Total Synthesis of (-)-C/D-cis-Dehydro-3-O-methyl-estradiols

Article abstract of DOI:10.1002/ejoc.201501341

A convergent synthesis of (-)-dehydro-3-O-methyl-C/D-cis-estradiol started from stereochemically defined substituted optically active 3-(2-arylethyl)-γ-butyrolactones. Regioselective bromination of the anisyl moiety, reductive ring opening of the iodolactone, and protecting-group changes led to a Weinreb amide. This then underwent an intramolecular Grignard reaction closing the B-ring to give a tetralone with defined configuration. Introduction of C-11 through an allyl Grignard addition and subsequent ring-closing metathesis gave a tetrahydro phenanthrene derivative. Oxidation of the side-chain alcohol resulted in the key aldehyde group, and a final samarium-diiodide-mediated reductive D-ring annulation resulted in the generation of the target dehydro-C/D-cis-estradiol derivatives with high stereoselectivity. Structure elucidation was carried out using NOEDS (nuclear Overhauser enhanced differential spectroscopy) analysis on the one hand, and conversion into known 3-O-methyl-13β-estradiols by double-bond hydrogenation on the other. Further efforts to use this estradiol synthetic strategy to generate more complex steroidal natural products and pharmaceutically interesting compounds are in progress.

Full text of DOI:10.1002/ejoc.201501341

DOI: 10.1002/ejoc.201501341
Full Paper
Steroids
Total Synthesis of (–)-C/D-cis-Dehydro-3-O-methyl-estradiols
Nora M. Kaluza,[a] Dieter Schollmeyer,[a] and Udo Nubbemeyer*[a]
Dedicated to Professor Horst Kunz on the occasion of his 75th birthday
Abstract: A convergent synthesis of (–)-dehydro-3-O-methyl-C/ cohol resulted in the key aldehyde group, and a final samarium-
D-cis-estradiol started from stereochemically defined substi- diiodide-mediated reductive D-ring annulation resulted in the
tuted optically active 3-(2-arylethyl)-γ-butyrolactones. Regiose- generation of the target dehydro-C/D-cis-estradiol derivatives
lective bromination of the anisyl moiety, reductive ring opening with high stereoselectivity. Structure elucidation was carried
of the iodolactone, and protecting-group changes led to a out using NOEDS (nuclear Overhauser enhanced differential
Weinreb amide. This then underwent an intramolecular Grig- spectroscopy) analysis on the one hand, and conversion into
nard reaction closing the B-ring to give a tetralone with defined known 3-O-methyl-13β-estradiols by double-bond hydrogena-
configuration. Introduction of C-11 through an allyl Grignard tion on the other. Further efforts to use this estradiol synthetic
addition and subsequent ring-closing metathesis gave a tetra- strategy to generate more complex steroidal natural products
hydro phenanthrene derivative. Oxidation of the side-chain al- and pharmaceutically interesting compounds are in progress.
Introduction
Compared to the better known C/D-trans-configured steroidal
natural products and pharmaceutically important compounds,
their congeners containing a C/D-cis ring junction are less wide-
spread.[1] Focussing on C/D-cis-configured steroid natural pro-
ducts with high biological activity, cardiac glycosides of the
cardenolide and bufadienolide families have been intensively
investigated.[2] In addition, the marine-sponge-derived Xesto-
bergsterols A–C and Contignasterol (Figure 1) show some anti-
histaminic properties.[3] Ritterazines A–M (highly active) as well
as Aglaiaglabretol B and Breynceanothanolic acid (less active)
have varying cytotoxic activities.[4]
(–)-C/D-cis-Estradiol has the basic tetracyclic framework with
configurationally defined B/C and C/D ring junctions. The
change from a C/D-trans to a C/D-cis configuration causes a
structural change in the shape of the steroid that results in a
significantly decreased affinity to the estrogen receptors, and a
loss of the original biological activity.[5] C/D-cis-Estradiol and its
derivatives have been discussed in the context of the investiga-
tion and development of new steroidal drugs, e.g., anti-cancer
drugs, without standard steroid–receptor interactions:[6] While
both Mifepristone (C/D-trans) and Onapristone (C/D-cis) show
progesterone-receptor-blocking properties, only Onapristone
Figure 1. Selected biologically active steroids, synthesis of (–)-C/D-cis-estrone.
also has a low antiglucocorticoide activity.[7]
tion of 13β/14α-(–)-estrone.[8] Several further syntheses of
steroidal compounds used the same reaction to establish a C/D-
cis ring junction.[9] Alternatively, reductions (Birch) and catalytic
hydrogenations of olefin precursors allowed the establishment
of a 13-methyl group and a 14-hydrogen with a cis configura-
tion.[10,11]
Originally, 13α/14α-(–)-estrone (13-epi-lumi-estrone) was pre-
pared by Butenandt by the one-step photochemical isomerisa-
[a] Institut für Organische Chemie, Johannes Gutenberg-Universität Mainz,
Duesbergweg 10–14, 55128 Mainz, Germany
E-mail: nubbemey@uni-mainz.de
http://www.chemie.uni-mainz.de/OC/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501341.
A long-term program in our group focusses on the syntheses
of steroids with a C/D-cis ring junction. A brief retrosynthesis of
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an estradiol derivative V is outlined in Figure 2: Estradiol V
should be generated from tetralone VIII by C-11 introduction
and C/D-ring closure using a radical cascade cyclisation via di-
ene VI or following a stepwise process via cyclohexadiene VII.
Tetralone VIII can be obtained from lactone IX by intramolecu-
lar Grignard reaction (X = Br) or by Vilsmeier cyclisation (X =
H) from amide X. Amide X (Xc represents an optically active
pyrrolidine moiety operating as a chiral auxiliary) is the product
of an auxiliary-directed zwitterionic ketene aza-Claisen re-
arrangement starting from (unsaturated) 4-arylbutanoic acid
fluoride XI (A/B ring fragment) and N-allylpyrrolidine XII (C/D
ring fragment) incorporating a trisubstituted olefin moiety.
Allylamine XII and arylbutanoic/butenoic acid derivative XI can
be synthesized by short reaction sequences as shown in Fig-
ure 3.
Figure 3. (–)-C/D-cis-estradiol: convergent synthesis of the key amide and
lactone according to ref.[13] (TPS = tert-butyldiphenylsilyl).
gave amide 8 after separation of the minor diastereomers and
careful structural elucidation. Finally, iodocyclisation delivered
lactone 9 in 68 % yield. Furthermore, most of the chiral auxiliary
(i.e., 2) could be recovered after the aqueous work-up, which
allows this material to be reused in another synthesis of allyl-
amine 5.
Results and Discussion
With the stereochemically defined substituted pyrrolidide 8 in
hand, we first attempted to generate tetralone 14 through
straightforward B-ring closure under Vilsmeier or Friedel–Crafts
conditions. However, these reactions failed because of acid-in-
duced side-reactions.[14] The in-situ-activated amide moiety
preferentially underwent cyclisation involving the double bond
to form lactones, leaving the aromatic core unaffected.[15]
Figure 2. Retrosynthesis of (–)-C/D-cis-estradiol.
