Synthesis of (+)-Vitepyrroloid A and (+)-Vitepyrroloid B by Late-Stage Ni-Catalyzed C(sp2)-C(sp3) Cross-Electrophile Coupling

Article abstract of DOI:10.1021/acs.joc.8b00882

A concise and scalable five-step synthesis of vitepyrroloids A and B, two cytotoxic labdane diterpenoid alkaloids from Vitex trifolia, is reported. The presented approach features a Ni-catalyzed cross-electrophile coupling between a (+)-sclareolide-derived alkyl iodide and 3-bromo-2-cyanopyrrole.

Full text of DOI:10.1021/acs.joc.8b00882

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Note
Synthesis of (+)-Vitepyrroloid A and (+)-Vitepyrroloid B by Late-
Stage Ni-Catalyzed C(sp2)-C(sp3) Cross-Electrophile Coupling
Martina Menger, Dieter Lentz, and Mathias Christmann
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00882 • Publication Date (Web): 18 May 2018
Downloaded from http://pubs.acs.org on May 18, 2018
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The Journal of Organic Chemistry
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Synthesis of (+)ꢀVitepyrroloid A and (+)ꢀVitepyrroloid B by Lateꢀ
Stage NiꢀCatalyzed C(sp2)ꢀC(sp3) CrossꢀElectrophile Coupling
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Martina Menger, Dieter Lentz, and Mathias Christmann*
Freie Universität Berlin, Institute of Chemistry and Biochemistry, Takustr. 3, 14195 Berlin, Germany
Supporting Information Placeholder
ABSTRACT: A concise and scalable fiveꢀstep synthesis of vitepyrroloids A and B, two cytotoxic labdane diterpenoid alkaloids
from Vitex trifolia, is presented. The presented approach features a Niꢀcatalyzed crossꢀelectrophile coupling between a (+)ꢀ
sclareolideꢀderived
alkyl
iodide
and
3ꢀbromoꢀ2ꢀcyanopyrrole.
Several species of the Vitex genus within the Lamiaceae
family are used in traditional medicines for treatment in variꢀ
ous therapeutic indications. In 2017, Zhao and Gu reported the
isolation of four cytotoxic diterpenoid alkaloids from the dried
leaves of Vitex trifolia L. (Verbenaceae), a small deciduous
shrub that is broadly distributed in South China.1 Vitepyrꢀ
roloids A–C (1–3, Figure 1) and D (not shown) share an unꢀ
precedented 2ꢀcyanopyrrole labdane core and differentiate in
both the oxidation pattern of the decalin fragment and the subꢀ
stituent at the pyrrole nitrogen. This general motif of an oxiꢀ
dized decalin linked to a heterocyclic moiety by an ethylene
bridge is also found in other natural products such as vitexlacꢀ
tam A,2 marrubiin3ꢀ5 and vitetrifolin H.6 Vitepyrroloid A disꢀ
played cytotoxic activity against a human nasopharyngeal
carcinoma cell line (CNE1) with an IC50 value of 8.7 ꢁM.
Deeper explorations of its biomedical potential were inhibited
by a low isolation yield of 3·10ꢀ5 %. Therefore, the developꢀ
ment of an efficient chemical synthesis of vitepyrroloid A
would allow for further biological studies.
of the decalin coupling partner 5, we identified the terpenoid
(+)ꢀsclareolide as potential starting material7ꢀ11 in accordance
with longꢀstanding interest in the utilization of terpene feedꢀ
stock as suitable building blocks,12ꢀ14 thus minimizing the
number of CꢀCꢀbond forming reactions.
When contemplating potential synthetic approaches, we
opted for a lateꢀstage sp2ꢀsp3 coupling between C12 and C13.
Such a disconnection might be applicable not only to the synꢀ
thesis of vitepyrroloid A but also enable the synthesis of the
other natural products shown in Figure 1. Among possible
coupling reactions, we favored a crossꢀelectrophile coupling
over the SuzukiꢀMiyaura coupling as an alkyl halide appeared
more readily accessible than a corresponding borane. As
shown in our retrosynthetic analysis (Figure 2), vitepyrroloid
A (1) can be disconnected into 3ꢀbromopyrrole 4 and alkyl
iodide 5. The pyrrole coupling partner 4 is accessible from the
commercially available pyrrole derivative 6. For the synthesis
Figure 1. Structures of vitepyrroloids AꢀC (1ꢀ3), vitexlacꢀ
tam A, marrubiin, and vitetrifolin H.
