Total synthesis of the proposed structure of trichodermatide A

Article abstract of DOI:10.1021/jo501206k

A short total synthesis of the published structure of racemic trichodermatide A is reported. Our synthesis involves a Knoevenagel condensation/Michael addition sequence, followed by the formation of tricyclic hexahydroxanthene-dione and a diastereoselective bis-hydroxylation. The final product, the structure of which was confirmed by X-ray crystallography, has NMR spectra that are very similar, but not identical, to those of the isolated natural product. Quantum chemically computed ¹³C shifts agree well with the present NMR measurements. (Chemical Equation Presented).

Full text of DOI:10.1021/jo501206k

Note
pubs.acs.org/joc
Total Synthesis of the Proposed Structure of Trichodermatide A
Eddie Myers,† Elena Herrero-Gomez,† Irina Albrecht,† Jennifer Lachs,† Peter Mayer,† Matti Hanni,†,‡
́
Christian Ochsenfeld,*,† and Dirk Trauner*,†
†Department of Chemistry and Center for Integrated Protein Science, University of Munich (LMU), Butenandtstraße 5-13, 81377
Munchen, Germany
̈
‡Department of Physics, Department of Radiology, University of Oulu, FIN-90014 Oulu, Finland
S
* Supporting Information
ABSTRACT: A short total synthesis of the published
structure of racemic trichodermatide A is reported. Our
synthesis involves a Knoevenagel condensation/Michael
addition sequence, followed by the formation of tricyclic
hexahydroxanthene-dione and a diastereoselective bis-hydrox-
ylation. The final product, the structure of which was
confirmed by X-ray crystallography, has NMR spectra that
are very similar, but not identical, to those of the isolated
natural product. Quantum chemically computed 13C shifts
agree well with the present NMR measurements.
he trichodermatides are a family of natural products with
unusual features that have attracted considerable
Scheme 1. Retrosynthetic Analysis of Trichodermatide A
T
attention in the chemical community (Figure 1). Isolated
the acetal and cleavage of the hemiacetal affords alkylidene-
bis-1,3-cyclohexanedione derivative 5, shown here in its
enolized form and as two conformers. The conformer on
the right side emphasizes that C7 (trichodermatide number-
ing) is a pseudo-asymmetric center. Dissection of 5 via a
retro-Michael reaction (→6), and then a retro-Knoevenagel
condensation, affords two 6-hydroxy-cyclohexane-1,3-diones of
opposite absolute configurations, 7 and ent-7, and chiral
dihydroxy aldehyde 8.
Figure 1. Proposed structures of the trichodermatides.
from the marine-derived fungus Trichoderma reesei by Pei and
co-workers, these compounds have shown a variety of
interesting bioactivities.1 Trichodermatide A, whose relative
and absolute configuration was elucidated using a combination
of NMR spectroscopy and CD measurements, has a
particularly interesting structure featuring a pentacyclic ring
system with eight stereocenters. Hiroya and co-workers have
recently reported its first total synthesis.2
In the forward direction, the formation of alkylidene-bis-1,3-
diones from aldehydes and 1,3-diones via Knoevenagel
The highly unusual carbon skeleton and the intricate
stereochemical features of trichodermatide A are best revealed
through a retrosynthetic analysis (Scheme 1). Hydrolysis of
Received: May 29, 2014
© XXXX American Chemical Society
A
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condensation and Michael addition is a well-documented
process.3 However, we deemed it unlikely that such a reaction
would proceed cleanly with a racemate of 4-hydroxy-
cyclohexane-1,3-dione 7 or a protected derivative thereof.
We, therefore, decided to simplify the synthetic plan by
introducing the two hydroxy groups at C2 and C10
(trichodermatide A numbering) at a later stage. It was
hoped that, by trapping the two cyclohexane-1,3-dione
moieties in a stiff polycyclic form, we would be able to
carry out a 2-fold hydroxylation with a high degree of
diastereoselectivity.
anthene-dione 13 with its bulky side chain exerts a
considerable degree of substrate control, overwhelming the
reagent control of enantiomerically pure oxaziridine 14. The
structure of 15 was unequivocally confirmed by conversion
into its bis-bromobenzoate 16 and single-crystal X-ray
analysis.8 The attractive “scorpion-like” structure of 16 in
the solid state is shown in Figure 2.
Our synthesis of racemic trichodermatide A started with the
dihydroxylation4 of known (E)-3-decen-1-ol 9 (Scheme 2).5
Scheme 2. Synthesis of Hexahydroxanthene-dione 15
Figure 2. X-ray structure of 16.
With ample amounts of 15 in hand, we studied its
desilylation and isomerization to trichodermatide A. The latter
seemingly only requires hydrolysis, followed by diastereoto-
pos-selective acetal formation and diastereoselective hemi-
acetal formation. We anticipated that both of these operations
could be carried out under thermodynamic control.