Following the convergent strategy, the synthesis of key inter- Therefore, a Grignard-type intramolecular acylation was consid-
mediate lactam 8 started from trans-4-hydroxy- -proline (1), 1,4- ered. This required a suitably positioned halide within the aro-
butanediol (3), and m-anisaldehyde (6) (Figure 3). An initial six- matic ring. Treatment of iodolactone 9 with 1 equiv. of bromine
step sequence allowed us to convert trans-4-hydroxy- -proline in acetic acid should allow the introduction of the desired 4-
L
L
(1) into (2S,3R)-4-tert-butoxy-2-(phenoxymethyl)pyrrolidine (2) bromide.[16] In our first attempts to carry out the bromination,
in about 28 % overall yield.[12] After generating allylic alcohol 4 we tried to maintain the TPS ether of the side-chain, but this
(three steps, 81 % yield from butanediol 3), it was activated as gave only moderate yields. Using short reaction times (30 min)
a mesylate. The mesylate was coupled with amine 2 using a and low reactant concentrations (40 mol/L), pure α-iodomethyl
palladium-catalysed reaction to give allylamine 5 (84 % yield). diastereomer 9α gave silyl ether 10aα (α-iodomethyl group) in
Chain-elongation of m-anisaldehyde 6 by Wittig olefination, ca. 25 % yield; the corresponding acetate (i.e., 10bα) was found
and subsequent transformation of the acid intermediate deliv- to be the major product (50 % yield). The analogous reaction
ered acid fluoride 7 (50 % yield). Then, a zwitterionic aza-Clai- of iodolactone 9β (β-iodomethyl group) gave silyl ether 10aβ
sen rearrangement (aza-ketene Claisen rearrangement) using (β-iodomethyl group) in 23 % yield, and the corresponding
key compounds 5 and 7 enabled the assembly of a γ,δ-unsatu- acetate (i.e., 10bβ) in ca. 54 % yield. A reaction time of 26 h
rated amide in 92 % yield, with almost complete simple anti- was necessary to achieve complete consumption of the starting
diastereoselectivity and a high asymmetric induction of about material. Because of the low stability of the silyl ether moiety
7.5:1.[13] Hydrogenation of the styryl olefin moiety (96 % yield) under the reaction conditions, the exchange of this protecting
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group for acetate could be enforced. Using a mixture of α- and
β-iodomethyl lactones 9, and running the bromination with a
high reactant concentration (120 mmol/L), 4-bromide 10b was
isolated in a yield of ca. 88 % (mixture of 10bα/β). The corre-
sponding 2,4- and 2,6-dibromides were found as minor pro-
ducts (<5 %).[17] However, 2,4-dibromolactone 10eβ crystallised,
which allowed us to check the absolute and relative configura-
tion of the stereogenic centres by X-ray analysis (Figure 4).[18]
Reductive ring-opening of iodolactones 10 was achieved using
zinc in acetic acid at 65 °C.[19] Acetate 10b proved to have the
optimal substitution pattern, and acid 11b was obtained in al-
most quantitative yield. In contrast, TPS-protected lactone 10a
gave the corresponding TPS acid (i.e., 11a) in about 56 % yield
(Scheme 1).[20]
Scheme 1. Synthesis of tetralone 14. α/β determines the position of the iodo-
methyl group. Reagents and conditions: i) Br2 (1 equiv.), AcOH, 23 °C, 1.5 h
[from 9β: 10aβ: 22.7 %, 10bβ: 53.9 %. from 9α: 10aα: 25.2 %, 10bα: 50 %.
from 9α/β: 10aα/β (R = TPS): 5 %, 10bα/β: 88 %]; ii) Zn, AcOH, 65 °C, 24 h
(from 10aβ: 11a 55.5 %; from 10bα/β: 11b 100 %); iii) CH2N2, Et2O (12b
77 %); iv) CDI, CH2Cl2, 23 °C, 2 h, then HN(Me)OMe·HCl, CH2Cl2, reflux, 2 d
(13b: 75 %); v) 1. NaOMe (cat.), MeOH, 23 °C, 12 h, 2. TPSCl, iPr2NEt, CH2Cl2,
23 °C, 12 d (12a: 48 % over two steps) or 2. TBSCl, imidazole, CH2Cl2, 23 °C,
2 d (13c: 96.5 % over two steps); vi) tBuLi, THF, –78 °C, 3.5 h [14: 100 % from
13c; 0 % (TPS ether) from 12a].
ment with tBuLi in THF.[26] Even though low temperatures and
just 1 equiv. of tBuLi were used, the cyclisation of ester 12a
preferentially gave a alcohol product. This indicates a rapid
tBuLi addition to an intermediate tetralone 14.[27] In contrast,
when halogen–metal exchange was applied to Weinreb amide
13c, no subsequent addition of tBuLi to the C=O group was
observed. After work-up using aqueous ammonium chloride,
key tetralone 14 was isolated in nearly quantitative yield. Again,
the material crystallised, which allowed us to prove by X-ray
Figure 4. X-ray structure of dibromolactone 10eβ (only selected hydrogens
are shown).
Before B-ring closure, appropriate functionalisation of carb-
oxylic acids 11 had to take place. Methyl ester formation using
acidified methanol failed because of competing lactonisa-
tion.[15] Starting from TPS acid 11a, esterification using EDCI
[1-ethyl-3-(3-dimethylaminopropyl)carbodiimide] and DMAP [4-
(dimethylamino)pyridine] gave a moderate 32 % yield of methyl
ester 12a. In contrast, reaction of acid 11b with diazomethane
delivered the corresponding methyl ester (i.e., 12b) in 77 %
yield.[21] With the aim of avoiding side-reactions during the
Grignard ring-closure reaction, the side-chain acetate was re-
placed by a silyl ether. Initial Zemplén transesterification gave
the corresponding alcohol in 97 % yield. However, subsequent
TPS-ether formation turned out to be very slow, and only 25 %
of ether 12a (85 % based on recovered starting material) was
obtained after 12 d.[22] Alternatively, treatment of acid 11b with
CDI (carbonyldiimidazole), DMAP, and N,O-dimethylhydroxyl-
amine gave Weinreb amide 13b in 75 % yield (Figure 5).[23,24]
When amide 13b was subjected to the sequence of Zemplén
cleavage and TBS-ether (TBS = tert-butyldimethylsilyl) forma-
tion, silyl-protected amide 13c was isolated in 97 % yield over
two steps.[25] Finally, B-ring formation was carried out by treat-
Figure 5. X-ray structure of Weinreb amide 13b (only selected hydrogens are
shown).
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analysis that the stereogenic centres had remained unchanged attempts to form the steroid backbone by radical cascade reac-
(Scheme 1, Figure 6).[28]
tions failed. Even though a wide variety of reaction conditions
were tested, no initial 5-exo-trig ring closure occurred. In some
experiments, especially in those where water was added, simple
reduction of the aldehyde group of 16 occurred. When reac-
tions were run in THF with HMPA (hexamethylphosphoramide)
as a cosolvent, some 7-endo-trig cyclisations took place to form
varying mixtures of tricycles 17a (about 4 %) and a mixture of
17b/18 (about 19 %). The facile attack of the initially formed
ketyl radical onto the sterically less hindered methylidene-
tetraline double bond predominated, delivering a stable inter-
mediate benzyl radical.[35] Finally, a second SmI2-induced reduc-
tion/protonation delivered diastereomers 17a and 17b, and
trapping with iodine (from the SmI2 preparation) and subse-
quent dehydroiodination gave alkene 18 (Scheme 2). Overall,
steric shielding of the 5-exo olefin position by the methyl group,
and low radical-stabilising ability of the isopropylidene moiety,
were proposed as the reasons for the failure of the initial 5-exo-
trig cyclisation.[36]
Figure 6. X-ray structure of tetralone 14 (only selected hydrogens are shown).
