Total synthesis of natural and non-natural δ 5,6δ12,13-jatrophane diterpenes and their evaluation as MDR modulators

Article abstract of DOI:10.1021/jo1019738

We report the details of the total synthesis of natural and non-natural jatropha-5,12-dienes. The successful tactic for the assembly of the strained trans-bicyclo[10.3.0]pentadecane scaffold employed a B-alkyl Suzuki-Miyaura cross-coupling for the formation of the C5/C6 double bond and a ring-closing metathesis for the construction of the C12/C13 double bond. The key step of the synthesis of the cyclopentane fragment, an uncatalyzed intramolecular carbonyl-ene reaction, was studied computationally by DFT calculations. The members of the ensemble of synthetic natural and non-natural jatrophanes were subsequently examined as modulators for the ABCB1, ABCG2, and ABCC1 efflux proteins, which are associated with multidrug resistance in cancer chemotherapy.

Full text of DOI:10.1021/jo1019738

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13
Jatrophane Diterpenes and their Evaluation as MDR-
Modulators
● SUPPORTING INFORMATION●
Christoph Schnabel†, Katja Sterz$, Henrik Müller$, Julia Rehbein†,ø, Michael Wiese*,$,
and Martin Hiersemann*,†
†Technische Universität Dortmund, Fakultät Chemie, D-44227 Dortmund, Germany
$Universität Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie II, D-53121 Bonn, Germany
ø Present address: Physical Organic Chemistry Centre, School of Chemistry, Cardiff University,
Cardiff CF10 3AT, U.K.
m.wiese@uni-bonn.de; martin.hiersemann@udo.edu
SI-2
SI-4
SI-7
SI-9
SI-42
General Experimental Methods
Chart of Synthesized Compounds
Kinetic Experiments
Experimental Procedures and Analytical Data for New Compounds
Biological Studies
SI-1

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
GENERAL EXPERIMENTAL METHODS
Methods and Materials: Unless otherwise stated, commercially available reagents were used as
purchased. Solvents were dried by passage through activated alumina columns of a solvent purification
system: tetrahydrofuran (THF), dichloromethane (CH2Cl2), diethylether (Et2O), acetonitrile, and toluene
(PhMe). Diisopropylamine was distilled from CaH2 and stored over activated 3 Å molecular sieves.
Methanol was distilled from magnesium and stored over activated 3 Å molecular sieves. Dimethyl
sulfoxide (DMSO, ≥99.5%, stored over molecular sieves) was used as purchased.
2-Iodoxybenzoic acid (IBX) was prepared according to the literature1 and was stored in the
refrigerator. The concentrations of n-BuLi and MeLi were determined employing 4-biphenylmethanol
as indicator.2
All moisture-sensitive reactions were performed in flame-dried septum-sealed glassware under an
atmosphere of argon. Reagents were transferred by means of syringe or cannula. Analytical TLC was
performed using pre-coated silica gel foils (4 cm). Visualization was achieved using 365 nm ultraviolet
irradiation followed by staining with the Kägi-Miescher reagent3 (p-anisaldehyde 2.53 vol%, acetic acid
0.96 vol%, ethanol 93.06 vol%, conc. H2SO4 3.45 vol%) or the KMnO4 reagent (3 g KMnO4, 20 g
K2CO3, 5 mL NaOH (5%), 300 mL H2O). Flash chromatography4 was performed using silica gel
(particle size 0.040−0.063 mm) and mixtures of cyclohexane and ethyl acetate as eluent. A
commercially available ozonizer with oxygen as source was employed with an amperage of 1 A.
1
(a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277−7287. b) Frigerio, M.; Santagostino, M. Tetrahedron
Lett. 1994, 35, 8019−8022.
2 Juaristi, E.; Martinez-Richa, A.; Garcia-Rivera, A.; Cruz-Sanchez, J. S. J. Org. Chem. 1983, 48, 2603−2606.
3 (a) Miescher, K. Helv. Chim. Acta 1946, 29, 743–752. (b) Stahl, E., Kaltenbach. U. J. Chromatog. 1961, 5, 351−355.
4 Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923−2925.
SI-2

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
1H NMR spectra were recorded at 400 MHz, 500 MHz, or 600 MHz. Chemical shifts are reported in
ppm relative to chloroform (δ 7.26 ppm).5 Signal splitting patterns are labeled by the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or overlap of non equivalent
13
resonances. C NMR spectra were recorded at 101 or 125 MHz. Chemical shifts are reported in ppm
relative to CDCl3 (77.1 ppm).5 The assignment of CH2 is based on APT (attached proton test). 19F NMR
spectra were recorded at 188 MHz. Chemical shifts are reported in ppm relative to C6F6 (−164.9 ppm).
11B NMR spectra were recorded at 96 MHz. Chemical shifts are reported in ppm relative to F3B•OEt2
(0.00 ppm).
Infrared spectra were recorded as a thin film on a KBr disk (“film on KBr”). Molecular formula
assignment was confirmed by combustion elemental analysis. High resolution mass spectra were
recorded on a LTQ Orbitrap spectrometer by electrospray ionization (ESI). Melting points were
measured with a capillary melting point device. For water determinations of solvents a coulometer
according to Karl Fischer was applied.
5 Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512−7515.
SI-3

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
CHART OF ALL SYNTHESIZED COMPOUNDS IN ORDER OF THEIR APPEARANCE
OH
OPMB
HO
HO
HO
CO2Me
TBSO
TBSO
TBSO
6
S1
S2
OPMB
OPMB
OPMB
TBSO
TBSO
TBSO
O
TBSO
TBSO
TBSO
S4
11
S3
OPMB
OPMB
OPMB
TBSO
TBSO
TBSO
TBSO
TBSO
TBSO
I
5
S5
16
O
O
O
EtO
HO
12
13
14
O
I
I
I
B
O
15
O
O
O
B
n-Bu4NF3B
O
4b
4a
SI-4

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
OH
O
HO
O
OPMB
OPMB
OPMB
OPMB
TBSO
TBSO
HO
19a
19c
OH
HO
O
TBSO
19b
22
O
O
HO
OH
OPMB
OPMB
TBSO
TBSO
23
20
O
HO
O
HO
H
H
O
O
O
O
O
O
HO
BzO
30
2
O
HO
O
BzO
H
H
BzO
BzO
BzO
30
31
O
HO
O
AcO
H
H
BzO
30
S6
O
AcO
O
AcO
H
H
O
O
BzO
BzO
O
S6
1b
SI-5

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
O
BzO
O
HO
H
O
H
O
O
BzO
HO
HO
2
32
O
O
HO
HO
N
H
O
O
H
O
2
33
O
O
HO
O
HO
Ph
H
H
O
O
O
O
HO
2
34
O
O
O
O
HO
HO
Ph
H
O
O
H
HO
HO
Ph
2
35
O
O
O
HO
HO
O
H
H
O
Ph
2
36
O
O
HO
O
HO
H
O
H
O
O
O
HO
2
S7
O
AcO
O
AcO
H
H
O
O
O
O
1a
S8
O
O
O
O
O
O
O
O
H
H
O
O
AcO
AcO
O
S9
S 10
SI-6

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
KINETIC EXPERIMENTS
Kinetic experiments were conducted in a sealed glass tube in decane at 180 °C (oil bath temperature).
1
The relative ratio of 8 to 6 and 7 was determined from the H NMR spectra of the crude product
1
mixture. The two diastereomers 6 and 7 possess sufficiently separated resonances in the H NMR
spectrum to enable a determination of the consumption of the substrate and the build-up of the product
as a function of time. Initial first order rate constants (ki) were calculated by considering the conversion
data from an initial 16 h reaction period.
FIGURE SI-1.
Ratio–versus–time-plot for the carbonyl–ene reaction of 8 to 6 and 7 at 180 °C in
decane. Averaged ratios from three replicates based on the integration of 1H NMR spectra.
The conversion of 8 to 6 and 7 was determined as a function of time; the resulting conversion–versus–
time-plot is depicted in Figure SI-1. The consumption of 8 proceeds with an initial first order rate
constant (kobs) of 8.8 × 10–5 s–1. The kobs for the formation of 6 (8.3 × 10–5 s–1) and 7 (1.2 × 10–5 s–1)
from 8 indicate that the formation of 6 proceeds 7 times faster than the formation of 7. This
approximated value corresponds to a difference in the free energy of activation (ΔΔG‡) of 1.7 kcal/mol.
The persisting residual amount of the substrate 8 indicates an apparent equilibrium concentration of 8 as
a consequence of an only weakly exergonic process.
SI-7

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
Next, we set out establishing experimentally that the ene reaction of 8 to 6 and 7 is reversible, and that
the formation of 6 is not only preferred kinetically but also thermodynamically. For that purpose, the
chromatographically separated diastereomers 6 and 7 were subjected to the reaction conditions of the
uncatalyzed carbonyl–ene reaction of 8. Hence, heating 6 in decane to 180 °C resulted in the formation
of a mixture of 6 and 7 via the retro-ene / ene reaction pathway (Figure SI-2); the apparent equilibrium
at 180 °C was reached after 90 h, thus providing an estimated equilibrium constant (K6/7 = 85/15,
ΔΔGr180°C = 1.6 kcal/mol). Subjecting 7 to analogous reaction conditions also resulted in the formation
of a 6/7 mixture (Figure SI-2). Again, the estimated equilibrium constant (K6/7 = 85/15) can be
determined from the conversion-versus-time plot; however, the apparent equilibrium was reached
already after 50 h, indicating that the conversion of 6 or 7 to a mixture of 6 and 7 proceeds with
different rates. Accordingly, the approximated initial rate constants indicate that 7 is consumed ten
times faster than 6. The equilibrium concentration of 8 was not determined in these experiments.
FIGURE SI-2.
Conversion–versus–time-plot for the retro-ene / ene reaction equilibrium between
6 and 7 at 180 °C in decane
SI-8

