Diastereotopos-differentiating allylic alkylation as a key step in the synthesis of γ-glutamyl boletine

Article abstract of DOI:10.1039/b917589j

A straightforward approach towards γ-glutamyl boletine is described, based on a diastereotopos-differentiating allylic alkylation of chelated amino acid ester enolates. Independent of the configuration of the leaving group in the allylic substrate, the allylation product is obtained as a single stereoisomer. Its configuration is solely controlled by the stereogenic center adjacent to the π-allyl complex formed.

Full text of DOI:10.1039/b917589j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Diastereotopos-differentiating allylic alkylation as a key step in the synthesis
of c-glutamyl boletine
Dnyaneshwar Gawas and Uli Kazmaier*
Received 26th August 2009, Accepted 22nd October 2009
First published as an Advance Article on the web 26th November 2009
DOI: 10.1039/b917589j
A straightforward approach towards g-glutamyl boletine is described, based on a
diastereotopos-differentiating allylic alkylation of chelated amino acid ester enolates. Independent of
the configuration of the leaving group in the allylic substrate, the allylation product is obtained as a
single stereoisomer. Its configuration is solely controlled by the stereogenic center adjacent to the p-allyl
complex formed.
Introduction
p-Allyl palladium complexes play an important role in modern
organic synthesis.1 With respect to the different synthetic appli-
cations, the allylic alkylation is probably the most popular one.2
Herein, a p-allyl complex is attacked by a nucleophile such as
an amine or a stabilized carbanion (in general, a malonate).
In contrast to the symmetrical malonates, reactions of b-keto
esters, as well as all other unsymmetric nucleophiles, are more
critical. Their reactions generate a stereogenic center that is
configurationally labile (if a-CH is present), giving mixtures of
stereoisomers.
Our group is investigating chelated enolates of amino acid esters
(such as A, Scheme 1) as nucleophiles for the synthesis of unnatural
amino acids.3 Chelation causes a marked enhancement of thermal
stability without having any negative influence on the reactivity of
these enolates. In contrast to the generally used malonates, with
our enolates, a stereogenic center is also formed at the a-position
Scheme 1 Pd-catalyzed allylic alkylations of chelated enolates A
of the amino acid (Scheme 1).4 Of course, the control of this
stereogenic centre is not a trivial issue, but the products obtained
if chiral allylic substrates with a stereogenic center close to the
allyl fragment, such as 2 or 3, are used, this center can control
the configuration of the p-allyl intermediate formed, giving rise to
substitution product 4 in excellent yield and diastereoselectivity,
independent of the substrate used.11
Herein, we describe an application of this diastereotopos-
differentiating protocol towards the synthesis of g-glutamyl bo-
letine 5 (Fig. 1), a metabolite of the Japanese mushroom Tylopilus
sp. (Boletaceae) showing antibiotic activity.12
are highly interesting structures, and therefore we decided to face
this challenge. Efficient stereocontrol can be achieved by using
chiral ligands5 or chiral allylic substrates.6 If peptide enolates are
used as nucleophiles, the stereochemical outcome of the allylation
can be controlled by the stereogenic information of the peptide
chain.7 The yields obtained are generally very high, even for very
complex, or even stannylated, amino acids.8 As a result of the
high reactivity of the chelated enolates, the allylations already
take place under very mild conditions at -78◦ C, which has an
extremely positive effect on the selectivity of the reaction. In many
cases, isomerization processes, such as p–s–p-isomerizations, can
be suppressed completely.9 This allowed us for the first time to use
C-nucleophiles in isomerization-free allylations of cis-configured
substrates such as 1 (Scheme 1).
Under certain circumstances, this isomerization can even be
suppressed for terminal p-allyl complexes, which are especially
sensitive towards isomerization.10 On the other hand, one can take
also advantage of such a fast isomerization process. For example,
Fig. 1 g-Glutamyl boletine.
