A Ring-Closing Enyne Metathesis Approach to Functionalized Semicyclic Dienes: The Total Synthesis of (-)-Tetrangomycin

Article abstract of DOI:10.1002/ejoc.201301627

The angucycline antibiotic (-)-tetrangomycin was synthesized in 13 steps (11 % overall yield) by using a stereoselective Diels-Alder reaction between a naphthoquinone and a semicyclic diene to construct the benz[a]anthraquinone ring system. The diene inte

Full text of DOI:10.1002/ejoc.201301627

FULL PAPER
DOI: 10.1002/ejoc.201301627
A Ring-Closing Enyne Metathesis Approach to Functionalized Semicyclic
Dienes: The Total Synthesis of (–)-Tetrangomycin
Lindon W. K. Moodie[a] and David S. Larsen*[b]
Keywords: Total synthesis / Asymmetric synthesis / Natural products / Cycloaddition / Metathesis
The angucycline antibiotic (–)-tetrangomycin was synthe-
sized in 13 steps (11% overall yield) by using a stereoselec-
tive Diels–Alder reaction between a naphthoquinone and a
semicyclic diene to construct the benz[a]anthraquinone ring
system. The diene intermediates were synthesized through a
ring-closing enyne metathesis reaction. The tertiary alcohol
at C-3 was installed by an asymmetric dihydroxylation reac-
tion. The relative stereochemistry of the dienes was verified
by the NMR analyses of the cycloadducts that were obtained
from their reaction with N-phenylmaleimide. Selective aro-
matization of the B ring was achieved under oxidative condi-
tions.
Introduction
The angucycline antibiotics are one of the largest families
of type II polyketide synthase natural products. Members
typically contain a tetracyclic benz[a]anthracene scaffold,
which characteristically differs by the degree of saturation,
oxygenation, and glycosylation. Angucyclines display a
range of biological activities, notably antibacterial and anti-
cancer, which have spurred interest in their total synthesis,
isolation, and biosynthesis. These aspects have been the
subject of several comprehensive reviews,[1] the most recent
of which was by Rohr and co-workers in 2012.[2] A com-
monly conserved substitution pattern among the angucy-
clines involves the oxygen functionality at the 1- and 3-posi-
tions as well as a methyl group at C-3 as exhibited by com-
pounds 1–5 (see Figure 1).
Figure 1. Examples of angucyclines that contain the C-3 methyl
and hydroxy functionalities.
We rationalized that access to a common synthetic inter-
mediate that contains the 1,3-oxygenation and substitution
pattern of the A ring could allow the syntheses of both
naturally occurring angucyclines and their analogues. Of
particular interested is (–)-tetrangomycin (1),[3] which has
been identified as a potential drug lead against methicillin-
resistant Staphylococcus aureus (MRSA).[4] Although vari-
ous strategies have been employed for synthetic studies of
the angucyclines,[5] the Diels–Alder reaction has proven to
be a reliable and efficient approach to construct the benz-
[a]anthraquinone skeleton.[6] Furthermore, enantioenriched
cycloadducts have been obtained by employing optically
active dienophiles,[7] dienes,[6a,6d–6g,8] and chiral Lewis ac-
ids.[6c] The synthesis of (–)-tetrangomycin (1) by the Kaliap-
pan research group employed a Diels–Alder approach in
which C-3 functionalized diene 7, synthesized by a ring-
closing enyne metathesis (RCEM) reaction, was treated
with bromojuglone 6 (see Scheme 1).[6a] Prior to isolation
or characterization, the resulting cycloadduct was treated
with base to effect the aromatization of the B ring and de-
acetylation. Removal of the protecting group and then pho-
tooxidation completed the total synthesis.
In the context of a general strategy towards a wider range
of angucyclines, the use of diene 7 has its limitations. The
introduction of the C-1 ketone functionality through a Nor-
rish type II photooxidation is well established in angucy-
cline chemistry.[6a,6c,7c,9] However, a general prerequisite for
this transformation is the aromaticity of the B ring, which
limits this approach to angucyclines that already contain
this motif. Accessing angucyclines of greater complexity
through further functionalization of the B ring would pres-
ent significant synthetic challenges. Another drawback of
[a] Department of Chemistry, University of Tromsø,
9037 Tromsø, Norway
[b] Department of Chemistry, University of Otago,
P. O. Box 56, Dunedin, New Zealand
E-mail: david.larsen@.otago.ac.nz
www.otago.ac.nz/chemistry
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301627.
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A Ring-Closing Enyne Metathesis Approach to Semicyclic Dienes
tified as an attractive strategy to synthesize dienes of this
type (see Figure 3).[13] Furthermore, Takayama and Fujish-
ima reported the synthesis of appropriately functionalized
enyne 13 during their studies of vitamin D analogues.[14]
This report entails the synthesis of semicyclic dienes using
a ring-closing enyne metathesis and demonstrates a proof
of concept through the total synthesis of the angucycline
(–)-tetrangomycin (1).
Scheme 1. Kaliappan synthesis of (–)-tetrangomycin (1).[6a] Rea-
gents and conditions: (a) C6H5CH3, 80 °C to 100 °C; (b) K2CO3,
MeOH, 62% over two steps; (c) 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ), CH2Cl2, pH = 7 buffer, 0 °C, 93%; (d) hv,
O2, C6H6, 64% (PMB = para-methoxybenzyl).
Figure 3. Retrosynthetic analysis of diene 9a.
dienes that lack substitution at C-1 is their lack of facial
selectivity in Diels–Alder reactions.[6c] Concurrent research
by our group is aimed at accessing enantiopure angucy- Results and Discussion
clines that contain an oxygenated hydroaromatic function-
Using a strategy based on the work of Takayama and
ality of the B ring (e.g., J-124131[10] aglycone 12, see Fig-
ure 2). Synthetic studies of compounds that are structurally
related to cycloadduct 11 have shown that the facial selec-
tivity of the oxidation of the C-4a–C-5 alkene is dictated by
the curved topology of the cycloadduct.[11] Hence, con-
trolling the diastereoselectivity of the Diels–Alder reactions
is of high priority.
Fujishima,[14] the synthesis began with the protection of
commercially available 3-methyl-but-3-en-1-ol (14) as its
para-methoxyphenyl (PMP) ether 15 (see Scheme 2).
Scheme 2. The asymmetric synthesis of enyne 13. Reagents and
conditions: (a) p-MeOC6H4OH, Ph3P, diisopropyl azodicarboxyl-
ate (DIAD), tetrahydrofuran (THF), 0 °C, 98%; (b) AD-mix-α,
CH3SO2NH2, tBuOH, H2O, 0 °C, 99%; (c) para-toluenesulfonyl
chloride (pTsCl), pyridine (py), 0 °C 95%; (d) lithium acetylide eth-
ylenediamine, dimethyl sulfoxide (DMSO), 95%; (e) TBSOTf (OTf
= trifluoromethylsulfonyl), collidine, CH2Cl2, quant.; (f) ceric am-
monium nitrate (CAN), MeCN/H2O, 0 °C, 87%; (g) Dess–Martin
periodinane, CH2Cl2, 99%; (h) C2H3MgBr, C6H5CH3, 95% (1.2:1.0
dr).
Figure 2. Functionalized diene 9a as a proposed intermediate to
angucyclines 1 and 12 (TBS = tert-butyldimethylsilyl).
The Sharpless asymmetric dihydroxylation of 15 pro-
vided diol 16 in high yield (99%). The primary hydroxy
Considering these limitations, we proposed the use of op- group of 16 was tosylated followed by treatment with lith-
tically enriched diene 9a (see Figure 2), which already con- ium acetylide ethylenediamine complex to afford 17 in 90%
tains the oxygen functionality at C-1 and, therefore, elimin- yield over two steps. The manipulation of the protecting
ates the need for a late-stage oxidation. Furthermore, it has groups afforded 18 in 87% yield from 17. Following the
been shown that semicyclic dienes that possess an allylic oxidative deprotection of the PMP-protected alcohol, the
oxygen functionality at C-1 exhibit high levels of facial sublimation of the benzoquinone byproduct prior to col-
selectivity during Diels–Alder reactions with quinone-based umn chromatography aided in the purification of 18. With
dienophiles.[6d,6e,7b,11,12] However, a survey of the literature alcohol 18 in hand, the sequence of oxidation and vinyla-
revealed a paucity of appropriately functionalized dienes. A tion reactions could be initiated. The oxidation of 18 by
rare example was reported by the Sulikowski group who treatment with Dess–Martin periodinane followed by treat-
synthesized 10 (see Figure 2) in an overall yield of 26% (14 ment of the corresponding aldehyde with freshly prepared
steps) from a quinic acid derivative.[6d] A RCEM was iden- vinylmagnesium bromide yielded enyne 13 as an inseparable
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mixture of diastereomers (approximately 1.2:1) in an overall
yield of 72% from 14. The success of our synthetic ap-
proach to tetrangomycin hinged upon the compatibility of
the RCEM reaction with enyne 13 (see Scheme 3).
Scheme 3. The RCEM of enyne 13 to afford separable dienes 9a
and 9b. Reagents and conditions: (a) 19 (10 mol-%), CH2Cl2
(0.045 m solution), argon, 9a (58%), 9b (30%).
The reaction conditions were screened to find that when
the RCEM of 13 was conducted using Grubbs first genera-
tion catalyst (19, 10 mol-%) under argon, chromatographi-
cally separable dienes 9a and 9b (faster and slower eluting,
respectively) were produced in a combined yield of 88%.
Attempts to discern the relative stereochemistry at C-1 and
C-3 of these dienes by using NOESY experiments were not
conclusive, but 9a and 9b were later found to be cis and
trans, respectively (vide infra), with regard to these groups.
Scheme 4. Diels–Alder reaction of diene 9a with N-phenylmaleim-
ide (20) and acid-catalyzed lactonization of 22 into 24. Reagents
and conditions: (a) C6H6, room temp., 21 (53%) and 22 (34%);
(b) para-toluenesulfonic acid (pTSA), MeOH, room temp., no reac-
tion; (c) pTSA, MeOH, room temp., 97%.
Interestingly, no improvement to reaction yield was ob- mon face, which confirmed that 21 was formed through an
served when an ethylene atmosphere[15] or other metathesis endo transition state. Examination of vicinal coupling con-
catalyst was utilized. The reactivity of 13 under an inert stants for the 1H NMR spectroscopic data of 21 and a
atmosphere could be attributed to its allylic hydroxy group, strong NOE correlation between H-2ax and H-9b, suggested
which has been shown to improve RCEM reactions.[16] Mo- a pseudo-trans-diaxial relationship between H-1 and the H-
sher’s ester analysis of both 9a and 9b indicated the enantio- 9b and H-2ax protons. This indicated that the cycloaddition
meric ratios of both dienes were greater than 95:5, which to give 21 occurred through a transition state in which dien-
verified high levels of asymmetric induction during the ophile 20 approached 9a from the face anti to the C-1 hy-
Sharpless asymmetric dihyroxylation (SAD) reaction. Ex- droxy group. Additionally, a strong NOE was observed be-
perimental work establishing the synthetic route to tetra- tween H-1 and the C-3 methyl group, which confirmed a
ngomycin (1) was developed using the racemates of the cis relationship between the C-1 and C-3 oxygen functional-
compounds as described in Scheme 2 (see Supporting Infor- ities of diene 9a. A similar analysis of cycloadduct 22 re-
mation). Additionally, dienes (Ϯ)-9a and (Ϯ)-9b were used vealed that it formed through an endo-syn transition state.
during the Mosher’s ester analysis. Enyne (Ϯ)-13 was syn- To reinforce this conclusion, we reasoned that the C-1 hy-
thesized in an overall yield of 66% from 14 using a synthetic droxy and C-9 imide carbonyl groups of syn adduct 22 were
sequence analogous to the asymmetric route, that is, aside in sufficient proximity for lactonization, whereas in anti ad-
from replacing the SAD reaction with an Upjohn dihydrox- duct 21, these groups were on opposite faces and, thus, were
ylation. The RCEM products, dienes (Ϯ)-9a and (Ϯ)-9b, unlikely to react. Our assumption was confirmed after 22
were obtained in 47 and 36% yield, respectively, after col- underwent lactonization (and concomitant TBS deprotec-
umn chromatography.
tion) under acidic conditions, but 21 remained unreacted.