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
EXPERIMENTAL PROCEDURES AND ANALYTICAL DATA FOR COMPOUND
OH
HO
HO
LiAlH4
THF, 0 °C to rt, 75 min
CO2Me
TBSO
TBSO
S1 (90%)
6
Diol S1: To a stirred solution of the ester 6 (2.73 g, 8.69 mmol, 1 equiv) in THF (42 mL,
4.8 mL/mmol 6) LiAlH4 (989 mg, 26.06 mmol, 3 eq) was carefully added at 0 °C. After being stirred for
75 minutes at ambient temperature, the reaction was carefully diluted at 0 °C by with saturated aqueous
NH4Cl solution. The phases were then separated, the aqueous layer was extracted with CH2Cl2 (5×), the
combined organic phases were dried (MgSO4) and concentrated at reduced pressure. After purification
by chromatography (cyclohexane/ethyl acetate 10/1 to 2/1), the diol S1 (2.25 g, 7.82 mmol, 90%) was
1
obtained as a white solid (mp: 57 °C): Rf 0.56 (cyclohexane/ethyl acetate 1/1); H NMR (400 MHz,
3
3
CDCl3) δ 0.00 (s, 3H), 0.05 (s, 3H), 0.86 (s, 9H), 1.08 (d, J = 7.0 Hz, 3H), 1.29 (dd, J = 9.7 Hz,
3
2
2J = 13.9 Hz, 1H), 1.63 (s, br, 2OH), 1.71−1.83 (m, 1H), 2.13 (dd, J = 9.0 Hz, J = 13.9 Hz, 1H), 2.20
3
2
2
(dd, J1 = 3J2 = 9.2 Hz, 1H), 3.43 (dAB, J = 11.0 Hz, 1H), 3.53 (dAB, J = 11.0 Hz, 1H), 3.70 (dd,
2
3
2
3
3J1 = 3J2 = 8.8 Hz, 1H), 5.17 (dd, J = 1.5 Hz, J = 17.3 Hz, 1H), 5.24 (dd, J = 1.5 Hz, J = 10.3 Hz,
3
3
3
1H), 5.87 (ddd, J1 = 9.2 Hz, J2 = 10.3 Hz, J3 = 17.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ −4.0
(CH3), −3.4 (CH3), 18.1 (C), 18.5 (CH3), 26.0 (3 × CH3), 39.9 (CH), 41.7 (CH2), 60.1 (CH), 70.3 (CH2),
78.9 (C), 83.1 (CH), 119.5 (CH2), 136.9 (CH); IR (film on KBr) ν 3310, 2955, 2930, 2860, 1125, 1045,
775 cm−1; Anal. Calcd for C15H30SiO3: C, 62.89; H, 10.55. Found: C, 62.8; H, 10.7; [α]25 +16.6 (c
D
0.308, CHCl3).
SI-9

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
NaH
TBAI (cat.)
PMBCl
THF, DMSO, 0 °C to rt,13 h
OH
OPMB
HO
HO
TBSO
TBSO
S2 (98%)
S1
PMB ether S2: To a solution of the diol S1 (729 mg, 2.562 mmol, 1 equiv) in THF (13 mL,
5 mL/mmol S1) and DMSO (6.5 mL, 2.5 mL/mmol S1) NaH (257 mg, 60% dispersion in mineral oil,
6.415 mmol, 2.5 equiv), TBAI (48 mg, 0.13 mmol, 0.05 equiv) and PMBCl (0.35 mL, 2.57 mmol,
1 equiv) were added at 0 °C. The reaction mixture was stirred for 13 hours at ambient temperature and
subsequently diluted with saturated aqueous NH4Cl solution. The phases were separated and the
aqueous layer was extracted with CH2Cl2 (3×). The combined organic phases were dried (MgSO4) and
concentrated at reduced pressure. Purification by chromatography (cyclohexane/ethyl acetate 100/1 to
50/1) provided the PMB ether S2 (1027 mg, 2.526 mmol, 98%) as a light yellow oil: Rf 0.52
1
(cyclohexane/ethyl acetate 5/1); H NMR (400 MHz, CDCl3) δ 0.00 (s, 3H), 0.04 (s, 3H), 0.86 (s, 9H),
3
3
3
1.06 (d, J = 6.5 Hz, 3H), 1.34 (dd, J1 = 9.0 Hz, J2 = 13.6 Hz, 1H), 1.68−1.80 (m, 1H), 2.13 (dd,
3
3
2
3J1 = 9.0 Hz, J2 = 13.6 Hz, 1H), 2.21 (dd, J1 = 3J2 = 9.2 Hz, 1H), 2.28 (s, 1H), 3.30 (dAB, J = 9.0 Hz,
3
2H), 3.70 (dd, J1 = 3J2 = 8.8 Hz, 1H), 3.81 (s, 3H), 4.47 (dAB, 2J = 11.5 Hz, 2H), 5.08 (dd, 2J = 1.9 Hz,
2
3
3
3J = 17.3 Hz, 1H), 5.17 (dd, J = 1.9 Hz, J = 10.5 Hz, 1H), 5.83 (ddd, J1 = 9.5 Hz, 3J2 = 10.5 Hz,
3
3
13
3J3 = 17.3 Hz, 1H), 6.88 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H); C NMR (101 MHz, CDCl3) δ
−4.0 (CH3), −3.4 (CH3), 18.1 (C), 18.6 (CH3), 26.0 (3 × CH3), 39.9 (CH), 42.9 (CH2), 55.3 (CH3), 59.9
(CH), 73.2 (CH2), 77.1 (CH2), 78.2 (C), 83.2 (CH), 113.8 (2 × CH), 118.8 (CH2), 129.3 (2 × CH), 130.1
(C), 136.6 (CH), 159.3 (C); IR (film on KBr) ν 3480, 2955, 2930, 2855, 1615, 1515, 1465, 1250, 1115,
875, 835, 775 cm−1; Anal. Calcd for C23H38SiO4: C, 67.94; H, 9.42. Found: C, 67.96; H, 9.43; [α]25
D
+18.6 (c 1.18, CHCl3).
SI-10

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
TBSOTf
2,6-lutidine
CH2Cl2, rt,13 h
OPMB
OPMB
HO
TBSO
TBSO
TBSO
S3 (88%)
S2
Bis(silyl) ether S3: To a solution of the alcohol S2 (344 mg, 0.846 mmol, 1 equiv) in CH2Cl2 (5 mL,
6 mL/mmol S2) 2,6-lutidine (0.42 mL, 3.618 mmol, 4.3 equiv) and TBSOTf (0.42 mL, 1.827 mmol,
2.2 equiv) were added. The reaction mixture was stirred for 13 hours at ambient temperature and then
diluted with saturated aqueous NH4Cl solution. The phases were separated and the aqueous layer was
extracted with CH2Cl2 (3×). The combined organic phases were dried (MgSO4) and concentrated at
reduced pressure. Purification by chromatography (cyclohexane to cyclohexane/ethyl acetate 100/1)
afforded the bis(silyl) ether S3 (388 mg, 0.745 mmol, 88%) as a light yellow oil: Rf 0.71
(cyclohexane/ethyl acetate 10/1); 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 6H), 0.03 (s, 3H), 0.06 (s, 3H),
3
3
3
0.86 (s, 18H), 1.06 (d, J = 6.5 Hz, 3H), 1.29 (dd, J1 = 8.5 Hz, J2 = 14.1 Hz, 1H), 1.71−1.83 (m, 1H),
2
3
2.23−2.34 (m, 2H), 3.22 (dAB, J = 8.8 Hz, 2H), 3.74 (dd, J1 = 3J2 = 9.0 Hz, 1H), 3.81 (s, 3H), 4.31
2
2
3
2
3
(dAB, J = 11.5 Hz, 2H), 4.97 (dd, J = 2.0 Hz, J = 17.6 Hz, 1H), 5.06 (dd, J = 2.0 Hz, J = 10.0 Hz,
3
3
3
3
1H), 5.82 (ddd, J1 = 7.5 Hz, J2 = 10.0 Hz, J3 = 17.6 Hz, 1H), 6.88 (d, J = 8.5 Hz, 2H), 7.24 (d,
13
3J = 8.5 Hz, 2H); C NMR (101 MHz, CDCl3) δ −4.0 (CH3), −3.3 (CH3), −2.4 (CH3), −2.4 (CH3), 18.2
(C), 18.6 (C), 19.2 (CH3), 26.1 (6 × CH3), 39.8 (CH), 42.6 (CH2), 55.4 (CH3), 60.5 (CH), 72.9 (CH2),
75.0 (CH2), 82.0 (C), 83.2 (CH), 113.7 (2 × CH), 117.8 (CH2), 129.2 (2 × CH), 130.6 (C), 137.4 (CH),
159.1 (C); IR (film on KBr) ν 2955, 2930, 2895, 2855, 1615, 1515, 1470, 1465, 1250, 1120, 1045, 835,
775 cm−1; Anal. Calcd for C29H52Si2O4: C, 66.87; H, 10.06; Found: C, 66.89; H, 9.72; [α]25 +4.2 (c
D
0.94, CHCl3).
SI-11