Results and discussion
Institut fu¨r Organische Chemie, Universita¨t des Saarlandes, D-66123
Saarbru¨cken, Germany. E-mail: u.kazmaier@mx.uni-saarland.de; Fax: +49
681 302 2409; Tel: +49 681 302 3409
We began our synthesis with the preparation of the required
allylic substrate 10 (Scheme 2). Racemic allyl alcohol 6 was
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a 1 : 1 diastereomeric mixture was formed by epimerization at the
a-position, as distinguished from 13C-NMR spectra.
In the first instance, from the two diastereomeric allyl carbon-
ates, the two diastereomeric p-allyl complexes C1 and C2 are
formed, which undergo a fast equilibration under the reaction
conditions (via p–s–p-isomerization). The sterically very demand-
ing TBDPS-protecting group probably directs the Pd-fragment
to the opposite face of the molecule, shifting the equilibrium
strongly to the p-allyl complex C2. Nucleophilic attack of the
chelated enolate on this complex then gives rise to the observed
product.11
Next, the TFA-protecting group was removed by saponification
in quantitative yield (Scheme 4). Alternatively, this protecting
group can also be removed under reductive conditions13 with
comparable success. Coupling with benzyl-protected glutamate
under standard conditions gave rise to dipeptide 13 in high yield.
Because our aim was to remove the benzylic protecting group
and the double bond in one final step, we next cleaved the silyl
protecting group. This was not as trivial as expected. Under
standard conditions the other protecting groups were also affected.
With TBAF (THF, 0 ◦C), cleavage of the benzyl ester was also
observed, and with HF in CH3CN, cleavage of the t-butylester
Scheme 2 Preparation of allylic substrate 10
subjected to an enzymatic kinetic resolution using an immobilized
Candida antarctica lipase (Novozym 435), giving rise to acetate 7
with excellent ee. Saponification and subsequent silyl protection
provided silyl ether 8 in almost quantitative yield. Ozonolysis
and subsequent Grignard addition towards the aldehyde obtained
gave rise to allylic alcohol 9 as a diastereomeric mixture (60%
ds). However, as already mentioned, the configuration of this
newly formed stereogenic center does not play any role for our
further synthesis. Esterification with ethyl chloroformate yielded
the required allyl carbonate 10.
With this allylic substrate in hand, we next investigated the
key step of our synthesis, the allylic alkylation (Scheme 3). The
expected amino acid derivative 11 was obtained in excellent yield
as a single stereoisomer. A perfect chirality transfer was observed
from the allyl moiety towards the a-position of the amino acid. It
should be mentioned that the corresponding allyl benzoate gave
a slightly lower yield and selectivity, providing also the second
diastereomer of 11, which allowed us to verify our results. In
addition, when stereoisomerically pure 11 was treated with LDA,
Scheme 3 Stereoselective allylic alkylation using 10
458 | Org. Biomol. Chem., 2010, 8, 457–462
Scheme 4 First attempts to synthesize 5
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also occurred, giving rise to a lactone derivative. Finally, the best
results were obtained by using HF in pyridine. The allyl alcohol
14 obtained was then subjected to oxidation. Our first attempts
were carried out with Dess–Martin periodinane (DMP). With four
equivalents of DMP, a complete conversion was observed after
twelve hours, but, unfortunately, the by-products formed from the
DMP could not be separated by chromatography. Therefore, we
switched to MnO2 as the oxidizing agent. With freshly activated
MnO2, the oxidation was also complete after two days, and
purification of 15 was not a problem in this case. Trifluoroacetic
acid (TFA) was used to cleave the t-butylester. After three hours, a
complete consumption of 15 was observed; however, the product
formed was not the desired carboxylic acid, but rather the lactone
16, resulting from a Michael addition of the carboxylic acid to
the a,b-unsaturated ketone. Therefore, we decided to remove the
double bond first, together with the benzylic protecting groups.
Subsequent acidic cleavage of the t-butylester provided 5 as the
corresponding TFA-salt.
Alternatively, for the preparation of the salt-free natural
product, the double bond was removed at an earlier stage
of the synthesis (Scheme 5). Hydrogenation of 11, subsequent
cleavage of the TFA-protecting group and coupling with protected
glutamate provided 17. Cleavage of the silyl protecting group was
carried out as described before for the unsaturated analogue 13.
