Late-stage C-H amination of abietane diterpenoids

Article abstract of DOI:10.1039/c9ob00272c

This study aims at highlighting the synthetic versatility of the rhodium-catalyzed C-H amination reactions using iodine(iii) oxidants for the late-stage functionalization of natural products. Inter-and intramolecular nitrene insertions have been performed from various abietane diterpenoids, leading to the amination of the C-3, C-6, C-7, C-11 and C-15 positions. Ca. 20 aminated compounds have been isolated with yields of up to 86% and high levels of regio-, chemo-and stereoselectivities.

Full text of DOI:10.1039/c9ob00272c

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Late-stage C–H amination of abietane
diterpenoids†
Cite this: DOI: 10.1039/c9ob00272c
María Ivana Lapuh,a,b Alejandro Dana,b Pablo H. Di Chenna, b Benjamin Darses,a
a
Fernando J. Durán*b and Philippe Dauban
*
This study aims at highlighting the synthetic versatility of the rhodium-catalyzed C–H amination reactions
using iodine(III) oxidants for the late-stage functionalization of natural products. Inter- and intramolecular
nitrene insertions have been performed from various abietane diterpenoids, leading to the amination of
the C-3, C-6, C-7, C-11 and C-15 positions. Ca. 20 aminated compounds have been isolated with yields
of up to 86% and high levels of regio-, chemo- and stereoselectivities.
Received 1st February 2019,
Accepted 14th March 2019
DOI: 10.1039/c9ob00272c
rsc.li/obc
new compounds that nature cannot produce as no known
Introduction
enzyme is programmed to convert a C–H into a C–N bond.4
Catalytic C–H functionalization has emerged in the last decade
Significant achievements in C(sp3)–H amination reactions
as a unique tool that opens new horizons in chemical syn- have recently been reported by application of metal-catalyzed
thesis with the aim to generate a greater molecular diversity nitrene transfers.5 Worth mentioning are the efficient proto-
and complexity.1 The ability to perform site-selective reactions cols that have been uncovered by combining dirhodium(II) cat-
through the development of appropriate conditions and well- alysis and iodine(III) oxidants.6 Selective inter- and intra-
designed catalysts provides rapid access to unprecedented molecular processes have been reported under these con-
functionalized molecules. Of particular relevance, in this ditions allowing the introduction of a nitrogen at specific
context, is the late-stage C–H functionalization of natural pro- sites. Thus, intermolecular reactions preferentially occur at
ducts and bioactive compounds. Such a simple transformation secondary benzylic and allylic positions or non-activated ter-
allows for the modification of sophisticated molecules in a tiary centres, whereas intramolecular reactions lead to the
single step thereby affording new products that would be selective amination of C–H bonds β- or γ- to the nitrene-donor
difficult to access by application of classical organic reactions functionality. Such a set of conditions, therefore, is appropri-
relying on the manipulation of existing functionalities.2
The late-stage C–H functionalization strategy can be useful nitrogen-containing scaffolds.
ate to derivatize any natural product to a large number of
when the introduction of a nitrogen functionality is con-
In this context, abietane diterpenoids of type A (Fig. 1) have
sidered in the course of a medicinal chemistry program. A appeared to us as a textbook case to apply dirhodium(II)-cata-
nitrogen group can indeed deeply impact either the activity or lyzed C–H amination reactions for the formation of a library of
the bioavailability of a pharmaceutical, a unique feature that diversely substituted amino compounds. These naturally
makes this atom present in more than 80% of the drugs occurring tricyclic diterpenoids isolated from terrestrial plant
approved by the U.S. FDA.3 The C–H amination reaction, there- sources have been the purpose of several synthetic studies that
fore, offers unique opportunities to modify a bioactive natural have led to the formation of a wide range of compounds dis-
product and fine tune its profile; particularly, it could afford playing either antimicrobial, antifungal, antiprotozoal, or anti-
cancer activities, to name but a few.7
With the aim to increase the variety of accessible analogues,
recent studies have demonstrated that catalytic C(sp3)–H
aInstitut de Chimie des Substances Naturelles, CNRS UPR 2301, Université
functionalization reactions can be successfully applied to
Paris-Sud, Université Paris-Saclay, 1, av. de la Terrasse, 91198 Gif-sur-Yvette, France.
dehydroabietic acid analogues (Fig. 1a). Amide-directed
E-mail: philippe.dauban@cnrs.fr
C(sp3)–H activation, thus, allows the introduction of alkyl,8a
amino,8b boryl,8c chloro,8d or aryl8e substituents selectively at
the C-19 position. Two isolated examples of amination at the
C-7 benzylic centre have also been reported following the
application of intermolecular C(sp3)–H amination.9 In this
communication, we, therefore, wish to present the results of
bUniversidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y
Técnicas, Unidad de Microanálisis y Métodos Físicos Aplicados a la Química
Orgánica (UMYMFOR), Departamento de Química Orgánica, Facultad de Ciencias
Exactas y Naturales, Pabellón 2, Ciudad Universitaria, Buenos Aires C1428EG,
Argentina. E-mail: fduran@qo.fcen.uba.ar
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob00272c
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Fig. 1 Background for the study.
our investigations on the application of catalytic nitrene trans-
fers to various abietane derivatives that has led to the isolation
of diversely substituted amino derivatives (Fig. 1b).
Scheme 1 Rhodium(II)-catalyzed intermolecular C(sp3)–H amination
reaction of dehydroabietic acid and podocarpic acid derivatives.
Reaction conditions: (a) Rh2(esp)2 2 mol%, TcesNH2 1 equiv., PhI(OPiv)2
2 equiv., benzene, rt. Tces = 2,2,2-trichloroethoxysulfonyl.
Results and discussion
Catalytic intermolecular C(sp3)–H amination reactions
We first investigated the application of catalytic intermolecular
nitrene C(sp3)–H insertions into various abietane derivatives
(Scheme 1). All the reactions were developed under stoichio-
metric conditions with respect to the starting material.
Substrates 1–5 are easily accessible from dehydroabietic acid,
with compound 2 being prepared following a sequence of acy-
lation–Baeyer–Villiger
oxidation–saponification–methylation
adapted from a synthesis of taiwaniaquinone F (see the
ESI†).10 Compounds 6–7 are directly obtained from podocarpic
acid. We, then, performed the C(sp3)–H amination reaction
using the conditions previously reported by Du Bois.11
When applied to dehydroabietic acid derivatives 1–5, the
reaction selectively affords products resulting from the
functionalization of the secondary benzylic C-7 centre. Very
Scheme 2 Rhodium(II)-catalyzed intermolecular C(sp3)–H amination
reaction of abietic acid derivatives. Reaction conditions: (a) Rh2(esp)2
2 mol%, TcesNH2 1 equiv., PhI(OPiv)2 2 equiv., benzene, rt.
good yields in the 46–86% range are obtained with the ponding dehydroabietic acid analogues 1 and 4, with higher
α-isomer being preferentially formed, with α : β ratios around selectivities in favour of the α-isomers but lower yields. These
4.5 : 1. Interestingly, starting from podocarpic acid derivatives results are reminiscent of previous observations made in the
6 and 7, the α-isomers 13 and 14 are exclusively isolated in total synthesis of hispidospermidin by Overman.12
75% and 76% yields respectively. We propose to rationalize Accordingly, a possible mechanism for the formation of 8 and
this excellent selectivity by the involvement of stereoelectronic 11 from, respectively, 15 and 16 would involve an initial formal
factors. According to the dihedral angle with the adjacent aro- ene reaction followed by an aromatization of the resulting 1,3-
matic ring, hyperconjugation could increase the reactivity of cyclohexadiene intermediate.
the α-C(sp3)–H bond, favouring the insertion from the α-face.
Surprisingly, the application of our reported conditions for
However, the lower selectivities observed with dehydroabietic catalytic stereoselective C(sp3)–H amination13 led to totally
acid substrates 1–5 might result from the increased steric hin- different results (Scheme 3). While they proved unsuccessful
drance provided by the C-18 substitution.
from aromatic abietanes 1–6, they afforded
a
single
The same reaction conditions were applied to abietic acid product arising from a C(sp3)–H amination reaction at the
derivatives 15 and 16 (Scheme 2). In both cases, we have iso- allylic centre C-15 in the case of abietane substrates 15 and 16.
lated the same products as those obtained from the corres- Such a switch in regioselectivity could be explained by steric
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Scheme 3 Catalytic intermolecular C(sp3)–H amination with sulfonimi-
damides. Reaction conditions: (a) Rh2(S- or R-nta)4 3 mol%, S*NH2 1.2
equiv., PhI(OPiv)2 1.4 equiv., TCE : MeOH 3 : 1, −35 °C. S*: (S)- or (R)-(N-
(p-toluenesulfonyl)-p-toluenesulfonimidoyl.