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
O3, Sudan Red B
CH2Cl2, MeOH, −78 °C
OPMB
OPMB
O
TBSO
TBSO
then PPh3
−78 °C to rt, over night
TBSO
TBSO
11 (99%)
S3
Aldehyde 11: To a solution of the alkene S3 (354 mg, 0.679 mmol, 1 equiv) in CH2Cl2 (4 mL,
6 mL/mmol S3) and methanol (2 mL, 3 mL/mmol S3) was added a catalytic amount of Sudan Red B.
The raspberry red solution was cooled to −78 °C and an ozone/oxygen mixture was passed through the
solution until the red color disappeared. The flask was then purged with argon for five minutes and PPh3
(552 mg, 2.104 mmol, 3.1 equiv) was subsequently added; the solution was then allowed to warm to
room temperature over night. Removal of the solvents at reduced pressure deliver the crude product
which was purified by vhromatography (cyclohexane to cyclohexane/ethyl acetate 100/1) to afford the
aldehyde 11 (355 mg, 0.678 mmol, 99%) as a clear oil: Rf 0.52 (cyclohexane/ethyl acetate 5/1);
1H NMR (400 MHz, CDCl3) δ −0.01 (s, 3H), 0.01 (s, 3H), 0.04 (s, 3H), 0.08 (s, 3H), 0.81 (s, 9H),
3
3
3
0.84 (s, 9H), 1.05 (d, J = 6.5 Hz, 3H), 1.32 (dd, J1 = 10.8 Hz, J2 = 13.1 Hz, 1H), 1.69−1.81 (m, 1H),
3
3
3
3
2.16 (dd, J1 = 8.3 Hz, J2 = 13.3 Hz, 1H), 2.65 (dd, J1 = 2.5 Hz, J2 = 8.0 Hz, 1H), 3.43 (dAB,
2J = 9.5 Hz, 2H), 3.81 (s, 3H), 4.24 (dd, 3J1 = 3J2 = 8.3 Hz, 1H), 4.48 (s, 2H), 6.88 (d, 3J = 8.5 Hz, 2H),
3
3
13
7.26 (d, J = 8.5 Hz, 2H), 9.72 (d, J = 2.5 Hz, 1H); C NMR (101 MHz, CDCl3) δ −4.4 (CH3), −4.3
(CH3), −2.7 (CH3), −2.5 (CH3), 17.8 (CH3), 18.0 (C), 18.3 (C), 25.8 (3 × CH3), 25.9 (3 × CH3), 40.3
(CH), 44.0 (CH2), 55.3 (CH3), 66.7 (CH), 73.0 (CH2), 76.7 (CH2), 77.6 (CH), 83.1 (C), 113.8 (2 × CH),
129.3 (2 × CH), 130.1 (C), 159.2 (C), 202.7 (C); IR (film on KBr) ν 2960, 2860, 1465, 1380, 1255,
1115, 1065, 885, 775 cm−1; Anal. Calcd for C28H50Si2O5: C, 64.32; H, 9.64; Found: C, 64.56; H, 9.67;
[α]25D +36.6 (c 1.28, CHCl3).
SI-12

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
1) [Ph3PCH2Cl]Cl
n-BuLi
THF, 0 °C, 2 h
then 11, rt, 45 min
2) LDA
THF, −78 °C, 5 min
then 0 °C, 5 min
OPMB
O
OPMB
TBSO
TBSO
TBSO
TBSO
S4 (85%)
11
Alkyne S4: n-BuLi (0.79 mL, 2.2 M in n-hexane, 1.738 mmol, 3.1 equiv) was added to a solution of
[Ph3PCH2Cl]Cl (775 mg, 2.231 mmol, 4 equiv) in THF (8 mL, 14.4 mL/mmol 11) at 0 °C and
subsequently stirred for 2 h at 0 °C. A solution of the aldehyde 11 (290 mg, 0.555 mmol, 1 equiv) in
THF (4 mL, 7.2 mL/mmol 11) was then added at 0 °C, stirred for 45 minutes at room temperature and
then diluted with saturated aqueous NH4Cl solution and CH2Cl2. The phases were separated, and the
aqueous layer was extracted with CH2Cl2 (3×).The combined organic phases were dried (MgSO4) and
concentrated under reduced pressure. The remaining solid was dissolved in CH2Cl2 (~1 mL) and
cyclohexane (~50 mL), filtered through a plug of Celite and the filtrate was concentrated under reduced
pressure. This procedure was repeated two times. Chromatographic purification (cyclohexane to
cyclohexane/ethyl acetate 100/1) afforded the vinyl chloride as light yellow oil: Rf 0.65
(cyclohexane/ethyl acetate 10/1).
A freshly prepared LDA solution [i-Pr2NH (0.74 mL, 5.265 mmol, 9.5 equiv) and n-BuLi (2.3 mL,
2.2 M in n-hexane, 5.06 mmol, 9.1 equiv) in THF for 20 minutes at 0 °C] was added at −78 °C to a
solution of the vinyl chloride in THF (3 mL, 5.4 mL/mmol 11). After stirring for five minutes at −78 °C
and for five minutes at 0 °C, the reaction mixture was diluted by the addition of saturated aqueous
NH4Cl solution. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (3×). The
combined organic phases were dried (MgSO4) and concentrated under reduced pressure.
Chromatographic purification (cyclohexane to cyclohexane/ethyl acetate 100/1) delivered the alkyne S4
1
(246 mg, 0.474 mmol, 85%) as a light yellow oil: Rf 0.63 (cyclohexane/ethyl acetate 10/1); H NMR
SI-13

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
(400 MHz, CDCl3) δ 0.06 (s, 3H), 0.07 (s, 3H), 0.10 (s, 3H), 0.15 (s, 3H), 0.88 (s, 9H), 0.90 (s, 9H),
3
3
3
1.05 (d, J = 6.5 Hz, 3H), 1.28 (dd, J1 = 8.0 Hz, J2 = 13.6 Hz, 1H), 1.70−1.81 (m, 1H), 2.01 (d,
3
3
4
3
4J = 2.0 Hz, 1H), 2.29 (dd, J1 = 10.5 Hz, J2 = 13.6 Hz, 1H), 2.63 (dd, J = 2.0 Hz, J = 9.3 Hz, 1H),
3.36 (dAB, 2J = 8.8 Hz, 2H), 3.81 (s, 3H), 3.90 (dd, 3J1 = 3J2 = 8.8 Hz, 1H), 4.45 (dAB, 2J = 11.5 Hz, 2H),
3
3
13
6.88 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H); C NMR (101 MHz, CDCl3) δ −4.3 (CH3), −3.5
(CH3), −2.4 (CH3), −2.2 (CH3), 18.1 (C), 18.6 (C), 19.2 (CH3), 26.0 (3 × CH3), 26.1 (3 × CH3), 39.7
(CH), 42.2 (CH2), 48.1 (CH), 55.3 (CH3), 71.5 (CH2), 73.0 (CH2), 74.3 (C), 81.3 (C), 83.8 (CH), 83.9
(CH), 113.8 (2 × CH), 129.2 (2 × CH), 130.4 (C), 159.2 (C); IR (film on KBr) ν 3310, 2955, 2930,
2855, 1615, 1515, 1250, 1140, 1115, 835, 775 cm−1; Anal. Calcd for C29H50Si2O4, 67.13; H, 9.71;
Found: C, 67.2; H, 10.0; [α]25D +10.7 (c 0.608, CHCl3).
n-BuLi
OPMB
THF, −78 °C, 30 min
then MeI
OPMB
TBSO
TBSO
−78 °C to rt, 16 h
TBSO
TBSO
S5 (97%)
S4
Alkyne S5: n-BuLi (0.94 mL, 1.9 M in n-hexane, 1.786 mmol, 2.8 equiv) was added at −78 °C to a
solution of the alkyne S4 (326 mg, 0.629 mmol, 1 equiv) in THF (7 mL, 11 mL/mmol S4). The reaction
mixture was stirred for 30 minutes at −78 °C, and MeI (0.56 mL, 8.993 mmol, 14.3 equiv) was
subsequently added at −78 °C. While warming to room temperature, the solution was stirred for
16 hours. After dilution with saturated aqueous NH4Cl solution, the phases were separated and the
aqueous layer was extracted with CH2Cl2 (3×). The combined organic phases were dried (MgSO4) and
concentrated under reduced pressure. Chromatography (cyclohexane to cyclohexane/ethyl acetate
100/1) provided the alkyne S5 (326 mg, 0.612 mmol, 97%) as a light yellow oil: Rf 0.48
(cyclohexane/ethyl acetate 20/1); 1H NMR (400 MHz, CDCl3) δ 0.06 (s, 6H), 0.10 (s, 3H), 0.14 (s, 3H),
SI-14