When a solution of 15 in THF was treated with an excess
amount of TBAF (10 equiv) and the mixture was allowed to
stir overnight at room temperature, conversion to a more
polar compound was observed. To our surprise, this
compound, which was isolated as an oil, turned out to be
8-epi-trichodermatide 17 (Scheme 3). The trans relationship
between protons at C7 and C8 was evident from the large
1
coupling constant found in the H NMR spectrum.
Scheme 3. Synthesis of 1, the Proposed Structure of
Trichodermatide A
Triple silylation of the resultant racemic triol using triethyl
chlorosilane gave 10, which could be selectively deprotected
and oxidized under Swern conditions.6 This gave aldehyde 11
contaminated with 10−15% of the silyl ether 10, from which
it could not be separated. However, this impurity did not
interfere in the subsequent Knoevenagel condensation/
Michael addition sequence using 1,3-cyclohexadione, which
afforded alkylidene-bis-cyclohexane-1,3-dione 12 in excellent
yield. Optimized conditions for this transformation included
the use of piperidine as a catalyst and the presence of an
excess amount of 1,3-cyclohexadione.
With 12 in hand, dehydrative cyclization to the vinylogous
anhydride 13 was investigated. This cyclization was effected
cleanly when a slight excess of tosyl chloride in methylene
chloride was added dropwise to a solution of 12, in the
presence of a base (NEt3) and a catalytic amount of DMAP.
Generation of the bis-lithium enolate and subsequent addition
of Davis’ (+)-(camphorsulfonyl)oxaziridine7 14 resulted in 2-
fold hydroxylation, yielding the desired compound 15 as the
major diastereomer. This result indicated that hexahydrox-
Convinced that trichodermatide A represents a thermody-
namic minimum, we next investigated the isomerization of 17
to the desired target compound. Several ways in which this
could be achieved can be imagined, including retro-Michael/
Michael addition and cycloreversion/cycloaddition. In the
event, we found that stirring a solution of 17 in CH2Cl2 in
the presence of excess pyrrolidine at room temperature
overnight gave a 55:45 mixture of the starting material 17 and
a new isomer (Scheme 3).9 This isomer was isolated as a
B
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white solid, facilitating its purification and structure
elucidation.
Information for details). The 13C NMR chemical shifts of the
different isomers were calculated at the MP2/SVP level of
theory, with the structures reoptimized using the RI-MP2/
SVP level of theory. In addition, calculations of 13C NMR
shifts were carried out at the MP2/TZVP (frag) + HF/
TZVP(full)-HF/TZVP(frag) level of theory starting from the
measured X-ray structure.12−15 Here, the intermediate
reference method16 was utilized in the calculation of the
NMR shieldings. All NMR computations employ gauge-
including atomic orbitals (GIAO).17 Basis sets as large as
def2-TZVP need to be used for the NMR calculations.
Furthermore, 13C shifts were computed for optimized
structures in the absence of solvent and including three
explicit DMSO solvent molecules.
Intriguingly, the NMR spectra of this new isomer closely,
but not fully, matched the spectra of enantiomerically pure 1
reported by Pei and co-workers.1 The most remarkable
difference was found for the signals at C8, the 13C signal of
which was found to resonate at 42.2 ppm instead of the
reported value of 38.1 ppm (150 MHz, d6-DMSO). The
proton at C8 is also shifted from 1.60 to 1.94 ppm (600
MHz, d6-DMSO). The analysis of 2D-NMR spectra measured
in d6-DMSO was confounded by extensive signal overlap, but
2D-NMR in CD3Cl showed the same key NOESY
correlations between H7 and H8, H16 and H7, H8 and
H10, and OH9 and H11, as reported by Pei and co-workers.1
HMBC correlations between OH9 and C8, OH9 and C9, and
H2 and C1 were also found. The identity of our compound
with the reported structure of trichodermatide A (1) was
firmly established using single-crystal X-ray analysis.10 The
structure of racemic 1 in the solid state is shown in Figure 3.
Computed shifts for the reported structure of trichoderma-
tide A were compared both to our experimental NMR data
(obtained from 1) and to the one reported by Pei and co-
workers.1 The agreement of theoretical vs experimental shifts
was better for our data set. The standard deviation (STD)
was found to be 1.6 ppm, in contrast to a STD of 2.8 ppm for
isolated trichodermatide. The inclusion of three DMSO
molecules lowers the standard deviation of the computed
carbon shifts with respect to present NMR measurements by
roughly 0.4 ppm, within the intermediate reference method,
with both the SVP and def2-TZVP basis set. With respect to
C8, where the mismatch between reported and synthesized
results was more evident, the computed shift was found to be
in good agreement with our experimental value (41.8 ppm vs
42.2 ppm). Unfortunately, comparison of the calculated
spectra of the other 12 isomers with the reported spectra of
the natural product was inconclusive and did not allow for
structural reassignment. Direct comparison of our synthetic
material with the natural product was also impossible due to
the unavailability of a sample from the isolation group.