Concerning the modification of sclareolide, the challenge lies
in realizing a 1,2ꢀtransposition of the C8 oxygen to C9 that
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controls the configurations of the two affected stereogenic
Page 2 of 6
Raising the temperature to 65 °C resulted after 1 day in the
formation of roughly equal amounts of the alkenes 9 and 10
(entry 2). Equilibration of the reaction mixture at 65 °C for 5
days (entry 3) afforded the desired ∆8,9ꢀisomer 9 as the major
product in 70% yield along with 30% of alkene 10. A further
increase of the reaction time or performing the reaction in a
pressure tube at 95 °C bath temperature (entry 4) did not
change isomeric ratios. After separation of 9 and 10 by colꢀ
umn chromatography, alkene 9 was epoxidized with in situ
generated trifluoroperoxyacetic acid (Scheme 2) to give 12 as
an inseparable 16:1 mixture of diastereomers. Reduction of the
ester and concomitant reductive opening10 of the epoxide moiꢀ
ety with LiAlH4 afforded diol 13 which was isolated as single
diastereomer in 76% yield. Finally, the terminal hydroxyl
group was converted to an iodide with I2/PPh3/imidazole17 to
give 5 in 91% yield.
1
2
3
4
5
6
7
8
centers.
NH
NH
sp2-sp3-
coupling
NH
CO2Me
CN
CN
13
Br
Br
12
4
6
O
O
OH
I
OH
9
9
8
H 8
9
H
10
11
12
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H
H
1
isolation yield: 8.6 mg
(+)-sclareolide (7)
5
from 30 kg of dried leaves
Figure 2. Retrosynthetic analysis.
Scheme 2. Synthesis of alkyl iodide 5.
The synthesis of bromopyrrole 4 commenced with the basic
hydrolysis of the commercially available methyl ester 615 folꢀ
lowed by formation of amide 8 using HOBt as activating agent
and ammonium chloride as nitrogen source (Scheme 1). Subꢀ
sequently, the amide 8 was dehydrated to nitrile 4 in 87%
yield using TFAA in pyridine.
Scheme 1. Synthesis of bromopyrrole 4.
The synthesis of the decalin fragment started from commerꢀ
cially available (+)ꢀsclareolide (7). Treatment with sulfuric
acid in methanol16 resulted in the methanolysis of the lactone
and elimination of the resulting tertiary alcohol at C8. The
ratio of ∆8,9ꢀalkene 9, ∆7,8ꢀalkene 10, and the exocyclic alkene
isomer 11 is strongly dependent on the reaction temperature
and reaction time (Table 1). At 23 °C, the reaction was comꢀ
plete after 3 days to afford a mixture of alkenes 9–11, with the
∆7,8ꢀalkene 10 as the major product (entry 1).
With the two functionalized building blocks 4 and 5 in hand, a
conservative coupling strategy might involve conversion of
alkyl iodide 5 into a nucleophilic coupling partner e.g. via
halogenꢀmetalꢀexchange or elimination/hydroboration. In orꢀ
der to avoid additional steps and the use of protecting groups,
a direct coupling reaction was sought that would tolerate the
functional groups present. Crossꢀelectrophile couplings have
witnessed a tremendous evolution in over the last two decꢀ
ades.18ꢀ20 Yet, they are far from being a standard transforꢀ
mation in the synthesis of natural products.21 Potential obstaꢀ
cles include reductive homocoupling, hydride functionalizaꢀ
tion and catalyst deactivation. The application of literatureꢀ
reported catalytic systems such as NiCl2/phen,22 CoBr2/P(pꢀ
Tol)3,23 PdCl2/amphos24 or NiI2(dme)25 did not yield any deꢀ
sired product. With the dual ligand NiI2·H2Oꢀsystem,26 only
traces of the desired product could be detected. Eventually, a
system developed by Qian and Gong,27 NiI2/bpy in dimethylaꢀ
cetamide (DMAc) with 3 equiv of Zn as reductant, afforded
vitepyrroloid A (1) in 12% yield (Table 2, entry 1). The use of
NaI (2 equiv) as additive increased the yield to 24% (entries
2,3). Weix19 suggested that NaI suppresses the formation of
homocoupling products. Raising the temperature from 50 to
70 °C further improved the yield to 40% (entry 4). Changing
the solvent to NMP and 1,4ꢀdioxane led to a decreased yield
(entries 5,6) while DMF and DMPU inhibited the reaction.