Although it was unknown how new dienes 9a and 9b There appears to be no clear rationale for the differences in
would act in a Diels–Alder reaction, it warranted investiga- the facial selectivity exhibited by 9a and 9b. Therefore, fur-
tion. Their reaction with N-phenylmaleimide (20) might re- ther investigation and comparison of results to studies of
sult in cycloadducts with sufficient rigidity to allow deter- the reactions of similar semicyclic dienes[17] are warranted.
mination of the relative configurations. With this in mind,
The Diels–Alder reaction between 20 and the slower elut-
a solution of the faster eluting diene 9a was treated with N- ing diene 9b afforded an uncharacterized cycloadduct, ac-
1
phenylmaleimide (20, see Scheme 4). The two cycloadducts cording to the H NMR analysis of the crude reaction ma-
21 and 22 were separated by chromatography in 53 and terial (see Scheme 5). Lactonization of this cycloadduct
34% yield, respectively.
during chromatography afforded 26 as the sole product.
NOE correlations were instrumental in determining the
Strong NOE correlations between H-9b and both H-1
relative orientations of the stereocenters at C-1, C-3, C-6a, and H-9a along with the propensity for lactonization sug-
C-9a, and C-9b of 21 and 22 (see Scheme 4). The hydrogen gested that 26 stemmed from the endo-syn cycloadduct 25,
atoms at C-9a and C-9b of 21 were found to share a com- in which dienophile 20 approached 9b from the same face
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A Ring-Closing Enyne Metathesis Approach to Semicyclic Dienes
Scheme 5. Diels–Alder reaction of diene 9b with N-phenylmaleim-
ide (20) and subsequent lactonization to afford 26. Reagents and
conditions: (a) N-phenylmaleimide (20), C6H6, room temp., then
SiO2, 64%.
as the C-1 hydroxy group. NOESY studies of 26 were con-
sistent with a trans relationship between the C-1 and C-3
oxygen functionalities of diene 9b.
To explore the utility of these dienes with regard to the
syntheses of angucyclines, (–)-tetrangomycin (1) was chosen
as the target natural product because of its biological activi-
ties.[4] The evolution of drug resistance in S. aureus is a
global health concern, and new classes of anti-infectious
agents are required for its control.[18] A recent screening
Scheme 6. First generation attempts towards tetrangomycin (1).
Reagents and conditions: (a) 6, C6H5CH3, 80 °C, 66%; (b) 1,8-di-
azabicyclo[5.4.0]undec-7-ene (DBU), C6H6, various temperatures
(–15 °C, 0 °C, and r.t.), Ͻ65%; (c) Ac2O, py, 4-(N,N-dimeth-
ylamino)pyridine (DMAP), CH2Cl2, 84%; (d) 6, toluene, 100 °C,
74%; (e) DBU, CH2Cl2, (Ϯ)-30 (53%), (Ϯ)-31 (18%).
Following these unsuccessful approaches, we investigated
of approximately 1300 natural products that examined the an oxidative B-ring aromatization strategy[6d] of model cy-
inhibition of staphyloxanthin biosynthesis, a virulence fac- cloadduct (Ϯ)-33, which lacked the functionality C-3 [for
tor produced by S. aureus that enhances host infection by the synthesis of (Ϯ)-32, see Supporting Information]. A
scavenging reactive oxygen species,[19] revealed 1 as a prom- screening of oxidants revealed that the treatment of (Ϯ)-33
ising drug lead.[4]
with pyridinium dichromate (PDC) followed by exposure to
With diene (Ϯ)-9a in hand, the next synthetic transfor- air effectively oxidized the C-1 hydroxy group to initiate the
mation to examine was its Diels–Alder reaction with aromatization of the B ring. An unidentified byproduct of
bromojuglone 6 (see Scheme 6). The reaction of the diene this reaction was often observed, and we believe this occur-
(Ϯ)-9a with 6 was conducted at 80 °C and afforded cycload- rence was associated with the required, long reaction times.
duct (Ϯ)-11 as the sole diastereomer. The relative stereo- The addition of 4 Å molecular sieves[20] allowed full conver-
chemistry at C-12a, C-12b, and C-1 suggested that the sion in 2 h and supressed the formation of a side product.
product was formed through an endo transition state, in The D-ring phenol of (Ϯ)-35 was revealed by using lithium
which the dienophile approached the face of the diene anti hydroxide.
to the allylic hydroxy group (see Scheme 6). The aromatiza-
With this success, the PDC-mediated oxidative aromati-
tion of the B ring of cycloadduct (Ϯ)-11 was attempted un- zation methodology was applied to cycloadduct (Ϯ)-11 to
der basic conditions. Unfortunately, this resulted in frag- afford (Ϯ)-36 in 92% yield after chromatography (see
mentation of the C-1–C-12b bond to form aldehyde (Ϯ)- Scheme 7). Unfortunately, all attempts to remove the TBS
27.
protecting group were met with decomposition. Investi-
To avoid this undesired reactivity, diene (Ϯ)-9 was acetyl- gations were conducted regarding the necessity of the TBS
ated under standard conditions. The Diels–Alder cycload- protecting group, and the optimum stage of the synthesis
dition between (Ϯ)-28 and 6 resulted in the isolation of (Ϯ)- for its removal. However, the protection of the tertiary
29 as a single diastereomer in 74% yield. The treatment of alcohol of enyne 13 was crucial for a successful RCEM re-
(Ϯ)-29 with DBU afforded (Ϯ)-30 and (Ϯ)-31 in 53 and action.[21]
14% yield, respectively. Although the NMR analysis of
After the RCEM, the treatment of diene 9a with tetra-n-
these compounds was indicative of B-ring aromatization, a butylammonium fluoride (TBAF) afforded the requisite
full characterization proved difficult because of their insta- diol 37 (see Scheme 8). Interestingly, trans-oxygenated diene
bility. Additionally, (Ϯ)-31, with the C-8 phenolic function- 9b could not be deprotected under the screened reaction
ality, was prone to epimerization at the C-1 stereocenter. conditions. The Diels–Alder reaction between 6 and 37
Attempts to advance these compounds towards the synthe- yielded cycloadduct 38 in 87% yield. The oxidative aromati-
sis of tetrangomycin (1) resulted in decomposition.
zation followed by the deprotection of the phenol com-
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Diels–Alder reaction with bromojuglone 6 and an oxidat-
ively triggered B-ring aromatization. Further research by
the Larsen group is focused on using these dienes to access
angucyclines that contain B-ring oxygen functionality and
their structural analogues.
Experimental Section
1
General Methods: The H and 13C NMR spectroscopic data were
recorded either at 400 MHz with a Varian 400-MR NMR system
or at 500 MHz with a Varian 500 MHz AR Premium Shielded
spectrometer. Chemical shifts were referenced to the CHCl3 resid-
ual solvent peak at δ = 7.26 ppm or the [D5]acetone residual solvent
peak at δ = 2.05 ppm. Chemical shifts of the carbon nuclei are
reported relative to CDCl3 at δ = 77.16 ppm and [D6]acetone at δ
= 29.84 ppm. High resolution mass spectrometry data were re-
corded with a Bruker microTOF mass spectrometer using electro-
spray ionization (ESI) in either the positive or negative modes. In-
frared spectra were recorded with a Bruker Optics Alpha FTIR
spectrometer [with a diamond attenuated total reflectance (ATR)
top plate]. Optical rotations ([α]TD) were recorded with a Jasco DIP-
1000 digital polarimeter using a 100 mm cell. The rotations were
measured using the sodium D line (589 nm) at ambient tempera-
ture. Samples were prepared at the reported concentration (g/
100 mL) in the solvent indicated. Melting points were determined
with a Mettler Toledo FP62 automatic melting point apparatus.
Thin layer chromatography was performed with Merck aluminium-
backed silica gel 60 (0.2 mm) plates. Compounds were initially de-
tected by using ultraviolet light and iodine. TLC plates were devel-
oped using either a 5% w/v solution of dodecamolybdophosphoric
acid in ethanol or an ethanolic vanillin stain with subsequent heat-
ing. Column chromatography was performed using silica gel (200–
400 mesh, 40–63 μm). Anhydrous solvents were obtained from a
PURE SOLV MD-6 solvent purification system. Powdered molecu-
lar sieves were flame-dried under vacuum immediately prior to use.
Scheme 7. Oxidative B-ring aromatization of model compound
(Ϯ)-33 and its application towards tetrangomycin. Reagents and
conditions: (a) 6, C6H5CH3, 70 °C, 88%; (b) PDC, molecular sieves
(MS, 4 Å), CH2Cl2, 78%; (c) LiOH (0.1 m aqueous solution), THF,
0 °C, 71%; (d) PDC, MS (4 Å), CH2Cl2, then air, 92%.
pleted the total synthesis of (–)-tetrangomycin. The optical
rotation and spectroscopic data of 1 were consistent with
those previously reported.[5h,6c]
1-(4-Methoxyphenoxy)-3-methyl-3-butene
(15):[14]
DIAD
(14.86 mL, 75.5 mmol) was added to a stirred solution of alcohol
14 (5.00 g, 58.1 mmol), p-methoxyphenol (21.60 g, 174.0 mmol),
and triphenylphosphine (19.81 g, 75.5 mmol) in THF (125 mL) at
0 °C. The reaction mixture was then warmed to room temperature
and stirred for 12 h. The solvent was removed under reduced pres-
sure, and the resulting residue was dissolved in Et2O (100 mL). Pe-
troleum ether (300 mL) was added, and the mixture was stirred
overnight to allow the precipitation of the triphenylphosphine ox-
ide. After filtration and evaporation of solvent, the mixture was
subjected to column chromatography (EtOAc/petroleum ether, 1:9)
to give 15 (10.90 g, 98% yield) as a colorless oil. 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 6.86–6.82 (m, 4 H), 4.88–4.85 (m, 1
H), 4.83–4.81 (m, 1 H), 4.05 (t, 3JH,H = 6.9 Hz, 2 H), 3.78 (s, 3 H),
Scheme 8. Total synthesis of (–)-tetrangomycin (1). Reagents and
conditions: (a) TBAF, 0 °C, THF, 77%; (b) 6, C6H5CH3, 80 °C,
87%; (c) PDC, MS (4 Å), CH2Cl2, 72%; (d) LiOH (0.1 m aqueous
solution), THF, 0 °C, 54%.