TCE:
1,1,2,2-
tetrachloroethane.
Scheme 4 Synthesis of the nitrogen- and fluorine-containing abietane
derivative 21. Reaction conditions: (a) BrCF2CO2Et, Cu, DMSO, 60 °C,
15 h; (b) LiOH 1.25 M, THF, MeCN, rt, 2 h, 19 81% (2 steps); (c) oxalyl
chloride, 10 mol% DMF, DCM, rt; (d) 2-mercaptopyridine N-oxide
sodium salt, DMAP, n-Bu3SnH, toluene, reflux, 2 h, 20 31% (3 steps); (e)
Rh2(esp)2 5 mol%, TcesNH2 1 equiv., PhI(OPiv)2 2 equiv., benzene, rt, 21
83%.
factors as the C-15 position is the more accessible reacting site
for the sterically demanding sulfonimidamide-derived reagent.
Matched and mismatched effects were also observed as higher
yields are recorded by using the (R,R)-pair of reagent and
catalyst.
Application of the catalytic intermolecular C(sp3)–H amination
to the synthesis of the fluorinated aminoabietane derivative 21
tions likely to be functionalized. The design of tethered
Increasing attention has been paid to the synthesis of fluori- reagents has indeed been shown to allow the modification of
nated compounds as fluorine might strongly influence either specific sites according to the nature of the nitrene donor.18
the lipophilicity, the metabolic stability, or the conformation To this end, sulfamates 22, 24, 26, 28, and 3019 as well as car-
of a drug.14 For example, the CF2H group is now considered as bamate 32 were easily prepared from abietic, dehydroabietic
a lipophilic H-bond donor acting as a bioisostere of a hydroxyl, and podocarpic acids (Scheme 5).
thiol, or amide group.14a The growing impact of fluorine is
Starting from sulfamate 22, the reaction delivers a single
demonstrated by its presence in nearly 30% of pharmaceuti- product resulting from the intramolecular C(sp3)–H amination
cals and agrochemicals, while it was absent in medicinal at the C-3 position. Compound 23 is isolated with a very good
chemistry until 1957. This, combined with the aforementioned yield of 71% as a single stereoisomer arising from the selective
ubiquity of nitrogen, led us to plan the synthesis of the modi- functionalization of the axial C-3(sp3)–H bond.20 The same
fied abietane diterpenoid 21 incorporating both nitrogen- and selectivity was observed from the unsaturated analogue 24 that
fluorine-containing functional groups (Scheme 4).
leads to the tetracyclic derivative 25 though with a lower yield
Starting from iodoarene 7, introduction of the ethyl difluor- of 42%. The latter could be explained by the formation of aziri-
oacetate moiety proceeds efficiently via copper(0)-mediated dine 34 arising from a dimerization process as a result of the
coupling in DMSO.15 After the selective saponification of the intermolecular alkene aziridination of the cyclic sulfamate 25
ethyl ester group, carboxylic acid 19 was isolated in 81% yield. (Fig. 2). We propose that 1,3-diaxial interaction induced by the
A three-step sequence involving a Barton decarboxylation reac- axial C-19 methyl substituent may prevent the reaction from
tion,16 then, affords the difluoromethyl derivative 20. proceeding at the equatorial C-3–H bond thereby explaining
Application of the rhodium(II)-catalyzed intermolecular C(sp3)– the selectivity observed for the amination of 22 and 24. The
H amination, finally, delivers the targeted molecule 21 with an podocarpic acid-derived sulfamate 26, on the other hand,
excellent yield of 83%.17 This transformation, to the best of allows for the isolation of the analogous C-3 aminated com-
our knowledge, highlights for the first time the compatibility pound 27 in 41% yield that arises from the amination from
of the C(sp3)–H amination reaction with the presence of a the β-face. Interestingly, products 23, 25, 27, and 34 are rare
CF2H group. This is a significant result in our case because examples of abietane diterpenoid analogues functionalized at
application of classical conditions for the introduction of the the A-ring.7
CF2H group all proved unsuccessful in the presence of an
amino function.17
When the same reaction conditions were applied to the
abietic acid derivative 28, a switch of regioselectivity was unex-
pectedly observed. Thus, the intramolecular C(sp3)–H insertion
takes place at the C-6 position delivering product 29 in 29%
Catalytic intramolecular C(sp3)–H amination reactions
We, then, turned our attention to the use of intramolecular yield as a single isomer.21 The latter is a rare example of a
nitrene C(sp3)–H insertions to increase the number of posi- 7-membered ring obtained by intramolecular C(sp3)–H amin-
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ation,22 the structure of which was corroborated by compari-
son between the NMR spectra of substrate 28 and the resulting
product 29 (see the chemical shifts of H-7, C-3 and C-6 in the
ESI†). The formation of the 7-membered cyclic sulfamate
could be rationalized by the increased reactivity of the allylic
C–H bond.
Additional intramolecular reactions have also been
designed by capitalizing on the presence of the phenol ring in
dehydroabietic acid derivatives. Classical reaction conditions
applied to sulfamate 30, therefore, allows for the amination of
the tertiary benzylic position in 76% yield. More significantly,
the use of carbamate 32 offers the opportunity to functionalize
the aromatic C-ring, thereby enhancing the potential of this
chemistry for late-stage amination. Following the recent proto-
col reported by Singh,23 the rhodium-catalyzed electrophilic
aromatic substitution, thus, proceeds at the ortho C(sp2)–H
bond thereby leading to the functionalization of the C-11
site.24
Conclusions
In conclusion, we have demonstrated that the rhodium(II)-cata-
lyzed C–H amination reaction with iodine(III) oxidants is a
useful tool for the late-stage functionalization of natural com-
pounds with the aim to produce new analogues. By application
of inter- and intramolecular processes and/or screening
different nitrene precursors and rhodium(II) complexes, we
have been able to selectively introduce an amino functional
group either at C-3, C-6, C-7, C-11 or C-15 positions of various
abietane diterpenoids. Ca. 20 derivatives were, thus, isolated
with yields ranging from 12% to 86%, but also with high levels
of chemo-, regio- and stereoselectivities. Worth mentioning is
the compatibility of the reaction conditions with the presence
of a CF2H group.
The difference in the regioselectivity observed between the
various abietane derivatives highlights that the course of the
nitrene insertion is controlled by the subtle balance of steric
and stereoelectronic factors. Such a study, therefore, is likely to
provide useful information with the aim to perform C(sp3)–H
functionalization reactions with high levels of predictability.
Work in that direction is in progress in our group through the
application of catalytic nitrene transfers to other classes of
natural products available at the ICSN.
Scheme 5 Rhodium(II)-catalyzed intramolecular C(sp3)–H amination.
Reaction conditions: Rh(II) complex 3 or 5 mol%, MgO, PhI(OAc)2 1.3 equiv.
Experimental
Melting points were measured in a Fisher-Johns melting point
apparatus and are uncorrected. Infrared spectra were recorded
on a PerkinElmer Spectrum BX FT-IR spectrometer and a
Scientific Nicolet iS50 FT-IR. Specific rotation was measured
on a PerkinElmer 343 polarimeter. Proton (1H) and carbon
(13C) NMR spectra were recorded on Bruker spectrometers:
Avance 300 MHz (QNP-C13, P31, or Dual C13 probe), Fourier
300 MHz (Easy probe, 1H and 13C standard 5 mm probe),
Fig. 2 Aziridine 34 resulting from a dimerization process from 24
according to an intramolecular C(sp3)–H amination followed by the
intermolecular alkene aziridination.
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Avance 500 MHz (BBO-ATM probe or BBI-ATM probe), General procedure 2: Intermolecular C(sp3)–H amination with
Avance II 500 MHz (BBO-ATM probe or BBI-ATM probe) and sulfonimidamides (compounds 17 and 18)
Avance Neo 500 (BBO-ATM probe or BBI-ATM probe). Fluorine
In an oven-dried tube were introduced activated 4 Å mole-
cular sieves (100 mg), Rh2[(S/R)-nta]4 (7.7 mg, 6.0 µmol),
(R/S)-N-(p-toluenesulfonyl)-p-toluenesulfonimidamide (77.9 mg,
0.240 mmol) and the substrate (0.200 mmol). The tube was
(19F) NMR were recorded on a Bruker Avance II spectrometer.