When two equivalents of the alkyl iodide 5 were used, vitepyrꢀ
roloid A (1) was isolated in 57% yield (entry 7). Manganese or
Table 1. Methanolysis/Elimination of (+)ꢀsclareolide (7).
entry
T [°C]
23
t [d]
3
9 [%]a
9
10 [%]a 11 [%]a
1
2
53
51
30
32
38
ꢀ
65
1
49
3
4b
65
5
70
ꢀ
95
7
68
ꢀ
b
aIsolated yields are displayed. The reaction was carried out
28
B2pin2 as reducing agents and other ligands than bpy did not
provide beneficial effects in either case. Under electrochemiꢀ
in a pressure tube.
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The Journal of Organic Chemistry
cal conditions,29 the product was formed in 21% yield (see
Supporting Information for additional screening results).
500 and 700 MHz, 13C NMR at 125 and 175 MHz with solvent
resonance as the internal standard (1H NMR: CDCl3 at
7.26 and DMSOꢀd6 at 2.50 , 13C NMR: CDCl3 at 77.0 and
1
2
3
4
5
6
7
8
Table 2. Crossꢀelectrophile coupling of 4 and 5.a
DMSOꢀd6 at 39.5 ). H NMR data are reported as follows:
1
NH
chemical shift, multiplicity (s = singlet, brs = broad singlet, d
= doublet, dd = doublet of doublet, t = triplet, m = multiplet),
coupling constant (Hz), and integration. High resolution mass
spectra were measured with a TOF mass spectrometer. TLC
visualization was accomplished using UV light, Cer(IV)ꢀ
sulfate solution in water, or acidic pꢀanisaldehyde solution in
ethanol. Yields refer to isolated yields after flash column
chromatography.
CN
I
NiI2(bpy) (10 mol%)
Zn (3 equiv), NaI
OH
OH
NH
+
conditions
CN
9
H
H
10
11
12
13
14
15
16
17
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Br
5
4
1
vitepyrroloid A ( )
3ꢀBromoꢀ1Hꢀpyrroleꢀ2ꢀcarboxamide (8). To a solution of meꢀ
thyl ester 6 (467 mg, 2.29 mmol, 1.0 equiv) in EtOH/H2O (1:1
v/v; 22.9 mL) was added NaOH (183 mg, 4.58 mmol, 2.0
equiv), and the mixture was heated to reflux for 16 h. Upon
concentration under reduced pressure, the residue was disꢀ
solved in EtOAc (50 mL) and successively washed with 1M
HCl (10 mL) and brine, dried over MgSO4, and concentrated
under reduced pressure. The crude carboxylic acid was disꢀ
solved in anhydrous CH2Cl2 (7.0 mL) and HOBt (351 mg,
2.60 mmol, 1.2 equiv), and EDCl (499 mg, 2.60 mmol, 1.2
equiv) were added subsequently. The mixture was stirred for
10 min at 23 °C before NH4Cl (173 mg, 3.23 mmol, 1.49
equiv) and NEt3 (0.45 mL, 3.26 mmol, 1.5 equiv) were added.
The reaction was stirred for 18 h and then quenched by the
addition of H2O (10 mL). After extraction with EtOAc (3 x
25 mL), the combined organic phases were washed with brine,
dried over MgSO4, and concentrated under reduced pressure.
After purification by column chromatography (nꢀ
pentane/EtOAc = 1:1) amide 8 (400 mg, 2.12 mmol, 98%) was
obtained as a colorless solid. Rf = 0.30 (nꢀpentane/EtOAc =
1:1); mp = 175–176 °C; IR: ṽ = 3458, 3298, 3161, 3133, 1640,
entry
1
2
3
4
NaI [equiv]
solvent
DMAc
DMAc
DMAc
DMAc
NMP
1,4ꢀdioxane
DMAc
temp [°C] 1 [%]
0
1
2
2
2
2
2
50
50
50
70
70
70
70
12
19
24
40
31
16
57
5
6
7b
aReaction conditions: 4 (1.0 equiv), 5 (1.0 equiv), NiI2(bpy) (10
mol%), Zn (3.0 equiv), solvent (0.16 M). b 2.0 equiv of alkyl ioꢀ
dide 5 were used.