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
3
3
3
0.88 (s, 9H), 0.90 (s, 9H), 1.04 (d, J = 7.0 Hz, 3H), 1.25 (dd, J1 = 8.0 Hz, J2 = 13.6 Hz, 1H),
5
3
3
1.67−1.79 (m, 1H), 1.76 (d, J = 2.0 Hz, 3H), 2.27 (dd, J1 = 10.5 Hz, J2 = 13.6 Hz, 1H), 2.63 (dd,
5J = 2.0 Hz, 3J = 9.5 Hz, 1H), 3.34 (dAB, 2J = 9.0 Hz, 2H), 3.81 (s, 3H), 3.83 (dd, 3J1 = 3J2 = 9.0 Hz, 1H),
2
3
3
13
4.45 (dAB, J = 11.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H); C NMR (101 MHz,
CDCl3) δ −4.4 (CH3), −3.8 (CH3), −2.4 (CH3), −2.3 (CH3), 3.8 (CH3), 18.2 (C), 18.5 (C), 19.2 (CH3),
25.9 (3 × CH3), 26.0 (3 × CH3), 39.4 (CH), 42.3 (CH2), 48.3 (CH), 55.3 (CH3), 73.0 (CH2), 74.5 (CH2),
78.6 (C), 78.7 (C), 81.4 (C), 84.2 (CH), 113.7 (2 × CH), 129.2 (2 × CH), 130.6 (C), 159.1 (C); IR (film
on KBr) ν 2955, 2930, 2855, 1615, 1515, 1385, 1250, 1135, 1110, 835, 775 cm−1; Anal. Calcd for
C30H52Si2O4, 67.61; H, 9.84; Found: C, 67.7; H, 9.7; [α]25D +16.6 (c 1.32, CHCl3).
Cp2Zr(H)Cl
THF, 60 °C, 30 min
then I2
THF, CH2Cl2, 0 °C to rt, 10 min
OPMB
OPMB
TBSO
TBSO
TBSO
TBSO
5 (56%)
I
S5
Vinyl iodide 5: Cp2Zr(H)Cl (301 mg, 1.11 mmol, 4.5 equiv) was added at room temperature to a
solution of the alkyne S5 (131 mg, 0.246 mmol, 1 equiv) in THF (5.5 mL, 22.4 mL/mmol S5). After the
gas evolution had ceased, the solution was stirred for 30 minutes at 60 °C and a solution of iodine
(saturated) in CH2Cl2 (5 mL, 20 mL/mmol S5) was subsequently added to the brownish-yellow reaction
mixture at 0 °C. A change of color from brown to yellow to dark purple was observed. After stirring for
ten minutes at 0 °C at room temperature, the reaction mixture was diluted with saturated aqueous
Na2S2O3 solution and with water. The phases were separated, and the aqueous layer was extracted with
CH2Cl2 (3×). The combined organic phases were dried (MgSO4) and concentrated under reduced
pressure. Chromatography (cyclohexane to cyclohexane/ethyl acetate 100/1) afforded the vinyl iodide 5
1
(91 mg, 0.138 mmol, 56%) as a light yellow oil: Rf 0.56 (cyclohexane/ethyl acetate 10/1); H NMR
(400 MHz, CDCl3) δ 0.03 (s, 3H), 0.04 (s, 3H), 0.05 (s, 3H), 0.06 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H),
SI-15

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
3
2
3
1.04 (d, J = 7.0 Hz, 3H), 1.27 (dd, J = 13.5 Hz, J = 8.5 Hz, 1H), 1.74−1.84 (m, 1H), 2.32 (dd,
4
3
3
2J = 3J = 12.0 Hz, 1H), 2.33 (d, J = 1.0 Hz, 3H), 2.64 (dd, J1 = J2 = 10.0 Hz, 1H), 3.20 (dAB,
3
2J = 9.0 Hz, 2H), 3.70 (dd, J1 = 3J2 = 9.0 Hz, 1H), 3.82 (s, 3H), 4.41 (dAB, 2J = 11.5 Hz, 2H), 6.21 (dd,
4
3
3
3J = 10.5 Hz, J = 1.0 Hz, 1H), 6.88 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H); 13C NMR
(101 MHz, CDCl3) δ −4.2 (CH3), −3.8 (CH3), −2.2 (CH3), −2.2 (CH3), 18.0 (C), 18.5 (C), 19.1 (CH3),
25.9 (3 × CH3), 26.0 (3 × CH3), 28.2 (CH3), 39.8 (CH), 42.6 (CH2), 55.3 (CH3), 56.2 (CH), 73.0 (CH2),
74.5 (CH2), 81.9 (C), 83.2 (CH), 96.3 (C), 113.8 (2 × CH), 129.3 (2 × CH), 130.3 (C), 140.9 (CH),
159.2 (C); IR (film on KBr) ν 2955, 2930, 2895, 2855, 1615, 1515, 1470, 1385, 1250, 1115, 1055, 835,
775 cm−1; Anal. Calcd for C30H53Si2O4I ([M]+): 660.2522; Found: 660.2498.
1
Allene 16. Characteristics of the allene moiety are highlighted in blue. H-NMR (400 MHz, CDCl3,
δ): 0.02−0.07 (4 × s, 4 × CH3-TBS), 0.86 (s, 3 × CH3-TBS), 0.88 (s, 3 × CH3-TBS), 1.05 (d, 3J = 6.7 Hz,
16-CH3), 1.27−1.30 (m, 1-CH2, 1HRe), 1.74−1.82 (m, 2-CH), 2.29−2.36 (m, 1-CH2, 1HRe + 4-CH), 3.27
2
(d, J = 9.0 Hz, 14-CH2 or OCH2Ar, 1H), 3.30 (d, 2J = 9.0 Hz, 14-CH2 or OCH2Ar, 1H), 3.66−3.70 (m,
3-CH), 3.81 (s, OCH3), 4.38 (d, 2J = 11.7 Hz, 14-CH2 or OCH2Ar, 1H), 4.47 (d, 2J = 11.7 Hz, 14-CH2 or
OCH2Ar, 1H), 4.56−4.64 (m, 17-CH2), 5.12−5.16 (m, 5-CH), 6.87 (d, 3J = 8.3 Hz, 2 × CH-PMB), 7.24
3
(d, J = 8.3 Hz, 2 × CH-PMB); 13C-NMR (101 MHz, CDCl3, δ): −4.0 (CH3), −3.9 (CH3), −2.4
(2 × CH3), 18.1 (C), 18.6 (C), 19.2 (CH3), 26.0 (3 × CH3), 26.1 (3 × CH3), 39.6 (CH), 42.3 (CH2), 55.3
(CH or CH3), 55.9 (CH or CH3), 73.0, 73.6, 75.1, 81.8, 83.4, 88.6, 113.7 (2 × CH), 129.2 (2 × CH),
130.6 (C), 159.1 (C), 210.1 (C); IR (KBr-Film, δ): 2955, 2929, 2895, 2856, 1956, 1614, 1514, 1385,
1250, 1118, 1041, 835, 775.
SI-16

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
1) LDA
allyl bromide
THF, −78 °C, 1 h
2) KOH
O
O
MeOH, H2O, reflux, 40 h
EtO
HO
12
13 (84%)
Carboxylic acid 13:6 n-BuLi (25 mL, 2 M in n-hexane, 50 mmol, 1.1 equiv) was added at −78 °C to a
solution of i-Pr2NH (7 mL, 50 mmol, 1.1 equiv) in THF (16 mL, 0.35 mL/mmol 12). After stirring for
15 min at −78 °C, ester 12 (6 mL, 45 mmol, 1 equiv) in THF (16 mL, 0.35 mL/mmol 12) was added
within 15 minutes and stirring was continued for 1 h. A solution of allyl bromide (4.4 mL, 51 mmol,
1.1 equiv) in THF (16 mL, 0.35 mL/mmol 12) was then added within 15 minutes. After stirring for 1 h
at −78 °C, the reaction mixture was carefully diluted with saturated aqueous NH4Cl solution. The layers
were subsequently separated, and the aqueous phase was extracted with CH2Cl2 (3×). The combined
organic phases were dried (MgSO4) and concentrated under reduced pressure. The crude product was
used without further purification: Rf 0.7 (cyclohexane/ethyl acetate 10/1, staining with KMnO4 reagent)
KOH (15 g, 227 mmol, 5 equiv) was added to a solution of the crude product in methanol (180 mL,
4 mL/mmol 12) and water (90 mL, 2 mL/mmol 12). After stirring for 40 h under reflux, the methanol
was removed under reduced pressure. The residue was acidified with aqueous HCl (1 M) to pH = 1 and
diluted with CH2Cl2. The layers were separated and the aqueous phase was extracted with CH2Cl2 (6×).
The combined organic phases were dried (MgSO4) and concentrated under reduced pressure.
Purification by chromatography (cyclohexane/ethyl acetate 10/1) provided the carboxylic acid 13
(4.84 g, 37.76 mmol, 84%) as a light yellow oil: Rf 0.77 (cyclohexane/ethyl acetate 2/1, staining with
1
3
KMnO4 reagent); H NMR (400 MHz, CDCl3) δ 1.20 (s, 6H), 2.30 (d, J = 7.5 Hz, 2H), 5.06−5.09 (m,
6
a) Pirkle, W. H.; Murray, P. G. J. Chromatogr. 1993, 641, 11−19. b) Rudler, H.; Harris, P.; Parlier, A.; Cantagrel, F.;
Denise, B.; Bellassoued, M.; Vaissermann, J. J. Organometal. Chem. 2001, 624, 186−202.
SI-17