Conclusions
We have described the synthesis of 1,3-functionalized se-
micyclic dienes 9a and 9b. The diene motif was forged by
using a ring-closing enyne metathesis and Sharpless asym-
metric dihydroxylation to form what becomes the C-3
stereocenter of the angucycline scaffold. Mosher’s ester
analysis of dienes 9a and 9b indicated that the SAD reac-
tion formed diol 16 with an enantiomeric ratio of 95:5. To
verify the potential of these dienes as synthetic intermedi-
ates for the angucycline natural products, (–)-tetrangomycin
(1) was synthesized in an overall yield of 11% (13 steps)
from commercially available alcohol 14. The crucial trans-
3
2.50 (t, JH,H = 6.9 Hz, 2 H), 1.83 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3, 25 °C): δ = 154.0, 153.2, 142.5, 115.7, 114.8,
112.1, 67.3, 55.8, 37.5, 23.0 ppm. IR (ATR): ν = 1505, 1225, 1038,
˜
822, 735 cm–1. HRMS (ESI): calcd. for C12H16NaO2 [M + Na]+
215.1048; found 215.1023. C12H16O2 (192.26): calcd. C 74.97, H
8.39; found C 75.10, H 8.68.
(+)-4-(4-Methoxyphenoxy)-2-methylbutane-1,2-diol [(+)-16]:[14] AD-
mix-α (14.0 g) and methanesulfonamide (0.989 g, 10.4 mmol) were
dissolved in a mixture of tert-butanol/H2O (1:1, 70 mL), and the
resulting mixture was cooled to 0 °C. To this, 15 (2.0 g, 10 mmol)
was added dropwise, and the reaction was stirred for 14 h. After
formations included a facially selective and regioselective quenching with sodium sulfite (16.08 g), the mixture was stirred for
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A Ring-Closing Enyne Metathesis Approach to Semicyclic Dienes
an additional 30 min. EtOAc (40 mL) was added, and the aqueous
layer extracted with EtOAc (3ϫ 40 mL). The combined organic
extracts were washed with brine (20 mL) and dried with MgSO4,
and the solvent was removed under reduced pressure. The resulting
residue was purified by column chromatography (EtOAc/petroleum
(2.60 g, 25.0 mmol) in CH2Cl2 (10 mL) at 0 °C, and the reaction
was stirred for 12 h. The mixture was then diluted with CH2Cl2
(50 mL), and the resulting solution was washed with H2O (30 mL)
and dried with MgSO4. The solvent was then removed under re-
duced pressure, and the compound was purified by column
ether, 4:1) to afford 16 (2.337 g, 99%) as a white solid; m.p. 52 °C. chromatography (EtOAc/petroleum ether, 1:10) to afford the title
[α]2D2 = +8.5 (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3, 25 °C):
δ = 6.88–6.77 (m, 4 H), 4.21–4.06 (m, 2 H), 3.77 (s, 3 H), 3.50 (dd,
compound (2.850 g, quant.) as a colorless oil. [α]2D2 = –12.1 (c =
1.0, CHCl3). 1H NMR (500 MHz, CDCl3, 25 °C): δ = 6.88–6.81
3
3
3JH,H = 11.1, 5.7 Hz, 1 H), 3.44 (dd, JH,H = 11.2, 5.9 Hz, 1 H),
(m, 4 H), 4.13–4.08 (m, 2 H), 3.77 (s, 3 H), 2.47 (dd, JH,H = 16.5,
3
3
3
2.10 (ddd, JH,H = 14.9, 7.9, 4.5 Hz, 1 H), 1.91 (ddd, 3JH,H = 14.9,
2.7 Hz, 1 H), 2.42 (dd, JH,H = 16.5, 2.7 Hz, 1 H), 2.17 (dt, JH,H
6.5, 4.3 Hz, 1 H), 1.25 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3, = 14.0, 7.1, 7.1 Hz, 1 H), 2.04 (dt, JH,H = 14.0, 7.1, 7.1 Hz, 1 H),
3
3
25 °C): δ = 154.40, 152.44, 115.69, 114.88, 72.48, 70.22, 65.59,
2.03 (t, JH,H = 2.6 Hz, 1 H), 1.43 (s, 3 H), 0.90 (s, 9 H), 0.12 (s, 3
H), 0.11 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ =
153.9, 153.3, 115.5, 114.8, 81.6, 74.4, 70.8, 64.9, 55.9, 41.0, 33.5,
55.87, 37.74, 24.32 ppm. IR (ATR): ν = 3314, 2918, 1506, 1465,
˜
1222, 1165, 1048 cm–1. HRMS (ESI): calcd. for C12H18NaO4 [M +
Na]+ 249.1097; found 249.1091. C12H18O4 (226.27): calcd. C 63.70,
H 8.02; found C 63.33, H 8.00.
28.0, 26.0, 18.4, –1.9, –2.0 ppm. IR (ATR): ν = 3309, 2119, 1617,
˜
1441, 1227, 1039, 826, 772 cm–1. HRMS (ESI): calcd. for
C20H32NaO3Si [M + Na]+ 371.2013; found 371.1999. C20H32O3Si
(348.56): calcd. C 68.91, H 9.25; found C 69.81, H 9.31.
(–)-1-(4-Methoxyphenoxy)-3-methyl-5-hexyn-3-ol [(–)-17]
(+)-4-(4-Methoxyphenoxy)-2-methyl-1-(4-methylphenylsulfonyl)-
2-butanol:[14] pTsCl (1.190 g, 6.2 mmol) was added to a solution of
diol 16 (1.177 g, 5.2 mmol) in pyridine (10 mL) at 0 °C. The reac-
tion was stirred for 3 h and then poured into H2O (30 mL), and
the product was extracted into Et2O (3ϫ 50 mL). The organic ex-
tracts were then washed with HCl (1 m aqueous solution, 20 mL),
H2O (20 mL), and brine (20 mL) and then dried with MgSO4. After
removal of the solvent, the crude residue was purified by column
chromatography (EtOAc/petroleum ether, 1:1–3:1) to give the title
compound (1.977 g, 95%) as a white solid; m.p. 51 °C. [α]2D2 = +9.1
(–)-3-tert-Butyldimethylsilyloxy-3-methyl-5-hexyn-1-ol [(–)-18]:[14] A
solution of the prepared silyl ether (0.546 g, 1.6 mmol) in aceto-
nitrile (20 mL) and H2O (6 mL) was stirred at 0 °C and then treated
with ceric ammonium nitrate (2.04 g, 37.0 mmol). After 5 min,
EtOAc (80 mL) and brine (80 mL) were added to the reaction mix-
ture to partition it into organic and aqueous layers. The aqueous
layer was separated and then extracted with EtOAc (3ϫ 30 mL).
The combined organic portions were washed with an aqueous solu-
tion of NaHCO3 (10 mL), H2O (10 mL), and brine (10 mL) and
then dried with MgSO4. The solvent was removed under reduced
pressure, and the flask that contained the crude mixture was fitted
with a reflux condenser and placed under vacuum. The flask was
then warmed to 40 °C by using a water bath until a majority of the
benzoquinone byproduct had sublimed to leave a brown oil. This
residue was then purified by column chromatography (EtOAc/pe-
troleum ether, 1:12–1:6) to provide 18 (0.331 g, 87%) as a brown
oil. [α]2D2 = –8.9 (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3,
1
(c = 1.44, CHCl3). H NMR (500 MHz, CDCl3, 25 °C): δ = 7.75
3
3
(d, JH,H = 8.2 Hz, 2 H), 7.28 (d, JH,H = 8.2 Hz, 2 H), 6.79–6.74
3
(m, 2 H), 6.74–6.70 (m, 2 H), 4.03–3.94 (m, 2 H), 3.91 (d, JH,H
=
3
9.6 Hz, 1 H), 3.87 (d, JH,H = 9.6 Hz, 1 H), 3.72 (s, 3 H), 2.99 (s,
1 H), 2.38 (s, 3 H), 2.00–1.88 (m, 2 H), 1.22 (s, 3 H) ppm. 13C
NMR (125 MHz, CDCl3, 25 °C): δ = 154.2, 152.4, 145.1, 132.6,
130.0, 128.0, 115.5, 114.7, 75.7, 71.0, 64.9, 55.8, 37.1, 24.5,
21.7 ppm. IR (ATR): ν = 3553, 2915, 1510, 1348, 1233, 1168, 1031,
˜
3
25 °C): δ = 3.82–3.79 (m, 2 H), 2.48 (dd, JH,H = 16.5, 2.7 Hz, 1
963, 817, 671 cm–1. HRMS (ESI): calcd. for C19H24NaO6S [M +
Na]+ 403.1186; found 403.1182. C19H24O6S (380.46): calcd. C
59.98, H 6.36, S 8.43; found C 59.97, H 6.28, S 8.23.
3
3
H), 2.38 (dd, JH,H = 16.5, 2.7 Hz, 1 H), 1.99 (t, JH,H = 2.7 Hz, 1
3
3
H), 1.95 (dt, JH,H = 14.0, 6.0 Hz, 1 H), 1.81 (dt, JH,H = 14.0,
6.0 Hz, 1 H), 1.37 (s, 3 H), 0.85 (s, 9 H), 0.12 (s, 3 H) 0.11 (s, 3
H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 81.38, 76.38,
70.91, 59.75, 43.15, 32.94, 28.78, 25.99, 18.25, –1.78, –1.88 ppm.
(–)-1-(4-Methoxyphenoxy)-3-methyl-5-hexyn-3-ol [(–)-17]:[14] Lith-
ium acetylide–ethylenediamine complex (3.600 g, 39.0 mmol) was
added to a solution of the prepared tosylate (2.464 g, 6.5 mmol) in
DMSO (43 mL) under argon. The reaction was stirred for 16 h and
then carefully quenched with H2O (15 mL). The reaction mixture
was then extracted into Et2O (3ϫ 30 mL), and the combined or-
ganic extracts were washed with brine (20 mL) and dried with
MgSO4. The solvent was removed in vacuo, and the resulting resi-
due was purified by column chromatography (EtOAc/petroleum
ether, 1:9–1:6) to provide 17 (1.490 g, 98%) as a colorless oil. [α]2D2
IR (ATR): ν = 3312, 2954, 2929, 2120, 1252, 1045, 1002, 832, 771,
˜
626 cm–1. HRMS (ESI): calcd. for C13H26NaO2Si [M + Na]+
265.1594; found 265.1569. C13H26O2Si (242.43): calcd. C 64.41, H
10.81; found C 65.15, H 10.61.
5-tert-Butyldimethylsilyloxy-5-methylocten-7-yn-3-ol (13)
(–)-3-tert-Butyldimethylsilyloxy-3-methyl-5-hexynal:[14] Alcohol 18
(248 mg, 1.0 mmol) in CH2Cl2 (3.0 mL) was added to a stirred
solution of Dess–Martin periodinane (560 mg, 1.3 mmol) in
CH2Cl2 (5 mL) under argon. The resulting mixture was stirred at
room temperature for 8 h and then filtered through Celite. The fil-
trate was concentrated as the water bath temperature was kept be-
low 20 °C, and the residue was purified by column chromatography
(Et2O/petroleum ether, 1:9) to afford the title compound (245 mg,
99%) as a colorless oil. The aldehyde was used immediately in the
next reaction step. [α]2D2 = –25.1 (c = 1.0, CHCl3). 1H NMR
1
= –14.9 (c = 1.0, CHCl3). H NMR (500 MHz, CDCl3, 25 °C): δ
= 6.88–6.78 (m, 4 H), 4.14–4.09 (m, 2 H), 3.73 (s, 3 H), 2.92 (s, 1
3
H), 2.45 (br. s, 2 H), 2.15–2.09 (m, 1 H), 2.08 (t, JH,H = 2.7 Hz, 1
H), 2.07–2.00 (m, 1 H), 1.36 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3, 25 °C): δ = 154.06, 152.54, 115.47, 114.69, 80.93, 71.53,
71.20, 65.49, 55.68, 39.13, 32.63, 26.79 ppm. IR (ATR): ν = 3452,
˜
2932, 2116, 1506, 1467, 1224, 1031, 824, 735 cm–1. HRMS (ESI):
calcd. for C14H18NaO3 [M + Na]+ 257.1148; found 257.1150.