The reported absolute configuration of 1 was confirmed by Xꢀ
ray diffraction. Moreover, it was possible to convert vitepyrꢀ
roloid A (1) into vitepyrroloid B (2) by Nꢀalkylation with ethyl
4ꢀbromobutyrate using sodium hydride in DMF (Scheme 3).
Scheme 3. Synthesis of Vitepyrroloid B (2) from 1 (displaceꢀ
ment ellipsoids are drawn at 50% probability level).
1
1590, 1461, 1443, 1425, 987, 729 cmꢀ1; H NMR (500 MHz,
DMSOꢀd6): δ = 11.81 (brs, 1H), 7.43 (brs, 1H), 7.03 – 6.88
(m, 1H), 6.81 (brs, 1H), 6.24 (t, J = 2.7 Hz, 1H); 13C NMR
(125 MHz, DMSOꢀd6): δ = 160.8, 123.0, 121.9, 112.5, 97.2;
HRMS (ESIꢀTOF) m/z: [M+H]+ calculated for C5H5BrN2OH
188.9658, found 188.9658; [M+Na]+ calculated for
C5H5BrN2ONa 210.9477, found 210.9476.
3ꢀBromoꢀ1Hꢀpyrroleꢀ2ꢀcarbonitrile (4). Amide 8 (212 mg,
1.12 mmol, 1.0 equiv) was dissolved in pyridine (5.7 mL), and
TFAA (0.63 mL, 4.48 mmol, 4.0 equiv) was added dropwise
at 0 °C. The reaction mixture was stirred at this temperature
for 2 h, then diluted with EtOAc (60 mL) and washed with
saturated NaHCO3 solution, 1M HCl and brine. The organic
phase was dried over MgSO4, and concentrated under reduced
pressure. The crude product was purified by column chromaꢀ
tography (nꢀpentane/EtOAc = 3:1) to give the nitrile 4
(166 mg, 0.971 mmol, 87%) as a colorless solid. Rf = 0.30 (nꢀ
pentane/EtOAc = 5:1); mp = 95–96 °C; IR: ṽ = 3321, 3145,
2217, 1426, 1388, 1001, 746 cmꢀ1; 1H NMR (700 MHz,
CDCl3): δ = 9.67 (brs, 1H), 6.90 (t, J = 3.0 Hz, 1H), 6.33 (t, J
= 2.7 Hz, 1H); 13C NMR (175 MHz, CDCl3): δ = 124.7,
113.3, 113.2, 108.7, 102.4; HRMS (ESIꢀTOF) m/z: [M+H]+
calculated for C5H3BrN2H 170.9553, found 170.9550;
[M+Na]+ calculated for C5H3BrN2Na 192.9372, found
192.9367.
In summary, the first synthesis of vitepyrroloids A and B has
been achieved in five and six steps respectively, from comꢀ
mercially available starting materials. The application of a
crossꢀelectrophile coupling strategy was key to rendering the
overall sequence concise and protectingꢀgroupꢀfree. With a
reliable access to vitepyrroloid A and its congeners, we are
now in a position to investigate their biological activity.