In summary, we have synthesized the proposed structure of
trichodermatide A (1) as a racemate and confirmed its
identity by X-ray crystallography. While our NMR spectra
came close, they did not fully match the published spectra. A
sample of the natural product for direct comparison was not
available. The recently reported total synthesis of trichoderma-
tide A by Hiroya et al.2 does not represent structural proof,
since epimerizations similar to the one in Scheme 3 could
have happened under their conditions as well. Interestingly,
the proposed structures of the simpler congeners trichoder-
matides B (2) and C (3) have been recently synthesized by
Hsung and co-workers,18 and the spectra of the synthetic,
racemic compounds were found to be in disagreement with
the published ones as well. According to our work, it is
possible that natural trichodermatide A is also an isomer of
compound 1, but we cannot confidently say which one it is.
Figure 3. X-ray structure of 1.
The batch of crystals with similar morphology from which the
single crystal for analysis was picked was redissolved and
subjected to NMR spectroscopy. The spectra thus obtained
were identical to those previously recorded.
Since the NMR spectra of our racemic material do not fully
match the spectra reported for trichodermatide A, the
question arises whether the real natural product could be a
closely related isomer of 1. Indeed, several stereoisomers of 1
and constitutional isomers involving different acetals can be
imagined. This number is even larger, when one takes the
possibility into account that the α-hydroxy ketone moieties
epimerize. In principle, all stereocenters in trichodermatide A,
with the exception of C15 and C16, could epimerize under
relatively mild conditions.
To explore this possibility, we calculated the relative
stability and NMR spectra of 13 possible stereoisomers with
their alkyl side chain at C17 truncated to a methyl group (see
the Supporting Information).11 According to our quantum-
chemical calculations, the published structure of trichoderma-
tide A indeed represents the lowest energy isomer of the
series by about 0.7 kcal/mol (results from the B3LYP/6-
31G(d) and RI-MP2/SVP calculations; see the Supporting
EXPERIMENTAL SECTION
■
All reactions were carried out under an inert N2 atmosphere in oven-
dried glassware. Flash column chromatography was performed using
the analytical grade solvents indicated and silica gel (40−63 μm, 60
Å) as the stationary phase. Reactions and chromatography fractions
were monitored with Merck silica gel 60 F254 glass plates and
visualized using a 254 nm UV lamp and/or by treatment with a
suitable dip, followed by heating: potassium permanganate and ceric
ammonium molybdate. Tetrahydrofuran (THF) was distilled from
sodium benzophenone ketyl. Diisopropylamine was distilled from
and stored over CaH2. n-Butyllithium (nBuLi) was titrated with
diphenylacetic acid prior to use. All other solvents, as well as starting
C
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materials and reagents, were used without further purification from
commercial sources.
yield). The analytical data for 10 are as follows: Rf = 0.33 (hexanes/
EtOAc 99:1); 1H NMR (300 MHz, CDCl3): δ = 3.77−3.59 (m,
3H), 3.54 (m, 1H), 1.87 (dtd, J(H,H) = 13.5, 8.3, 2.6 Hz, 1H), 1.60
(m, 1H), 1.51−1.38 (m, 2H), 1.34−1.10 (m, 8H), 0.98−0.89 (m,
27H), 0.86 (t, J(H,H) = 7.0 Hz, 3H), 0.62−0.45 ppm (m, 18H); 13C
NMR (75 MHz, CDCl3): δ = 75.2, 71.6, 60.0, 33.6, 31.8, 30.2, 29.5,
26.6, 22.6, 14.1, 6.92 (3C), 6.86 (3C), 6.7 (3C), 5.15 (3C), 5.07
(3C), 4.4 ppm (3C); HRMS (ESI): m/z calcd for C28H64O3Si3 +
Na+: 555.4061 [M + Na+]; found: 555.4055.