C14H18O3 (234.29): calcd. C 71.77, H 7.74; found C 71.77, H 7.93.
3
(500 MHz, CDCl3, 25 °C): δ = 9.89 (t, JH,H = 2.8 Hz, 1 H), 2.72
(dd, 3JH,H = 15.0, 2.6 Hz, 1 H), 2.59–2.51 (m, 2 H), 2.45 (dd, 3JH,H
(–)-3-tert-Butyldimethylsilyloxy-3-methyl-5-hexyn-1-ol [(–)-18]
3
= 16.6, 2.7 Hz, 1 H), 2.06 (t, JH,H = 2.7 Hz, 1 H), 1.45 (s, 3 H),
(–)-3-tert-Butyldimethylsilyloxy-1-(4-methoxyphenoxy)-3-methyl-5- 0.86 (s, 9 H), 0.13 (s, 3 H), 0.11 (s, 3 H) ppm. 13C NMR (125 MHz,
hexyne:[14] tert-Butyldimethylsilyl triflate (2.88 mL, 12.3 mmol) was
added dropwise to a solution of 17 (1.92 g, 8.2 mmol) and collidine
CDCl3, 25 °C): δ = 202.65, 80.60, 74.30, 71.68, 54.59, 33.77, 28.10,
25.83, 18.27, –1.99 ppm.
Eur. J. Org. Chem. 2014, 1684–1694
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1689

L. W. K. Moodie, D. S. Larsen
FULL PAPER
5-tert-Butyldimethylsilyloxy-5-methylocten-7-yn-3-ol (13):[14]
A
73.04, 67.22, 46.49, 38.31, 30.90, 25.84, 18.23, –2.04, –2.44 ppm.
solution of the aldehyde (418 mg, 1.7 mmol) in toluene (11.2 mL)
was stirred under argon at –78 °C and then treated with freshly
IR (ATR): ν = 3308, 2927, 2855, 2362, 1606, 1250, 1090, 1027, 990,
˜
832, 805 cm–1. HRMS (ESI): calcd. for C15H28NaO2Si [M + Na]+
prepared vinylmagnesium bromide in THF (7.2 mL, 4.2 mmol). 291.1751; found 291.1725. C15H28O2Si (268.47): calcd. C 67.11, H
The reaction was warmed to room temperature and then stirred for
2 h. After quenching with saturated NH4Cl (5 mL), the aqueous
layer was extracted with EtOAc (3ϫ 10 mL). The combined or-
ganic extracts were washed with brine (10 mL) and dried with
MgSO4. The solvent was removed in vacuo, and the compound was
purified by column chromatography (Et2O/petroleum ether, 1:9) to
provide the title compounds (442 mg, 95%, inseparable mixture of
10.51; found C 67.39, H 10.68.
Cycloadducts (–)-22 and (–)-21: A solution of N-phenylmaleimide
(9.2 mg, 0.053 mmol) and diene 9a (15 mg, 0.056 mg) in toluene
(250 μL) was stirred for 40 h under an inert atmosphere. The sol-
vent was removed in vacuo. The resulting residue was purified by
column chromatography (EtOAc/petroleum ether, 1:9–1:1) and
then recrystallized (CH2Cl2 and petroleum ether) to yield 22
(8.5 mg, 34%) as a white solid; m.p. 147.1 °C. The column was then
flushed with EtOAc, and the resulting eluent was removed under
reduced pressure to yield 21 (13.2 mg, 53%) as an opaque gum.
diastereomers, 1.2:1) as a colorless oil. IR (ATR): ν = 3474, 3312,
˜
2954, 2929, 2119, 1253, 1103, 990, 831, 772, 628 cm–1. HRMS
(ESI): calcd. for C15H28NaO2Si [M + Na]+ 291.1751; found
291.1741. C15H28O2Si (268.47): calcd. C 67.11, H 10.51; found C
67.21, H 10.58. Data for diastereomer 1: 1H NMR (500 MHz,
1
Data for 22: [α]2D2 = –129 (c = 0.22, CHCl3). H NMR (500 MHz,
3
CDCl3, 25 °C): δ = 7.45 (t, JH,H = 7.6 Hz, 1 H), 7.37–7.32 (m, 4
3
CDCl3, 25 °C): δ = 5.91–5.81 (m, 1 H), 5.28 (dt, JH,H = 17.1,
3
3
H), 5.75 (t, JH,H = 3.7 Hz, 1 H), 4.20 (dq, JH,H = 10.5, 2.9 Hz, 1
3
1.5 Hz, 1 H), 5.08 (ddt, JH,H = 10.4, 3.0, 1.5 Hz, 1 H), 4.52–4.44
3
3
H), 3.75 (d, JH,H = 10.6 Hz, 1 H), 3.36 (t, JH,H = 9.5 Hz, 1 H),
3
3
(m, 1 H), 3.48 (t, JH,H = 1.7 Hz, 1 H), 2.53 (dd, JH,H = 16.4,
3.19 (ddd, 3JH,H = 10.6, 9.5, 2.8 Hz, 1 H), 2.82 (d, 3JH,H = 19.1 Hz,
3
3
2.6 Hz, 1 H), 2.43 (dd, JH,H = 16.4, 2.7 Hz, 1 H), 2.04 (t, JH,H
=
3
3
1 H), 2.64 (d, JH,H = 9.3 Hz, 1 H), 2.48 (ddq, JH,H = 19.2, 10.6,
2.7 Hz, 1 H), 1.90 (dd, 3JH,H = 14.6, 10.1 Hz, 1 H), 1.76 (dd, 3JH,H
= 14.6, 2.1 Hz, 1 H), 1.46 (s, 3 H), 0.89 (s, 9 H), 0.17 (s, 6 H) ppm.
13C NMR (125 MHz, CDCl3, 25 °C): δ = 141.22, 114.01, 81.13,
76.74, 71.29, 69.96, 47.41, 34.33, 26.73, 25.95, 18.21, –1.86 ppm.
3.3 Hz, 1 H), 2.42 (dd, 3JH,H = 13.0, 2.9 Hz, 1 H), 2.13 (d, JH,H
=
3
3
3
13.1 Hz, 1 H), 2.00 (dt, JH,H = 14.6, 3.0 Hz, 1 H), 1.59 (dd, JH,H
= 14.5, 3.1 Hz, 1 H), 1.32 (s, 3 H), 0.84 (s, 9 H), 0.16 (s, 3 H), 0.12
(s, 3 H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 178.91,
178.20, 132.72, 130.02, 129.17, 128.44, 127.09, 123.45, 77.47, 69.82,
50.34, 45.07, 40.98, 39.96, 36.54, 30.75, 26.11, 20.71, 18.19, –1.57,
1
Data for diastereomer 2: H NMR (500 MHz, CDCl3, 25 °C): δ =
3
5.91–5.81 (m, 1 H), 5.28 (dt, JH,H = 17.1, 1.5 Hz, 1 H), 5.08 (ddt,
3
3JH,H = 10.4, 3.0, 1.5 Hz, 1 H), 4.52–4.44 (m, 1 H), 3.70 (t, JH,H
–1.61 ppm. IR (ATR): ν = 2955, 2929, 1702, 1383, 1252, 1193,
˜
3
= 1.7 Hz, 1 H), 2.66 (dd, JH,H = 16.5, 2.6 Hz, 1 H), 2.49 (ddd,
1145, 1093 cm–1. HRMS (ESI): calcd. for C25H35NNaO4Si [M +
3
3JH,H = 16.5, 2.7, 1.1 Hz, 1 H), 2.02 (t, JH,H = 2.7 Hz, 1 H), 1.93
Na]+ 464.2228; found 464.2197. Data for 21: [α]2D2 = –48 (c = 0.5,
3
3
(dd, JH,H = 14.6, 2.2 Hz, 1 H), 1.69 (ddd, JH,H = 14.6, 10.4,
1.0 Hz, 1 H), 1.44 (s, 3 H), 0.88 (s, 9 H), 0.18 (s, 6 H) ppm. 13C
NMR (125 MHz, CDCl3, 25 °C): δ = 141.14, 114.01, 80.99, 77.28,
71.27, 70.07, 47.11, 31.50, 28.90, 25.95, 18.13, –1.86 ppm.
1
3
CHCl3). H NMR (500 MHz, CDCl3, 25 °C): δ = 7.46 (t, JH,H
=
7.6 Hz, 2 H), 7.39 (t, 3JH,H = 7.4 Hz, 1 H), 7.21 (d, 3JH,H = 8.2 Hz,
2 H), 5.65 (s, 1 H), 4.22 (td, 3JH,H = 9.9, 5.6 Hz, 1 H), 3.65 (t, 3JH,H
3
= 8.3 Hz, 1 H), 3.24 (ddd, JH,H = 8.5, 7.0, 4.3 Hz, 1 H), 2.62 (dt,
3JH,H = 16.0, 4.9 Hz, 1 H), 2.50 (t, JH,H = 8.9 Hz, 1 H), 2.32 (d,
3
3-tert-Butyldimethylsilyloxy-5-ethenyl-3-methylcyclohex-5-en-1-ol
[(+)-9a and (+)-9b]: Grubbs first generation catalyst (35 mg
0.04 mmol) was added to a solution of enyne 13 (115 mg,
0.40 mmol) in CH2Cl2 (9.5 mL) under argon. After 24 h, the 1H
NMR spectrum of an aliquot from the reaction mixture revealed
complete conversion. DMSO (150 μL, 2.1 mmol) was added, and
the reaction mixture was stirred for an additional 16 h. The solvent
was removed under reduced pressure, and the residue was subjected
to column chromatography (EtOAc/petroleum ether, 1:15) to afford
9a (56 mg, 58%) and the slower eluting diastereomer 9b (35 mg,
30%). Data for 9a: [α]2D2 = +74.06 (c = 0.5, CHCl3). 1H NMR
3JH,H = 16.0 Hz, 1 H), 2.24 (d, JH,H = 14.4 Hz, 1 H), 2.21–2.13
3
3
(m, 2 H), 1.81 (dd, JH,H = 13.5, 10.1 Hz, 1 H), 1.26 (s, 3 H), 0.83
(s, 9 H), 0.10 (s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3, 25 °C): δ = 178.77, 178.49, 137.47, 131.80, 129.33, 128.90,
126.60, 120.91, 73.20, 67.94, 48.00, 46.06, 43.43, 41.32, 40.03,
30.11, 25.87, 24.76, 18.07, –1.84, –1.95 ppm. IR (ATR): ν = 2924,
˜
2853, 1699, 1499, 1378, 1252, 1183, 1139, 1037 cm–1. HRMS (ESI):
calcd. for C25H35NNaO4Si [M + Na]+ 464.2228; found 464.2198.