The first strategy to complete the steroid synthesis was
based on a radical cascade process. Thus, the conversion of the
keto group of tetralone 14 into an exo-methylene group was
addressed. Various attempted methylenation reactions, includ-
ing Peterson, Wittig, Lombardo, and Tebbe olefinations, failed
or gave only disappointing yields of methylene tetraline 15.[29]
The best results were achieved by using the Petasis method.[30]
Methylenation using the Schrock carbene gave the desired ole-
fin (i.e., 15) in 90 % yield. Then, the TBS group was removed
with TBAF (tetrabutylammonium fluoride) solution in THF, and
the resulting alcohol (86 %) was converted into the correspond-
ing aldehyde (i.e., 16). The choice of oxidation procedure
proved to be crucial. Swern oxidation led to mixtures of chlorin-
ated products, and in several runs the exo-methylene group
isomerised to give a dihydronaphthalene moiety.[31] Under Ley's
conditions [TPAP (tetrapropylammonium perruthenate), NMO
(N-methylmorpholine N-oxide)], which are neutral and less
electrophilic, aldehyde 16 was obtained in 59 % yield
(Scheme 2).[32]
The failure of the attempted radical cascade reaction re-
quired a change of strategy, and we now focussed on a step-
wise closure of C-ring and D-ring. Starting from key tetralone
14, allylmagnesium chloride addition delivered alcohol 19 in
96 % yield as a mixture of diastereomers. Then, a ring-closing
metathesis using Grubbs (I) catalyst (2.5 mol-%) resulted in the
formation of the C-ring.[29a,37] The resulting tertiary benzylic
alcohol underwent immediate dehydration to give 1,3-tetra-
hydronaphthalene 20 in 94 % yield. Since the cyclohexadiene
moiety in 20 was highly susceptible to dehydrogenation, all
subsequent reactions required careful exclusion of oxygen and
avoidance of strongly oxidising conditions. TBAF-mediated
cleavage of the TBS ether gave an intermediate alcohol (80 %
yield). Again, the choice of conditions for the subsequent oxid-
ation proved to be crucial. Swern oxidation caused an immedi-
ate aromatisation of the C-ring moiety, and no cyclohexadienyl
aldehyde 21 was isolated.[31,38] In contrast, carefully monitored
oxidation using TPAP/NMO (Ley's conditions) gave aldehyde 21
in 78.4 % yield (63 % over two steps; Scheme 3).[32]
When aldehyde 21 was subjected to SmI2-mediated reduc-
tive cyclisation conditions, the D-ring closure to generate de-
hydro-13β-estradiol derivatives took place.[3,39] Treatment of 21
with freshly prepared SmI2 solution in THF/HMPA delivered a
mixture of regioisomeric Δ9(11) olefin 22a (14.2 %) and Δ11(12)
olefin 23 (10.5 %). In addition, Δ9(11) iodide 22b was obtained
in 10.6 % yield. Upon standing (preferentially in CDCl3), Δ9(11)
isomer 22a underwent slow double-bond isomerisation to form
Δ8(9)-dehydro-13β-estradiol derivative 24 (mixtures of 22a and
24 were obtained).[40] All isomers were separated by column
chromatography and preparative HPLC. The relative configura-
tion of the new stereogenic centres in 22 and 23 was proved
by NOEDS (nuclear Overhauser enhanced differential spectro-
scopy) analysis. This indicated that this key step, installing C-
13 and C-17 of the steroid backbone, proceeded with a high
diastereoselectivity (remote stereocontrol, 1,2-asymmetric in-
duction).[41] In this series, the lack of a sterically unhindered
Scheme 2. SmI2 cyclisation of exomethylenetetraline 16. Reagents and condi-
tions: i) Cp2TiMe2, PhMe, 65 °C, 20 h (15: 90 %); ii) 1. TBAF, THF, AcOH, 23 °C,
44 h; 2. TPAP (5 mol-%), NMO, CH2Cl2, MS (3 Å), 23 °C, 2 h (16: 51 % over
two steps); iii) SmI2, 5 % HMPA in THF, 23 °C, 1.5 h (17a: 4 %, mixture of 17b/
18: 18 %).
Aldehyde 16 served as the starting material for samarium- terminal alkene and the increased radical-acceptor properties
diiodide-induced reductive cyclisations.[33,34] Unfortunately, all of the aryl butadiene subunit represented the driving force to
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tion state with a quasi-cis arrangement of 14-CH, the adjacent
13-C-methyl group, and the oxygen, to give the C/D-cis ring
junction with 14-CH and 13-CMe in a β configuration in b. The
resulting cinnamyl radical mesomers (i.e., b1 and b2) were
trapped by a second equivalent of SmI2 to form the correspond-
ing cinnamyl anion (i.e., c1 and c2), which finally underwent α-
protonation at C-12 to give Δ9(11)-dehydroestradiol derivative
22a, and at C-10 to give Δ11(12)-dehydroestradiol derivative 23
(cis relative to 9-CH), respectively. NOEDS analyses of dehydro-
estradiols 22a and 23 always showed contacts between 18-Me
and 14-CH, as well as between 8-CH and 17-CH, which allowed
us to assign the relative configurations of the new stereogenic
centres. Alternatively, trapping with iodine delivered α-12-
iodide Δ9(11)-dehydroestradiol derivative 22b (with the iodide
trans to the 13-CMe group). Here, NOEDS contacts of cis 18-Me/
14-CH/12-CH groups, as well as cis 8-CH/17-CH groups, pro-
vided conclusive evidence. Finally, hydrogenation of Δ9(11)-de-
hydroestradiol 22a gave a mixture of 3-O-methylestradiols 25.
Literature data published for major diastereomer 25α (both en-
antiomers) were found to be incomplete. However, the pub-
lished data and measured data for 25α were consistent. In con-
trast, a complete set of data for ent-25β was published by
Schönecker et al. The data obtained for minor diastereomer
25β were in excellent agreement with these literature data,
which confirms the correct assignment of both the relative and
absolute configurations of all the stereogenic centres of the 3-
O-methylestradiols (Figure 7).
Scheme 3. Synthesis of (–)-C/D-cis-3-O-methylestradiols. Reagents and condi-
tions: i) H2C=CHCH2MgCl, THF, –78 °C to –20 °C, 4 h (19: 96 %); ii) Grubbs (I)
catalyst (2 × 2.5 mol-%), CH2Cl2, reflux, 22 h + 24 h (20: 94 %); iii) 1. TBAF,
THF, AcOH, 23 °C, 42 h, 2. TPAP (5 mol-%), NMO, CH2Cl2, MS (3 Å), 23 °C, 2 h
(21: 63 % over two steps); iv) SmI2, 5 % HMPA in THF, –40 °C to –20 °C, 1.5 h
(22a: 8.2 %, 22b: 10.6 %, 23: 10.5 %); v) CDCl3 (cat. H+) 23 °C (2:3 mixture of
22a and 24: 6 %); vi) 1,4-cyclohexadiene, Pd/C (5 %), EtOH, 23 °C, 2 d (25α:
86 %, 25β: 14 %).
start the crucial 5-exo-trig cyclisation. However, the overall yield
of the ring closure (about 35 % overall) still requires optimisa-
tion. Analysis of literature precedent revealed that reductive
five-membered ring annulation reactions between an aldehyde
and a cyclohexadiene (without an angular methyl group) have
been described through Ni-catalysed hydrosilylation (40–60 %
yield).[42] SmI2-induced 5-exo-trig cyclisations involving sterically
congested olefins always required α,β-unsaturated carbonyl sys-
tems as radical acceptors, and yields of up to 60–70 % have
been reported for selected examples.[43]
For analytical purposes, completion of the 3-O-methylestra-
diol synthesis required the removal of the C-ring double bond.
