei, H. Mellatyar, A. Asadi, A. Akbarzadeh, R. Sheervalilou, N. Zarghami,
Chem. Biol. Drug Des. 93 (2019) 760.
[16] R.R.A. Kitson, C.-H. Chuan, R. Xiong, H.E.L. Williams, A.L. Davis, W. Lewis,
D.L. Dehn, D. Siegel, S.M. Roe, C. Prodromou, D. Ross, C.J. Moody, Nat. Chem.
307 (2013).
Dimethylethylenediamine (9 mL, 0.080 mmol, 5 eq.) was added
to a stirred solution of 19-trifluoromethylgeldanamycin 30 (10 mg,
0.016 mmol,1.0 eq.) in THF (1 mL) under argon and the mixture was
stirred at room temperature for 1 h before being concentrated in
vacuo and the residue was purified by flash chromatography on
silica gel, eluting with 9:1 ethyl acetate/methanol / 4:1 ethyl ac-
etate/methanol, to give the title compound 51 (8 mg, 73%) as a
purple glass; TLC Rf ¼ 0.20 (9:1 ethyl acetate/methanol, det: purple
by eye, KMnO4/
D
); (Found: M þ Hþ, 685.3401C33H48F3N4Oþ8 , re-
quires 685.3419); dH (500 MHz; DMSO-d6) 9.37 (1H, br. s, O]
CeNH), 7.13e6.86 (3H, m, H-3þNH2), 6.60 (1H, t, J 11.7, H-4),
6.42e6.28 (1H, m, NH), 5.86e5.72 (1H, m, H-9), 5.57e5.47 (1H, m,
H-5), 4.99 (1H, m, H-7), 4.45e4.37 (1H, m, H-6), 4.24e4.16 (1H, m,
OH), 3.64e3.50 (2H, m, H-29), 3.32e3.27 (1H, m, H-11), 3.22 (3H, s,
OMe-27), 3.20 (3H, s, OMe-28), 3.19e3.14 (2H, m, H-30), 2.59e2.56
(1H, m, H-15), 2.47e2.45 (1H, m, H-15-obscured by solvent peak),
2.33e2.12 (8H, m, Me-31þH-10þH-12), 1.93 (3H, s, Me-22),
1.90e1.82 (1H, m, H-14), 1.63 (3H, br. s, Me-23), 1.28e1.20 (1H, m,
H-13), 0.94 (3H, d, J 6.4, Me-25), 0.88e0.83 (1H, m, H-13), 0.81 (3H,
d, J 6.4, Me-24); dC (125 MHz; DMSO-d6) 181.2 (q, JC-F 8, C]O-18),
178.8 (C]O-21), 173.2 (C]O-1), 156.2 (OC]ONH2), 145.9 (C-17),
144.0 (q, JC-F 7, C-20), 138.6 (CH-9), 133.5 (C-2), 132.6 (C-8), 132.1
(CH-5), 128.5 (CH-3), 126.0 (CH-4), 123.4 (q, JC-F 13, C-19), 118.4 (q,
JC-F 122, C-26), 108.0 (C-16), 80.9 (CH-6), 79.8 (CH-7), 72.4 (CH-11),
72.1 (CH-12), 56.5 (CH2-30), 56.4 (Me-27), 55.9 (Me-28), 44.5 (Me-
31), 42.6 (CH2-29), 32.6 (CH-10), 32.5 (CH2-15), 29.1 (CH2-13), 28.4
(CH-14), 22.5 (Me-25), 13.6 (Me-24), 13.1 (Me-23), 12.4 (Me-22); m/
z (ESI) 685 ([MþH]þ, 100%), 707 ([MþNa]þ, 16%).
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Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
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Appendix A. Supplementary data
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Supplementary data to this article can be found online at
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