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
3
3
3
13
2H), 5.77 (ddd, J1 = 7.5 Hz, J2 = 9.5 Hz, J3 = 17.1 Hz, 1H), 11.72 (s, br, 1H); C NMR (101 MHz,
CDCl3) δ 24.7 (2 × CH3), 42.3 (C), 44.5 (CH2), 118.3 (CH2), 134.0 (CH), 184.6 (C); IR (film on KBr) ν
3200, 3080, 2980, 2930, 1700, 1640, 1475, 1235, 1180, 920 cm−1.
MeLi
Et2O, −78 °C, 1 h
O
O
reflux, 1 h
HO
13
14 (69%)
Ketone 14:7 Methyllithium (15.4 mL, 1.6 M in Et2O, 24.64 mmol, 2.2 equiv) was added to a cooled
(−78 °C) solution of the carboxylic acid 13 (1.43 g, 11.14 mmol, 1 equiv) in Et2O (50 mL,
4.5 mL/mmol 13). After stirring the reaction mixture for 1 h at −78 °C and, subsequently, at reflux for
1h, water was added at 0 °C. The phases were separated, and the aqueous layer was extracted with Et2O
(3×). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure
(40 °C, 850 mbar). The residue was purified by Kugelrohr distillation (80 °C, 35 mbar)) to deliver the
ketone 14 (963 mg, 7.63 mmol, 69%) as a colorless liquid: Rf 0.72 (cyclohexane/ethyl acetate 5/1);
1H NMR (400 MHz, CDCl3) δ 1.12 (s, 6H), 2.12 (s, 3H), 2.25 (d, 3J = 7.5 Hz, 2H), 5.02−5.06 (m, 2H),
3
3
3
5.67 (ddd, J1 = 7.5 Hz, J2 = 10.4 Hz, J3 = 17.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 24.1
(2 × CH3), 25.4 (CH3), 44.0 (CH2), 47.8 (C), 118.0 (CH2), 134.0 (CH), 213.5 (C); IR (film on KBr) ν
2975, 2935, 1705, 1640, 1470, 1385, 1355, 1135, 915, 735 cm−1.
7 House, H. O.; Chu, C.-Y., Phillips, W. V.; Sayer, T. S. B.; Yau, C.-C. J. Org. Chem. 1977, 42, 1709−1717.
SI-18

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
B(OMe)3
MeLi
THF, −78 °C, 1 h
TMSCl
−78 °C to rt, 12 h
pinacol
THF, Et2O, rt, 3 d
O
I
I
I
B
O
15 (51%)
Iodide 15:8 MeLi (16.6 mL, 1.5 M in Et2O, 24.9 mmol, 1 equiv) was added at −78 °C very carefully
within 20 minutes to a solution of diiodomethane (2 mL, 24.8 mmol, 1 equiv) and B(OMe)3 (2.8 mL,
25.1 mmol, 1 equiv) in THF (30 mL, 1.2 mL/mmol CH2I2). After being stirred for 1 h at −78 °C,
TMSCl (3.2 mL, 25.2 mmol, 1 equiv) was added. The solution was stirred for 12 h while warming to
room temperature. A white solid formed which was dissolved by the addition of pinacol (2.97 g,
25.1 mmol, 1 equiv) in Et2O (5 mL, 0.2 mL/mmol pinacol). The resulting red solution was stirred for 3
d at ambient temperature followed by the addition of water. The phases were separated, the aqueous
layer was extracted with Et2O (3×), the combined organic phases were dried (MgSO4) and concentrated
under reduced pressure (40 °C, 850 mbar to 90 °C, 20 mbar). Chromatographic purification of the
residue (cyclohexane/ethyl acetate 100/1 to 50/1 to 20/1) followed by Kugelrohr distillation (70 °C,
1 mbar) afforded the iodide 15 (3.41 g, 12.73 mmol, 51%) as a light orange, oily liquid: Rf 0.51
(cyclohexane/ethyl acetate 10/1, staining with KMnO4 reagent); 1H NMR (400 MHz, CDCl3) δ 1.23 (s,
13
11
12H), 2.12 (s, 2H); C NMR (101 MHz, CDCl3) δ −23.0 (br, CH2), 24.4 (4 × CH3), 84.1 (2 × C); B-
NMR (96 MHz, CDCl3): δ 31.47 (s); IR (film on KBr) ν 2980, 2930, 1470, 1410, 1325, 1145, 970, 845,
675 cm−1.
8
a) Wuts, P. G. M.; Thompson, P. A. J. Organomet. Chem. 1982, 234, 137−141. b) Mears, R. J.; Whiting, A.
Tetrahedron 1993, 49, 177−186. c) Phillion, D. P.; Neubauer, R.; Andrew, S. S. J. Org. Chem. 1986, 51, 1610−1612.
SI-19

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
LDA, THF, 0 °C
then ketone 14
−78 °C, 1 h
O
O
then iodide 15
O
O
−78 °C to rt, over night
I
B
B
+
O
O
14
15
4b (61%)
Boronic acid ester 4b: n-BuLi (4.75 mL, 2 M in n-hexane, 9.5 mmol, 1.4 equiv) was added to a
solution of i-Pr2NH (1.43 mL, 10.175 mmol, 1.5 equiv) in THF (15 mL, 2.2 mL/mmol 14) at 0 °C. After
stirring for 15 minutes at 0 °C and cooling to −78 °C, a solution of the ketone 14 (863 mg, 6.84 mmol,
1 equiv) in THF (2 mL, 0.3 mL/mmol 14) was added. The iodide 15 (2.02 g, 7.9 mmol, 1.1 equiv) in
THF (1.5 mL, 0.2 mL/mmol 14) was then added and he light yellow solution was stirred over night
while warming to ambient temperature. Saturated aqueous NH4Cl solution was subsequently added, the
layers were separated, and the aqueous phase was extracted with CH2Cl2 (3×). The combined organic
phases were dried (MgSO4) and concentrated under reduced pressure. Purification of the residue by
chromatography (cyclohexane to cyclohexane/ethyl acetate 100/1 to 50/1 to 20/1) provided the boronic
acid ester 4b (1.11 g, 4.17 mmol, 61%) as a pale yellow oil. Rf 0.44 (cyclohexane/ethyl acetate 10/1);
1H NMR (400 MHz, CDCl3) δ 0.83 (t, 3J = 6.8 Hz, 2H), 1.09 (s, 6H), 1.20 (s, 12H), 2.22 (d, 3J = 7.0 Hz,
3
3
3
3
2H), 2.60 (t, J = 6.8 Hz, 2H), 4.97−5.00 (m, 2H), 5.65 (ddd, J1 = 7.0 Hz, J2 = 9.5 Hz, J3 = 17.6 Hz,
1H); 13C NMR (101 MHz, CDCl3) δ 5.2 (br, CH2), 24.4 (2 × CH3), 24.8 (4 × CH3), 32.6 (CH2), 44.3
(CH2), 46.9 (C), 83.0 (2 × C), 117.7 (CH2), 134.4 (CH), 215.8 (C); 11B-NMR (96 MHz, CDCl3): δ 33.96
(s); IR (film on KBr) ν 2975, 2930, 1705, 1640, 1470, 1385, 1315, 1245, 1145, 970, 915 cm−1; Anal.
Calcd for C15H27BO3: C, 67.68; H, 10.22; Found: C, 67.8; H, 10.5.
1) KHF2
MeCN, H2O, rt, 30 min
O
2) n-Bu4NOH•30H2O
O
CH2Cl2, H2O, rt, 5 min
O
B
n-Bu4NF3B
O
4b
4a (70%)
SI-20