Unless otherwise specified, proton (1H) and carbon (13C) NMR
spectra were recorded at 18 °C in base-filtered CDCl3 or CD2Cl2 on
spectrometers operating at 300 Hz, 400 and 600 MHz for proton
1
nuclei (75 MHz, 100 and 150 MHz for carbon nuclei). For H NMR
spectra, signals arising from residual proton forms of the solvent
1
were used as the internal standards. H NMR data are recorded as
follows: chemicals shift (δ) [multiplicity, coupling constant(s) J
(Hz), relative integral], where multiplicity is defined as s = singlet; d
= doublet; t = triplet; q = quartet; m = multiplet; br = broad, or
combinations of the above. The residual peaks of CHCl3 (δ 7.24
Aldehyde 11. Oxalyl chloride (2.61 mL, 30.47 mmol) was added
to a 500 mL flask containing 175 mL of dry CH2Cl2 under N2. The
solution was cooled to −78 °C, and DMSO (2.76 mL, 39.00 mmol)
was added dropwise. The resulting solution was stirred for 15 min at
−78 °C. TES-protected triol 10 (12.98 g, 24.37 mmol) was added to
the solution dropwise over 30 min. The resulting solution was then
allowed to warm slowly to −55 °C and was then stirred at that
temperature for approximately 90 min. The solution was then cooled
to −78 °C, NEt3 (16.95 mL, 121.85 mmol) was added slowly over a
5 min period, and the solution was allowed to warm to 0 °C over 1
h. The reaction mixture was poured into sat. aq. NaHCO3 (300 mL),
and the layers were separated. The aqueous layer was extracted with
CH2Cl2 (150 mL). The combined organic layers were dried over
MgSO4 and concentrated under reduced vacuum. The crude residue
was purified using silica gel column chromatography (hexanes, then
3% EtOAc in hexanes as eluent) to give 8.14 g of a pale yellow
liquid. The 1H NMR spectrum of the material showed that it
contained the aldehyde 11 and the TES-protected triol 10 in a molar
ratio of 9:1. The material was used directly in the next step. The
analytical data for pure sample of 11 are as follows: Rf = 0.30
1
ppm) or CH2Cl2 peak (δ 5.32 ppm) were used as reference for H
NMR spectra (for CDCl3 or CD2Cl2, respectively). The central peak
(δ 77.16 ppm) of the CDCl3 “triplet” was used as reference for
proton-decoupled 13C NMR spectra. Mass spectroscopy (MS)
experiments were performed either on an electron ionization (EI)
or on an electrospray ionization (ESI) instrument using a time-of-
flight analyzer. Infrared (IR) spectra were recorded on an FTIR
system equipped with an attenuated total reflection (ATR)
measuring unit. Suitable crystals for single-crystal diffractometry
were selected by means of a polarization microscope and placed on
the tip of a glass fiber. The data collections were performed on four-
circle diffractometers at 293 K (16) and 173 K (1) using MoKα
radiation (λ = 0.71073 Å). The structures were solved by direct
methods with SIR9719 and refined by least-squares methods against
F2 with SHELXL-97.20 In 16, the disorder of ethyl groups has been
described by split models. All nondisordered non-hydrogen atoms
were refined anisotropically; all disordered atoms have been refined
isotropically. The hydrogen atoms were placed in ideal geometry
riding on their parent atoms.
Alcohol 9. Under a nitrogen atmosphere, a solution of
commercially available 3-decyn-1-ol (5.17 g, 33.52 mmol) in THF
(9 mL) was added to a solution of LiAlH4 (3.78 g, 100.55 mmol) in
diglyme (50 mL) and THF (15 mL) at 0 °C. The mixture was
heated at reflux for 72 h, then cooled to room temperature, and
slowly quenched with water and 10% NaOH. This mixture was then
poured into 10% aq. HCl and extracted into hexane. The combined
organic layers were washed with water, then brine, dried over
MgSO4, and concentrated in vacuo. Vacuum distillation (bp 70 °C,
6.5 × 10−1 mbar) provided alkene 9 as a colorless oil (4.12 g, 79%).
Rf = 0.57 (hexanes/EtOAc 7:3). The analytical data for 9 matched
those provided in the literature.21
3,4-syn-Decane-1,3,4-triol. NMO (0.56 g, 4.82 mmol) and
K2OsO4·2H2O (12 mg, 0.032 mmol) were added to a solution of
alkene 9 (0.50 g, 3.2 mmol) in acetone/H2O (1:1, 10 mL). The
resulting solution was stirred at room temperature for 12 h. A
saturated solution of sodium sulfite (20 mL) was added, and the
mixture was allowed to stir for 15 min. CH2Cl2 (50 mL) was added,
and the layers were separated. The aqueous layer was further
extracted with CH2Cl2 (50 mL). The combined organic layers were
washed with saturated ammonium chloride (50 mL) and brine (50
mL), dried over MgSO4, and concentrated under reduced pressure.