Lactonization of (–)-22: para-Toluenesulfonic acid (approximately
1 mg) was added to a stirred solution of 22 (3.6 mg, 0.008 mmol)
in MeOH (1.0 mL). After 4 h, TLC indicated the consumption of
the starting material, and the solvent was removed under reduced
pressure. The product was purified by column chromatography
(EtOAc) to afford 24 (2.2 mg, 82%). 1H NMR (500 MHz, [D6]acet-
3
(500 MHz, CDCl3, 25 °C): δ = 6.41 (dd, JH,H = 17.6, 10.8 Hz, 1
3
3
H), 5.91 (d, JH,H = 3.5 Hz, 1 H), 5.17 (d, JH,H = 17.6 Hz, 1 H),
3
3
5.05 (d, JH,H = 10.8 Hz, 1 H), 4.18 (br. s, 1 H), 3.34 (d, JH,H
9.7 Hz, 1 H), 2.47 (d, JH,H = 18.1 Hz, 1 H), 2.10–2.05 (m, 1 H),
=
3
3
2.07–2.02 (m, 1 H), 1.73 (dd, JH,H = 13.9, 5.3 Hz, 1 H), 1.36 (s, 3
3
one, 25 °C): δ = 9.39 (s, 1 H), 7.65 (dd, JH,H = 8.7, 1.2 Hz, 2 H),
H), 0.83 (s, 9 H), 0.14 (s, 3 H), 0.04 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3, 25 °C): δ = 139.47, 134.27, 130.11, 112.76,
73.37, 65.74, 44.24, 38.01, 30.29, 25.88, 18.06, –1.96, –2.34 ppm.
3
3
7.29 (dd, JH,H = 8.5, 7.5 Hz, 2 H), 7.04 (tt, JH,H = 7.6, 1.1 Hz, 1
3
3
H), 5.77 (dq, JH,H = 4.0, 2.0 Hz, 1 H), 4.83 (td, JH,H = 4.2,
1.9 Hz, 1 H), 3.78 (dd, 3JH,H = 6.0, 3.2 Hz, 1 H), 3.16 (s, 1 H), 2.93
IR (ATR): ν = 3379, 2927, 2364, 1606, 1253, 1125, 1096 cm–1
.
˜
(ddd, 3JH,H = 11.9, 6.1, 3.3 Hz, 1 H), 2.52 (dq, 3JH,H = 11.9, 2.6 Hz,
HRMS (ESI): calcd. for C15H28NaO2Si [M + Na]+ 291.1751; found
291.1745. C15H28O2Si (268.47): calcd. C 67.11, H 10.51; found C
3
1 H), 2.49–2.41 (m, 1 H), 2.30–2.25 (m, 1 H), 2.20 (dt, JH,H
=
3
15.8, 2.3 Hz, 1 H), 2.19 (dd, JH,H = 13.3, 2.5 Hz, 1 H), 1.91 (dd,
3JH,H = 16.2, 4.0 Hz, 1 H), 1.21 (s, 3 H) ppm. 13C NMR (125 MHz,
[D6]acetone, 25 °C): δ = 177.33, 171.18, 140.40, 131.52, 129.44,
127.40, 124.12, 120.45, 80.63, 70.59, 47.01, 44.41, 42.35, 40.93,
39.34, 30.55, 25.38 ppm. HRMS (ESI): calcd. for C19H21NNaO4
[M + Na]+ 350.1363; found 350.1364.
67.31, H 10.58. Data for 9b: [α]2D2 = +33.83 (c = 0.5, CHCl3). H
1
3
NMR (500 MHz, CDCl3, 25 °C): δ = 6.39 (dd, JH,H = 17.5,
10.8 Hz, 1 H), 5.76 (s, 1 H), 5.14 (d, JH,H = 17.6 Hz, 1 H), 5.02
3
3
3
(d, JH,H = 10.7 Hz, 1 H), 4.59–4.47 (m, 1 H), 2.30 (d, JH,H
=
17.3 Hz, 1 H), 2.18 (dddd, 3JH,H = 12.3, 6.0, 2.1, 1.2 Hz, 1 H), 2.10
3
(dt, JH,H = 17.3, 2.5 Hz, 1 H), 1.38–1.32 (m, 1 H), 1.36 (s, 3 H),
0.79 (s, 9 H), 0.08 (s, 3 H), –0.01 (s, 3 H) ppm. 13C NMR Lactone (–)-26: N-Phenylmaleimide (9.2 mg, 0.053 mmol) and (+)-
(125 MHz, CDCl3, 25 °C): δ = 139.25, 135.09, 131.28, 112.54, 9b (14.2 mg, 0.053 mg) were dissolved in toluene (300 μL), and the
1690
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1684–1694

A Ring-Closing Enyne Metathesis Approach to Semicyclic Dienes
resulting mixture was stirred for 30 h under an inert atmosphere.
The solvent was removed in vacuo, and the resulting residue was
purified by column chromatography (EtOAc/petroleum ether, 1:6–
1:1). Recrystallization (CH2Cl2 and petroleum ether) provided 26
H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 202.00, 188.72,
182.60, 162.71, 145.24, 136.83, 136.82, 133.69, 133.37, 131.92,
129.65, 126.88, 124.52, 119.72, 116.34, 75.20, 55.42, 49.73, 28.16,
26.04, 18.39, –1.75 ppm. IR (ATR): ν = 2928, 1636, 1599, 1455,
˜
(15.0 mg, 64%) as a white solid; m.p. 259 °C. [α]2D2 = –3.3 (c =
1356, 1262, 830, 771 cm–1. HRMS (ESI): calcd. for C25H29O5Si
1
0.285, CHCl3). H NMR (500 MHz, CDCl3, 25 °C): δ = 10.01 (s, [M – 2H + H]+ 437.1779; found 437.1778.
3
3
1 H), 7.59 (d, JH,H = 7.6 Hz, 2 H), 7.32 (dd, JH,H = 8.5, 7.4 Hz,
(؎)-1-Acetoxy-3-tert-butyldimethylsilyloxy-5-ethenyl-3-methyl-
cyclohex-5-ene [(؎)-28]: Diene (Ϯ)-9a (98 mg, 0.37 mmol) and 4-
(dimethylamino)pyridine (approximately 1 mg) were dissolved in a
mixture of pyridine (1 mL) and acetic anhydride (1 mL), and the
reaction was stirred for 14 h under nitrogen. The reaction mixture
was diluted with CH2Cl2 (10 mL), and the resulting solution was
washed with HCl (1 m aqueous solution, 5 mL), an aqueous solu-
tion of NaHCO3 (5 mL), H2O (5 mL), and brine (5 mL). The or-
ganic extract was dried with MgSO4, and the solvent was removed
under reduced pressure. The residue was purified by column
chromatography (Et2O/petroleum ether, 1:5) to afford (Ϯ)-28
(95 mg, 84 %) as a colorless oil. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 6.36 (dd, 3JH,H = 17.5, 10.8 Hz, 1 H), 5.60 (s, 1 H), 5.40
(ddd, 3JH,H = 8.8, 6.6, 2.6 Hz, 1 H), 5.22 (d, 3JH,H = 17.5 Hz, 1 H),
3
3
1 H), 7.10 (t, JH,H = 7.4 Hz, 1 H), 5.76 (dd, JH,H = 4.5, 1.8 Hz,
3
3
1 H), 4.78 (td, JH,H = 4.3, 2.3 Hz, 1 H), 3.45 (dd, JH,H = 6.0,
3
2.7 Hz, 1 H), 3.00 (s, 1 H), 2.93 (ddd, JH,H = 12.5, 5.6, 2.8 Hz, 1
3
3
H), 2.55 (dtt, JH,H = 17.1, 4.7, 2.0 Hz, 1 H), 2.46 (ddq, JH,H
=
=
3
17.8, 12.5, 2.5 Hz, 1 H), 2.32–2.27 (m, 2 H), 2.23 (d, JH,H
3
12.8 Hz, 1 H), 1.90 (dd, JH,H = 15.6, 4.3 Hz, 1 H), 1.20 (s, 3 H),
0.86 (s, 9 H), 0.11 (s, 3 H), 0.11 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3, 25 °C): δ = 178.33, 171.37, 138.49, 131.49, 129.06, 126.39,
124.27, 120.06, 80.41, 73.31, 48.74, 43.65, 43.27, 42.14, 41.78,
28.36, 26.27, 25.85, 18.06, –1.72, –1.75 ppm. IR (ATR): ν = 3316,
˜
2927, 1756, 1693, 1597, 1530, 1438, 1239, 1182, 1144, 1112 cm–1.
HRMS (ESI): calcd. for C25H35NNaO4Si [M + Na]+ 464.2228;
found 464.2218.
3
3
(؎)-8-Acetoxy-12a-bromo-3-tert-butyldimethylsilyloxy-
1,2,3,4,6,6a,12a,12b-octahydro-1-hydroxy-3-methylbenz[a]-
anthracene-7,12-dione [(؎)-11]: Bromojuglone 6 (19 mg,
0.065 mmol) was added to a solution of (Ϯ)-9a (17.5 mg, 0.
065 mmol) in toluene (640 μL). The reaction mixture was heated at
80 °C for 12 h. Upon concentration of the reaction mixture, the
residue was purified by flash column chromatography through a
short plug of silica (EtOAc/petroleum ether, 1:4–1:1), and the prod-
uct was triturated with CH2Cl2 and petroleum ether to afford (Ϯ)-
11 (24.4 mg, 66%) as a white amorphous foam; m.p. Ͼ80 °C (dec).
5.08 (d, JH,H = 10.8 Hz, 1 H), 2.29 (br. s, 2 H), 2.07 (dd, JH,H
=
3
12.2, 6.7 Hz, 1 H), 2.06 (s, 3 H), 1.78 (dd, JH,H = 12.3, 8.7 Hz, 1
H), 1.25 (s, 3 H), 0.86 (s, 9 H), 0.11 (s, 3 H), 0.10 (s, 3 H) ppm. 13
C
NMR (101 Hz, CDCl3, 25 °C): δ = 170.95, 138.57, 138.00, 125.52,
113.73, 72.25, 70.13, 42.64, 39.53, 27.87, 25.86, 21.49, 18.09, –1.81,
–1.82 ppm. IR (ATR): ν = 2955, 2928, 1734, 1373, 1233, 1198,
˜
1126, 1023, 832 cm–1. HRMS (ESI): calcd. for C17H30NaO3Si [M
+ Na]+ 333.1856; found 333.1840. C17H30O3Si (310.51): calcd. C
65.76, H 9.74; found C 66.00, H 9.74.
3
1H NMR (500 MHz, CDCl3, 25 °C): δ = 8.16 (dd, JH,H = 7.9,
(؎)-1,8-Diacetoxy-12a-bromo-3-tert-butyldimethylsilyloxy-
1,2,3,4,6,6a,12a,12b-octahydro-3-methylbenz[a]anthracene-7,12-
dione [(؎)-29]: Bromojuglone 6 (45 mg, 0.15 mmol) was added to
a solution of (Ϯ)-28 (66 mg, 0.21 mmol) in toluene (2 mL) under
argon. The reaction was heated at 100 °C for 45 h, cooled to room
temperature, and then concentrated under reduced pressure. Purifi-
cation by column chromatography (EtOAc/petroleum ether, 1:9–
1:3) and recrystallization (CH2Cl2 and petroleum ether) afforded
(Ϯ)-29 (68 mg, 74%) as thin white crystals; m.p. 75.4 °C. 1H NMR
3
3
1.1 Hz, 1 H), 7.74 (t, JH,H = 7.9 Hz, 1 H), 7.34 (dd, JH,H = 8.0,
1.2 Hz, 1 H), 5.62 (s, 1 H), 3.60 (dd, 3JH,H = 6.0, 3.4 Hz, 1 H), 3.40
(br. s, 1 H), 2.95 (d, 3JH,H = 10.1 Hz, 1 H), 2.88 (d, 3JH,H = 19.1 Hz,
1 H), 2.54 (ddd, 3JH,H = 18.3, 6.0, 2.8 Hz, 1 H), 2.37 (s, 3 H), 2.30–
3
3
2.22 (m, 2 H), 1.91 (dd, JH,H = 11.6, 3.4 Hz, 1 H), 1.56 (t, JH,H
= 11.3 Hz, 1 H), 1.08 (s, 3 H), 0.82 (s, 9 H), 0.06 (s, 3 H), 0.05 (s,
3 H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 192.09, 190.09,
169.62, 148.64, 136.16, 135.07, 131.46, 129.04, 126.69, 125.91,
121.16, 72.97, 69.98, 68.52, 58.63, 56.24, 50.78, 50.76, 27.08, 25.83,
3
(500 MHz, CDCl3, 25 °C): δ = 8.07 (d, JH,H = 7.8 Hz, 1 H), 7.73
3
3
(t, JH,H = 7.9 Hz, 1 H), 7.37 (dd, JH,H = 8.0, 1.2 Hz, 1 H), 5.65
24.27, 21.15, 18.01, –1.83 ppm. IR (ATR): ν = 3480, 1775, 1693,
˜
3
3
1594, 1257, 1179, 1132, 1037, 831, 772, 726 cm–1. HRMS (ESI):
calcd. for C27H3679BrO6Si [M + H]+ 563.1459; found 563.1465.