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
Trifluoroborate 4a: KHF2 (317 mg, 4.056 mmol, 2.92 equiv) was added to a solution of the boronic
acid ester 4b (368 mg, 1.382 mmol, 1 equiv) in MeCN (8 mL, 6 mL/mmol 4b) and water (1.4 mL,
1 mL/mmol 4b). The reaction mixture was stirred for 30 min at room temperature and decanted
(acetone) to separate insoluble salts. The solvents were removed under reduced pressure. The residue
was dissolved in acetone (~2 mL) and subsequently diluted with cyclohexane (~50 mL). After filtration
the crude product was recrystallized from cyclohexane to afford the potassium trifluoroborate (276 mg,
1.122 mmol, 81%) as white foam: Rf 0.59 (cyclohexane/ethyl acetate 1/2).
The potassium trifluoroborate (276 mg, 1.122 mmol, 1 equiv) was dissolved in a separation funnel in
CH2Cl2 (3 mL, 2.7 mL/mmol 4b). After adding n-Bu4NOH•30H2O (902 mg, 1.128 mmol, 1 equiv) and
water (3 mL, 2.7 mL/mmol 4b), the separation funnel was shaken for 5 min. The layers were separated,
and the aqueous phase was extracted with CH2Cl2 (3×). The combined organic phases were dried
(MgSO4) and concentrated under reduced pressure. After drying (50 °C, 5×10−2 mbar, 2 h) the
trifluoroborate 4a (434 mg, 0.966 mmol, 86%) was obtained as a light yellow oil: Rf 0.51
1
3
(cyclohexane/ethyl acetate 1/2); H NMR (400 MHz, CDCl3) δ 0.34 (qt, J (1H-1H) = 3J (1H-
3
3
19F) = 7.0 Hz, 2H), 0.93 (t, 3J = 7.5 Hz, 12H), 1.02 (s, 6H), 1.36 (tq, J1 = J2 = 7.5 Hz, 8H), 1.57 (tt,
3
3
3
3
3J1 = J2 = 7.5 Hz, 8H), 2.18 (d, J = 7.0 Hz, 2H), 2.43 (t, J = 7.0 Hz, 2H), 3.18 (t, J = 7.5 Hz, 8H),
3
3
3
4.81−4.86 (m, 2H), 5.59 (ddd, J1 = 7.0 Hz, J2 = 9.5 Hz, J3 = 17.1 Hz, 1H); 13C NMR (101 MHz,
CDCl3) δ 13.7 (4 × CH3), 19.7 (4 × CH2), 23.9 (4 × CH2), 24.3 (2 × CH3), 34.2 (CH2), 44.2 (CH2), 47.3
(C), 58.6 (4 × CH2), 117.1 (CH2), 135.0 (CH), 219.5 (C);9 19F-NMR (188 MHz, CDCl3): δ −144.6 (s);
IR (film on KBr) ν 3485, 2965, 2935, 2875, 1695, 1640, 1470, 1385, 1315, 1220, 1050, 1020, 915, 885
cm−1; Anal. Calcd for C25H51BONF3: C, 66.80; H, 11.44; N, 3.12; Found: C, 66.5; H, 11.3; N, 2.8.
9 No resonance for the carbon atom which is connected to the boron atom could be detected.
SI-21

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
OH
O
HO
H2SO4•SiO2
MeOH, rt, 3 h
O
OPMB
OPMB
TBSO
HO
19a
19c (65%)
Triol 19c: H2SO4•SiO2 (27 mg) was added at ambient temperature to a solution of the diene 19a
(153 mg, 0.255 mmol, 1 equiv) in methanol (1.3 mL, 5 mL/mmol 19a). The reaction mixture was stirred
for 3 h at ambient temperature. Saturated aqueous NaHCO3 solution was then added, the phases were
separated, and the aqueous phase was extracted with CH2Cl2 (5×). The combined organic phases were
dried (MgSO4) and concentrated under reduced pressure. Chromatographic purification
(cyclohexane/ethyl acetate 5/1 to 1/1) of the residue afforded the triol 19c (74 mg, 0.166 mmol, 65%) as
a light yellow oil. Triol 19c was obtained as a 1:1 mixture of C9 epimers: Rf 0.27 (cyclohexane/ethyl
1
3
acetate 1/1); H NMR (400 MHz, CDCl3) δ 0.90 (s, 3 + 3H), 0.94 (s, 3 + 3H), 1.12 (d, J = 6.3 Hz,
3
2
3 + 3H), 1.31 (dd, J = 9.5 Hz, J = 13.8 Hz, 1 + 1H), 1.52−1.62 (m, 1 + 1H), 1.64−17.3 (m, 1 + 1H),
3
2
1.69 (s, 3 + 3H), 1.74−1.83 (m, 1 + 1H), 1.88−2.14 (m, 6 + 6H), 2.19 (dd, J = 9.3 Hz, J = 13.3 Hz,
1 + 1H), 2.31−2.39 (m, 1 + 1H), 2.44 (dd, 3J1 = 3J2 = 9.6 Hz, 1 + 1H), 3.06 (d, 3J = 9.0 Hz, 1 + 1H), 3.39
(dAB, 2J = 10.9 Hz, 1 + 1H), 3.46 (dAB, 2J = 10.9 Hz, 1 + 1H), 3.60 (dd, 3J1 = 3J2 = 9.0 Hz, 1 + 1H), 3.80
3
(s, 3 + 3H), 4.50−4.56 (m, 2 + 2H), 5.00−5.05 (m, 2 + 2H), 5.23 (d, J = 10.0 Hz, 1 + 1H), 5.79−5.89
(m, 1 + 1H), 6.88 (d, 3J = 8.5 Hz, 2 + 2H), 7.28 (d, 3J = 8.5 Hz, 2 + 2H); 13C NMR (101 MHz, CDCl3) δ
17.2 (1 + 1CH3), 18.3 (1 + 1CH3), 23.6 (2 + 2CH3), 29.6 (1 + 1CH2), 38.0 (1 + 1CH2), 39.0 (1 + 1CH),
39.1 (1 + 1C), 42.0 (1 + 1CH2), 43.8 (1 + 1CH2), 53.4 (1 + 1CH), 55.4 (1 + 1CH3), 70.1 (1 + 1CH2),
74.8 (1 + 1CH2), 79.5 (1 + 1C), 83.5 (1 + 1CH), 86.7 (1 + 1CH), 113.8 (2 + 2CH), 117.2 (1 + 1CH2),
121.1 (1 + 1CH), 129.0 (2 + 2CH), 131.3 (1 + 1C), 135.5 (1 + 1CH), 142.1 (1 + 1C), 159.1 (1 + 1C); IR
(film on KBr) ν 3425, 2955, 2930, 2870, 1615, 1515, 1465, 1250, 1065, 1035 cm−1; Anal. Calcd for
C27H42O5: C, 72.61; H, 9.48; Found: C, 72.3; H, 9.4.
SI-22

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
TEMPO
PhI(OAc)2
CH2Cl2, rt, 1 h
OH
HO
O
OPMB
OPMB
TBSO
TBSO
19b
22 (52%)
Ketone 22: TEMPO (1 mg, 0.006 mmol, 0.6 equiv) and PhI(OAc)2 (19 mg, 0.059, 5.5 equiv) were
added at ambient temperature to a solution of the diol 19b (6 mg, 0.011 mmol, 1 equiv) in CH2Cl2
(0.6 mL, 55 mL/mmol 19b). After stirring for 1 h at room temperature, the reaction mixture was diluted
with cyclohexane. After concentration under reduced pressure and chromatographic purification
(cyclohexane/ethyl acetate 10/1) of the crude product, the ketone 22 (3 mg, 0.006 mmol, 52%) was
obtained as a light yellow oil. Ketone 22 was obtained as a 1:1 mixture of C9 epimers: Rf 0.79
(cyclohexane/ethyl acetate 2/1); 1H NMR (400 MHz, CDCl3) δ −0.01 (s, 3 + 3H), 0.08 (s, 3 + 3H), 0.88
3
(s, 9 + 9H + 3 + 3H), 0.93 (s, 3 + 3H), 1.15 (d, J = 6.3 Hz, 3 + 3H), 1.55−1.72 (m, 2 + 2H), 1.65 (s,
3
2
3 + 3H), 1.82 (dd, J = 12.0 Hz, J = 18.6 Hz, 1 + 1H), 2.01−2.19 (m, 4 + 4H), 2.30−2.37 (m, 1 + 1H),
2.59 (dd, 3J = 8.1 Hz, 2J = 18.6 Hz, 1 + 1H), 3.04−3.12 (m, 2 + 2H), 3.60 (dd, 3J1 = 8.9 Hz,
3J2 = 17.4 Hz, 1 + 1H), 3.80 (s, 3 + 3H), 4.51−4.56 (m, 2 + 2H), 4.93 (d, 3J = 8.2 Hz, 1 + 1H), 4.99−5.04
3
3
(m, 2 + 2H), 5.79−5.90 (m, 1 + 1H), 6.87 (d, J = 8.5 Hz, 2 + 2H), 7.28 (d, J = 8.5 Hz, 2 + 2H);
13C NMR (101 MHz, CDCl3) δ −4.3 (1 + 1CH3), −3.9 (1 + 1CH3), 17.2 (1 + 1CH3), 17.6 (1 + 1CH3),
18.0 (1 + 1C), 23.6 (2 + 2CH3), 25.9 (3 + 3CH3), 29.5 (1 + 1CH2), 37.7 (1 + 1C), 38.4 (1 + 1CH), 39.1
(1 + 1CH2), 43.8 (1 + 1CH2), 45.1 (1 + 1CH2), 55.3 (1 + 1CH3), 59.5 (1 + 1CH), 74.6 (1 + 1CH2), 82.6
(1 + 1CH), 86.8 (1 + 1CH), 113.7 (2 + 2CH), 117.0 (1 + 1CH2), 119.6 (1 + 1CH), 129.1 (2 + 2CH),
131.4 (1 + 1C), 135.6 (1 + 1CH), 141.8 (1 + 1C), 159.0 (1 + 1C), 215.0 (1 + 1C); IR (film on KBr) ν
2955, 2930, 2855, 1745, 1615, 1515, 1465, 1385, 1360, 1250, 1120, 1100, 1040, 865, 835, 775 cm−1;
HRMS (ESI) Calcd for C32H53O4Si ([M+H]+): 529.3708; Found: 529.3704.
SI-23