EXPERIMENTAL SECTION
General Information. All reactions sensitive to moisture
and/or air were performed under an argon atmosphere using
Schlenk techniques. Reagents and solvents were obtained from
commercial sources and used as received unless otherwise
noted. NiI2(bpy) and analogs were prepared according to literꢀ
ature.30 Nuclear magnetic resonance spectra (1H NMR, 13C
NMR) were recorded at the following frequencies: 1H NMR at
Methyl
2ꢀ((8aS)ꢀ2,5,5,8aꢀtetramethylꢀ3,4,4a,5,6,7,8,8aꢀ
octahydronaphthalenꢀ1ꢀyl)acetate (9).31,32 To a solution of (+)ꢀ
sclareolide 7 (1.00 g, 4.00 mmol) in MeOH (19 mL), was addꢀ
ed conc. H2SO4 (0.7 mL) and the mixture heated to reflux for
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The Journal of Organic Chemistry
5 days. MeOH was distilled off and the residue was dissolved
Page 4 of 6
two steps) was obtained as a colorless solid after column
chromatography (nꢀpentane/EtOAc = 5:1). Rf = 0.42 (nꢀ
pentane/EtOAc = 5:1); mp = 76–77 °C; [α]D24 = +16.6 (CHCl3,
c = 1.0); IR: ṽ = 3336, 2963, 2933, 2870, 1455, 1386, 1362,
1133, 1046, 1038, 720 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ =
3.84 (td, J = 10.7, 2.7 Hz, 1H), 3.72 (dt, J = 9.9, 4.3 Hz, 1H),
2.48 (brs, 1H), 2.34 (brs, 1H), 2.04 (ddd, J = 15.2, 9.5, 3.9 Hz,
1H), 1.74 – 1.66 (m, 1H), 1.58 – 1.43 (m, 7H), 1.38 – 1.19 (m,
4H), 1.15 (td, J = 13.5, 3.9 Hz, 1H), 0.90 (d, J = 6.7 Hz, 3H),
0.88 (s, 3H), 0.87 (s, 3H), 0.83 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ = 78.5, 61.6, 46.3, 43.2, 41.9, 37.7, 35.5, 33.8, 33.5,
31.8, 31.3, 22.0, 21.6, 18.7, 16.4, 15.9; HRMS (ESIꢀTOF) m/z:
[M+Na]+ calculated for C16H30O2Na 277.2138, found
277.2152.
1
2
3
4
5
6
7
8
in Et2O (100 mL), washed with H2O, saturated NaHCO3 soluꢀ
tion, and brine. The organic phase was dried over MgSO4 and
concentrated under reduced pressure. The crude alkene mixꢀ
ture was separated by column chromatography (nꢀ
pentane/Et2O = 120:1 to 80:1) to give alkenes ꢂ8,9ꢀ 9 (740 mg,
2.80 mmol, 70%) and ꢂ7ꢀ10 (317 mg, 1.20 mmol, 30%) as
1
colorless oils. 9: Rf = 0.46 (nꢀpentane/Et2O = 40:1); H NMR
(500 MHz, CDCl3): δ = 3.66 (s, 3H), 3.08 (d, J = 16.8 Hz,
1H), 2.97 (d, J = 17.0 Hz, 1H), 2.11 (dd, J = 11.5, 6.8 Hz, 1H),
2.02 (dd, J = 17.9, 6.4 Hz, 1H), 1.72 – 1.62 (m, 2H), 1.61 –
1.57 (m, 1H), 1.56 (s, 6H), 1.49 – 1.34 (m, 3H), 1.21 (dd, J =
12.7, 1.9 Hz, 1H), 1.19 – 1.07 (m, 2H), 0.92 (s, 6H), 0.88 (s,
6H), 0.83 (s, 6H); 13C NMR (125 MHz, CDCl3): δ = 173.6,
134.0, 130.4, 51.8, 51.5, 41.7, 38.7, 36.4, 33.8, 33.4, 33.3,
33.0, 21.8, 20.2, 19.9, 19.1 (2C). 10: Rf = 0.47 (nꢀ
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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40
41
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45
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(1R,2R,8aS)ꢀ1ꢀ(2ꢀIodoethyl)ꢀ2,5,5,8aꢀ