C27H35BrO6Si (563.56): calcd. C 57.54, H 6.26; found C 57.75, H
6.50.
(s, 1 H), 3.59 (t, JH,H = 5.6 Hz, 1 H), 3.17 (d, JH,H = 10.3 Hz, 1
H), 2.82–2.66 (m, 1 H), 2.56–2.47 (m, 1 H), 2.36 (s, 3 H), 2.31 (dd,
3
3JH,H = 13.0, 1.8 Hz, 1 H), 2.27 (d, JH,H = 13.6 Hz, 1 H), 2.11 (d,
3JH,H = 11.7 Hz, 1 H), 1.77 (s, 3 H), 1.49 (t, 3JH,H = 11.1 Hz, 1 H),
1.19 (s, 3 H), 0.82 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm. The
signal for H-1 was not observed. 13C NMR (125 MHz, CDCl3,
25 °C): δ = 192.31, 189.48, 169.21, 168.93, 149.51, 149.06, 135.00,
134.82, 129.95, 126.24, 122.02, 72.29, 70.62, 57.09, 53.07, 50.82,
46.64, 26.75, 25.81, 21.51, 21.16, 20.93, 18.01, –1.83, –1.87 ppm.
The resonances associated with C-7a and C-12a could not be deter-
(؎)-4-(5Ј-Hydroxy-9Ј,10Ј-dihydro-9Ј,10Ј-dioxoanthracene-2Ј-yl)-3-
tert-butyldimethylsilyloxy-3-methylbutanal [(؎)-27]: A solution of
(Ϯ)-11 (42 mg, 0.076 mmol) in benzene (3.8 mL) was cooled to
0 °C and treated with 1,8-diazabicycloundec-7-ene (12 μL,
0.084 mmol). After 5 min, the reaction was quenched with an aque-
ous solution of NH4Cl (4 mL), and the product was extracted into
Et2O (2ϫ 10 mL). The combined extracts were washed with H2O
(5 mL) and brine (5 mL) and then dried with MgSO4. The solvent
was removed under reduced pressure, and the product was purified
by column chromatography (Et2O/petroleum ether, 1:6–1:3) to af-
mined. IR (ATR): ν = 2953, 1774, 1753, 1704, 1363, 1225,
˜
1183, 1022, 834, 774, 730 cm–1. HRMS (ESI): calcd. for
C29H3779BrNaO7Si [M + Na]+ 627.1390; found 627.1384.
C29H37BrO7Si (605.60): calcd. C 57.52, H 6.16; found C 57.66, H
6.37.
1
ford (Ϯ)-27 (22 mg, 65%) as an orange gum. H NMR (500 MHz,
3
CDCl3, 25 °C): δ = 12.64 (s, 1 H), 9.91 (t, JH,H = 2.7 Hz, 1 H),
Aromatization of (؎)-29: 1,8-Diazabicycloundec-7-ene (11 μL,
0.073 mmol) was added to a stirred solution of (Ϯ)-29 (22 mg,
0.036 mmol) in CH2Cl2 (3 mL) in an open vessel. After 15 min, the
reaction was quenched with saturated aqueous NH4Cl (2 mL), and
the product was extracted into Et2O (2ϫ 10 mL). The combined
extracts were washed with H2O (5 mL) and brine (5 mL) and then
dried with MgSO4. The solvent was removed in vacuo, and the
3
3
8.24 (d, JH,H = 7.9 Hz, 1 H), 8.14 (d, JH,H = 1.7 Hz, 1 H), 7.84
3
3
(dd, JH,H = 7.5, 1.1 Hz, 1 H), 7.68 (dd, JH,H = 8.4, 7.5 Hz, 1 H),
7.68 (dd, JH,H = 7.9, 1.9 Hz, 1 H), 7.31 (dd, JH,H = 8.4, 1.1 Hz,
1 H), 3.11 (d, JH,H = 13.1 Hz, 1 H), 3.04 (d, JH,H = 13.1 Hz, 1
H), 2.58 (dd, JH,H = 15.0, 2.9 Hz, 1 H), 2.53 (dd, JH,H = 14.8,
3
3
3
3
3
3
2.8 Hz, 1 H), 1.40 (s, 3 H), 0.90 (s, 9 H), 0.13 (s, 3 H), 0.03 (s, 3
Eur. J. Org. Chem. 2014, 1684–1694
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1691

L. W. K. Moodie, D. S. Larsen
FULL PAPER
residue was subjected to column chromatography (EtOAc/petro-
leum ether, 1:1) to afford a minor product that was tentatively as-
signed as (Ϯ)-31 (3.2 mg, 18%) as a yellow film and the slower
eluting major product (Ϯ)-30 (10 mg, 53%) as a yellow film. The
instability of (Ϯ)-30 and (Ϯ)-31 precluded their full characteriza-
169.61, 151.02, 149.92, 137.10, 136.26, 135.26*, 134.36, 133.12,
129.42, 129.37, 125.82, 124.26, 39.28, 30.17, 22.90, 21.31 ppm.
*Two coincidental carbon signals. IR (ATR): ν = 2937, 2358, 1766,
˜
1668, 1590, 1276, 1183 cm–1. HRMS (ESI): calcd. for C20H14NaO5
[M + Na]+ 357.0733; found 357.0707. C20H14O5 (334.33): calcd. C
71.85, H 4.22; found C 71.98, H 4.12.
1
tion. Data for (Ϯ)-30: H NMR (500 MHz, [D6]acetone, 25 °C): δ
3
3
= 8.19 (d, JH,H = 8.0 Hz, 1 H), 8.12 (dd, JH,H = 7.8, 1.2 Hz, 1
2,3,4-Trihydro-8-hydroxybenz[a]anthracene-1,7,12-trione (35):[23]
LiOH (0.1 m solution, 1.2 mL, 0.12 mmol) was added to a solution
of 34 (16.0 mg, 0.05 mmol) in THF (1 mL) at 0 °C. After 2 h, the
reaction was quenched with an aqueous solution of NH4Cl (2 mL)
and then diluted with EtOAc. The aqueous layer was extracted into
EtOAc (2ϫ 5 mL), and the combined organic extracts were washed
with brine and dried with MgSO4. The solvent was removed under
reduced pressure, and the crude product was recrystallized (CH2Cl2
and petroleum ether) to afford 35 (10 mg, 71%) as orange crystals;
3
3
H), 7.93 (t, JH,H = 7.9 Hz, 1 H), 7.71 (d, JH,H = 8.1 Hz, 1 H),
7.55 (dd, JH,H = 8.0, 1.2 Hz, 1 H), 6.76 (dd, JH,H = 6.7, 4.4 Hz,
1 H), 3.22 (d, JH,H = 16.3 Hz, 1 H), 3.06 (d, JH,H = 16.4 Hz, 1
H), 2.41 (s, 3 H), 2.37 (ddd, JH,H = 14.3, 6.8, 1.1 Hz, 1 H), 2.20
3
3
3
3
3
3
(ddd, JH,H = 14.3, 4.4, 1.7 Hz, 1 H), 1.91 (s, 3 H), 1.42 (s, 3 H),
0.74 (s, 9 H), 0.13 (s, 3 H), 0.04 (s, 3 H) ppm. 13C NMR (125 MHz,
[D6]acetone, 25 °C): δ = 185.52, 182.27, 170.33, 169.63, 150.70,
145.00, 137.89, 136.33, 136.21, 136.15, 135.54, 132.46, 130.23,
127.89, 126.00, 124.85, 71.02, 68.82, 46.06, 43.83, 29.12, 26.05,
1
m.p. 174.8 °C. H NMR (500 MHz, CDCl3, 25 °C): δ = 12.30 (s, 1
1
21.15, 20.85, 18.50, –1.82, –1.92 ppm. Data for (Ϯ)-31: H NMR
3
3
H), 8.30 (d, JH,H = 8.0 Hz, 1 H), 7.70 (dd, JH,H = 7.5, 1.5 Hz, 1
3
(400 MHz, CDCl3, 25 °C): δ = 12.42 (s, 1 H), 8.32 (d, JH,H
=
=
3
H), 7.68–7.64 (m, 1 H), 7.57 (d, JH,H = 8.0 Hz, 1 H), 7.28 (dd,
3
3
8.0 Hz, 1 H), 7.73 (dd, JH,H = 7.6, 0.8 Hz, 1 H), 7.65 (t, JH,H
3JH,H = 8.0, 1.5 Hz, 1 H), 2.94 (t, JH,H = 5.9 Hz, 2 H), 2.92 (t,
3
3
3
7.9 Hz, 1 H), 7.53 (d, JH,H = 8.0 Hz, 1 H), 7.28 (dd, JH,H = 7.7,
3JH,H = 7.0 Hz, 2 H), 2.27–2.20 (m, 2 H) ppm. 13C NMR
(125 MHz, CDCl3, 25 °C): δ = 199.27, 187.71, 187.73, 162.25,
151.62, 137.18*, 136.04, 135.18, 133.65, 132.98, 128.96, 123.85,
119.81, 115.61, 39.24, 30.20, 22.84 ppm. *Two coincidental carbon
3
3
0.7 Hz, 1 H), 6.83 (dd, JH,H = 6.7, 4.8 Hz, 1 H), 3.16 (d, JH,H
=
=
3
3
17.1 Hz, 1 H), 2.91 (d, JH,H = 16.7 Hz, 1 H), 2.33 (ddd, JH,H
3
14.2, 6.9, 1.0 Hz, 1 H), 2.22 (ddd, JH,H = 14.7, 5.0, 1.6 Hz, 1 H),
1.96 (s, 3 H), 1.37 (s, 3 H), 0.75 (s, 9 H), 0.10 (s, 3 H), 0.02 (s, 3
H) ppm. HRMS (ESI): calcd. for C27H32NaO6Si [M + Na]+
503.1860; found 503.1865.
signals. IR (ATR): ν = 2923, 1704, 1667, 1634, 1588, 1450, 1361,
˜
1277, 1261, 1217, 780, 718 cm–1. HRMS (ESI): calcd. for
C18H12NaO4 [M + Na]+ 315.0628; found 315.0639. C18H12O4
(292.29): calcd. C 73.97, H 4.14; found C 73.82, H 4.31.