Catalytic hydrogenation of Δ9(11)-dehydroestradiol 22a with
cyclohexadiene/Pd/C in methanol gave an 86:14 mixture of
(–)-10-epi-C/D-cis-estradiol (–)-25α and (–)-C/D-cis-estradiol (–)-
25β in quantitative yield.[44] The analytical data of the target
molecules were found to be consistent with those published in
the literature, proving the general applicability of the strategy
(Scheme 3).[45]
The stereochemical outcome of the SmI2-induced reductive
cyclisation can be rationalised as follows. After the first SmI2-
mediated reduction of aldehyde 21, the resulting ketyl radical
a undergoes 5-exo-trig addition to the sterically more shielded
methyl-substituted terminus of the cyclohexadiene moiety. This
ring-closing reaction goes through an envelope-shaped transi-
Figure 7. Stereoselectivity of C/D-ring closure and final hydrogenation start-
ing from dihydrophenanthrene 21.
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Monobromination of Iodolactones 9 (α,β-Iodomethyl Group):
Iodolactones 9 (8.02 g, 11.96 mmol, 1.0 equiv.) in AcOH (100 mL)
were treated dropwise with bromine (1.91 g, 0.61 mL, 11.96 mmol,
Conclusions
A new synthesis of optically active C/D-cis-3-O-methylestradiol
diastereomers has been completed. Starting from 1,4-butane- 1 equiv.). The mixture was stirred for 1.5 h at room temperature.
Then, the AcOH was removed in vacuo, and the residue was dis-
solved in CH2Cl2. The remaining bromine was destroyed with
Na2S2O3 solution (10 % aq.). The aqueous layer was extracted with
CH2Cl2 (3 ×), the organic phase was dried (MgSO4), and the solvents
were removed in vacuo. The crude product was purified by column
chromatography (gradient EtOAc/petroleum ether, 1:10–1:4) to give
TPS ethers 10a (α,β-iodomethyl group; 454 mg, 0.61 mmol, 5.1 %)
as a clear colourless oil, and acetates 10b (α,β-iodomethyl group;
5.81 g, 10.5 mmol, 87.8 %) as a clear colourless oil. For spectroscopic
data, see the Supporting Information.
diol (3), m-anisole (6), and selected enantiopure pyrrolidine de-
rivatives 2, an auxiliary-directed convergent sequence devel-
oped earlier allowed the generation of configurationally de-
fined iodolactones 9 as suitable starting materials. Then, a six-
step sequence of bromination, protecting-group transforma-
tions, and intramolecular Grignard addition to close the B-ring
delivered key tetralone 14 in high yield. Introduction of the
missing C-11 atom was achieved through a Petasis olefination
(→ 15) or by an allyl Grignard reagent addition (→ 19). A first
attempt to use a radical cyclisation cascade to install the C- and
D-rings in a single step from tetraline 15 failed. A competing 7-
endo-trig ring closure involving the sterically less hindered
styryl olefin moiety and delivering tricycles 17 and 18 was fa-
voured over the originally planned initial 5-exo-trig cyclisation
involving an unactivated isopropylidene double bond as the
starting step. A stepwise closure of the C- and D-rings allowed
the generation of the desired steroidal framework. Ring-closing
metathesis and accompanying dehydration (→ 20), protecting-
group removal, and carefully controlled oxidation of the pri-
mary alcohol gave 21, containing an aryl cyclohexadiene moi-
ety with improved radical-acceptor properties. SmI2-mediated
reductive radical cyclisation diastereoselectively gave dehydro-
estradiols with a C/D-cis ring junction as a mixture of olefin
regioisomers 22 and 23, showcasing the applicability of this
late key step. The relative configuration of the newly formed
stereogenic centres was proved by NOEDS analysis. Further-
more, hydrogenation of the double bond of cyclohexene 22
gave a mixture of 3-O-methylestradiols 25α (major) and 25β
(minor), and the data of these compounds matched with those
published in the literature for (+)-3-O-methyl-9-epi-13β-estra-
diol (major) and (+)-3-O-methyl-9-epi-13β-estradiol and (–)-3-O-
methyl-13β-estradiol (enantiomer, minor). Further work using
and optimising this strategy to synthesise new steroidal natural
products and pharmaceutically important compounds with
other substitution patterns is in progress.
Reductive Ring-Opening of Iodolactones 10b (α,β-Iodomethyl
Group): Iodolactones 10b (5.97 g, 10.79 mmol, α,β-iodomethyl
group) in AcOH (40 mL) were treated portionwise with zinc (7.05 g,
107.9 mmol, 10 equiv.). The mixture was stirred for 24 h at 65 °C.
The mixture was then cooled to 23 °C, and excess HCl (1
M aq.) was
added. The mixture was extracted with Et2O (5 ×). The organic lay-
ers were dried (MgSO4), and the solvents were removed in vacuo.
The residue was purified by column chromatography (EtOAc/hex-
anes, 1:2) to give acid 11b (4.68 g, 10.79 mmol, nearly 100 %) as a
clear colourless oil.
(2R,3R)-3-(3-Acetoxypropyl)-2-[2-(2-bromo-5-methoxyphenyl)-
ethyl]-4-methyl-4-pentenoic Acid (11b): Rf = 0.25 (EtOAc/petro-
leum ether, 1:2). [α]D22 = 14.0 (c = 1.01, CH2Cl2). IR: ν = 3084 (b), 2937
˜
(s), 2855 (s), 1735 (b), 1705 (b), 1595 (m), 1572 (m), 1472 (s), 1366
(m), 1279 (s), 1240 (b), 1164 (s), 1050 (s), 896 (m), 812 (w) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.30–1.38 (m, 1 H, 4-H), 1.41–1.64
(m, 2 H, 5-H), 1.54–1.64 (m, 1 H, 4-H), 1.66 (s, 3 H, 17-H), 1.81–1.95
3
(m, 2 H, 7-H), 2.03 (s, 3 H, 20-H), 2.33 (m, 1 H, 3-H), 2.50 (td, JH,H
=
3
3
3
3.9, JH,H = 9.9 Hz, 1 H, 2-H), 2.66 (ddd, JH,H = 6.3, JH,H = 10.2,
3
3
2
2JH,H = 13.4 Hz, 1 H, 8-H), 2.74 (ddd, JH,H = 5.8, JH,H = 10.4, JH,H
=
13.4 Hz, 1 H, 8-H), 3.76 (s, 3 H, 15-H), 4.02 (m, 2 H, 6-H), 4.77 (s, 1
4
H, 18-H), 4.85 (s, 1 H, 18-H), 6.63 (dd, 3JH,H = 8.7, JH,H = 3.0 Hz, 1 H,
4
3
12-H), 6.77 (d, JH,H = 3.0 Hz, 1 H, 10-H), 7.39 (d, JH,H = 8.7 Hz, 1 H,
13-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.73 (C-17), 20.95
(C-20), 25.51 (C-4), 26.20 (C-5), 29.64 (C-7), 34.48 (C-8), 48.98, 49.14
(C-3, C-2), 55.38 (C-15), 64.30 (C-6), 113.39 (C-12), 114.31 (C-18),
114.62 (C-14), 116.04 (C-10), 133.29 (C-13), 141.68 (C-9), 144.28 (C-
16), 158.88 (C-11), 171.22 (C-19), 180.77 (C-1) ppm. HRMS (ESI):
calcd. for C20H27O523NaBr 449.0940; found 449.0926.