Subsequent Swern oxidation provided ketone 18, which was easily
converted into 5 by removing the protecting groups under standard
conditions.
Experimental
General remarks
All reactions were carried out in oven-dried glassware (100 ◦C) un-
der nitrogen. All solvents were dried before use: THF was distilled
from LiAlH4, and CH2Cl2 from CaH2. The products were purified
by flash chromatography on silica gel (0.063–0.2 mm). Mixtures of
ethyl acetate and hexanes were generally used as eluents. Analysis
by TLC was carried out on commercially precoated Polygram SIL-
G/UV 254 plates (Machery-Nagel, Dueren). Visualization was
accomplished with UV light, KMnO4 solution, Ce–Mo reagent or
1
iodine. H- and 13C-NMR spectroscopic analysis was performed
on Bruker AC-500 or Bruker DRX-500 spectrometers. Chemical
shifts are reported on the d (ppm) scale, and the coupling
constants are given in Hz. The values for enantiomeric excess
were determined by GCMS-QP2010 using a Chirasil–Dex-CB
column. Optical rotations were measured on a Perkin–Elmer
polarimeter PE 341. HRMS were measured with a Finnigan MAT
95S mass spectrometer. Elemental analyses were carried out at the
Department of Chemistry at Saarland University.
(S)-Hept-1-en-3-ol acetate (7)14. To a solution of racemic alco-
hol 6 (22.8 g, 200 mmol) in vinyl acetate (330 mL), Novozym 435
(6.6 g) was added under stirring. The progress of the reaction was
monitored by GC. After stirring vigorously at room temperature
for 4 h, the enzyme was filtered off and was washed with diethyl
ether. The organic phases were combined and evaporated to give
approximately a 1 : 1 mixture of alcohol (R)-6 and acetate (S)-
7 respectively. This mixture was separated by chromatography
(silica, hexanes–ether, 100 : 0 to 95 : 5), which gave acetate (S)-7
(12.48 g, 42%, > 99% ee) as colorless oil, [a]2D0 = + 13.1◦ (c 1.1,
CHCl3); and unreacted alcohol (R)-6 (9.12 g, 40%, > 90% ee) as
1
colorless oil. (S)-7: H-NMR (400 MHz, CDCl3): d = 5.78–5.70
(m, 1H), 5.21–5.11 (m, 3H), 2.03 (s, 3H), 1.65–1.22 (m, 6H), 0.86
(t, J = 6.8 Hz, 3H); 13C-NMR (100 MHz, CDCl3): d = 170.3,
136.6, 116.4, 74.8, 33.9, 27.2,◦22.4, 21.2, 13. 9;◦GC (Chirasil–Dex-
◦
CB, 1. 80 C, 10 min; 2. 10 C min-1, 3. 100 C, 5 min): (S)-(7):
tR = 11.61 min, (R)-(7): tR = 9.86 min.
(S)-Hept-1-en-3-ol (6):14. To a stirred solution of acetate (S)-7
(11.7 g, 75 mmol) in 80% MeOH (100 mL), K2CO3 (20.7 g,
150 mmol) was added. After completion of the reaction (as
indicated by TLC) the solvent was evaporated in vacuo. Water
was added to the residue, and the solution was extracted twice
with diethyl ether. The combined organic layers were dried over
Na2SO4. After evaporation of the solvent, the crude product was
purified by flash chromatography (hexanes–diethyl ether, 90 : 10◦)
to give alcohol (S)-6 (8.38 g, 98%) as a colorless oil, [a]2D0 = + 9.0
(c 1.0, CHCl3). 1H-NMR (400 MHz, CDCl3): d = 5.85 (ddd, J =
16.9, 10.4, 6.2 Hz, 1H), 5.26–5.06 (dd, J = 17.2, 10.4 Hz, 2H), 4.06
(q, J = 6.2 Hz, 1H), 1.68 (sbr, 1H), 1.62–1.47 (m, 2H), 1.43–1.26
(m, 4H), 0.89 (t, J = 7.1, 3H); 13C-NMR (100 MHz, CDCl3): d =
141.3, 114.4, 73.2, 36.7, 27.4, 22.6, 13.9. GC (Chirasil–Dex-CB,
Scheme 5 Alternative approach towards 5
Conclusion
In conclusion, we have shown that diastereotopos-differentiating
allylic alkylations are a versatile tool for the synthesis of func-
tionalized unusual amino acids. If isomeric mixtures of allylic
substrates are used, a fast equilibration of the intermediate
p-allyl-complexes results in the formation of only one allylation
product in excellent yield and selectivity. Further applications of
this straightforward protocol are currently under investigation.