Carbon (13C) spectra were recorded at 126 or 75 MHz, using a
broadband decoupled mode with the multiplicities obtained
using a JMOD or DEPT sequence. NMR experiments were
capped with a rubber septum and purged with argon.
carried out in deuterated chloroform (CDCl3). Chemical
Anhydrous and degassed 1,1,2,2-tetrachloroethane (0.75 ml)
and methanol (0.25 ml) were added under argon. The tube was
cooled to −78 °C, and PhI(OPiv)2 (115 mg, 0.280 mmol) was
added. The mixture was stirred at −35 °C for 3 days. After
shifts (δ) are reported in parts per million (ppm) with refer-
ence to tetramethylsilane (TMS) or residual solvent peaks as
internal standards. The following abbreviations are used for
the proton spectra multiplicities: s: singlet, d: doublet,
dilution with DCM (3 ml), the molecular sieves were removed
t: triplet, q: quartet, sept: septet, m: multiplet, dd: doublet of
by filtration and the filtrate was evaporated to dryness under
doublets, dt: doublet of triplets, td: triplet of doublets, ddd:
reduced pressure. The oily residue was purified by flash
chromatography, affording the following C–H insertion
doublet of doublet of doublets, tdd: triplet of doublet of
doublets, qt: quartet of triplets, tt: triplet of triplets, and br:
products.
broad. Coupling constants (J) are reported in hertz (Hz). Mass
spectra were obtained with an LCT (Micromass) or with a
Bruker MicroTOF-Q II instrument using electrospray ionization
and from a time of flight analyzer for the high resolution mass
spectra (HRMS). Thin layer chromatography was performed on
silica gel 60 F254 on aluminium plates (Merck) and visualized
under a UVP Mineralight UVLS-29 lamp (254 nm) and by stain-
ing with acidic solutions of vanillin in ethanol, p-anisaldehyde
in ethanol, potassium permanganate or cerium molybdate.
Flash chromatography was conducted on Merck silica gel 60
(40–63 µm) at medium pressure (300 mbar) or on puriFlash
Spot II (Interchim) unless otherwise stated. All reagents were
obtained from commercial suppliers unless otherwise stated.
The rhodium catalysts Rh2(NHCOCF3)4 and Rh2(S- or R-nta)4
were prepared according to the literature procedures from
Methyl 7-(((2,2,2-trichloroethoxy)sulfonyl)amino)-
8,11,13-abietatrien-18-oate (8)
8 was prepared following general procedure 1 starting from 1
(189 mg, 0.600 mmol). After purification by flash chroma-
tography (petroleum ether/EtOAc 90 : 10), compound 8 (206 mg,
63%) was obtained as a white amorphous solid. Integration by
1H NMR provides a ratio of 5 : 1 α : β isomers. The same
compound was prepared as well starting from 15 (190 mg,
0.600 mmol). Purification affords 8 (114 mg, 36%). Integration
by NMR provides a ratio of >20 : 1 α : β isomers.
NMR signals of the major isomer α: 1H NMR (500 MHz,
CDCl3) δ 7.30 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.15
(dd, J = 8.3, 2.0 Hz, 1H), 5.48 (d, J = 8.1 Hz, 1H), 4.80–4.75
(m, 1H), 4.75 (d, J = 10.8 Hz, 1H), 4.69 (d, J = 10.8 Hz, 1H), 3.73
(s, 3H), 2.87 (sept, J = 6.9 Hz, 1H), 2.31 (dd, J = 12.6, 1.2 Hz,
1H), 2.34–2.26 (m, 1H), 2.12 (ddd, J = 14.1, 12.7, 4.9 Hz, 1H),
1.85–1.69 (m, 4H), 1.65 (td, J = 14.2, 13.5, 4.6 Hz, 1H), 1.43 (td,
rhodium(II) acetate which was purchased from the Alfa Aesar
company.13,25 Sulfonimidamides were prepared following the
previously published protocols.13,26 Where necessary, organic
solvents were routinely dried and/or distilled prior to use and
stored over molecular sieves under argon. Organic extracts were
dried over sodium sulfate (Na2SO4).
J = 13.0, 3.9 Hz, 1H), 1.28 (s, 3H), 1.23 (d, J = 6.9 Hz, 6H), 1.20
(s, 3H). 13C NMR (126 MHz, CDCl3) δ 178.9, 147.3, 147.1,
132.8, 128.5, 127.1, 124.9, 93.9, 78.1, 54.2, 52.6, 47.1, 40.7,
General procedure 1: Intermolecular C(sp3)–H amination reac-
tion with Rh2(esp)2 and TcesNH2 (compounds 8–14 and 21)
38.0, 37.4, 36.9, 33.7, 29.2, 24.3, 24.1, 24.0, 18.6, 16.5. NMR
signals of the minor isomer β that can be distinguished:
1H NMR (500 MHz, CDCl3) δ 7.38 (d, J = 1.9 Hz, 1H), 7.19 (d,
J = 8.1 Hz, 1H), 7.15 (dd, J = 8.3, 2.0 Hz, 1H), 7.13 (dd, J = 8.3,
1.9 Hz, 1H), 4.92–4.82 (m, 1H), 4.74 (d, J = 10.8 Hz, 1H), 4.71
(d, J = 10.8 Hz, 1H), 3.67 (s, 3H), 1.92–1.83 (m, 2H). 13C NMR
(126 MHz, CDCl3) δ 178.4, 147.9, 147.2, 133.0, 126.5, 126.1,
124.8, 55.7, 52.3, 47.3, 37.3, 36.7, 33.8, 31.5, 25.6, 24.2, 18.5. IR
(ATR, neat): ν = 3271, 2955, 2935, 1725, 1705, 1435, 1362, 1248,
1179, 1127, 1052, 980, 894, 748, 720 cm−1. HRMS ESI (+):
m/z [M + Na]+ calcd for C23H32Cl3NNaO5S+: 562.0959; found:
562.0959.
A flask containing TcesNH2 (137 mg, 0.600 mmol) and
benzene (0.60 ml) was charged with Rh2(esp)2 (9.1 mg,
12 µmol) and substrate (0.600 mmol). To this bright green
mixture was added a 0.83 M benzene solution of PhI(OPiv)2
(1.40 ml, 1.20 mmol) via a syringe pump over 3 h. Following
the transfer of the oxidant, the solution was stirred at 23 °C for
2–4 h. DCM (5 ml) and 2 ml of a saturated aqueous solution of
thiourea were then added, and the orange biphasic mixture
was stirred vigorously for 30 min. The contents were trans-
ferred to a separatory funnel, and the organic phase was col-
lected. The aqueous layer was extracted with DCM (2 × 10 ml).
The combined organic extracts were washed with a 0.1 M pH 7
Na2HPO4/NaH2PO4 buffer (2 × 10 ml), dried over Na2SO4, fil-
Methyl 7-(((2,2,2-trichloroethoxy)sulfonyl)amino)-12-methoxy-
8,11,13-abietatrien-18-oate (9)
tered, and the filtrate was concentrated under reduced 9 was prepared following general procedure 1 starting from 2
pressure. Purification of the isolated material by flash chroma- (207 mg, 0.600 mmol). After purification by flash chroma-
tography afforded the desired product.
tography (petroleum ether/EtOAc 85 : 15), product 9 (239 mg,
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70%) was obtained as a white amorphous solid. Integration by Integration by NMR provides a ratio of 4.6 : 1 α : β isomers.
1H NMR provides a ratio of 5 : 1 α : β isomers.
The same compound was prepared as well starting from 16
NMR signals of the major isomer α: 1H NMR (500 MHz, (198 mg, 0.600 mmol). Purification affords 11 (71 mg, 21%).
CDCl3) δ 7.23 (s, 1H), 6.67 (s, 1H), 5.37 (d, J = 7.8 Hz, 1H), 4.74 Integration by 1H NMR provides a ratio of >10 : 1 α : β isomers.