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
O
O
HO
H2C=C(Me)MgBr
THF, 0 °C, 30 min
OH
OPMB
OPMB
TBSO
TBSO
20
23 (68%)
α-Hydroxyketone 23: H2C=C(Me)MgBr (0.78 mL, 0.5 M in THF, 0.39 mmol, 2.5 equiv) was added
to a cooled (0 °C) solution of the aldehyde 20 (87 mg, 0.156 mmol, 1 equiv) in THF (1 mL,
6.4 mL/mmol 20). The solution was stirred for 30 min at 0 °C. Saturated aqueous NH4Cl solution was
added followed by the separation of the phases and the extraction of the aqueous phase with CH2Cl2
(4×). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure.
Purification by chromatography (cyclohexane/ethyl acetate 20/1) afforded the α-hydroxyketone 23
(59 mg, 0.106 mmol, 68%) as a light yellow oil. α-Hydroxyketone 23 was obtained as a mixture of
1
C9/C14 epimers: Rf 0.63 (cyclohexane/ethyl acetate 2/1); H NMR (400 MHz, CDCl3) δ 0.10 (s, 3H),
3
0.15 (s, 3H), 0.87 (s, 3H), 0.91 (s, 3H), 0.93 (s, 9H), 0.95 (d, J = 8.0 Hz, 3H), 1.42 (s, 1H), 1.45−1.63
(m, 2H), 1.66 (s, 3H), 1.92−2.02 (m, 2H), 2.09−2.14 (m, 1H), 2.19−2.27 (m, 2H), 2.32−2.43 (m, 1H),
2.95−3.02 (m, 2H), 3.21−3.33 (m, 1H), 3.41−3.49 (m, 1H), 3.77−3.81 (m, 3H), 4.48−4.51 (m, 2H),
4.77−4.81 (m, 2H), 4.98−5.04 (m, 2H), 5.77−5.88 (m, 1H), 6.86−6.89 (m, 2H), 7.25−7.28 (m, 2H);
13C NMR (101 MHz, CDCl3) δ −4.8 (CH3), −4.5 (CH3), 16.5 (CH3), 18.0 (C), 19.0 (CH3), 23.6
(2 × CH3), 25.8 (3 × CH3), 29.4 (CH2), 37.9 (CH2), 39.1 (C), 40.3 (CH), 41.5 (CH2), 43.8 (CH2), 51.1
(CH), 55.4 (CH3), 73.5 (CH), 74.5 (CH2), 76.1 (CH), 86.6 (CH), 113.8 (2 × CH), 117.0 (CH2), 119.7
(CH), 128.9 (2 × CH), 131.4 (C), 135.5 (CH), 139.5 (C), 159.1 (C), 212.1 (C); IR (film on KBr) ν 2955,
2930, 2855, 1715, 1515, 1470, 1465, 1250, 1075, 1040, 835, 775 cm−1; HRMS (ESI) Calcd for
C33H55O5Si ([M+H]+): 559.3813; Found: 559.3810.
SI-24

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
PPh3
BzOH
DIAD
THF, 0 °C, 2.5 h
O
HO
O
HO
H
H
O
O
HO
BzO
30 (87%)
2
3-O-Benzoylcharaciol (30): PPh3 (55 mg, 0.21 mmol, 2 equiv), benzoic acid (25 mg, 0.205 mmol,
2 equiv) and DIAD (0.045 mL, 0.213 mmol, 2 equiv) were added at 0 °C to a solution of 3-epi-
characiol (2) (34 mg, 0.102 mmol, 1 equiv) in THF (2 mL, 20 mL/mmol 2). After being stirred for 2.5 h
at 0 °C, the reaction mixture was diluted with saturated aqueous NH4Cl solution. The phases were
separated and the aqueous layer was extracted with CH2Cl2 (4×). The combined organic phases were
dried (MgSO4), concentrated under reduced pressure and the residue was purified by chromatography
(cyclohexane/ethyl acetate 20/1 to 10/1) to deliver 3-O-benzoylcharaciol (30) (39 mg, 0.089 mmol,
1
87%) as a white solid (mp: 78 °C): Rf 0.54 (cyclohexane/ethyl acetate 2/1); the H NMR peak
1
assignments were deduced from H-1H COSY spectra and are listed on the basis of the jatrophane
1
3
numbering; H NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.8 Hz, 16-CH3), 1.11 (s, 18- or 19-CH3), 1.19
3
(s, 18- or 19-CH3), 1.40 (s, 17-CH3), 1.58 (dd, J = 12.1 Hz, 2J = 13.6 Hz, 1-CH2, 1HRe), 1.74 (s,
20-CH3), 1.96−2.08 (m, 8-CH2), 2.22−2.30 (m, 2-CH), 2.31 (s, 1OH), 2.39−2.51 (m, 11-CH2), 2.61 (dd,
3J1 = 3.8 Hz, 3J2 = 10.3 Hz, 4-CH), 2.76−2.82 (m, 7-CH2, 1H), 2.88−2.95 (m, 7-CH2, 1H), 3.27 (dd,
3
3
3J = 8.3 Hz, 2J = 13.6 Hz, 1-CH2, 1HSi), 5.36 (d, J = 10.3 Hz, 5-CH), 5.53 (dd, J1 = 3J2 = 3.8 Hz,
3
3
3-CH), 7.05 (dd, J1 = 3J2 = 5.9 Hz, 12-CH), 7.51 (dd, J1 = 3J2 = 7.7 Hz, 2 × CHar), 7.62 (dd,
3
13
3J1 = 3J2 = 7.7 Hz, CHar), 8.03 (d, J1 = 7.7 Hz, 2 × CHar); C NMR (101 MHz, CDCl3) δ 12.6 (CH3),
14.4 (CH3), 16.4 (CH3), 24.1 (CH3), 25.1 (CH3), 33.9 (CH2), 35.1 (CH2), 38.8 (CH), 40.4 (CH2), 48.1 (C
or CH2), 48.4 (C or CH2), 52.8 (CH), 82.9 (CH), 90.6 (C), 120.4 (CH), 128.7 (2 × CH), 129.6 (2 × CH),
130.0 (C), 133.3 (CH), 135.8 (C), 138.9 (C), 144.5 (CH), 166.1 (C), 201.0 (C), 215.2 (C); IR (film on
SI-25

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
KBr) ν 3485, 2970, 2930, 1705, 1650, 1450, 1385, 1275, 1115, 1010, 715 cm−1; HRMS (ESI) Calcd for
C27H35O5 ([M+H]+): 439.2479; Found: 439.2476; [α]25D +162.4 (c 1.55, CHCl3).
Bz2O
TMSOTf (cat.)
PhMe, rt, 80 min
O
HO
O
BzO
H
H
O
O
BzO
BzO
30
31 (62%)
3-O-15-O-Dibenzoylcharaciol (31): Benzoic anhydride (14 mg, 0.062 mmol, 2.9 eq) and TMSOTf
(one drop) were added at ambient temperature to a solution of 3-O-benzoylcharaciol (30) (9 mg,
0.021 mmol, 1 equiv) in toluene (1.4 mL, 67 mL/mmol 30); the initially colorless solution changed
color to pink. After being stirred for 80 min at ambient temperature, the reaction mixture was diluted
with methanol and saturated aqueous NH4Cl solution. The phases were separated, and the aqueous layer
was extracted with CH2Cl2 (4×). The combined organic phases were dried (MgSO4) and concentrated
under reduced pressure. Chromatographic purification (cyclohexane/ethyl acetate 20/1 to 10/1) of the
residue provided 3-O-15-O-dibenzoylcharaciol (31) (7 mg, 0.013 mmol, 62%) as a clear oil: Rf 0.57
1
1
(cyclohexane/ethyl acetate 2/1). The H NMR peak assignments were deduced from H–1H COSY
1
spectra and are listed on the basis of the jatrophane numbering: H NMR (400 MHz, CDCl3) δ 0.41 (s,
3
18- or 19-CH3), 0.97 (d, J = 6.5 Hz, 16-CH3), 1.06 (s, 18- or 19-CH3), 1.43 (s, 17-CH3), 1.74 (s,
3
20-CH3), 1.77 (dd, J = 12.3 Hz, 2J = 13.8 Hz, 1-CH2, 1HRe), 1.98−2.04 (m, 8-CH2), 2.21 (dd,
3J = 6.8 Hz, 2J = 18.8 Hz, 11-CH2, 1H), 2.30−2.44 (m, 2-CH + 11-CH2, 1H), 2.81 (dd,
3
2
3J1 = 3.9 Hz, 3J2 = 10.4 Hz, 4-CH), 2.88−2.91 (m, 7-CH2), 3.57 (dd, J = 8.3 Hz, J = 13.8 Hz, 1-CH2,
1HSi), 5.56 (dd, 3J1 = 3J2 = 3.4 Hz, 3-CH), 5.67 (d, 3J = 10.4 Hz, 5-CH), 6.51 (dd, 3J1 = 3J2 = 5.1 Hz, 12-
CH), 7.28 (dd, 3J1 = 3J2 = 7.8 Hz, 2 × CHar), 7.52−7.56 (m, 3 × CHar), 7.63−7.67 (m, 1 × CHar), 8.03 (d,
3J = 7.5 Hz, 2 × CHar), 8.18 (d, 3J = 7.5 Hz, 2 × CHar); 13C NMR (101 MHz, CDCl3) δ 12.2 (CH3), 14.0
(CH3), 16.4 (CH3), 23.0 (CH3), 25.1 (CH3), 27.0 (CH2), 35.2 (CH2), 39.2 (CH), 40.0 (CH2), 46.8 (CH2),
SI-26