◦
◦
◦
1. 80 C, 10 min; 2. 10 C min-1, 3. 100 C, 5 min): (S)-(6): tR
12.08 min, (R)-(6): tR = 12.33 min.
=
(3S)-3-tert-Butyldiphenylsilyloxy-1-heptene (8). To a stirred
solution of alcohol (S)-6 (2.51 g, 22.0 mmol) in◦CH2Cl2 (20 mL),
imidazole (2.24 g, 33.0 mmol) was added at 0 C. After 15 min,
tert-butyldiphenylsilylchloride (7.23 g, 26.4 mmol) in CH2Cl2
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(5mL) was added, and the reaction was allowed to warm up to
room temperature. After completion of the reaction (as indicated
by TLC), the salty mixture was diluted with water, and the
aqueous layer was extracted twice with CH2Cl2. The combined
organic layers were washed with brine, dried over Na2SO4,
and concentrated in vacuo. The crude product was purified by
chromatography (silica, hexanes–EtOAc) to afford (S)-8 (7.69 g,
99%) as a colorless oil, [a]2D0 = + 20.2◦ (c 1.0, CHCl3). 1H-NMR
(400 MHz, CDCl3): d = 7.72–7.34 (m, 10H), 5.81 (ddd, J = 16.9,
10.4, 6.2 Hz, 1H), 4.98 (dd, J = 17.1, 11.1 Hz, 2H), 4.15 (q,
J = 6.3 Hz, 1H), 1.52–1.36 (m, 2H), 1.28–1.12 (m, 4H), 1.08 (s,
9H), 0.80 (t, J = 6.6 Hz, 3H); 13C-NMR (100 MHz, CDCl3): d =
140.9, 136.0, 135.9 (2C), 134.6 (2C), 134.4, 129.5, 129.4, 127.4
(2C), 127.3 (2C), 114.1, 74.7, 37.3, 27.1 (3C), 26.6, 22.6, 19.4,
14.0. HPLC (Chiralcel OD-H, hexane, 100%, 1 mL min-1): (S)-
(8): tR = 3.92 min, (R)-(8): tR = 4.80 min. HRMS (EI) calcd
for C23H32OSi [M]+: 352.2222. Found: 352.2219. Anal. calcd for
C23H32OSi (352.22): C, 78.35; H, 9.15. Found: C, 78.44; H, 8.78.
as a colorless oil. Mixture of diastereomers: 1H-NMR (400 MHz,
CDCl3): d = 7.75–7.34 (m, 10H), 5.99–5.90 (m, 1H), 5.35–5.23 (m,
2H), 5.00–4.97 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.84 (m, 1H),
1.48–1.38 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.14–1.03 (m, 4H), 1.08
(s, 9H), 0.72 (t, J = 7.2 Hz, 3H); 13C-NMR (100 MHz, CDCl3):
d = 154.6, 136.2 (2C), 136.0 (2C), 134.4, 133.4, 132.4, 129.6 (2C),
129.5 (2C), 127.4 (2C), 119.4, 81.4, 74.4, 63.7, 32.7, 27.4, 27.0 (3C),
22.4, 19.5, 14.3, 13.8). Selected signals of the minor diastereomer:
1H-NMR (400 MHz, CDCl3): d = 5.85–5.76 (m, 1H), 5.13 (t,
J = 6.5 Hz, 1H), 4.11–3.99 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H); 13C-
NMR (100 MHz, CDCl3): d = 154.5, 136.1 (2C), 135.9 (2C), 133.9,
133.8, 132.8, 129.5 (2C), 129.4 (2C), 127.4 (2C), 118.7, 80.7, 73.9,
63.6, 32.4, 27.0 (3C), 26.4, 22.4, 19.5, 14.1, 13.8. HPLC (Reprosil
100 Chiral-NR 8 mm, hexane, 100%, 1 mL min-1): tR = 8.65 min
(62%), 9.72 min (38%). HRMS (EI) calcd for C27H39O4Si [M +
H]+: 455.2618. Found: 455.2632.