(؎)-8-Acetoxy-12a-bromo-1,2,3,4,6,6a,12a,12b-octahydro-1-
hydroxybenz[a]anthracene-7,12-dione [(؎)-33]: Bromojuglone 6
(300 mg, 1.0 mmol) was added to a solution of (Ϯ)-32 (140 mg,
1.1 mmol) in toluene (2 mL), and the resulting mixture was heated
at 70 °C for 20 h. After cooling to room temperature, the solvent
was removed under reduced pressure, and the product was recrys-
tallized (CH2Cl2, Et2O, and petroleum ether) to provide (Ϯ)-33
(؎)-8-Acetoxy-3-tert-butyldimethylsilyloxy-2,3,4-trihydro-3-meth-
ylbenz[a]anthracene-1,7,12-trione [(؎)-36]: Pyridinium dichromate
(27 mg, 0.071 mmol) and molecular sieves (4 Å, 35 mg) were added
to a solution of (Ϯ)-11 (10 mg, 0.018 mmol) in CH2Cl2 (1.7 mL)
under argon. After 2 h, the reaction vessel was exposed to air, and
the reaction was diluted with CH2Cl2. The resulting mixture was
stirred vigorously for an additional 2 h. Et2O (15 mL) was added,
and the reaction mixture was filtered through Celite®. The solvent
was removed under reduced pressure, and the residue was purified
by column chromatography (EtOAc/petroleum ether, 1:2) to afford
(Ϯ)-36 (7.8 mg, 92%) as an amorphous orange solid. 1H NMR
1
(418 mg, 88%) as a white solid; m.p. 155 °C. H NMR (500 MHz,
3
CDCl3, 25 °C): δ = 8.18 (dd, JH,H = 7.9, 1.2 Hz, 1 H), 7.74 (t,
3
3JH,H = 7.9 Hz, 1 H), 7.34 (dd, JH,H = 8.0, 1.2 Hz, 1 H), 5.62 (td,
3
3JH,H = 4.2, 1.5 Hz, 1 H), 3.62 (dd, JH,H = 6.2, 2.8 Hz, 1 H), 3.34
(br. s, 1 H), 2.96 (d, 3JH,H = 10.5 Hz, 1 H), 2.92 (d, 3JH,H = 17.6 Hz,
3
1 H), 2.52 (dtd, JH,H = 17.8, 5.7, 2.5 Hz, 1 H), 2.38 (s, 3 H), 2.29–
3
(500 MHz, CDCl3, 25 °C): δ = 8.23 (d, JH,H = 8.0 Hz, 1 H), 8.09
2.25 (m, 1 H), 1.98–1.86 (m, 2 H), 1.75–1.67 (m, 1 H), 1.33–1.23
(m, 2 H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 192.15,
190.34, 169.63, 148.60, 136.42, 134.98, 134.77, 128.92, 126.65,
126.17, 118.31, 71.90, 70.23, 59.44, 56.03, 37.20, 35.83, 24.96,
3
3
(dd, JH,H = 7.7, 1.2 Hz, 1 H), 7.77 (t, JH,H = 7.9 Hz, 1 H), 7.49
3
3
(d, JH,H = 8.1 Hz, 1 H), 7.38 (dd, JH,H = 8.0, 1.2 Hz, 1 H), 3.13
3
3
(dd, JH,H = 16.5, 1.3 Hz, 1 H), 3.09 (d, JH,H = 16.4 Hz, 1 H),
3
3
3.03 (dd, JH,H = 15.2, 1.6 Hz, 1 H), 2.92 (d, JH,H = 15.2 Hz, 1
H), 2.48 (s, 3 H), 1.50 (s, 3 H), 0.61 (s, 9 H), 0.10 (s, 3 H), 0.01 (s,
3 H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 196.57, 183.43,
181.11, 169.66, 149.85, 147.76, 137.45, 135.42, 135.39, 135.25,
134.28, 133.76, 129.76, 129.20, 125.83, 124.22, 74.81, 54.62, 45.65,
23.64, 21.18 ppm. IR (ATR): ν = 3457, 2934, 1772, 1690, 1186,
˜
1059, 727 cm–1. HRMS (ESI): calcd. for C20H1979BrNaO5 [M +
Na]+ 441.0308; found 441.0301. C20H19BrO5 (419.27): calcd. C
57.29, H 4.57, Br 19.08; found C 57.39, H 4.48, Br 18.48.
8-Acetoxy-2,3,4-trihydrobenz[a]anthracene-1,7,12-trione (34):[22]
Pyridinium dichromate (18 mg, 0.048 mmol) and molecular sieves
(4 Å, 48 mg) were added to a solution of (Ϯ)-33 (10 mg,
0.024 mmol) in CH2Cl2 (4 mL) under argon. After 1 h, the reaction
vessel was exposed to air, and the reaction was diluted with
CH2Cl2. The resulting mixture was stirred vigorously for an ad-
ditional 1 h. Et2O (10 mL) was added, and the reaction mixture
was filtered through Celite®. The solvent was removed, and the
residue was purified by column chromatography (EtOAc/petroleum
29.84, 25.54, 21.31, 17.98, –2.13, –2.17 ppm. IR (ATR): ν = 2949,
˜
2361, 1766, 1663, 1592, 1278, 1192, 1110, 827, 771 cm–1. HRMS
(ESI): calcd. for C27H30NaO6Si [M + Na]+ 501.1704; found
501.1691. C27H30O6Si (478.62): calcd. C 67.76, H 6.32; found C
67.64, H 6.17.
(+)-5-Ethenyl-3-methylcyclohex-5-en-1,3-diol [(+)-37]: TBAF (1.0 m
in THF, 0.79 mL, 0.79 mmol) was added to a stirred solution of 9a
(71 mg, 0.26 mmol) in THF (4 mL) at 0 °C. After stirring for 4 h,
ether, 2:1) to afford 34 (6.2 mg, 78 %) as yellow crystals; m.p. the reaction mixture was diluted with EtOAc (20 mL), and H2O
1
3
199.3 °C. H NMR (500 MHz, CDCl3, 25 °C): δ = 8.21 (d, JH,H (10 mL) was added. The aqueous layer was extracted with EtOAc
3
3
= 8.1 Hz, 1 H), 8.11 (dd, JH,H = 7.8, 1.2 Hz, 1 H), 7.78 (t, JH,H
= 7.9 Hz, 1 H), 7.54 (d, JH,H = 8.1 Hz, 1 H), 7.39 (dd, JH,H
(2ϫ 10 mL). The combined organic layers were washed with brine
(10 mL) and dried with MgSO4, and the solvent was removed in
vacuo. The product was purified by column chromatography
(EtOAc/petroleum ether, 1:2–1:1) to afford 37 (31 mg, 77%) as a
3
3
=
=
3
3
8.0, 1.2 Hz, 1 H), 2.93 (t, JH,H = 6.0 Hz, 2 H), 2.90 (t, JH,H
7.0 Hz, 2 H), 2.48 (s, 3 H), 2.23 (qd, 3JH,H = 6.8, 5.6 Hz, 2 H) ppm.
13C NMR (125 MHz, CDCl3, 25 °C): δ = 198.94, 183.36, 181.10, colorless oil. [α]2D2 = +136.1 (c = 0.75, CHCl3). 1H NMR (500 MHz,
1692
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1684–1694

A Ring-Closing Enyne Metathesis Approach to Semicyclic Dienes
3
CDCl3, 25 °C): δ = 6.42 (dd, JH,H = 17.6, 10.8 Hz, 1 H), 5.92 (d,
of EtOAc (15 mL). The aqueous layer was extracted into EtOAc
(3ϫ 10 mL), and the combined organic extracts were washed with
3JH,H = 4.1 Hz, 1 H), 5.23 (d, 3JH,H = 17.5 Hz, 1 H), 5.08 (d, 3JH,H
= 10.8 Hz, 1 H), 4.33 (t, JH,H = 4.8 Hz, 1 H), 3.05 (s, 1 H), 2.51 brine and dried with MgSO4. The solvent was removed under re-
3
3
3
(s, 1 H), 2.40 (d, JH,H = 17.4 Hz, 1 H), 2.18 (d, JH,H = 17.4 Hz,
duced pressure, and the crude product was recrystallized (CH2Cl2
and petroleum ether) to afford (–)-1 (4.2 mg, 54%) as yellow crys-
1 H), 2.03 (d, 3JH,H = 14.2 Hz, 1 H), 1.79 (dd, 3JH,H = 14.2, 4.9 Hz,
1 H), 1.36 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = tals; m.p. 164.5 °C. [α]2D2 = –133.6 (c = 0.25, CHCl3).[5h,6c] 1H NMR
3
139.17, 135.45, 128.80, 113.62, 69.74, 65.65, 42.13, 38.64,
(500 MHz, CDCl3, 25 °C): δ = 12.26 (s, 1 H), 8.33 (d, JH,H
=
3
30.57 ppm. IR (ATR): ν = 3339, 2967, 2923, 1605, 1411, 1373,
8.0 Hz, 1 H), 7.69–7.65 (m, 2 H), 7.56 (d, JH,H = 8.1 Hz, 1 H),
˜
1012, 899 cm–1. HRMS (ESI): calcd. for C9H14NaO2 [M + Na]+
177.0886; found 177.0883.
7.28 (dd, JH,H = 7.0, 2.5 Hz, 1 H), 3.18 (s, 2 H), 3.13 (d, JH,H =
3
3
3
14.8 Hz, 1 H), 3.02 (d, JH,H = 14.9 Hz, 1 H), 1.53 (s, 3 H) ppm.
13C NMR (125 MHz, CDCl3, 25 °C): δ = 197.04, 187.58, 183.20,
162.21, 147.66, 137.24, 136.31, 135.89, 135.34, 133.90, 133.83,
129.57, 123.81, 119.77, 115.56, 72.75, 54.10, 44.26, 30.35 ppm. IR
(+)-8-Acetoxy-12a-bromo-1,2,3,4,6,6a,12a,12b-octahydro-1,3-di-
hydroxy-3-methylbenz[a]anthracene-7,12-dione [(+)-38]: A solution
of diene 37 (24 mg, 0.16 mmol) and 6 (43 mg, 0.14 mmol) in tolu-
ene (1.1 mL) was heated at 80 °C for 20 h under argon. The solvent
was removed. The residue was purified by column chromatography
(EtOAc/petroleum ether, 2:1–1:0) and recrystallized (CH2Cl2 and
petroleum ether) to give 38 (55 mg, 87%) as a white solid; m.p.
87.9 °C. [α]2D2 = +62.4 (c = 0.16, CHCl3). 1H NMR (500 MHz, [D6]-
(ATR): ν = 3504, 3389, 2923, 1697, 1670, 1634, 1588, 1453, 1360,
˜
1265, 1216, 1157, 1110, 1075, 823, 782, 771, 719 cm–1. HRMS
(ESI): calcd. for C19H15O5 [M + H]+ 323.0914; found 323.0914.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR of key compounds as well as
experimental protocols for the syntheses of (Ϯ)-9a, (Ϯ)-9b, and the
Mosher’s esters.
3
acetone, 25 °C): δ = 8.08 (dd, JH,H = 7.9, 1.2 Hz, 1 H), 7.82 (t,
3JH,H = 7.9 Hz, 1 H), 7.44 (dd, 3JH,H = 8.0, 1.2 Hz, 1 H), 5.64 (dq,
3JH,H = 5.5, 2.1 Hz, 1 H), 3.78 (d, JH,H = 5.9 Hz, 1 H), 3.74 (d,
3
3JH,H = 6.5 Hz, 1 H), 3.64 (s, 1 H), 3.07 (br. s, 1 H), 2.99 (dd, 3JH,H
3
= 18.0, 5.6 Hz, 1 H), 2.88 (d, JH,H = 10.7 Hz, 1 H), 2.51 (ddq,
Acknowledgments
3JH,H = 18.0, 5.9, 2.7 Hz, 1 H), 2.29 (s, 3 H), 2.20 (dd, JH,H
=
3
3
3
12.3, 2.5 Hz, 1 H), 2.14 (d, JH,H = 12.9 Hz, 1 H), 1.80 (ddd, JH,H
The authors would like to thank the John Edmond Postgraduate
Scholarship in Chemistry (to L. W. K. M.) and the University of
Otago for the financial support.