The crude residue was purified by column chromatography
(CH2Cl2/MeOH 19:1 as eluent) to give the corresponding triol as
a clear oil (0.43 g, 71% yield). Rf = 0.38 (CHCl3/MeOH 17:3). The
analytical data for 3,4-syn-decane-1,3,4-triol matched those given in
the literature.19
Silyl Ether 10. Imidazole (34.9 g, 512.8 mmol) was added to a
500 mL flask containing a solution of 3,4-syn-decane-1,3,4-triol
(12.18 g, 64.1 mmol) in 250 mL of DMF. The solution was cooled
to 0 °C, and TESCl (64.4 mL, 384.6 mmol) was added dropwise
over a period of 10 min. The resulting solution was allowed to warm
to room temperature and was stirred for 12 h. The reaction mixture
was poured into water (2500 mL), and the resulting aqueous mixture
was extracted into diethyl ether (3 × 1000 mL). The combined
organic layers were washed with brine (1000 mL), dried over
MgSO4, and concentrated under reduced vacuum. The crude residue
was purified using silica gel column chromatography (hexanes as
eluent) to give the protected triol 10 as a clear oil (31.4 g, 92%
1
(hexanes/EtOAc 19:1); H NMR (400 MHz, CDCl3): δ = 9.76 (dd,
J(H,H) = 2.9, 1.9 Hz, 1H), 4.18 (dt, J(H,H) = 8.4, 4.2 Hz, 1H), 3.59
(ddd, J(H,H) = 8.8, 4.5, 2.7 Hz, 1H), 2.65 (ddd, J(H,H) = 15.8, 4.0,
1.9 Hz, 1H), 2.44 (ddd, J(H,H) = 15.8, 8.3, 2.9 Hz, 1H), 1.64 (m,
1H), 1.45 (m, 1H), 1.34−1.13 (m, 8H), 0.96−0.89 (m, 18H), 0.86
(t, J(H,H) = 7.0 Hz, 3H), 0.60−0.52 ppm (m, 12H); 13C NMR (100
MHz, CDCl3): δ = 201.9, 74.8, 70.5, 45.7, 31.8, 30.3, 29.4, 26.4,
22.6, 14.1, 6.8 (3C), 6.7 (3C), 5.0 (3C), 4.9 (3C); IR (thin film): ν
= 2953, 2935, 2913, 2876, 1730, 1458, 1238, 1091, 1003, 720 cm−1;
HRMS (ESI): m/z calcd for C22H48O3Si2 + Na+: 439.3040 [M +
Na+]; found: 439.3033.
Alkylidene-bis-cyclohexane-1,3-dione 12. Crude aldehyde 11
(17.62 mmol as determined using 1H NMR spectroscopy;
contaminated with TES-protected triol 10) was dissolved in
CH2Cl2 (250 mL). 1,3-Cyclohexadione (8.77 g, 78.27 mmol) and
piperidine (200 mL, 1.96 mmol) were added, and the resulting
solution was stirred at room temperature for 48 h. The reaction
mixture was concentrated under reduced pressure, and the crude
residue was purified directly by silica gel column chromatography
(1−5% EtOAc in hexanes, gradient) to give the title compound as a
white solid (10.4 g, 95% yield). Analytic data for 12 are as follows: Rf
1
= 0.36 (hexanes/EtOAc 17:3); H NMR (400 MHz, CD2Cl2): δ =
12.96 (s, 1H), 12.31 (s, 1H), 4.12 (dd, J(H,H) = 10.9, 3.3 Hz, 1H),
3.56 (ddd, J(H,H) = 9.2, 4.3, 2.2 Hz, 1H), 3.42 (ddd, J(H,H) = 10.4,
4.3, 2.2 Hz, 1H), 2.81 (ddd, J(H,H) = 13.6, 11.0, 2.3 Hz, 1H), 2.50−
2.38 (m, 4H), 2.34−2.23 (m, 4H), 1.95−1.71 (m, 4H), 1.56 (m,
1H), 1.47 (m, 1H), 1.37 (ddd, J(H,H) = 13.9, 10.4, 3.4 Hz, 1H),
1.32−1.07 (m, 8H), 1.00−0.91 (m, 18H), 0.88 (t, J(H,H) = 7.0 Hz,
3H), 0.62−0.54 ppm (m, 12H); 13C NMR (100 MHz, CD2Cl2): δ =
193.1, 192.5, 191.0, 190.6, 120.0, 117.2, 75.7, 74.2, 34.2, 33.9, 33.6,
33.0, 32.4, 31.4, 30.9, 30.2, 27.3, 25.9, 23.2, 20.5, 20.3, 14.4, 7.4
(3C), 7.3 (3C), 5.8 (3C), 5.7 ppm (3C); IR (thin film): ν = 2951,
2933, 2875, 1578, 1424, 1378, 1194, 1005, 980, 932, 908, 894, 738,
724 cm−1; HRMS (ESI): m/z calcd for C34H62O6Si2 + Na+:
645.3983 [M + Na+]; found: 645.3969.