(d, J = 10.8 Hz, 1H), 4.76–4.69 (m, 1H), 4.69 (d, J = 10.8 Hz,
NMR signals for the major isomer α: 1H NMR (500 MHz,
1H), 3.81 (s, 3H), 3.73 (s, 3H), 3.22 (sept, J = 6.6 Hz, 1H), 2.33 CDCl3) δ 7.27 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.17
(dd, J = 12.7, 1.3 Hz, 1H), 2.30–2.23 (m, 1H), 2.09 (ddd, J = (dd, J = 8.2, 2.0 Hz, 1H), 5.08 (d, J = 7.1 Hz, 1H), 4.83–4.77 (m,
14.2, 12.7, 4.8 Hz, 1H), 1.85–1.71 (m, 4H), 1.67 (td, J = 13.3, 1H), 4.73 (s, 2H), 3.97 (d, J = 11.3 Hz, 1H), 3.77 (d, J = 11.4 Hz,
4.3 Hz, 1H), 1.47 (td, J = 13.2, 3.2 Hz, 1H), 1.28 (s, 3H), 1.21 1H), 2.87 (sept, J = 6.8 Hz, 1H), 2.33–2.26 (m, 1H), 2.25–2.19
(s, 3H), 1.20 (d, J = 6.9 Hz, 3H), 1.19 (d, J = 6.9 Hz, 3H). (m, 1H), 2.06 (s, 3H), 1.99 (ddd, J = 14.1, 12.9, 4.7 Hz, 1H), 1.86
13C NMR (126 MHz, CDCl3) δ 178.8, 157.3, 148.2, 136.2, 128.1, (dd, J = 12.9, 1.4 Hz, 1H), 1.88–1.65 (m, 2H), 1.53 (td, J = 13.5,
124.7, 106.0, 93.9, 78.1, 55.5, 53.9, 52.6, 47.2, 40.7, 38.1, 37.7, 4.3 Hz, 1H), 1.45–1.32 (m, 2H), 1.23 (d, J = 7.0 Hz, 6H), 1.19 (s,
36.8, 29.2, 26.8, 24.3, 22.9, 22.6, 18.7, 16.5. NMR signals of the 3H), 0.93 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 171.3, 147.7,
1
minor isomer β that can be distinguished: H NMR (500 MHz, 147.3, 132.2, 128.2, 127.3, 125.1, 93.9, 78.0, 71.4, 54.2, 39.2,
CDCl3) δ 7.30 (s, 1H), 6.68 (s, 1H), 4.86–4.79 (m, 1H), 3.67 38.2, 37.8, 36.5, 35.2, 33.7, 26.2, 24.8, 24.2, 24.0, 21.1, 18.6,
(s, 3H), 3.28–3.19 (m, 1H), 1.29 (s, 3H). 13C NMR (126 MHz, 17.8. NMR signals of the minor isomer β that can be distin-
1
CDCl3) δ 178.4, 156.9, 148.9, 135.9, 125.8, 124.8, 106.1, 78.3, guished: H NMR (500 MHz, CDCl3) δ 7.39 (d, J = 2.0 Hz, 1H),
55.6, 55.4, 53.8, 52.4, 47.3, 43.9, 37.6, 36.7, 31.6, 27.0, 25.5, 7.21 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 8.2, 2.1 Hz, 1H), 5.00–4.90
22.8, 22.7, 18.5. IR (ATR, neat): ν = 3260, 2951, 1703, 1502, (m, 1H), 4.77 (d, J = 10.9 Hz, 1H), 4.74 (d, J = 10.9 Hz, 1H), 3.90
1435, 1361, 1249, 1178, 1046, 976, 957, 848, 749, 721 cm−1
.
(d, J = 11.2 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 2.51–2.44 (m,
HRMS ESI (+): m/z [M + Na]+ calcd for C24H34Cl3NNaO6S+: 1H), 2.03 (s, 3H), 0.94 (s, 3H). 13C NMR (126 MHz, CDCl3)
592.1065; found: 592.1042.
δ 148.1, 147.1, 133.0, 126.5, 126.0, 124.9, 78.3, 72.0, 55.9, 43.2,
38.3, 36.7, 35.3, 33.8, 26.2, 25.9, 18.4, 17.6. IR (ATR, neat):
ν = 2953, 2836, 1716, 1641, 1572, 1492, 1464, 1435, 1375, 1291,
1264, 1252, 1237, 1216, 1189, 1173, 1149, 1136, 1070, 1049,
Methyl 7-(((2,2,2-trichloroethoxy)sulfonyl)amino)-
12-iodo-8,11,13-abietatrien-18-oate (10)
10 was prepared following general procedure 1 starting from 3 973, 877, 802, 788, 773, 734, 771 cm−1. HRMS ESI (+): m/z
(265 mg, 0.600 mmol). After purification by flash chroma- [M + NaMeCN]+ calcd for C26H37Cl3N2NaO5S+: 617.1381; found:
tography (petroleum ether/EtOAc 90 : 10), product 10 (345 mg, 617.1394.
86%) was obtained as a white amorphous solid. Integration by
7-(((2,2,2-Trichloroethoxy)sulfonyl)amino)-18-methoxyabieta-
8,11,13-triene (12)
1H NMR gives a ratio of 5 : 1 α : β isomers.
NMR signals of the major isomer α: 1H NMR (500 MHz,
CDCl3) δ 7.68 (s, 1H), 7.31 (s, 1H), 5.67 (d, J = 8.1 Hz, 1H), 4.73 12 was prepared following general procedure 1 from 5
(d, J = 10.8 Hz, 1H), 4.75–4.70 (m, 1H), 4.68 (d, J = 10.8 Hz, (180 mg, 0.600 mmol). After purification by flash chroma-
1H), 3.71 (s, 3H), 3.10 (sept, J = 6.7 Hz, 1H), 2.25 (br d, J = tography (petroleum ether/EtOAc 90 : 10), compound 12
12.6 Hz, 1H), 2.29–2.19 (m, 1H), 2.10 (ddd, J = 14.1, 12.7, was obtained (145 mg, 46%) as a white amorphous solid.
5.1 Hz, 1H), 1.91–1.65 (m, 4H), 1.60 (td, J = 13.2, 4.7 Hz, 1H), Integration by 1H NMR provides a ratio of 4.4 : 1 α : β isomers.
1.42 (td, J = 13.1, 4.4 Hz, 1H), 1.27 (s, 3H), 1.22 (d, J = 6.7 Hz,
NMR signals of the major isomer α: 1H NMR (500 MHz,
6H), 1.19 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 178.9, 149.1, CDCl3) δ 7.27 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.13
148.9, 136.1, 133.6, 128.0, 102.0, 93.8, 78.1, 53.6, 52.6, 46.9, (dd, J = 8.2, 2.0 Hz, 1H), 5.61 (d, J = 8.5 Hz, 1H), 4.75–4.71 (m,
40.5, 37.9, 37.8, 37.4, 36.8, 29.0, 24.3, 23.2, 23.1, 18.5, 16.4. 1H), 4.69 (s, 2H), 3.38 (d, J = 9.2 Hz, 1H), 3.36 (s, 3H), 2.86
NMR signals of the minor isomer β that can be distinguished: (sept, J = 6.9 Hz, 1H), 2.81 (d, J = 9.2 Hz, 1H), 2.27–2.20 (m,
1H NMR (500 MHz, CDCl3) δ 7.66 (s, 1H), 7.38 (s, 1H), 5.09 1H), 2.12–2.01 (m, 1H), 1.99–1.92 (m, 1H), 1.91 (d, J = 12.6 Hz,
(d, J = 9.2 Hz, 1H), 4.84–4.75 (m, 1H), 3.67 (s, 3H), 3.11 (sept, 1H), 1.86–1.62 (m, 3H), 1.40–1.27 (m, 2H), 1.23 (d, J = 6.9 Hz,
J = 6.7 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 178.3, 149.9, 6H), 1.19 (s, 3H), 0.82 (s, 3H). 13C NMR (75 MHz, CDCl3)
148.7, 136.0, 133.9, 125.6, 101.4, 93.6, 78.3, 55.3, 52.4, 47.2, δ 147.7, 146.9, 133.0, 128.4, 126.8, 125.2, 93.9, 80.9, 78.1,
37.1, 36.6, 31.1, 25.6, 18.3, 16.5. IR (ATR, neat): ν = 3257, 59.3, 54.7, 42.8, 39.1, 38.7, 37.9, 36.8, 35.5, 33.7, 26.0, 24.2
2957, 2869, 1700, 1469, 1434, 1362, 1247, 1179, 977, 849, (1C + 1C), 24.0, 18.9, 18.0. NMR signals of the minor isomer β
752, 721 cm−1. HRMS ESI (−): m/z [M + H]− calcd for that can be distinguished: 1H NMR (500 MHz, CDCl3) δ 7.36
C23H30Cl3INO5S−: 663.9960; found: 663.9969.
(d, J = 2.0 Hz, 1H), 7.10 (dd, J = 8.2, 2.0 Hz, 1H), 4.88–4.80 (m,
1H), 4.76 (d, J = 10.8 Hz, 1H), 3.30 (s, 3H), 3.21 (d, J = 9.2 Hz,
1H, 1H), 2.50–2.42 (m, 1H), 1.55 (td, J = 13.6, 4.3 Hz, 1H), 1.22
(d, J = 7.0 Hz, 6H), 0.86 (s, 3H). 13C NMR (75 MHz, CDCl3)
7-(((2,2,2-Trichloroethoxy)sulfonyl)amino)-8,11,13-abietatrien-
18-yl acetate (11)
11 was prepared following general procedure 1 from 4 δ 148.4, 146.8, 133.1, 126.3, 125.8, 125.0, 81.9, 78.3, 59.4, 56.1,
(197 mg, 0.600 mmol). After purification by flash chroma- 42.8, 38.5, 37.7, 37.3, 35.4, 33.8, 28.7, 25.8, 18.7, 17.9. IR (ATR,
tography (petroleum ether/EtOAc 90 : 10), product 11 was neat): ν = 3322, 2961, 2929, 2865, 1447, 1418, 1363, 1177, 1102,
obtained (213 mg, 64%) as
a
white amorphous solid. 1088, 1023, 969, 874, 857, 837, 766, 753, 717 cm−1. HRMS ESI
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(−): m/z [M + H]− calcd for C23H33Cl3NO4S−: 524.1201; found: (m, 1H), 5.48–5.41 (m, 1H), 3.65 (s, 3H), 2.43 (s, 3H), 2.40 (s,
524.1215.