3
= 12.4, 4.6, 2.5 Hz, 1 H), 1.54 (dd, JH,H = 12.0, 11.0 Hz, 1 H),
0.96 (s, 3 H) ppm. 13C NMR (125 MHz, [D6]acetone, 25 °C): δ =
192.17, 189.59, 169.51, 149.33, 137.79, 135.56, 132.05, 129.25,
127.29, 127.08, 121.62, 69.99, 68.49, 68.39, 60.26, 56.10, 51.44,
51.22, 26.48, 23.91, 20.98 ppm. IR (ATR): ν = 3470, 3400, 2980,
˜
[1] a) K. Krohn, J. Rohr, Top. Curr. Chem. 1997, 188, 127–195; b)
J. Rohr, R. Thiericke, Nat. Prod. Rep. 1992, 9, 103–137; c)
M. C. Carreno, A. Urbano, Synlett 2005, 1–25.
[2] M. K. Kharel, P. Pahari, M. D. Shepherd, N. Tibrewal, S. E.
Nybo, K. A. Shaaban, J. Rohr, Nat. Prod. Rep. 2012, 29, 264–
325.
2897, 1745, 1714, 1696, 1596, 1366, 1313, 1262, 1208 cm–1. HRMS
(ESI): calcd. for C21H2179BrNaO6 [M + Na]+ 471.0414; found
471.0418.
(–)-Tetrangomycin [(–)-1]
[3] a) M. Dann, D. V. Lefemine, F. Barbatschi, P. Shu, M. P.
Kunstmann, L. A. Mitscher, N. Bohonos, Antimicrob. Agents
Chemother. 1965, 5, 832–835; b) M. P. Kuntsman, L. A.
Mitscher, J. Org. Chem. 1966, 31, 2920–2925.
[4] K. Sakai, N. Koyama, T. Fukuda, Y. Mori, H. Onaka, H. Tom-
oda, Biol. Pharm. Bull. 2012, 35, 48–53.
(–)-8-Acetoxy-3-tert-butyldimethylsilyloxy-3-methyl-2,3,4-tri-
hydrobenz[a]anthracene-1,7,12-trione:[3b] Pyridinium dichromate
(85 mg, 0.23 mmol) and molecular sieves (4 Å, 142 mg) were added
to a solution of 38 (32 mg, 0.07 mmol) in CH2Cl2 (8 mL) under
argon. After 2 h, the reaction vessel was exposed to air, and the
reaction was diluted with CH2Cl2. The resulting mixture was stirred
vigorously for an additional 2 h. Et2O (35 mL) was added, and the
resulting mixture was filtered through Celite®. The solvent was re-
moved under reduced pressure, and the residue was purified by
column chromatography (EtOAc/petroleum ether, 1:2–3:1) to af-
ford the title compound (18.8 mg, 72%) as a yellow solid; m.p.
179.4 °C (EtOAc/petroleum ether). [α]2D2 = –24.7 (c = 0.45, CHCl3).
[5] a) K. Krohn, N. Böker, U. Flörke, C. Freund, J. Org. Chem.
1997, 62, 2350–2356; b) M. Yamaguchi, T. Okuma, A. Horigu-
chi, C. Ikeura, T. Minami, J. Org. Chem. 1992, 57, 1647–1649;
c) K. Ohmori, K. Mori, Y. Ishikawa, H. Tsuruta, S. Kuwahara,
N. Harada, K. Suzuki, Angew. Chem. 2004, 116, 3229; Angew.
Chem. Int. Ed. 2004, 43, 3167–3171; d) K. Mori, K. Ohmori,
K. Suzuki, Angew. Chem. 2009, 121, 5743; Angew. Chem. Int.
Ed. 2009, 48, 5633–5637; e) X. Y. Yang, B. Q. Fu, B. Yu, J. Am.
Chem. Soc. 2011, 133, 12433–12435; f) W. R. Roush, R. J. Ne-
itz, J. Org. Chem. 2004, 69, 4906–4912; g) K. Sato, N. Asao, Y.
Yamamoto, J. Org. Chem. 2005, 70, 8977–8981; h) C. Ke-
senheimer, A. Kalogerakis, A. Meissner, U. Groth, Chem. Eur.
J. 2010, 16, 8805–8821.
[6] a) K. P. Kaliappan, V. Ravikumar, J. Org. Chem. 2007, 72,
6116–6126; b) K. Krohn, K. Khanbabaee, Liebigs Ann. Chem.
1994, 1109–1112; c) J. S. Landells, D. S. Larsen, J. Simpson,
Tetrahedron Lett. 2003, 44, 5193–5196; d) V. A. Boyd, G. A.
Sulikowski, J. Am. Chem. Soc. 1995, 117, 8472–8473; e) K.
Kim, V. A. Boyd, A. Sobti, G. A. Sulikowski, Isr. J. Chem.
1997, 37, 3–22; f) M. C. Carreño, M. Ribagorda, A. Somoza,
A. Urbano, Angew. Chem. 2002, 114, 2879; Angew. Chem. Int.
Ed. 2002, 41, 2755–2757; g) M. C. Carreno, A. Somoza, M.
Ribagorda, A. Urbano, Chem. Eur. J. 2007, 13, 879–890.
[7] a) M. C. Carreno, A. Urbano, C. Di Vitta, Chem. Commun.
1999, 817–818; b) M. C. Carreño, A. Urbano, J. Fischer, An-
gew. Chem. 1997, 109, 1695; Angew. Chem. Int. Ed. Engl. 1997,
3
1H NMR (500 MHz, CDCl3, 25 °C): δ = 8.25 (d, JH,H = 8.1 Hz,
3
3
1 H), 8.10 (dd, JH,H = 7.7, 1.3 Hz, 1 H), 7.78 (t, JH,H = 7.9 Hz,
3
3
1 H), 7.54 (d, JH,H = 8.1 Hz, 1 H), 7.39 (dd, JH,H = 8.1, 1.3 Hz,
3
3
1 H), 3.18 (s, 2 H), 3.12 (d, JH,H = 14.8 Hz, 1 H), 3.00 (d, JH,H
= 14.8 Hz, 1 H), 2.48 (s, 3 H), 1.51 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3, 25 °C): δ = 196.76, 183.47, 180.99, 169.58,
149.89, 147.09, 137.26, 135.47, 135.32, 134.98, 134.50, 133.99,
130.04, 129.35, 125.78, 124.22, 72.77, 54.05, 44.19, 30.24,
21.30 ppm. IR (ATR): ν = 2919, 1770, 1700, 1690, 1665, 1590,
˜
1267, 1182 cm–1. HRMS (ESI): calcd. for C21H16NaO6 [M + Na]+
387.0839; found 387.0811.
(–)-Tetrangomycin [(–)-1]:[3b,5h,6c] LiOH (0.1 m solution, 740 μL,
0.74 mmol) was added to a solution of the prepared 8-acetoxy tet-
rangomycin (9.0 mg, 0.025 mmol) in THF (2 mL) at 0 °C. After
3 h, the reaction was quenched with an aqueous solution of NH4Cl
(5 mL), and the resulting mixture was partitioned by the addition
Eur. J. Org. Chem. 2014, 1684–1694
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1693

L. W. K. Moodie, D. S. Larsen
FULL PAPER
36, 1621–1623; c) M. C. Carreno, A. Urbano, C. Di Vitta, [17]
Chem. Eur. J. 2000, 6, 906–913.
[8] K. P. Kaliappan, V. Ravikumar, Synlett 2007, 977–979.
[9] a) M. Oka, H. Kamei, Y. Hamagishi, K. Tomita, T. Miyaki,
M. Konishi, T. Oki, J. Antibiot. 1990, 43, 967–976; b) K.
a) M. J. Fisher, W. J. Hehre, S. D. Kahn, L. E. Overman, J. Am.
Chem. Soc. 1988, 110, 4625–4633; b) S. C. Datta, R. W. Franck,
R. Tripathy, G. J. Quigley, L. Huang, S. Chen, A. Sihaed, J.
Am. Chem. Soc. 1990, 112, 8472–8478; c) J. A. Funel, L.
Ricard, J. Prunet, Chem. Commun. 2005, 4833–4835.
a) E. A. Bancroft, JAMA, J. Am. Med. Assoc. 2007, 298, 1803–
1804; b) R. M. Klevens, M. A. Morrison, J. Nadle, S. Petit, K.
Gershman, S. Ray, L. H. Harrison, R. Lynfield, G. Dumyati,
J. M. Townes, A. S. Craig, E. R. Zell, G. E. Fosheim, L. K.
McDougal, R. B. Carey, S. K. Fridkin, JAMA, J. Am. Med.
Assoc. 2007, 298, 1763–1771.
Krohn, K. Khanbabaee, Angew. Chem. Int. Ed. Engl. 1994, 33,
99–100.
[18]
[10] S. Naito, K. Nakase, M. Tsukamoto, H. Nishioka, S. Naka-
jima, M. Hirayama, S. Yoshida (Banyu Pharmaceutical Co.,
Ltd., Japan), JP2001261688, 2001.
[11] D. S. Larsen, M. D. O’Shea, J. Org. Chem. 1996, 61, 5681–
5683.
[19]
[20]
A. Clauditz, A. Resch, K. P. Wieland, A. Peschel, F. Gotz, In-
fect. Immun. 2006, 74, 4950–4953.
S. Czernecki, C. Georgoulis, C. L. Stevens, K. Vijayakumaran,
[12] a) D. S. Larsen, M. D. O’Shea, J. Chem. Soc. Perkin Trans. 1
1995, 1019–1028; b) M. C. Carreño, A. Urbano, C. Di Vitta, J.
Org. Chem. 1998, 63, 8320–8330.
Tetrahedron Lett. 1985, 26, 1699–1702.
[13] S. T. Diver, A. J. Giessert, Chem. Rev. 2004, 104, 1317–1382.
[14] H. Takayama, T. Fujishima (Chugai Seiyaku Kabushiki Kai-
sha, Japan), EP1174424A1, WO2000064870, 2000.
[15] M. Mori, N. Sakakibara, A. Kinoshita, J. Org. Chem. 1998,
63, 6082–6083.
[16] a) T. Imahori, H. Ojima, H. Tateyama, Y. Mihara, H. Takah-
ata, Tetrahedron Lett. 2008, 49, 265–267; b) T. Imahori, H.
Ojima, Y. Yoshimura, H. Takahata, Chem. Eur. J. 2008, 14,
10762–10771; c) Y. A. Lin, B. G. Davis, Beilstein J. Org. Chem.
2010, 6, 1219–1228.
[21] a) C. S. Poulsen, R. Madsen, J. Org. Chem. 2002, 67, 4441–
4449; b) J. A. Funel, J. Prunet, J. Org. Chem. 2004, 69, 5516–
5516.
[22] V. A. Boyd, J. Reibenspies, G. A. Sulikowski, Tetrahedron Lett.
1995, 36, 4001–4004.
[23] J. R. Cui, Y. J. Jian, Y. K. Wu, S. M. Wang, Chin. J. Chem.
2006, 24, 1163–1169.
Received: October 30, 2013
Published Online: January 9, 2014
1694
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Eur. J. Org. Chem. 2014, 1684–1694