Experimental Section
(R)-3,4-Dihydro-2-[(R)-6-tert-butyldimethylsiloxy-2-methylhex-
1-en-3-yl]-6-methoxynaphthalen-1(2H)-one (14): Under Ar, a so-
lution of TBS Weinreb amide 13c (3.05 g, 5.621 mmol) in dry THF
General Remarks: Reaction solvents were dried by standard proce-
dures before use when necessary. All reactions including moisture-
or air-sensitive reagents were carried out under an argon atmos- (150 mL) was cooled to –78 °C. Then, tert-butyllithium (1.9
M
in
phere. 1H, 13C, and 2D (COSY, HSQC, HMBC, NOESY) NMR spectra
were recorded at room temperature with a Bruker ARX400, AV400,
or AV600 spectrometer in CDCl3 using the signal of residual CHCl3
as an internal standard. The additional signals from the amide's
rotamers are given in square brackets. IR spectra were recorded
with a Jasco FT/IR-400 plus spectrometer. High-resolution mass
spectra (HRMS) were recorded with a Waters Q Tof Ultima 3 Micro-
pentane; 3.9 mL, 7.41 mmol, 1.3 equiv.) was added dropwise over
30 min while stirring at –78 °C. After 3 h, the reaction was quenched
by the addition of saturated aq. NH4Cl. The mixture was warmed to
room temperature, then the aqueous layer was extracted with Et2O
(4 ×). The organic phases were dried (MgSO4), and the solvents were
removed in vacuo. The crude material was purified by column chro-
matography (gradient EtOAc/petroleum ether, 1:20–1:10) to give
mass spectrometer. Optical rotations were recorded with a Perkin– tetralone 14 (2.22 g, 5.61 mmol, 100 %) as a colourless oil, which
Elmer P 241 polarimeter. Column chromatography was carried out crystallised at –18 °C. Rf = 0.51 (EtOAc/petroleum ether, 1:4), m.p.
on MN silica gel 60M from Macherey–Nagel (grain size: 0.040– 37 °C. [α]D21 = –9.9 (c = 1.27, CH Cl ). IR: ν = 2962 (w), 2931 (s), 2856
˜
2
2
0.063 mm). The progress of reactions was monitored by thin-layer
chromatography (TLC) on aluminium sheets pre-coated with silica
gel 60 F254 silica gel from Merck. HPLC: tR = peak retention time,
k = retention factor = (tR – t0)/t0.
(s), 1675 (s), 1600 (m), 1494 (s), 1462 (m), 1350 (m), 1270 (s), 1250
(s), 1098 (s), 1030 (w), 892 (m), 836 (s), 774 (s), 668 (w) cm–1 1H
NMR (400 MHz, CDCl3, COSY): δ = 0.01 (s, 6 H, 19-H), 0.87 (s, 9 H,
21-H), 1.34–1.59 (m, 4 H, 15-H, 16-H), 1.75 (s, 3 H, 18-H), 1.93 (dtd,
.
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3
2
3
3JH,H = 4.4, JH,H = 10.2, JH,H = 10.3 Hz, 1 H, 7-H), 2.11 (ddd, JH,H
=
[α]D26 = 216.6 (c = 1.03, CH2Cl2). IR: ν = 3026 (w), 2929 (s), 2855 (s),
˜
3
2
3
4.5, JH,H = 10.0, JH,H = 14.3 Hz, 1 H, 7-H), 2.49 (dt, JH,H = 4.5,
1607 (s), 1570 (w), 1495 (s), 1471 (m), 1443 (w), 1260 (m), 1251 (s),
1232 (s), 1096 (b, s), 1052 (w), 960 (m), 833 (s, b), 812 (s), 774 (s),
715 (w), 660 (w) cm–1. 1H NMR (400 MHz, CDCl3, COSY): δ = 0.08 (s,
6 H, 20-H), 0.92 (s, 9 H, 22-H), 1.43–1.80 (m, 5 H, 7-H, 15-H, 16-H),
3JH,H = 10.3 Hz, 1 H, 8-H), 2.85 (m, 2 H, 6-H, 14-H), 2.96 (td, JH,H
=
3
2
5.0, JH,H = 16.7 Hz, 1 H, 6-H), 3.50–3.62 (m, 2 H, 17-H), 3.84 (s, 3 H,
11-H), 4.64 (s, 1 H, 12-H), 4.87 (s, 1 H, 12-H), 6.66 (d, JH,H = 2.7 Hz,
4
4
3
3
1 H, 4-H), 6.80 (dd, JH,H = 2.5, JH,H = 8.7 Hz, 1 H, 2-H), 7.97 (d,
1.86 (s, 3 H, 18-H), 2.11 (m, 1 H, 7-H), 2.25 (br. d, JH,H = 15.8 Hz, 1
3JH,H = 8.7 Hz, 1 H, 1-H) ppm. 13C NMR (100 MHz, CDCl3, HSQC,
H, 14-H), 2.50 (br. t, JH,H = 14.1 Hz, 1 H, 8-H), 2.80 (dd, JH,H = 3.3,
3
3
HMBC): δ = –5.31 (C-19), 18.27 (C-20), 21.65 (C-18), 23.87 (C-7), 24.85 3JH,H = 8.4 Hz, 2 H, 6-H), 3.66 (m, 2 H, 17-H), 3.80 (s, 3 H, 19-H), 5.87
3
4
3
(C-15), 25.92 (C-21), 28.63 (C-6), 31.09 (C-16), 44.00 (C-14), 49.99
(C-8), 55.33 (C-11), 63.16 (C-17), 111.80 (C-12), 112.31 (C-4), 112.98
(d, JH,H = 5.6 Hz, 1 H, 12-H), 6.32 (dd, JH,H = 2.4, JH,H = 5.8 Hz, 1
4
4
H, 11-H), 6.61 (d, JH,H = 2.6 Hz, 1 H, 4-H), 6.73 (dd, JH,H = 2.6,
(C-2), 126.54 (C-10), 129.87 (C-1), 145.57 (C-13), 146.17 (C-5), 163.20 3JH,H = 8.8 Hz, 1 H, 2-H), 7.57 (d, JH,H = 8.8 Hz, 1 H, 1-H) ppm. 13C
3
(C-3), 198.21 (C-9) ppm. HRMS (ESI): calcd. for C24H38O3Si23Na
425.2488; found 425.2496.