3H), 2.31–2.19 (m, 1H), 2.13–1.94 (m, 2H), 1.90–1.70 (m, 4H),
1.70–1.52 (m, 5H), 1.36 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H),
1.17–0.96 (m, 2H), 0.78 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 179.1, 144.4, 142.9, 140.6, 139.6, 138.1, 134.8, 129.6 (2C),
Methyl 7α-(((2,2,2-trichloroethoxy)sulfonyl)amino)-O-methyl-
podocarpate (13)
13 was prepared following general procedure 1 starting from 6 129.3 (2C), 128.1 (2C), 126.9 (2C), 126.3, 124.8, 61.3, 52.0, 50.5,
(181 mg, 0.600 mmol). After purification by flash chromato- 46.6, 45.1, 38.4, 37.4, 34.5, 27.8, 26.7, 26.0, 25.3, 22.2, 21.7
graphy (petroleum ether/EtOAc 80 : 20), 13 was obtained (1C + 1C), 18.2, 17.1, 14.1. IR (ATR, neat): ν = 3219, 2990, 2929,
(240 mg, 76%) as a white amorphous solid.
2860, 1721, 1597, 1300, 1244, 1148, 1103, 1088, 1017, 975,
[α]2D0 = +77.6 (c = 1.00 in CHCl3). 1H NMR (500 MHz, CDCl3) 908, 812, 727 cm−1. HRMS ESI (+): m/z [M + Na]+ calcd for
+
δ 7.33 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 6.78 (dd, J = C35H46N2NaO5S2 : 661.2740; found: 661.2721.
8.4, 2.6 Hz, 1H), 4.84 (d, J = 6.2 Hz, 1H), 4.83–4.79 (m, 1H),
4.74 (d, J = 10.6 Hz, 1H), 4.72 (d, J = 11.0 Hz, 1H), 3.79 (s, 3H),
3.65 (s, 3H), 2.63–2.57 (m, 1H), 2.38–2.30 (m, 1H), 2.26–2.17
15-[N-(R)-(p-Toluenesulfonyl)-p-toluene-sulfonimidoyl]methyl-
abietadien-18-oate (17b)
(m, 2H), 1.98 (qt, J = 13.6, 3.5 Hz, 1H), 1.69 (dd, J = 13.0, 1.3 17b was prepared following general procedure 2 starting from
Hz, 1H), 1.70–1.62 (m, 1H), 1.37 (td, J = 13.3, 3.9 Hz, 1H), 1.31 15 (63.3 mg, 0.200 mmol) and the (R,R) pair of reagents. After
(s, 3H), 1.13 (td, J = 13.6, 4.1 Hz, 1H), 0.98 (s, 3H). 13C NMR purification by flash chromatography (DCM/EtOAc 95 : 5), com-
(75 MHz, CDCl3) δ 177.6, 160.0, 150.6, 131.6, 124.7, 112.7, pound 17b was obtained (63 mg, 48%) as a yellow amorphous
111.2, 93.8, 78.1, 55.4, 54.2, 51.5, 46.5, 43.7, 39.2, 38.7, 37.6, solid.
28.5, 27.8, 22.2, 19.9. IR (ATR, neat): ν = 3258, 2947, 2878,
[α]2D0 = −70.0 (c = 1.00 in CHCl3). 1H NMR (300 MHz, CDCl3)
2847, 1723, 1701, 1610, 1434, 1359, 1269, 1230, 1177, 1147, δ 7.82 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.25 (d, J =
1047, 980, 847, 752, 721 cm−1. HRMS ESI (+): m/z [M + Na]+ 8.2 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 6.29 (s, 1H), 5.94–5.88 (m,
calcd for C21H28Cl3NNaO6S+: 550.0595; found: 550.0597.
1H), 5.44–5.36 (m, 1H), 3.62 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H),
2.09–1.96 (m, 2H), 1.95–1.85 (m, 2H), 1.81–1.66 (m, 4H),
1.65–1.44 (m, 4H), 1.44 (s, 3H), 1.32 (s, 3H), 1.23 (s, 3H),
1.13–0.98 (m, 1H), 0.64 (s, 3H), 0.24–0.08 (m, 1H). 13C NMR
Methyl 7α-(((2,2,2-trichloroethoxy)sulfonyl)amino)-13-iodo-
O-methylpodocarpate (14)
14 was prepared following general procedure 1 starting from 7 (75 MHz, CDCl3) δ 179.0, 144.2, 142.9, 140.6, 137.8, 137.6,
(257 mg, 0.600 mmol). After purification by flash chroma- 134.6, 129.6 (2C), 129.3 (2C), 128.2 (2C), 127.3, 126.9 (2C),
tography (petroleum ether/EtOAc 80 : 20), compound 14 was 124.7, 60.9, 52.0, 50.2, 46.6, 44.9, 38.3, 37.2, 34.4, 28.6, 27.1,
obtained (295 mg, 75%) as a white amorphous solid.
25.9, 25.7, 21.7 (1C + 1C), 21.4, 18.1, 17.1, 14.2. IR (ATR, neat):
[α]2D0 = +70.3 (c = 1.00 in CHCl3). 1H NMR (500 MHz, CDCl3) ν = 3219, 2948, 2928, 2875, 2836, 1720, 1598, 1433, 1380, 1300,
δ 7.82 (s, 1H), 6.68 (s, 1H), 4.88 (d, J = 6.4 Hz, 1H), 4.79–4.75 1250, 1147, 1107, 1087, 1067, 1016, 970, 906, 811, 726 cm−1
.
(m, 1H), 4.75 (d, J = 10.8 Hz, 1H), 4.73 (d, J = 10.8 Hz, 1H), 3.85 HRMS ESI (+): m/z [M + Na]+ calcd for C35H46N2NaO5S2 :
(s, 3H), 3.66 (s, 3H), 2.60–2.53 (m, 1H), 2.38–2.31 (m, 1H), 661.2740; found: 661.2756.
2.26–2.19 (m, 1H), 2.20 (ddd, J = 14.9, 13.1, 4.2 Hz, 1H), 1.99
+
15-[N-(S)-(p-Toluenesulfonyl)-p-toluene-sulfonimidoyl]abietadien-
(qt, J = 13.8, 3.6 Hz, 1H), 1.71–1.65 (m, 1H), 1.66 (dd, J = 12.9,
18-yl acetate (18a)
1.6 Hz, 1H), 1.37 (td, J = 13.3, 4.1 Hz, 1H), 1.31 (s, 3H), 1.13
(td, J = 13.6, 4.2 Hz, 1H), 0.98 (s, 3H). 13C NMR (126 MHz, 18a was prepared following general procedure 2 starting from
CDCl3) δ 177.5, 158.6, 151.0, 141.0, 126.8, 107.7, 93.7, 84.3, 16 (66.1 mg, 0.200 mmol) and the (S,S) pair of reagents. After
78.1, 56.5, 53.6, 51.6, 46.3, 43.7, 39.2, 38.9, 37.5, 28.5, 27.9, purification by flash chromatography (DCM/EtOAc 95 : 5), com-
22.1, 19.8. IR (ATR, neat): ν = 3257, 2945, 2881, 2849, 1722, pound 18a was obtained (15 mg, 12%) as a yellow amorphous
1701, 1590, 1486, 1442, 1358, 1303, 1281, 1228, 1175, 1147, solid.
1
1081, 1042, 980, 957, 846, 746, 721 cm−1. HRMS ESI (−): m/z
[α]2D0 = +8.0 (c = 0.34 in CHCl3). H NMR (500 MHz, CDCl3)
[M
−
H]− calcd for C21H26Cl3INO6S−: 651.9596; found: δ 7.82 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.26 (d, J =
651.9643.