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
47.6 (C), 52.4 (CH), 81.9 (CH), 94.1 (C), 120.6 (CH), 128.5 (2 × CH), 128.6 (2 × CH), 129.6 (C), 129.9
(2 × CH), 130.0 (C), 130.5 (2 × CH), 133.1 (CH), 133.7 (CH), 135.9 (C), 139.7 (C), 140.2 (CH), 165.8
(C), 165.9 (C), 198.1 (C), 214.6 (C); HRMS (ESI) Calcd for C34H39O6 ([M+H]+): 543.2741; Found:
543.2737.
Ac2O
TMSOTf (cat.)
CH2Cl2, rt, 10 min
O
HO
O
AcO
H
H
O
O
BzO
BzO
30
S6 (80%)
15-O-Acetyl-3-O-benzoylcharaciol (S6): Acetic anhydride (0.06 mL, 0.635 mmol, 35 eq) and
TMSOTf (one drop) were added at ambient temperature to a solution of 3-O-benzoylcharaciol (30)
(8 mg, 0.018 mmol, 1 equiv) in CH2Cl2 (2 mL, 111 mL/mmol 30); the initially colorless solution
changed color to pink. After being stirred for 10 min at ambient temperature, the reaction mixture was
diluted with methanol and saturated aqueous NH4Cl solution. The phases were separated, and the
aqueous layer was extracted with CH2Cl2 (3×). The combined organic phases were dried (MgSO4) and
concentrated under reduced pressure. Chromatographic purification (cyclohexane/ethyl acetate 5/1) of
the residue provided 15-O-acetyl-3-O-benzoylcharaciol (S6) (7 mg, 0.015 mmol, 80%) as a white solid
1
(mp: 155 °C): Rf 0.59 (cyclohexane/ethyl acetate 2/1). H NMR peak assignments were deduced from
1
1H–1H COSY spectra and are listed on the basis of the jatrophane numbering; H NMR (400 MHz,
3
CDCl3) δ 0.97 (d, J = 7.0 Hz, 16-CH3), 1.03 (s, 18- or 19-CH3), 1.18 (s, 18- or 19-CH3), 1.43 (s, 17-
3
CH3), 1.62 (dd, J = 2J = 13.4 Hz, 1-CH2, 1HRe), 1.72 (s, 20-CH3), 2.00−2.07 (m, 8-CH2), 2.18 (s,
2
3
acetate-CH3), 2.24−2.34 (m, 2-CH), 2.35 (dd, J = 18.3 Hz, J = 5.0 Hz, 11-CH2, 1H), 2.43 (dd,
2J = 18.3 Hz, J = 7.0 Hz, 11-CH2, 1H), 2.68 (dd, J1 = 4.0 Hz, J2 = 10.5 Hz, 4-CH), 2.77−2.84 (m, 7-
3
3
3
3
2
CH2, 1H), 2.91−2.99 (m, 7-CH2, 1H), 3.40 (dd, J = 8.0 Hz, J = 13.4 Hz, 1-CH2, 1HSi), 5.47−5.51 (m,
3
3
3-CH + 5-CH), 6.40 (dd, J1 = 3J2 = 5.6 Hz, 12-CH), 7.49 (dd, J1 = 3J2 = 7.5 Hz, 2 × CHar), 7.62 (dd,
SI-27

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
3
13
3J1 = 3J2 = 7.5 Hz, CHar), 8.07 (d, J1 = 7.5 Hz, 2 × CHar); C NMR (101 MHz, CDCl3) δ 12.1 (CH3),
13.9 (CH3), 16.2 (CH3), 21.5 (CH3), 24.2 (CH3), 25.0 (CH3), 33.7 (CH2), 35.3 (CH2), 39.1 (CH), 40.1
(CH2), 46.5 (CH2), 47.8 (C), 51.9 (CH), 81.7 (CH), 93.2 (C), 120.8 (CH), 128.6 (2 × CH), 129.7
(2 × CH), 130.2 (C), 133.2 (CH), 135.8 (C), 139.0 (C), 139.3 (CH), 166.0 (C), 170.4 (C), 198.5 (C),
215.0 (C); IR (film on KBr) ν 2970, 2930, 1780, 1705, 1660, 1385, 1275, 1245, 1115, 715 cm−1; Anal.
Calcd for C29H36O6: C, 72.48; H, 7.55; Found: C, 72.6; H, 7.7; [α]25D +51.0 (c 0.95, CHCl3).
O
AcO
O
AcO
m-CPBA
CH2Cl2, rt, 15 h
H
H
O
O
BzO
BzO
O
S6
1b (69%)
15-O-Acetyl-3-O-benzoylcharaciol-(5R,6R)-oxide (1b): m-CPBA (5 mg, 0.029 mmol, 2 equiv) was
added at ambient temperature to a solution of 15-O-acetyl-3-O-benzoylcharaciol (S6) (7 mg,
0.015 mmol, 1 equiv) in CH2Cl2 (2 mL, 48 mL/mmol S6). The reaction mixture was stirred for 15 h at
ambient temperature and then diluted with saturated aqueous Na2S2O3 solution. The phases were
separated, and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic phases were
dried (MgSO4) and concentrated under reduced pressure. Purification of the residue by chromatography
(cyclohexane/ethyl acetate 5/1 to 2/1) provided 15-O-acetyl-3-O-benzoylcharaciol-(5R,6R)-oxide (1b)
1
(5 mg, 0.01 mmol, 69%) as a white solid (mp: 187 °C): Rf 0.33 (cyclohexane/ethyl acetate 2/1). H
1
NMR peak assignments were deduced from H–1H COSY spectra and are listed on the basis of the
1
3
jatrophane numbering: H NMR (400 MHz, CDCl3) δ 0.97 (d, J = 6.5 Hz, 16-CH3), 1.04 (s, 18-CH3),
3
1.08 (s, 19-CH3), 1.28 (s, 17-CH3), 1.72 (dd, J = 2J = 13.6 Hz, 1-CH2, 1HRe), 1.77 (s, 20-CH3), 1.87
(dd, 3J1 = 3.8 Hz, 3J2 = 8.9 Hz, 4-CH), 1.92−2.04 (m, 8-CH2), 2.15−2.29 (m, 2-CH + 7-CH2, 1HSi), 2.27
3
(s, acetate-CH3), 2.42−2.55 (m, 11-CH2), 2.84−2.91 (m, 7-CH2, 1HRe), 3.33 (dd, J = 7.3 Hz,
3
3
2J = 13.6 Hz, 1-CH2, 1HSi), 3.39 (d, J = 8.9 Hz, 5-CH), 5.67 (dd, J1 = 3J2 = 3.8 Hz, 3-CH), 6.04−6.07
SI-28

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
3
3
(m, 12-CH), 7.49 (dd, J1 = 3J2 = 7.5 Hz, 2 × CHar), 7.61 (dd, J1 = 3J2 = 7.5 Hz, CHar), 8.09 (d,
3J1 = 7.5 Hz, 2 × CHar); 13C NMR (101 MHz, CDCl3) δ 12.2 (CH3), 13.6 (CH3), 16.8 (CH3), 21.5 (CH3),
23.3 (CH3), 25.1 (CH3), 32.1 (CH2), 32.9 (CH2), 38.6 (CH), 39.4 (CH2), 47.9 (CH2), 48.0 (C), 51.5
(CH), 59.4 (CH), 61.4 (C), 80.7 (CH), 90.1 (C), 128.5 (2 × CH), 129.8 (2 × CH), 130.3 (C), 133.1 (CH),
135.6 (CH), 136.9 (C), 165.5 (C), 170.3 (C), 199.9 (C), 213.6 (C); IR (film on KBr) ν 2970, 2930, 1720,
1670, 1385, 1270, 1245, 1110, 710 cm−1; HRMS (ESI) Calcd for C29H37O7 ([M+H]+): 497.2534; Found:
497.2529; [α]25D −20.6 (c 0.34, CHCl3).
Table SI-1. 1D-NOE experiment, irradiation at 5.67 ppm (3-CH).
O
O
O
2
4
3
O
H
O
O
O
entry
observable NOE
conclusion
1
2
2.15−2.29 ppm 2-CH (strong)
1.87 ppm 4-CH (strong)
2-CH and 3-CH are cis
4-CH and 3-CH are cis
SI-29

Total Synthesis of Natural and Non-Natural Δ5,6Δ12,13 Jatrophane Diterpenes and their Evaluation as MDR-Modulators
Table SI-2. 1D-NOE experiment, irradiation at 3.39 ppm (5-CH).
O
O
O
19
12
H5
O
O
O
O
8
entry
observable NOE
1.92−2.04 ppm 8-CH2 (strong)
conclusion
1
2
3
4
5
/
/
/
/
/
6.04−6.07 ppm 12-CH (strong)
1.08 ppm 19-CH3 (weak)
2.27 ppm acetate-CH3 (weak)
8.09 ppm 2 × aryl-CH (weak)
SI-30