tetramethyldecahydronaphthalenꢀ1ꢀol (5). To a solution of 13
(136 mg, 0.535 mmol, 1.0 equiv) in anhydrous THF (11 mL)
was added PPh3 (154 mg, 0.588 mmol, 1.1 equiv), imidazole
(73.0 mg, 1.07 mmol, 2.0 equiv), and I2 (149 mg, 0.588 mmol,
1.1 equiv), and the mixture stirred for 1 h at 23 °C. The reacꢀ
tion was quenched by the addition of saturated Na2S2O3 soluꢀ
tion (20 mL), extracted with Et2O (3 x 30 mL). The combined
organic phases were dried over MgSO4 and concentrated unꢀ
der reduced pressure. The crude product was purified by colꢀ
umn chromatography (nꢀpentane/Et2O = 30:1) giving the ioꢀ
1
pentane/Et2O = 40:1); H NMR (500 MHz, CDCl3): δ = 5.47
– 5.39 (m, 1H), 3.68 (s, 3H), 2.49 (d, J = 9.5 Hz, 1H), 2.42 –
2.35 (m, 1H), 2.17 (dd, J = 16.5, 9.7 Hz, 1H), 2.04 – 1.95 (m,
1H), 1.84 (dddt, J = 17.5, 12.0, 4.5, 2.4 Hz, 1H), 1.75 – 1.65
(m, 1H), 1.56 – 1.53 (m, 3H), 1.53 – 1.37 (m, 3H), 1.28 (dd, J
= 12.2, 4.7 Hz, 1H), 1.18 (td, J = 13.1, 3.6 Hz, 1H), 1.09 (td, J
= 13.0, 3.9 Hz, 1H), 0.88 (s, 3H), 0.86 (s, 3H), 0.75 (s, 3H);
13C NMR (125 MHz, CDCl3): δ = 175.5, 133.8, 122.9, 51.9,
50.7, 49.9, 42.2, 39.2, 36.1 33.3, 33.1, 23.8, 22.0, 21.5, 18.9,
14.1 (2C).
dide 5 (177 mg, 0.485 mmol, 91%) as a colorless solid.
Rf = 0.61 (nꢀpentane/Et2O = 30:1); mp = 45–47 °C; [α]D
25
Methyl
2ꢀ((1aR,7aS,7bS)ꢀ1a,4,4,7aꢀ
=
tetramethyloctahdronaphtho[1,2ꢀb]oxirenꢀ7b(1aH)ꢀyl)acetate
(12). TFAA (0.21 mL, 1.51 mmol, 2.0 equiv) was added
dropwise to a suspension of UHP (156 mg, 1.66 mmol, 2.2
equiv) in MeCN (4.6 mL) at 0 °C. The resulting solution was
stirred for 45 min and then added to a suspension of alkene 9
(200 mg, 0.756 mmol, 1.0 equiv) and NaH2PO4ꢃ2H2O
(538 mg, 3.02 mmol, 4.0 equiv) in CH2Cl2 (9.2 mL) at –20 °C.
The mixture was stirred for 2 h at this temperature, then dilutꢀ
ed with H2O (10 mL) and extracted with Et2O (4 x 20 mL).
The combined organic phases were dried over MgSO4 and
concentrated under reduced pressure. After purification by
column chromatography (nꢀpentane/Et2O = 8:1) the epoxide
12 (193 mg, 0.688 mmol, 86%, d.r. = 16:1, in total 91%) was
obtained as colorless oil. Rf = 0.36 (nꢀpentane/Et2O = 8:1); IR:
ṽ = 2946, 2924, 1741, 1457, 1434, 1380, 1333, 1266, 1194,
1161 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ = 3.65 (s, 3H), 2.84
(d, J = 15.9 Hz, 1H), 2.50 (d, J = 15.9 Hz, 1H), 1.96 – 1.79 (m,
2H), 1.74 – 1.66 (m, 1H), 1.54 – 1.48 (m, 2H), 1.45 (dd, J =
12.9, 2.4 Hz, 1H), 1.40 – 1.32 (m, 3H), 1.29 (s, 3H), 1.27 –
1.20 (m, 1H), 1.15 (td, J = 12.7, 5.2 Hz, 1H), 0.97 (s, 3H),
0.82 (s, 3H), 0.78 (s, 3H) 13C NMR (125 MHz, CDCl3): δ =
171.7, 69.8, 63.7, 52.0, 43.1, 41.6, 38.9, 35.00, 34.9, 34.0,
33.3, 29.8, 22.7, 21.8, 18.8, 17.6, 17.3; HRMS (ESIꢀTOF) m/z:
[M+Na]+ calculated for C17H28O3Na 303.1930, found
303.1937.