Vinylogous Anhydride 13. NEt3 (31.55 mmol, 4.4 mL) and
DMAP (0.63 mmol, 77 mg) were added to a solution of bis(1,3-
cyclohexadione) compound 12 (6.31 mmol, 3.93 g) in CH2Cl2 (150
mL) at room temperature. A solution of TsCl (6.94 mmol, 1.32 g)
in CH2Cl2 (10 mL) was then added dropwise, and the solution was
stirred for 2 h. The reaction mixture was poured into saturated
D
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Note
aqueous NaHCO3 (100 mL). The organic layer was separated, and
the aqueous layer was extracted with another portion of CH2Cl2
(150 mL). The combined organic layers were dried over MgSO4 and
evaporated under reduced pressure. The resulting oil was purified
using silica gel column chromatography using 10% EtOAc/Hexanes
containing 1% NEt3 to give the title compound 13 as an oil (3.3 g,
87% yield). The compound was not stable, even when stored at −20
°C and so needs to be consumed within a few days. Analytic data for
reduced pressure. The crude residue was purified using silica gel
column chromatography (hexanes/ethyl acetate 4:1 as eluent) to give
the title compound as an oil (47 mg, 60% yield). Analytic data for 16
1
are as follows: Rf = 0.35 (hexanes/EtOAc 4:1); H NMR (600 MHz,
CDCl3): δ = 7.91−7.94 ppm (m, 4H), 7.55−7.59 (m, 4H), 5.56 (dd,
J(H,H) = 11.7, 5.1 Hz, 1H), 5.52 (dd, J(H,H) = 11.3, 5.0 Hz, 1H),
4.02 (dd, J(H,H) = 8.0, 3.0 Hz, 1H), 3.41−3.48 (m, 2H), 2.79−2.87
(m, 2H), 2.55−2.63 (m, 2H), 2.39−2.45 (m, 2H), 2.26−2.34 (m,
2H), 1.67 (ddd, J(H,H) = 13.9, 8.8, 1.8 Hz, 1H), 1.50 (m, 1H), 1.42
(ddd, J(H,H) = 13.9, 9.8, 3.0 Hz, 1H), 1.36 (m, 1H), 1.18−1.28 (m,
6H), 1.02−1.10 (m, 2H), 0.90−0.96 (m, 18H), 0.84 (t, J(H,H) = 8.0
Hz, 3H), 0.50−0.68 ppm (m, 12H); 13C NMR (150 MHz, CDCl3):
δ = 191.1, 190.3, 164.9, 164.8, 164.0, 163.4, 131.7 (4C), 131.4 (2C),
131.4 (2C), 128.7, 128.5, 128.4, 128.3, 117.0, 116.5, 75.5, 72.85,
72.82, 72.4, 36.4, 31.8, 30.2, 29.6, 27.1 (2C), 26.9, 25.8, 25.5, 23.3,
22.6, 14.0, 7.1 (6C), 5.4 (3C), 5.3 ppm (3C); IR (thin film): ν =
2954, 1728, 1690, 1267, 1167, 1116, 1101, 1012, 749 cm−1; HRMS
(ESI): m/z calcd for C48H66Br2O9Si2 + Na+: 1023.2510 [M + Na+];
found: 1023.2511. Single crystals suitable for X-ray crystallography
were obtained by recrystallization from hexanes.
1
13 are as follows: Rf = 0.19 (hexanes/EtOAc 17:3); H NMR (300
MHz, CDCl3): δ = 3.84 (br dd, J(H,H) = 9.0, 2.7 Hz, 1H), 3.58
(ddd, J(H,H) = 9.5, 4.2, 2.0 Hz, 1H), 3.46 (ddd, J(H,H) = 8.8, 4.1,
2.4 Hz, 1H), 2.58−2.20 (m, 8H), 2.05−1.90 (m, 4H), 1.62−1.48 (m,
2H), 1.40−1.10 (m, 10H), 1.02−0.84 (m, 18H), 0.84 (t, J(H,H) =
7.0 Hz, 3H), 0.80−0.47 ppm (m, 12H); 13C NMR (75 MHz,
CDCl3): δ = 197.1, 196.4, 165.3, 165.0, 118.6, 117.9, 75.6, 72.7, 39.1,
37.1, 37.1, 31.4, 30.3, 29.6, 27.4, 27.2, 26.8, 22.6, 21.9, 20.3, 19.9,
14.1, 7.10 (3C), 7.07 (3C), 5.33 (3C), 5.32 ppm (3C); IR (thin
film): ν = 2952, 2874, 1672, 1378, 1173, 1130, 1093, 742 cm−1;
HRMS (ESI): m/z calcd for C34H60O5Si2 + Na+: 627.3877 [M +
Na+]; found: 627.3863.
Diol 15. THF (5 mL) and diisopropylamine (1.19 mmol, 0.167
mL) were added to a 50 mL Schlenk flask under an N2 atmosphere,
and the resulting solution was cooled to 0 °C. 2.5 M nBuLi in
hexanes (1.19 mmol, 0.47 mL) was added, and the resulting mixture
was allowed to stir at 0 °C for approximately 20 min. The solution
was then cooled to −78 °C (dry ice/acetone), and the diketone 13
(0.496 mmol, 300 mg) was added dropwise as a solution in THF (1
mL). The mixture was stirred at that temperature for 20 min. A
solution of Davis oxaziridine 14 (1.49 mmol, 341 mg) in THF (2
mL) was added dropwise, and once all of it had been added, the
flask was removed from the −78 °C cooling bath and placed in an
ice bath. After 5 min, the reaction mixture was poured into a flask
containing 10 mL of phosphate-buffered H2O (300 mM, pH 7).