NMR (75 MHz, CDCl3, HSQC, HMBC): δ = –5.31 (C-20), 18.33 (C-21),
21.11 (C-18), 24.91 (C-15), 25.95 (C-22), 28.06 (C-16), 29.01 (C-7),
30.93 (C-6), 38.63 (C-8), 43.19 (C-14), 55.19 (C-19), 63.56 (C-17),
112.77, 112.99 (C-2, C-4), 114.75 (C-11), 122.14 (C-12), 124.45 (C-1),
127.53 (C-10), 133.35 (C-9), 137.88 (C-13), 138.41 (C-5), 158.28 (C-3)
ppm. MS (FD, 5 kV/8 mA/min): m/z (%) = 396.267 (100) [M – H2]+,
397.268 [M – H]+, 398.256 (9) [M]+. HRMS (ESI): calcd. for C25H39O2Si
[M + H]+ 399.2719; found 399.2716. In several runs, some of the
initial cyclohexenol product was isolated. This intermediate under-
goes elimination of H2O on standing. For some data for the cyclo-
hexenol intermediate see the Supporting Information.
(2R)-1-Allyl-1,2,3,4-tetrahydro-2-[(R)-6-tert-butyldimethylsiloxy-
2-methylhex-1-en-3-yl]-6-methoxynaphthalen-1-ol (19): Under
Ar, a solution of tetralone 14 (1.0 g, 2.484 mmol) in THF (125 mL)
was cooled to –78 °C. Allylmagnesium chloride (1.7
M in THF; 2.4 mL,
4.08 mmol, 1.6 equiv.) was added dropwise over 20 min. Then, the
mixture was stirred for 4 h over which time it was allowed to warm
up to –20 °C. The mixture was then recooled to –78 °C, and the
reaction was quenched by the addition of saturated aq. NH4Cl. The
aqueous layer was extracted with Et2O (4 ×), the organic phases
were dried (MgSO4), and the solvents were removed in vacuo. The
3-[(1R,10aR)-7-Methoxy-2-methyl-1,9,10,10a-tetrahydro-
crude material was purified by column chromatography (gradient phenanthren-1-yl]propanal (21): Ley oxidation: Alcohol 20a
EtOAc/petroleum ether, 1:20–1:10) to give allyl alcohol 19 (1.06 g,
2.39 mmol, 96.3 %) as a colourless oil (presumably an inseparable
mixture of diastereomers). Rf = 0.33 (EtOAc/petroleum ether, 1:10).
(173 mg, 0.605 mmol) was dissolved in CH2Cl2 (15 mL) in a flame-
dried flask in the presence of molecular sieves (3 Å) under Ar. N-
Methylmorpholine N-oxide (NMO; 128 mg, 1.089 mmol, 1.8 equiv.)
[α]D21 = 56.8 (c = 1.05, CH Cl ). IR: ν = 3532 (b), 2954 (s), 2927 (s), and tetrapropyl ammonium perruthenate (TPAP; 10.6 mg,
˜
2
2
2856 (s), 1636 (w), 1608 (m), 1498 (s), 1472 (m), 1438 (w), 1254 (s),
1094 (b, s), 1040 (b, m), 1004 (m), 911 (m), 836 (s), 808 (m), 774 (s),
733 (m), 664 (w) cm–1. 1H NMR (400 MHz, CDCl3, COSY): δ = 0.04 (s,
0.0302 mmol, 0.05 equiv.) were added, and the mixture was stirred
at 23 °C for 1 h. The molecular sieves were removed by filtration,
and the filtrate was diluted with CH2Cl2, and washed with saturated
6 H, 20-H), 0.89 (s, 9 H, 22-H), 1.20–1.46 (m, 3 H, 15-H, 16-H), 1.68– aq. Na2S2O3. The aqueous layer was extracted with CH2Cl2 (3 ×).
1.74 (m, 1 H, 16-H), 1.76 (s, 3 H, 18-H), 1.79–1.87 (m, 1 H, 7-H), 1.95– The organic phases were washed with brine [reextraction of the
3
3
2.05 (m, 1 H, 7-H), 2.09 (m, 1 H, 8-H), 2.33 (ddd, JH,H = 3.4, JH,H
=
aqueous layer with CH2Cl2 (3 ×)], and dried (MgSO4), and the sol-
vent was removed in vacuo. The crude product was purified by
column chromatography (EtOAc/petroleum ether, 1:4) to give alde-
hyde 21 (135 mg, 0.475 mmol, 78.4 %) as a clear colourless oil. Rf =
0.59 (EtOAc/petroleum ether, 1:2). [α]D27 = 220.0 (c = 0.96, CH2Cl2).
3
3
8.0, JH,H = 11.3 Hz, 1 H, 14-H), 2.54 (t, JH,H = 6.9 Hz, 2 H, 11-H),
2.64 (td, 3JH,H = 5.9, JH,H = 18.0 Hz, 1 H, 6-H), 2.78 (ddd, JH,H = 6.1,
2
3
3JH,H = 9.6, JH,H = 17.2 Hz, 1 H, 6-H), 3.02 (s, 1 H, O-H), 3.57 (t,
2
3JH,H = 6.1 Hz, 2 H, 17-H), 3.79 (s, 3 H, 19-H), 4.63 (s, 1 H, 12-H), 4.79
3
3
(s, 1 H, 12-H), 5.02 (d, JH,H = 17.0 Hz, 1 H, 24-H), 5.03 (d, JH,H
=
IR: ν = 2931 (s), 2834 (s), 2722 (w), 1720 (s), 1606 (s), 1496 (s), 1466
˜
3
3
3
10.5 Hz, 1 H, 24-H), 5.75 (dddd, JH,H = 6.5, JH,H = 7.8, JH,H = 10.8, (m), 1443 (m), 1270 (m), 1233 (s), 1162 (m), 1047 (s), 834 (m), 812
3JH,H = 16.8 Hz, 1 H, 23-H), 6.58 (d, JH,H = 2.7 Hz, 1 H, 4-H), 6.76
(s) cm–1
.
1H NMR (600 MHz, CDCl3, COSY): δ = 1.56 (m, 1 H, 7-H),
4
4
3
3
(dd, JH,H = 2.7, JH,H = 8.7 Hz, 1 H, 2-H), 7.50 (d, JH,H = 8.7 Hz, 1 H,
1.82 (s, 3 H, 18-H), 1.95 (ddd, 3JH,H = 5.3, 3JH,H = 10.2, 2JH,H = 14.7 Hz,
1-H) ppm. 13C NMR (100 MHz, CDCl3, HSQC, HMBC): δ = –5.29 (C-
1 H, 15-H), 2.03 (m, 1 H, 7-H), 2.11 (ddt, JH,H = 4.1, JH,H = 10.9,
3
3
20), 18.30 (C-21), 19.17 (C-18), 21.29 (C-7), 25.54 (C-16), 25.94 (C-22), 2JH,H = 14.8 Hz, 1 H, 15-H), 2.36 (m, 1 H, 14-H), 2.38 (m, 1 H, 8-H),
3
3
2
26.39 (C-6), 30.33 (C-15), 41.70 (C-14), 44.74 (C-8), 48.35 (C-11), 55.05 2.44 (m, 1 H, 16-H), 2.57 (br. dd, JH,H = 5.7, JH,H = 10.9, JH,H
=
(C-19), 63.04 (C-17), 76.42 (C-9), 112.12 (C-2), 112.63, 112.66 (C-4, C- 17.6 Hz, 1 H, 16-H), 2.81 (m, 2 H, 6-H), 3.79 (s, 3 H, 19-H), 5.89 (br.