(2S,6S,E)-tert-Butyl 6-(tert-butyldiphenylsilyloxy)-2-(trifluo-
roacetamido)dec-4-enoate (11). Hexamethyldisilazane (3.15 g,
19.5 mmol) was dissolved in THF (20 mL) in a Schlenk flask
under argon. After the solution was cooled to -78 ◦C, n-BuLi
(1.6 M, 10.9 mL, 17.4 mmol) was added slowly. The reaction
mixture was stirred for 20 min at this temperature, and then the
cooling bath was removed and the stirring was continued for a
further 15 min. In a second Schlenk, TFA-Gly-OtBu (1.59 g,
7.0 mmol) was dissolved in THF (40 mL). The solution was
cooled to -78 ◦C, before the freshly prepared LHMDS was
added. After 15 min, a solution of dried ZnCl2 (1.05 g, 7.7 mmol)
in THF (5 mL) was added, and stirring was continued for 30 min.
A solution was prepared from (allylPdCl)2 (12 mg, 0.033 mmol)
and PPh3 (34 mg, 0.13 mmol) in THF (5 mL), which was added
(4S)-4-(tert-Butyldiphenylsilyloxy)-1-octen-3-ol (9). To a solu-
tion of alkene 8 (2.82 g, 8.0 mmol) in CH2Cl2 (50 mL), ozone was
◦
passed through for 30 min at -78 C. The reaction was allowed
to warm up to room temperature before dimethylsulfide (0.99 g,
16 mmol) was added. After addition of water, the aqueous phase
was washed twice with dichloromethane. The combined organic
layers were dried over Na2SO4. After evaporating the solvent
in vacuo, the crude product was dissolved in dry THF (2 mL), and
the solution was added dropwise to a vinylmagnesium bromide
solution (1.31 g, 10 mL 1.0 M solution in THF, 10 mmol) at -20 ◦C
under nitrogen. The reaction mixture was allowed to warm up to
room temperature for 2 h before it was quenched at 0 ◦C with
aq. NH4Cl. The aqueous phase was extracted three times with
ethyl acetate (25 mL each) and the combined organic layers were
dried over Na2SO4. After removing the solvents in vacuo, the crude
product was purified by flash chromatography (hexanes–EtOAc,
70 : 30), which gave the desired allyl alcohol 9 (2.24 g, 5.86 mmol,
73%) as a colorless liquid (60% ds). Mixture of diastereomers:
1H-NMR (400 MHz, CDCl3): d = 7.70–7.36 (m, 10H), 5.89–5.79
(m, 1H), 5.33–5.14 (m, 2H), 4.11–4.03 (m, 1H), 3.79–3.64 (m, 1H),
2.21 (d, J = 5.3 Hz, 1H), 1.56–0.97 (m, 15H), 0.73 (t, J = 6.9 Hz,
3H); 13C-NMR (100 MHz, CDCl3): d = 138.5, 136.4, 135.9, 135.9,
134.0, 133.9, 133.8, 133.5, 129.8, 129.7, 129.6, 127.7, 127.6, 127.5,
127.4, 116.4, 116.0, 76.7, 76.6, 75.6, 74.2, 32.9, 31.7, 27.6, 27.1
(3C), 22.6, 22.5, 19.6, 19.5, 13.8. HPLC (Reprosil 100 Chiral-NR
8 mm, hexane–iPrOH, 99 : 1, 1 mL min-1): tR = 9.14 min (62%),
10.31 min (38%). HRMS (EI) calcd for C24H33OSi [M - OH]+:
365.2306. Found: 365.2306. Anal. calcd for C24H34O2Si (382.23):
C, 75.34; H, 8.96. Found: C, 75.48; H, 8.41.