CH2Cl2 (100 mL), and 100 mL of phosphate-buffered H2O (300
mM, pH 7) was then added. The organic layer was separated, and
the aqueous layer was extracted with another portion of CH2Cl2
(100 mL). The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The crude material was then
triturated using 10% EtOAc in hexanes (2 × 5 mL), the insoluble
oxaziridine byproduct being discarded. The resulting oil was purified
by silica gel column chromatography to give the title compound 15
(150 mg, 47% yield). Other fractions contained a mixture of other
diastereomers (∼30 mg, ∼10% yield, slightly more polar than title
compound) and a mixture of monohydroxylated compounds (∼30
mg, ∼10% yield, which were slightly less polar than the title
compound). Analytic data for 15 are as follows: Rf = 0.39 (hexanes/
Compound 17. Under an atmosphere of N2, TBAF as a 1 M
solution in THF (20 mmol, 20 mL) was added using a syringe to a
dry flask containing triethylsilyl-protected tetraol 15 (1 mmol, 0.65
g). The resulting light-brown solution was stirred overnight at room
temperature. The reaction mixture was poured into a flask containing
300 mL of phosphate-buffered H2O (300 mM, pH 7), and resulting
mixture was extracted with CH2Cl2 (2 × 100 mL). The combined
organic layers were dried over MgSO4 and concentrated under
reduced pressure. The crude residue was purified by silica gel column
chromatography (CH2Cl2/acetone 3:1 as eluent) to give the title
compound 17 as a foamy solid, together with a minor isomer that
could not be fully characterized (222 mg, 53% yield). Analytic data
1
for 17 are as follows: Rf = 0.20 (CH2Cl2/acetone 3:1); H NMR
(600 MHz, CDCl3): δ = 4.21 ppm (t, J(H,H) = 2.6 Hz, 1H; H15),
4.17 (t, J(H,H) = 6.6 Hz, 1H; H16), 4.05 (dd, J(H,H) = 12.9, 5.6
Hz, 1H; H2), 3.97 (br. s, 1H; OH), 3.95 (t, J(H,H) = 3.0 Hz, 1H;
H10), 3.85 (br. s, 1H; OH), 2.93 (br. app. t, J(H,H) = 12.5 Hz, 1H;
H7), 2.74 (ddd, J(H,H) = 14.0, 5.0, 2.5 Hz, 1H; H14), 2.64 (dddd,
J(H,H) = 17.5, 12.6, 5.2, 3.0 Hz, 1H; H4), 2.44 (dddd, J(H,H) =
17.5, 5.2, 2.0, 2.0 Hz, 1H; H4′), 2.35 (dddd, J(H,H) = 12.7, 5.4, 5.4,
2.2 Hz, 1H; H3), 2.18 (ddd, J(H,H) = 13.8, 13.8, 5.4 Hz, 1H; H12),
2.05 (d, J(H,H) = 12.5 Hz, 1H; H8), 1.98 (dddd, J(H,H) = 14.7,
14.7, 4.5, 2.5 Hz, 1H; H11), 1.91 (m, 1H; H11′), 1.80 (dddd,
J(H,H) = 12.7, 12.7, 12.7, 5.5 Hz, 1H; H3′), 1.60−1.66 (m, 2H;
H12′, H14′), 1.43−1.56 (m, 2H; H17, H17′), 1.21−1.35 (m, 9H;
OH, H18−H21, H18′−H21′), 0.87 ppm (t, J(H,H) = 6.8 Hz, 3H;
H22, H22′, H22″); 13C NMR (150 MHz, CDCl3): δ = 198.2 (C1),
169.1(C5), 111.5 (C6), 106.3 (C13), 98.8 (C9), 80.8 (C16), 77.7
(C15), 71.3 (C2), 69.7 (C10), 42.7 (C8), 35.5 (C17), 31.7 (alkyl
chain), 31.0 (C14), 29.8 (C3), 29.1 (alkyl chain), 27.4 (C4), 26.7
(C12), 25.3 (alkyl chain), 24.9 (C11), 22.6 (alkyl chain), 22.2 (C7),
14.0 ppm (C22); IR (thin film): ν = 3410 (brd), 1627, 1592 cm−1;
HRMS (ESI): m/z calcd for C22H32O7: 408.2148 [M]; found:
408.2108.
1
EtOAc 3:2); H NMR (600 MHz, CDCl3): δ = 4.07−4.13 ppm (m,
2H), 4.01 (br d, J(H,H) = 8.0 Hz, 1H), 3.82 (d, J(H,H) = 1.8 Hz,
1H), 3.78 (d, J(H,H) = 1.7 Hz, 1H), 3.43−3.47 (m, 2H), 2.68−2.77
(m, 2H), 2.41−2.49 (m, 4H), 1.83−1.93 (m, 2H), 1.76 (ddd, J(H,H)
= 14.4, 8.1, 1.6 Hz, 1H), 1.31−1.43 (m, 2H), 1.46 (m, 1H), 1.18−
1.28 (m, 6H), 1.04−1.09 (m, 2H), 0.97 (app t, J(H.H) = 8.0 Hz,
6H), 0.90 (app t, J(H,H) = 8.0 Hz, 6H), 0.85 (t, J(H,H) = 7.0 Hz,
3H), 0.43−0.68 (m, 18H); 13C NMR (150 MHz, CDCl3): δ = 198.2,
197.4, 164.4, 164.1, 115.3, 114.3, 75.4, 73.0, 71.6, 71.5, 35.4, 31.8,
30.3, 30.2, 29.9, 29.6, 26.8, 26.2, 26.0, 23.6, 22.6, 14.0, 7.04 (3C),
7.00 (3C), 5.4 (3C), 5.3 ppm (3C); IR (thin film): ν = 3480, 2951,
2874, 1671, 1374, 1361, 1170, 1089, 1075, 1003, 723 cm−1; HRMS
(ESI): m/z calcd for C34H60O7Si2 + Na+: 659.3775 [M + Na+];
found: 659.3760.