3
3
12), 117.30 (C-24), 127.61 (C-1), 134.50 (C-23), 135.35 (C-10), 137.32 d, JH,H = 5.8 Hz, 1 H, 12-H), 6.27 (br. d, JH,H = 5.7 Hz, 1 H, 11-H),
(C-5), 150.82 (C-13), 158.09 (C-3) ppm. HRMS (ESI): calcd. for 6.60 (d, 4JH,H = 2.6 Hz, 1 H, 4-H), 6.73 (dd, 4JH,H = 2.6, JH,H = 8.8 Hz,
3
3
C27H44O3Si23Na 467.2957; found 467.2958.
1 H, 2-H), 7.54 (d, JH,H = 8.8 Hz, 1 H, 1-H), 9.84 (s, 1 H, 17-H) ppm.
13C NMR (151 MHz, CDCl3, HSQC): δ = 21.11 (C-18), 21.35 (C-15),
29.50 (C-7), 30.76 (C-6), 38.81 (C-8), 39.62 (C-16), 42.76 (C-14), 55.20
(C-19), 112.84 (C-2), 112.97 (C-4), 114.61 (C-11), 122.80 (C-12), 124.53
(C-1), 127.36 (C-10), 133.34 (C-5), 135.58 (C-13), 138.18 (C-9), 158.41
(C-3), 202.28 (C-17) ppm. HRMS (ESI): calcd. for C19H22O223Na [M +
Na]+ 305.1517; found 305.1515.
1-tert-Butyldimethylsilyl-3-[(1R,10aR)-1,9,10,10a-tetrahydro-7-
methoxy-2-methylphenanthren-1-yl]propan-1-ol (20): Under Ar,
allyl alcohol 19 (240 mg, 0.539 mmol) and Grubbs (I) catalyst [benz-
ylidene bis(tricyclohexylphosphine) ruthenium dichloride; 11 mg,
0.0135 mmol, 0.025 equiv.] in CH2Cl2 (30 mL) were heated to reflux
for 22 h. Then, a second portion of Grubbs (I) catalyst (11 mg,
0.0135 mmol, 0.025 equiv.) was added, and heating was continued
for 24 h. The mixture was then cooled, and the solvents were re-
moved in vacuo. The crude material was purified by column
(8α,13β,14β,17β)-3-Methoxyestra-1,3,5(10),9(11)-tetraen-17-ol
(22a), (8α,14β)-12-Iodo-3-methoxyestra-1,3,5(10),9(11)-tetraen-
17-ol (22b), (8α,9α,13β,14β,17β)-3-Methoxyestra-1,3,5-
chromatography (EtOAc/petroleum ether, 1:20) to give tetrahydro- (10),11(12)-tetraen-17-ol (23), and (14β)-3-Methoxyestra-
phenanthrene 20 (202 mg, 0.507 mmol, 94 %) as a colourless glass- 1,3,5(10),8(9)-tetraen-17-ol (24): A solution of aldehyde 21
like oil that solidified upon storing at –18 °C (very susceptible to (35 mg, 0.124 mmol) in THF (4 mL) and HMPA (0.25 mL) was de-
oxidation). Rf = 0.56 (EtOAc/petroleum ether, 1:10), m.p. 35 °C.
gassed by freezing the mixture (–196 °C), removing the gas in
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3
3
vacuo, and refilling with Ar (3 ×). Then, a freshly prepared SmI2
solution (excess, volume not determined) was added by cannula
with stirring at –40 °C over about 30 min until the blue colour of
unreacted SmI2 remained for several minutes, and no reactant was
detected by means of TLC control. The mixture was stirred for a
further 1 h at –20 °C, then the mixture was diluted with CH2Cl2
2.05–2.16 (m, 2 H, 15-H, 7-H), 2.32 (ddd, JH,H = 8.2, JH,H = 12.9,
2JH,H = 19.4 Hz, 1 H, 16-H), 2.86–2.90 (m, 2 H, 6-H), 3.14 (br. s, 1 H,
3
3
12-H), 3.74 (s, 3 H, 19-H), 4.56 (dd, JH,H = 6.8, JH,H = 15.0 Hz, 1 H,
17-H), 5.98 (s, 1 H, 11-H), 6.60 (m, 2 H, 2-H, 4-H), 7.42 (d, JH,H
3
=
9.5 Hz, 1 H, 1-H) ppm. 13C NMR (151 MHz, CD2Cl2, HSQC, HMBC):
δ = 20.55 (C-18), 26.25 (C-15), 30.69, 30.94 (C-6, C-7), 32.12 (C-16),
39.48 (C-8), 41.09 (C-12), 45.73 (C-14), 51.33 (C-13), 55.65 (C-19),
73.69 (C-17), 113.04, 113.46 (C-2, C-4), 120.63 (C-11), 125.41 (C-1),
128.67 (C-9), 134.60 (C-10), 137.91 (C-5), 159.02 (C-3) ppm. MS (FD,
5 kV/8 mA/min): m/z (%) = 284.1 (100) [M – I]+. MS (ESI): m/z (%) =
433.28 (3.6) [M + Na]+, 305.23 (4.5) [M – HI + Na]+.
(30 mL), and quenched with HCl (1
N aq.; 30 mL). The aqueous
layer was extracted with CH2Cl2 (3 ×), the organic phases were dried
(MgSO4), and the solvents were removed in vacuo. The crude prod-
uct was purified by column chromatography (EtOAc/petroleum
ether, 1:4) and preparative HPLC (Nucleosil 50-5, ID = 32 × 238 mm,
diethyl ether/hexane, 15:85, 48 mL/min, 47 bar) to give alcohol 23
(3.7 mg, 0.013 mmol, 10.5 %) as a clear colourless oil, alcohol 22a
(2.9 mg, 0.0102 mmol, 8.2 %) as a clear colourless oil, alcohol 22b
(5.4 mg, 0.0132 mmol, 10.6 %) as a clear colourless oil, and a mix-
ture of alcohols 22a and 24 (2.1 mg, 7.38 μmol, 6.0 %) as a clear
colourless oil (this latter fraction was formed from the product mix-
ture after column chromatography after standing in CDCl3 for NMR
spectroscopic measurements).
Data for 24: Rf = 0.54 (EtOAc/petroleum ether, 1:2). HPLC: k = 8.4,
tR = 9.4 min. [α]D28 = 38.4 (c = 0.38, CH Cl ). IR: ν = 3442 (b, OH),
˜
2
2
2926 (s), 2875 (s), 2831 (m), 1725 (w), 1606 (s), 1572 (w), 1498 (s),
1465 (s), 1430 (m), 1375 (w), 1304 (w), 1250 (s), 1163 (s), 1087 (m),
1037 (s), 863 (w), 812 (m) cm–1 1H NMR (600 MHz, CDCl3, COSY):
.