+26.9 (CHCl3, c = 1.0); IR: ṽ = 3594, 2937, 2896, 2867, 1458,
1384, 1319, 1171, 958 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ =
3.31 – 3.13 (m, 2H), 2.34 (ddd, J = 14.6, 11.8, 6.4 Hz, 1H),
2.04 (ddd, J = 14.6, 11.4, 5.6 Hz, 1H), 1.74 (dqd, J = 13.2, 6.6,
4.1 Hz, 1H), 1.60 – 1.47 (m, 4H), 1.47 – 1.41 (m, 1H), 1.36
(dt, J = 12.1, 2.9 Hz, 1H), 1.32 – 1.28 (m, 2H), 1.28 – 1.18 (m,
2H), 1.18 – 1.07 (m, 1H), 0.90 (s, 3H), 0.88 (d, J = 6.7 Hz,
3H), 0.87 (s, 3H), 0.83 (s, 3H); 13C NMR (125 MHz, CDCl3):
δ = 79.1, 46.5, 43.2, 41.8, 40.4, 37.0, 33.8, 33.5, 32.0, 31.1,
22.1, 21.6, 18.6, 16.5, 16.1, 4.1; HRMS (ESIꢀTOF) m/z:
[M+Na]+ calculated for C16H29IONa 387.1155, found
387.1156.
General Procedure for CrossꢀElectrophile Coupling. Exꢀ
ample for entry 7. (+)ꢀVitepyrroloid A (1). Iodide 5 (35.0 mg,
0.0960 mmol, 2.0 equiv), nitrile 4 (8.20 mg, 0.0480 mmol, 1.0
equiv), Zn (9.40 mg, 0.144 mmol, 3.0 equiv), NaI (14.4 mg,
0.0960 mmol, 2.0 equiv) and NiI2(bpy) (2.20 mg, 0.600 µmol,
10 mol%) were placed in a Schlenk flask under an argon atꢀ
mosphere and the flask evacuated and flashed with argon (3
x). Afterwards, anhydrous DMAc (0.3 mL) was added and the
brown mixture was stirred for 16 h at 70 °C. The mixture was
diluted with H2O (5.0 mL) and the resulting black solution was
extracted with EtOAc (4 x 15 mL), dried over MgSO4, and
concentrated under reduced pressure. (+)ꢀVitepyrroloid A was
obtained after column chromatography (nꢀpentane/EtOAc =
6.5:1) and subsequent recrystallization (MeOH) as a colorless
(1R,2R,8aS)ꢀ1ꢀ(2ꢀHydroxyethyl)ꢀ2,5,5,8aꢀ
tetramethyldecahydronaphthalenꢀ1ꢀol (13). LiAlH4 (118 mg,
3.11 mmol, 5.5 equiv) was suspended in anhydrous THF
(2.2 mL) and a solution of epoxide 12 (159 mg, 0.567 mmol,
d.r. = 16:1, 1.0 equiv) in anhydrous THF (10 mL) was added
dropwise. The mixture was heated to 60 °C and stirred at this
temperature for 16 h. After cooling to 23 °C, the reaction was
quenched by the careful addition of EtOAc (10 mL) and 1M
HCl (10 mL). The reaction mixture was extracted with EtOAc
(4 x 30 mL), dried over MgSO4, and concentrated under reꢀ
duced pressure. Diol 13 (117 mg, 0.460 mmol, 81%, 76% over
solid (9.00 mg, 0.0274 mmol, 57%).
25
Rf = 0.31 (nꢀpentane/EtOAc = 5:1); mp = 158–160 °C; [α]D
=
+8.64 (MeOH, c = 0.87), Lit.1: [α]D = +10 (MeOH, c = 0.2);
IR: ṽ = 3599, 3344, 2933, 2916, 2863, 2209, 1457, 1444,
1405, 1382, 1258, 1133, 759 cmꢀ1; 1H NMR (700 MHz,
CDCl3): δ = 8.48 (brs, 1H) 6.84 (t, J = 2.9 Hz, 1H), 6.14 (t, J =
2.7 Hz, 1H), 2.67 (ddd, J = 21.2, 12.0, 5.7 Hz, 2H), 1.94 (ddd,
J = 14.4, 12.2, 6.0 Hz, 1H), 1.84 – 1.81 (m, 1H), 1.73 – 1.68
(m, 1H), 1.60 – 1.48 (m, 6H), 1.42 (dd, J = 12.0, 2.6 Hz, 1H),
1.38 – 1.34 (m, 1H), 1.33 – 1.24 (m, 2H), 1.16 (td, J = 13.2,
25
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The Journal of Organic Chemistry
We thank Tommaso Pecchioli and Gregor Nagel (both FU Berlin)
3.5 Hz, 1H), 0.96 (d, J = 6.7 Hz, 3H), 0.95 (s, 3H), 0.88 (s,
3H), 0.84 (s, 3H); 13C NMR (175 MHz, CDCl3): δ = 138.0,
123.2, 114.2, 110.0, 99.2, 77.0, 46.4, 43.3, 41.7, 36.6, 35.7,
33.8, 33.4, 31.9, 31.3, 23.3, 22.0, 21.6, 18.6, 16.4, 16.2;
HRMS (ESIꢀTOF) m/z: [M+Na]+ calculated for C21H32N2ONa
351.2407, found 351.2402; [M+K]+ calculated for
C21H32N2OK 367.2147, found 367.2164.