Compound 1, Proposed as Trichodermatide A. Pyrrolidine
(6 mL, 0.0735 mmol) was added to a solution of 17 (10 mg, 0.0245
mmol) in CH2Cl2 (0.5 mL). The resulting solution was stirred
overnight at room temperature. The reaction mixture was poured
into a flask containing 10 mL of phosphate-buffered H2O (300 mM,
pH 7), and the resulting biphasic mixture was stirred vigorously for
15 min. CH2Cl2 (10 mL) was added, and the layers were separated.
The aqueous layer was extracted with another portion of CH2Cl2 (10
mL). The combined organic layers were dried over MgSO4 and
Bis-bromobenzoate 16. NEt3 (55 mL, 0.392 mmol) and DMAP
(2.0 mg, 0.016 mmol) were added to a solution of 15 (50 mg, 0.079
mmol) in CH2Cl2 (2 mL). The solution was cooled to 0 °C, and p-
bromobenzoyl chloride (51 mg, 0.235 mmol) was added in one
portion. The resulting solution was allowed to stir at that
temperature for 5 h. The reaction mixture was diluted with
CH2Cl2 (10 mL) and was poured into sat. aq. NaHCO3 (10 mL),
and the layers were separated. The aqueous layer was further
extracted with two portions of CH2Cl2 (10 mL). The combined
organic layers were dried over MgSO4 and concentrated under
1
concentrated under reduced pressure. The H NMR spectrum of the
crude material showed that it consisted of a 55:45 mixture of starting
material 17 and the required isomer 1 (Rf = 0.19, CH2Cl2/acetone
3:1). Compound 1 was purified using silica gel flash chromatography
(CH2Cl2/acetone 3:1 as eluent), followed by trituration in CH3CN.
Trichodermatide A 1 was obtained as a white solid (3 mg, 30%
yield). 1H and 13C NMR spectral data for 1 are provided in the
E
dx.doi.org/10.1021/jo501206k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Supporting Information. In CDCl3, 1 exists predominantly as one
isomer; in d6-DMSO, 1 exists as a mixture of isomers. IR (thin film):
ν = 3339 (brd), 1647, 1596 cm−1; HRMS (ESI): m/z calcd for
C22H31O7: 407.2070 [M − H+]; found: 407.2075. X-ray quality
crystals were obtained by recrystallization from acetonitrile.
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.;
Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma,
K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.;
Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui,
Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong,
M. W.; Gonzalez, C., Pople, J. A. Gaussian, Inc.: Wallingford, CT,
2004.
ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectra, X-ray data of 1 and 16, Cartesian coordinates
of optimized isomers, figures, and computed 13C NMR shifts.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Turbomole: TURBOMOLE V6.2 2010, a development of
University of Karlsruhe and Forschungszentrum Karlsruhe GmbH,
1989-2007, TURBOMOLE GmbH, since 2007; available from
http://www.turbomole.com.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: christian.ochsenfeld@uni-muenchen.de (C.O.).
*E-mail: dirk.trauner@lmu.de (D.T.).
Notes
■
(13) RI-MP2 method: (a) Weigend, F.; Haser, M. Theor. Chem.
̈
Acc. 1997, 97, 331−340. (b) Weigend, F.; Haser, M.; Patzelt, H.;
̈
Ahlrichs, R. Chem. Phys. Lett. 1998, 294, 143−152.
(14) def2-TZVP basis set: Weigend, F.; Ahlrichs, R. Phys. Chem.
Chem. Phys. 2005, 7, 3297−3305.
The authors declare no competing financial interest.
(15) SVP basis set: Schafer, A.; Horn, H.; Ahlrichs, R. J. Chem.
̈
ACKNOWLEDGMENTS
D.T. and C.O. acknowledge financial support by the Deutsche
Forschungsgemeinschaft (SFB 749). This work was also
supported by the Ludwig-Maximilians Universitat (LMU
Research Fellowship to E.M.), the Alexander von Humboldt
Foundation (postdoctoral fellowship to E.H.-G.), and the
Fonds der Chemischen Industrie (graduate fellowship to I.B.).
M.H. thanks Dr. Boris Maryasin (Munich) for helpful
discussions.
■
Phys. 1992, 97, 2571−2577.
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dx.doi.org/10.1021/jo501206k | J. Org. Chem. XXXX, XXX, XXX−XXX