δ = 1.00 (s, 3 H, 18-H), 1.41–1.54 (m, 3 H, 12-H, 15-H), 1.61–1.66 (m,
1 H, 16-H), 2.06–2.13 (m, 1 H, 7-H), 2.15–2.20 (m, 1 H, 16-H), 2.21–
2.30 (m, 3 H, 7-H, 14-H, 15-H), 2.33–2.43 (m, 2 H, 11-H), 2.72 (m, 2
H, 6-H), 3.80 (s, 3 H, 19-H), 3.83 (dd, 3JH,H = 6.8, JH,H = 10.7 Hz, 1 H,
3
Data for 23: Rf = 0.61 (EtOAc/petroleum ether, 1:2). HPLC: k = 11.0,
4
4
3
tR = 12 min. [α]D28 = 59.3 (c = 0.10, CH2Cl2). IR: ν = 3408 (b, OH),
17-H), 6.69 (d, JH,H = 2.5 Hz, 1 H, 4-H), 6.72 (dd, JH,H = 2.7, JH,H
=
˜
8.4 Hz, 1 H, 2-H), 7.12 (d, JH,H = 8.4 Hz, 1 H, 1-H) ppm. 13C NMR
(151 MHz, CDCl3, HSQC, HMBC, NOESY): δ = 18.42 (C-18), 22.27 (C-
11), 28.34 (C-7), 28.91 (C-6), 29.26 (C-12), 29.63 (C-15), 32.29 (C-16),
43.63 (C-13), 48.08 (C-14), 55.26 (C-19), 80.74 (C-17), 110.81 (C-2),
113.38 (C-4), 122.78 (C-1), 123.77 (C-9), 129.44 (C-10), 134.56 (C-
8), 137.03 (C-5), 157.74 (C-3) ppm. HRMS (ESI): calcd. for C19H25O2
285.1855; found 285.1851.
3
2927 (s), 2869 (s), 1735 (w), 1715 (w), 1608 (s), 1499 (s), 1457 (s),
1255 (s), 1234 (m), 1154 (w), 1092 (w), 1039 (s), 799 (w), 668 (w)
1
cm–1. H NMR (600 MHz, CDCl3, COSY, NOESY): δ = 1.09 (s, 3 H, 18-
H), 1.60–1.67 (m, 3 H, 7-H, 15-H, 16-H), 1.80–1.86 (m, 4 H, 7-H, 14-
H, 16-H, 15-H), 2.02 (m, 1 H, 8-H), 2.72–2.76 (m, 2 H, 6-H), 3.40 (m,
3
1 H, 9-H), 3.73 (m, 1 H, 17-H), 3.78 (s, 3 H, 19-H), 5.51 (dd, JH,H
=
3
3
3
2.7, JH,H = 10.2 Hz, 1 H, 12-H), 5.94 (dd, JH,H = 2.7, JH,H = 10.2 Hz,
4
4
1 H, 11-H), 6.61 (d, JH,H = 2.5 Hz, 1 H, 4-H), 6.75 (dd, JH,H = 2.7,
3JH,H = 8.5 Hz, 1 H, 2-H), 7.13 (d, JH,H = 8.4 Hz, 1 H, 1-H) ppm. 13C
3
NMR (151 MHz, CDCl3, HSQC, HMBC): δ = 26.49, 26.68 (C-15, C-16),
27.02 (C-18), 29.81 (C-6), 32.03 (C-7), 35.53 (C-9), 37.75 (C-8), 44.68
(C-13), 46.28 (C-14), 55.21 (C-19), 81.68 (C-17), 112.37 (C-4), 113.12
(C-2), 128.80 (C-12), 129.87 (C-1), 132.36 (C-10), 134.44 (C-11), 138.13
(C-5), 157.46 (C-3) ppm. HRMS (ESI): calcd. for C19H25O2 285.1855;
found 285.1856.
Acknowledgments
The authors thank the Deutsche Forschungs-Gemeinschaft
(DFG) for support of this work.
Data for 22a: Rf = 0.54 (EtOAc/petroleum ether, 1:2). HPLC: k = 12.4,
tR = 13.5 min. [α]24 = –33.2 (c = 0.19, CH Cl ). IR: ν = 3403 (b, OH),
˜
2
2
D
Keywords: Asymmetric synthesis · Natural products ·
Steroids · Metathesis · Cyclization · Radical reactions
2924 (s), 2853 (s), 1738 (w), 1606 (s), 1571 (w), 1497 (s), 1464 (s),
1279 (s), 1257 (s), 1232 (s), 1162 (m), 1076 (m), 1036 (s), 812 (m),
716 (w) cm–1. 1H NMR (600 MHz, CD2Cl2, COSY, NOESY): δ = 0.94 (s,
3 H, 18-H), 1.38–1.45 (m, 2 H, 7-H, 15-H), 1.51–1.59 (m, 2 H, 14-H,
16-H), 1.92 (tdd, 3JH,H = 2.1, 3JH,H = 4.1, 3JH,H = 9.5 Hz, 1 H, 8-H), 2.03
(ddd, 3JH,H = 4.3, 3JH,H = 8.9, 2JH,H = 12.4 Hz, 1 H, 7-H), 2.05–2.11 (m,
4 H, 12-H, 15-H, 16-H), 2.77 (m, 2 H, 6-H), 3.76 (s, 3 H, 19-H), 3.87 (t,
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4
3
3JH,H = 6.6 Hz, 1 H, 17-H), 6.14 (dt, JH,H = 3.6, JH,H = 7.0 Hz, 1 H,
4
4
3
11-H), 6.60 (d, JH,H = 2.6 Hz, 1 H, 4-H), 6.69 (dd, JH,H = 2.7, JH,H
=
8.7 Hz, 1 H, 2-H), 7.47 (d, JH,H = 8.7 Hz, 1 H, 1-H) ppm. 13C NMR
(151 MHz, CD2Cl2, HSQC, HMBC): δ = 22.43 (C-18), 28.55 (C-15),
30.06 (C-7), 31.06 (C-6), 32.04 (C-16), 34.82 (C-12), 40.38 (C-8), 44.08
(C-13), 49.36 (C-14), 55.65 (C-19), 80.18 (C-17), 112.90 (C-2), 113.38
(C-4), 117.93 (C-11), 125.13 (C-1), 128.69 (C-10), 136.05 (C-9), 138.64
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found 285.1846.
3
Data for 22b: Rf = 0.46 (EtOAc/petroleum ether, 1:2). HPLC: k = 13.4,
tR = 14.5 min. [α]24 = –40.5 (c = 0.36, CH Cl ). IR: ν = 3449 (b, OH),
˜
2
2
D
2924 (s), 2853 (s), 1724 (w), 1606 (s), 1497 (s), 1464 (s), 1377 (m),
1276 (s), 1255 (s), 1233 (s), 1164 (w), 1073 (m), 1054 (s), 1036 (s),
953 (m), 890 (m), 811 (m), 713 (m) cm–1. 1H NMR (600 MHz, CD2Cl2,
COSY, NOESY): δ = 1.13 (s, 3 H, 18-H), 1.30–1.41 (m, 1 H, 7-H), 1.47
3
3
2
(ddd, JH,H = 3.2, JH,H = 9.7, JH,H = 13.1 Hz, 1 H, 15-H), 1.55 (m, 1
3
H, 14-H), 1.60–1.67 (m, 1 H, 16-H), 2.86 (t, JH,H = 10.9 Hz, 1 H, 8-H),
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Received: October 19, 2015
Published Online: November 25, 2015
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