7.7 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.20 (s, 1H), 5.95–5.91 (m,
1H), 5.50–5.46 (m, 1H), 3.81 (d, J = 10.9 Hz, 1H), 3.68 (d, J =
11.0 Hz, 1H), 2.42 (s, 3H), 2.40 (s, 3H), 2.28–2.21 (m, 1H), 2.06
(s, 3H), 2.09–1.95 (m, 2H), 1.87–1.79 (m, 1H), 1.79–1.70 (m,
15-[N-(S)-(p-Toluenesulfonyl)-p-toluene-sulfonimidoyl]methyl-
abietadien-18-oate (17a)
17a was prepared following general procedure 2 starting from 2H), 1.69–1.62 (m, 1H), 1.62–1.52 (m, 2H), 1.49 (dd, J = 11.7,
15 (63.3 mg, 0.200 mmol) and the (S,S) pair of reagents. After 5.3 Hz, 1H), 1.46–1.32 (m, 2H), 1.37 (s, 3H), 1.24 (s, 3H),
purification by flash chromatography (DCM/EtOAc 95 : 5), com- 1.15–1.05 (m, 1H), 1.01–0.92 (m, 1H), 0.94 (s, 3H), 0.79 (s, 3H).
pound 17a was obtained (37 mg, 29%) as a yellow amorphous 13C NMR (75 MHz, CDCl3) δ 171.4, 144.4, 142.9, 140.6, 139.9,
solid.
138.2, 134.7, 129.6 (2C), 129.3 (2C), 128.0 (2C), 126.9 (2C),
1
[α]2D0 = +1.9 (c = 0.53 in CHCl3). H NMR (300 MHz, CDCl3) 126.2, 125.0, 72.8, 61.5, 50.3, 44.3, 38.8, 36.4, 36.3, 34.7, 27.5,
δ 7.82 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 26.6, 25.3, 24.3, 22.5, 21.8, 21.7, 21.2, 18.1, 17.9, 14.2. IR (ATR,
8.8 Hz, 2H), 7.25 (d, J = 9.1 Hz, 2H), 6.20 (s, 1H), 5.93–5.88 neat): ν = 3231, 2924, 2849, 1733, 1598, 1451, 1379, 1299, 1238,
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1150, 1105, 1069, 1034, 976, 812, 749, 702 cm−1. HRMS ESI (+): (4aS,4bR,10bS,12aR)-8-Isopropyl-4a,10b-dimethyl-
m/z [M + Na]+ calcd for C36H48N2NaO5S2 :675.2897; found: 1,4,4a,4b,5,6,10b,11,12,12a-decahydrophenanthro-
+
675.2918.
[2,1-d][1,2,3]oxathiazine 2,2-dioxide (23)
Sulfamate 22 (76.0 mg, 0.208 mmol), Rh2(CF3CONH)4 (3.8 mg,
6.0 µmol) and MgO (15.3 mg, 0.380 mmol) were charged in a
sealed tube under an argon atmosphere. Anhydrous benzene
(1.0 ml) was then added, followed by PhI(OAc)2 (83.7 mg,
0.260 mmol). The reaction mixture was stirred at 65 °C
for 16 h, filtered through a pad of Celite and washed with
EtOAc. After concentration under reduced pressure, the brown
residue was purified by flash chromatography (petroleum
ether/EtOAc 90 : 10) to afford 23 (54 mg, 71%) as a white amor-
phous solid.
15-[N-(R)-(p-Toluenesulfonyl)-p-toluene-sulfonimidoyl]abietadien-
18-yl acetate (18b)
18b was prepared following general procedure 2 starting from
16 (66.1 mg, 0.200 mmol) and the (R,R) pair of reagents. After
purification by flash chromatography (DCM/EtOAc 95 : 5), com-
pound 18b was obtained (47 mg, 36%) as a yellow amorphous
solid.
[α]2D0 = −22.5 (c = 1.00 in CHCl3). 1H NMR (300 MHz, CDCl3)
δ 7.82 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.26 (d, J =
8.3 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 6.29 (s, 1H), 5.96–5.88 (m,
1H), 5.49–5.40 (m, 1H), 3.79 (d, J = 10.8 Hz, 1H), 3.64 (d, J =
10.8 Hz, 1H), 2.41 (s, 3H), 2.38 (s, 3H), 2.04 (s, 3H), 2.06–1.96
(m, 2H), 1.96–1.85 (m, 2H), 1.78–1.61 (m, 2H), 1.60–1.35 (m,
6H), 1.44 (s, 3H), 1.33 (s, 3H), 0.92 (s, 3H), 1.00–0.79 (m, 1H),
0.64 (s, 3H), 0.22–0.05 (m, 1H). 13C NMR (75 MHz, CDCl3)
δ 171.4, 144.2, 143.0, 140.6, 138.0, 137.7, 134.5, 129.6 (2C),
129.3 (2C), 128.2 (2C), 127.2, 126.9 (2C), 125.0, 72.7, 61.0,
50.0, 44.1, 38.8, 36.4, 36.2, 34.6, 28.5, 27.1, 25.7, 24.2, 21.7
(1C + 1C), 21.6, 21.2, 18.1, 17.9, 14.3. IR (ATR, neat): ν = 3237,
2927, 1733, 1597, 1447, 1432, 1380, 1299, 1240, 1149, 1089,
1067, 1033, 976, 908, 812, 729, 697 cm−1. HRMS ESI (+):
[α]2D0 = +11.3 (c = 1.00 in CHCl3). 1H NMR (300 MHz, CDCl3)
δ 7.13 (d, J = 8.2 Hz, 1H), 7.03 (dd, J = 8.2, 1.9 Hz, 1H), 6.93
(d, J = 1.9 Hz, 1H), 4.45 (d, J = 12.4 Hz, 1H), 4.33 (d, J = 9.7 Hz,
1H), 4.22 (d, J = 12.6 Hz, 1H), 3.68 (dt, J = 9.6, 3.3 Hz, 1H),
3.03–2.93 (m, 2H), 2.84 (sept, J = 6.9 Hz, 1H), 2.32–2.15 (m,
2H), 2.13 (dd, J = 11.4, 3.2 Hz, 1H), 1.91–1.69 (m, 3H), 1.59 (td,
J = 15.3, 3.7 Hz, 1H), 1.27 (s, 3H), 1.23 (d, J = 7.0 Hz, 6H), 0.95
(s, 3H). 13C NMR (75 MHz, CDCl3) δ 146.6, 145.8, 134.3, 127.1,
124.4, 123.9, 77.6, 59.6, 37.1, 36.6, 34.5, 33.6, 31.5, 29.5, 25.6,
24.1 (1C + 1C), 23.1, 18.2, 16.6. IR (ATR, neat): ν = 3288, 2957,
2869, 1498, 1563, 1413, 1356, 1173, 1054, 993, 972, 928, 884,
821, 781, 710, 664 cm−1. HRMS ESI (+): m/z [M + H]+ calcd for
C20H30NO3S+: 364.1941; found: 364.1950.
m/z [M + Na]+ calcd for C36H48N2NaO5S2 : 675.2897; found:
+
675.2896.
Methyl 7α-(((2,2,2-trichloroethoxy)sulfonyl)amino)-
13-difluoromethyl-O-methylpodocarpate (21)
(4aS,4bR,10bS,12aR)-8-Isopropyl-4a,10b-dimethyl-
1,4,4a,4b,10b,11,12,12a-octahydrophenanthro[2,1-d][1,2,3]-
oxathiazine 2,2-dioxide (25) and aziridine (34)
21 was prepared following general procedure 1 starting from
20 (106 mg, 0.300 mmol), TcesNH2 (68.5 mg, 0.300 mmol), Sulfamate 24 (218 mg, 0.600 mmol), Rh2(esp)2 (13.6 mg,
Rh2(esp)2 (11.4 mg, 15.0 µmol) and PhI(OPiv)2 (244 mg, 18.0 µmmol) and MgO (45.9 mg, 1.14 mmol) were charged in
0.600 mmol). The oxidant was added over 1.5 h. After puri- a sealed tube under an argon atmosphere. Then anhydrous
fication by flash chromatography (petroleum ether/EtOAc DCM (3.0 ml) was added and the mixture was cooled to
85 : 15), the desired compound was obtained as a white amor- 0 °C with an ice bath before adding PhI(OAc)2 (251 mg,
phous solid (109 mg, 83%).
0.780 mmol). The reaction mixture was stirred at r.t. for 16 h,
[α]2D0 = +84.8 (c = 1.00 in CHCl3). 1H NMR (500 MHz, CDCl3) filtered through a pad of Celite and washed with EtOAc. After
δ 7.59 (br s, 1H), 6.86 (t, J = 55.5 Hz, 1H), 6.81 (br s, 1H), concentration under reduced pressure, the brown residue was
4.96–4.91 (m, 1H), 4.85–4.80 (m, 1H), 4.74 (d, J = 10.9 Hz, 1H), purified by flash chromatography (petroleum ether/EtOAc
4.72 (d, J = 10.9 Hz, 1H), 3.85 (s, 3H), 3.66 (s, 3H), 2.66–2.60 90 : 10 to 80 : 20) to afford 25 (92 mg, 42%) as a white amor-
(m, 1H), 2.37–2.31 (m, 1H), 2.27–2.21 (m, 1H), 2.20 (ddd, J = phous solid and 34 (74 mg, 17%) as a yellow amorphous solid.