for helpful discussions and Christiane Groneberg (FU Berlin) for
analytical support. We acknowledge the assistance of Hendrik
Schröder (FU Berlin) for the electrochemical reaction.
1
2
3
4
5
6
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8
9
(+)ꢀVitepyrroloid
B
(2). (+)ꢀVitepyrroloid
A
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24 µmol, 1.0 equiv) dissolved in anhydrous DMF (0.7 mL)
was treated with NaH (1.3 mg, 32 µmol, 60 w% 1.3 equiv).
The solution was stirred for 20 min at 23 °C before ethyl 4ꢀ
bromobutyrate (4.50 µL, 32 µmol, 1.3 equiv) was added and
stirring was continued for 16 h at 85 °C. The mixture was diꢀ
luted with H2O (3.0 mL) and the resulting yellow solution was
extracted with EtOAc (4 x 15 mL), dried over MgSO4, and
concentrated under reduced pressure. (+)ꢀVitepyrroloid B
(8.0 mg, 19 µmol, 79%) was obtained after column chromaꢀ
tography (nꢀpentane/EtOAc = 5:1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
23
Rf = 0.34 (nꢀpentane/EtOAc = 5:1); [α]D = +9.8 (MeOH, c =
0.70), Lit.1: [α]D = +9 (MeOH, c = 0.2); IR: ṽ = 3510, 2933,
25
2868, 2209, 1458, 1444, 1408, 1374, 1239, 1182, 1024, 738,
651 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ = 6.72 (d, J =
2.5 Hz, 1H), 6.02 (d, J = 2.4 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H),
4.04 (t, J = 6.9 Hz, 2H), 2.80 – 2.52 (m, 2H), 2.28 (t, J =
7.2 Hz, 2H), 2.11 (p, J = 7.0 Hz, 2H), 1.96 – 1.86 (m, 1H),
1.84 – 1.78 (m, 1H), 1.73 – 1.65 (m, 1H), 1.62 – 1.40 (m, 8H),
1.37 – 1.29 (m, 3H), 1.28 – 1.24 (t, J = 7.2 Hz, 3H), 1.15 (td, J
= 13.1, 3.4 Hz, 1H), 0.96 (d, J = 7.2 Hz, 3H), 0.94 (s, 3H),
0.87 (s, 3H), 0.84 (s, 3H); 13C NMR (125 MHz, CDCl3): δ =
172.8, 138.5, 126.7, 114.2, 109.6, 102.3, 77.4, 61.1, 48.2,
46.8, 43.6, 42.1, 37.0, 36.1, 34.1, 33.7, 32.2, 31.7, 31.2, 26.6,
24.0, 22.4, 22.0, 19.0, 16.8, 16.6, 14.6; HRMS (ESIꢀTOF) m/z:
[M+Na]+ calculated for C27H42N2O3Na 465.3087, found
465.3101; [M+K]+ calculated for C27H42N2O3K 481.2851,
found 481.2841.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Screening, spectroscopic, and Xꢀray crystallography data (PDF)
Accession Codes
CCDC 1819079 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing daꢀ
ta_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: mathias.christmann@fuꢀberlin.de
ORCID
Mathias Christmann: 0000ꢀ0001ꢀ9313ꢀ2392
Notes
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Proline. Aust. J. Chem. 2009, 62, 683‒691.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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