14.9, 13.1, 4.0 Hz, 1H), 1.99 (qt, J = 14.0, 3.7 Hz, 1H), 1.70 (dd,
Compound 25. [α]D20 = −72.0 (c = 1.00 in CHCl3). 1H NMR
J = 13.0, 1.6 Hz, 1H), 1.72–1.64 (m, 1H), 1.38 (td, J = 13.3, (300 MHz, CDCl3) δ 7.12 (dd, J = 8.0, 1.6 Hz, 1H), 7.06 (d, J =
4.0 Hz, 1H), 1.32 (s, 3H), 1.14 (td, J = 13.6, 4.2 Hz, 1H), 0.99 8.0 Hz, 1H), 6.97 (d, J = 1.6 Hz, 1H), 6.67 (dd, J = 9.6, 3.1 Hz,
(s, 3H). 13C NMR (126 MHz, CDCl3) δ 177.5 (s), 157.6 (t, J = 1H), 5.78 (dd, J = 9.6, 2.8 Hz, 1H), 4.42 (d, J = 9.4 Hz, 1H), 4.35
5.5 Hz), 153.4 (d, J = 1.9 Hz), 128.5 (t, J = 5.6 Hz), 124.7 (s), (d, J = 12.4 Hz, 1H), 4.27 (d, J = 12.4 Hz, 1H), 3.71 (dt, J = 9.5,
122.0 (t, J = 22.5 Hz), 111.3 (t, J = 236.0 Hz), 107.9 (s), 93.7 (s), 3.2 Hz, 1H), 2.96–2.79 (m, 2H), 2.24 (tt, J = 16.6, 4.3 Hz, 1H),
78.1 (s), 55.8 (s), 54.0 (s), 51.6 (s), 46.2 (s), 43.7 (s), 39.3 (s), 2.16–2.06 (m, 1H), 1.84 (td, J = 13.0, 3.8 Hz, 1H), 1.90–1.75 (m,
39.1 (s), 37.5 (s), 28.4 (s), 27.8 (s), 22.1 (s), 19.8 (s). 19F NMR 1H), 1.25 (d, J = 7.0 Hz, 6H), 1.11 (s, 3H), 1.05 (s, 3H). 13C NMR
(471 MHz, CDCl3) δ −114.5 (d, J = 299.0 Hz), −116.0 (d, J = (75 MHz, CDCl3) δ 147.1, 144.2, 132.3, 130.5, 126.5, 125.8,
299.0 Hz). IR (ATR, neat): ν = 3284, 3107, 2955, 2853, 1728, 125.1, 121.7, 77.1, 59.1, 38.0, 37.4, 33.8, 33.5, 28.8, 24.1
1702, 1514, 1469, 1432, 1349, 1266, 1228, 1179, 1153, 1179, (1C + 1C), 23.0, 21.0, 17.6. IR (ATR, neat): ν = 3306, 2962, 2942,
1076, 1047, 1018, 965, 853, 843, 755, 144, 122, 634, 530 cm−1
HRMS ESI(+): m/z [M + Na]+ calcd for C22H28Cl3F2NNaO6S+: 927, 891, 823, 787, 775 cm−1. HRMS ESI (+): m/z [M + H]+ calcd
.
2925, 2868, 1469, 1442, 1420, 1362, 1188, 1050, 1025, 994, 969,
600.0563, found: 600.0569.
for C20H28NO3s+: 362.1784; found: 362.1783.
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Compound 34. 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = cooled to 0 °C with an ice bath before adding PhI(OAc)2
2.0 Hz, 1H), 7.23 (dd, J = 8.1, 2.0 Hz, 1H), 7.09 (d, J = 8.1 Hz, (168 mg, 0.520 mmol). The mixture was stirred at r.t. for 19 h
1H), 7.08 (d, J = 8.0 Hz, 1H), 7.05 (dd, J = 8.0, 1.7 Hz, 1H), 6.90 (until the disappearance of the starting material by TLC),
(d, J = 1.7 Hz, 1H), 6.55 (dd, J = 9.6, 3.0 Hz, 1H), 5.91 (dd, J = filtered through a pad of Celite and washed with EtOAc. After
9.6, 2.6 Hz, 1H), 4.55 (d, J = 12.5 Hz, 1H), 4.38 (d, J = 12.5 Hz, concentration under reduced pressure, the brown residue was
1H), 4.22–4.16 (m, 2H), 4.11 (d, J = 9.5 Hz, 1H), 3.85 (d, J = purified by flash chromatography (petroleum ether/EtOAc
7.4 Hz, 1H), 3.79–3.73 (m, 1H), 3.18 (dd, J = 7.6, 6.1 Hz, 1H), 85 : 15) to afford 29 (42 mg, 29%) as a slightly yellow solid.
2.93 (sept, J = 6.9 Hz, 1H), 2.85 (sept, J = 7.0 Hz, 1H), 2.40 (t,
M.p.: 123–125 °C. [α]D20 = −40.0 (c = 1.00 in CHCl3). 1H NMR
J = 2.9 Hz, 1H), 2.28–2.14 (m, 2H), 2.21 (d, J = 6.4 Hz, 1H), (300 MHz, CDCl3) δ 5.78 (s, 1H), 5.25 (t, J = 2.7 Hz, 1H, H-7),
2.12–2.05 (m, 1H), 1.85–1.73 (m, 4H), 1.70–1.54 (m, 3H), 1.29 4.39 (d, J = 10.3 Hz, 1H), 4.12 (d, J = 12.1 Hz, 1H), 4.14–4.02
(d, J = 6.5 Hz, 3H), 1.28 (s, 3H), 1.28 (d, J = 6.4 Hz, 3H), 1.23 (d, (m, 1H, H-6), 3.61 (d, J = 12.2 Hz, 1H), 2.26 (sept, J = 6.8 Hz,
J = 7.0 Hz, 3H), 1.23 (d, J = 7.0 Hz, 3H), 1.18 (s, 3H), 1.10 (s, 1H), 2.18–1.97 (m, 2H), 1.94–1.74 (m, 4H), 1.74–1.55 (m, 1H),
3H), 1.08 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 148.0, 147.1, 1.37 (d, J = 10.0 Hz, 1H), 1.37–1.28 (m, 1H), 1.25 (s, 3H),
146.4, 145.3, 132.6, 129.1, 129.0, 127.9, 127.8 (1C + 1C), 125.9, 1.32–1.18 (m, 1H), 1.17–1.06 (m, 2H), 1.03 (d, J = 6.7 Hz, 3H),
124.8, 122.8, 121.8, 81.2, 77.8, 58.9, 45.5, 40.3, 40.2, 39.6, 37.6, 1.02 (d, J = 6.8 Hz, 3H), 0.85 (s, 3H). 13C NMR (75 MHz, CDCl3)
37.0, 36.8, 35.5, 34.7, 34.1, 33.8, 33.7, 29.5, 26.0, 24.2, 24.1 δ 149.8, 138.9, 121.5, 118.7, 82.3, 60.3, 50.8 (C-6), 49.4, 38.6,
(1C + 1C), 23.9, 22.7, 20.9, 18.2, 17.8, 17.2. IR (ATR neat): ν = 38.3, 37.8, 35.4 (C-3), 35.2, 27.2, 22.0, 21.3, 20.8, 18.2, 17.7,
2559, 2932, 2869, 2097, 1682, 1462, 1444, 1359, 1177, 994, 974, 14.0. IR (ATR, neat): ν = 3828, 2921, 2851, 1712, 1655, 1446,
909, 858, 828, 773, 718 cm−1. HRMS ESI (−): m/z [M + H]− 1424, 1338, 1178, 1036, 971, 951, 931, 890, 850, 779 cm−1
.
calcd for C40H53N2O6S2−: 721.3350; found: 721.3310.
HRMS ESI(+): m/z [M + H]+ calcd for C20H32NO3S+: 366.2097;
found: 366.2097.
(4aR,4bR,10bS,12aS)-9-Methoxy-4a,10b-dimethyl-
1,4,4a,4b,5,6,10b,11,12,12a-decahydrophenanthro-
[2,1-d][1,2,3]oxathiazine 2,2-dioxide (27)
Methyl(4R,4aR,12bS)-4,8,8,12b-tetramethyl-
1,2,3,4,4a,5,6,8,9,12b-decahydrophenanthro[2,3-][1,2,3]-
oxathiazine-4-carboxylate 10,10-dioxide (31)
Sulfamate 26 (70.7 mg, 0.200 mmol), Rh2(esp)2 (4.6 mg,
6.0 µmol) and MgO (15.3 mg, 0.380 mmol) were charged in a Compound 30 (80.0 mg, 0.195 mmol), Rh2(CF3CONH)4
sealed tube under an argon atmosphere. Anhydrous DCM (3.8 mg, 5.9 µmol), and MgO (14.9 mg, 0.371 mmol) were
(1.0 ml) was then added, followed by PhI(OAc)2 (83.7 mg, charged in a round bottom flask under an argon atmosphere.
0.260 mmol). The reaction mixture was stirred at r.t. for 16 h, Then anhydrous DCM (2.4 ml) was added and the mixture was
filtered through a pad of Celite and washed with EtOAc. After cooled to 0 °C with an ice bath before adding PhI(OAc)2
concentration under reduced pressure, the brown residue was (81.7 mg, 0.254 mmol). The mixture was stirred at r.t. until the
purified by flash chromatography (petroleum ether/EtOAc disappearance of the starting material by TLC, filtered through
85 : 15) to afford compound 27 (29 mg, 41%) as a white solid.
a pad of Celite and washed with EtOAc. After concentration
M.p.: Decomposition at 265 °C. [α]2D0 = +2.9 (c = 0.75 in under reduced pressure, the brown residue was purified by
1
CHCl3). H NMR (500 MHz, CDCl3) δ 6.97 (d, J = 8.4 Hz, 1H), flash chromatography (petroleum ether/EtOAc 85 : 15) to
6.78 (d, J = 2.6 Hz, 1H), 6.70 (dd, J = 8.4, 2.6 Hz, 1H), 5.17 (d, afford 31 (62 mg, 76%) as a slightly pink solid.
J = 11.7 Hz, 1H), 4.87 (d, J = 5.9 Hz, 1H), 4.10 (dd, J = 11.8, 2.2
M.p.: Decomposition at 230 °C. [α]2D0 = +49.5 (c = 0.92 in
1
Hz, 1H), 3.78 (s, 3H), 3.06–2.99 (m, 1H), 2.98–2.91 (m, 1H), CHCl3). H NMR (300 MHz, CDCl3) δ 6.86 (s, 1H), 6.85 (s, 1H),
2.88–2.78 (m, 1H), 2.76 (qd, J = 13.9, 3.4 Hz, 1H), 2.42 (dt, J = 4.55 (s, 1H), 3.67 (s, 3H), 2.92–2.81 (m, 2H), 2.26–2.16 (m, 1H),
13.3, 3.6 Hz, 1H), 2.08–1.94 (m, 2H), 1.71–1.60 (m, 1H), 1.59 2.17 (dd, J = 12.3, 2.1 Hz, 1H), 1.92–1.62 (m, 5H), 1.69 (s, 3H),
(d, J = 13.0 Hz, 1H), 1.51 (td, J = 13.7, 3.6 Hz, 1H), 1.42 (s, 3H), 1.68 (s, 3H), 1.47 (td, J = 12.3, 4.7 Hz, 1H), 1.49–1.38 (m, 1H),
1.28 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 158.1, 149.0, 130.1, 1.27 (s, 3H), 1.20 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 179.0,
126.3, 111.7, 110.1, 75.2, 64.1, 55.5, 49.8, 37.5, 37.0, 36.1, 29.5, 151.4, 147.7, 132.8, 126.7, 125.1, 114.8, 60.1, 52.2, 47.6, 44.5,
25.5, 24.7, 24.3, 19.0. IR (ATR, neat): ν = 3349, 3318, 3254, 37.9, 37.4, 36.7, 31.0, 30.9, 29.4, 25.0, 21.5, 18.5, 16.7. IR (ATR,
2985, 2951, 2916, 2162, 1607, 1575, 1503, 1434, 1357, 1251, neat): ν = 3219, 2999, 2940, 2926, 2873, 2846, 1694, 1496, 1437,
1185, 1039, 973, 928, 833, 760, 552, 540, 532 cm−1. HRMS ESI 1401, 1384, 1358, 1254, 1155, 1110, 1020, 991, 905, 853, 845,
(+): m/z [M + Na]+ calcd for C18H25NNaO4S+: 374.1396; found: 756 cm−1. HRMS ESI (+): m/z [M + H]+ calcd for C21H30NO5S+:
374.1392.
408.1839; found: 408.1851.
(3aR,3a1R,7aS,12aR,12bR)-10-Isopropyl-3a,12b-dimethyl-
2,3,3a,3a1,7,7a,11,12,12a,12b-decahydro-1H,4H-phenanthro-
[10,1-de][1,2,3]oxathiazepine 6,6-dioxide (29)
Methyl(7aR,8R,11aS)-4-isopropyl-8,11a-dimethyl-2-oxo-
1,2,6,7,7a,8,9,10,11,11a-decahydrophenanthro[4,3-d]oxazole-
8-carboxylate (33)
Compound 28 (147 mg, 0.400 mmol), Rh2(CF3CONH)4 In a sealed tube equipped with a magnetic bar under an argon
(7.6 mg, 12 µmol) and MgO (30.6 mg, 0.760 mmol) were atmosphere, carbamate 32 was added (224 mg, 0.600 mmol)
charged in a round bottom flask under an argon atmosphere. followed by MgO (53.2 mg, 1.32 mmol), PhI(OAc)2 (251 mg,
Then anhydrous DCM (2.4 ml) was added and the mixture was 0.780 mmol), 4 Å MS (200 wt%), and Rh2(octanoate)4 (23.4 mg,
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30.0 µmol) and anhydrous toluene (4.0 ml). The reaction
vessel was sealed and was stirred at 100 °C until the dis-
appearance of the starting material (12 h). The reaction
mixture was then filtered through a pad of Celite and the
residue obtained after the concentration under reduced
pressure was dissolved in DCM and 5 ml of a saturated solu-
tion of thiourea were added. The orange biphasic mixture was
stirred vigorously for 30 min. The content was transferred to a
separatory funnel, and the organic phase was collected. The
aqueous layer was extracted with DCM (2 × 15 ml). The com-
bined organic extracts were washed with brine (2 × 15 ml),
dried over Na2SO4, filtered, and the filtrate was concentrated
under reduced pressure. Purification of the isolated material
by flash chromatography (petroleum ether/EtOAc 8 : 2)
afforded the desired product (95 mg, 43% yield) as a pale
yellow solid.
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M.p.: Decomposition at 241 °C. [α]2D0 = +99.4 (c = 1.00 in
1
CHCl3). H NMR (500 MHz, CDCl3) δ 9.64 (s, 1H), 6.68 (s, 1H),
3.69 (s, 3H), 3.18 (sept, J = 6.9 Hz, 1H), 2.95 (ddd, J = 16.4,
12.0, 6.3 Hz, 1H), 2.86 (ddd, J = 16.8, 6.2, 1.4 Hz, 1H),
2.43–2.36 (m, 1H), 2.27 (dd, J = 12.2, 1.8 Hz, 1H), 1.93–1.84 (m,
1H), 1.81 (td, J = 12.6, 3.3 Hz, 1H), 1.81–1.70 (m, 2H),
1.70–1.64 (m, 1H), 1.58 (td, J = 12.6, 3.5 Hz, 1H), 1.43–1.37
(m, 1H), 1.36 (s, 3H), 1.30 (s, 3H), 1.29 (d, J = 6.9 Hz, 3H), 1.28
(d, J = 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 179.0, 156.3,
140.3, 131.9, 130.2, 129.1, 125.7, 121.2, 52.2, 48.0, 46.3, 37.8,
36.9, 36.3, 31.5, 28.3, 22.6, 22.4, 22.0, 21.8, 18.5, 16.8. IR (ATR,
neat): ν = 3248, 3228, 2964, 2945, 2929, 2875, 1745, 1731, 1716,
1637, 1590, 1430, 1414, 1386, 1332, 1247, 1206, 1175, 1134,
1113, 1084, 1053, 936, 882, 813, 792, 762, 727 cm−1. HRMS ESI
+
(+): m/z [M + H]+ calcd for C22H30NO4 : 372.2169; found:
372.2168.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We wish to thank the ECOS-Sud Committee (Action A15E04),
the Saint Exupery Program (grant to M. I. L.), the French
National Research Agency (program no ANR-11-IDEX-0003-02,
CHARMMMAT ANR-11-LABX-0039, and ANR-15-CE29-0014-01),
the CONICET (project no 22920170100012CO), the
Universidad de Buenos Aires (projects no 20020150100121BA
and 20020120200272BA), and the Institut de Chimie des
Substances Naturelles for their support.
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