◦
to the chelated enolate at -78 C. At the same temperature, the
allyl substrate 10 (1.91 g, 4.2 mmol) was added in THF (5 mL),
before the mixture was allowed to warm to room temperature
overnight. The solution was diluted with ether before 1 M KHSO4
was added. After separation of the layers, the aqueous layer
was extracted three times with ether (20 mL each), and the
combined organic layers were dried over Na2SO4. The solvent was
evaporated in vacuo, and the crude product was purified by flash
chromatography (hexanes–EtOAc, 95 : 5) giving rise to the amino
acid derivative 11 (2.43 g, 4.1 mmol, 98%) as a yellowish liquid.
1H-NMR (400 MHz, CDCl3): d = 7.67–7.33 (m, 10H), 6.76 (d,
J = 7.1 Hz, 1H), 5.52 (dd, J = 15.4, 6.4 Hz, 1H), 5.26–5.10 (m,
1H), 4.45 (q, J = 7.1 Hz, 1H), 4.12 (m, 1H), 2.59–2.38 (m, 2H),
1.45 (s, 9H), 1.43–1.07 (m, 6H), 1.05 (s, 9H), 0.79 (t, J = 6.9 Hz,
3H); 13C-NMR (100 MHz, CDCl3): d = 169.1, 156.3, 138.8 (2C),
135.9 (2C), 135.8 (2C), 134.4, 134.2, 129.6, 129.5, 127.5 (2C),
127.4 (2C), 122.0, 83.3, 73.6, 52.4, 37.3, 33.9, 27.9 (3C), 27.0
(3C), 26.6, 22.5, 19.3, 13.8. HRMS (EI) calcd for C32H44F3NO4Si
[M]+: 591.2922. Found: 591.2920. Anal. calcd for C32H44F3NO4Si
(591.29): C, 64.95; H, 7.49; N, 2.37. Found: C, 64.84; H, 7.72; N,
2.40.
(4S)-4-(tert-Butyldiphenylsilyloxy)oct-1-en-3-yl ethyl carbonate
(10). To a solution of alcohol 9 (2.10 g, 5.50 mmol) and ethyl
chloroformate (0.89 g, 8.25 mmol) in CH2Cl2 (20 mL) at 0 ◦C,
pyridine (0.65 g, 8.25 mmol) was added, as well as a catalytic
amount of DMAP. The reaction was allowed to stir at this temper-
ate until completion (TLC). The reaction mixture was neutralized
with 1 N HCl solution, and the aqueous phase was extracted
three times with CH2Cl2 (25 mL each). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by flash chromatography (hexanes–
EtOAc, 95 : 5) providing allyl substrate 10 (2.20 g, 4.85 mmol, 88%)
Dipeptide 13. K2CO3 (2.346 g, 17.0 mmol) was added to a
solution of TFA-protected amino acid 11 (2.0 g, 3.4 mmol) in 90%
MeOH (20 mL) at room temperature. The reaction was stirred
(36 h) until the removal of the TFA-group was complete (TLC).
The solvent was removed in vacuo and the crude product was
dissolved in water. The aqueous phase was extracted three times
with CHCl3 (25 mL each). The combined organic layers were dried
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over Na2SO4. After removing the solvent in vacuo, the primary
amine 12 was obtained in 98% yield (1.64 g, 3.3 mmol). This crude
amine 12 was used directly without further purification for the
subsequent peptide coupling.
128.4 (2C), 128.3 (2C), 128.2, 128.1, 128.0 (2C), 82.8, 67.3, 67.0,
53.4, 51.8, 39.6, 35.4, 32.0, 28.2, 27.9 (3C), 26.1, 22.3, 13.8; HRMS
(EI) calcd for C34H44N2O8 [M]+: 608.3098. Found: 608.3048. Anal.
calcd for C34H44N2O8 (608.30): C, 67.09; H, 7.29; N, 4.60. Found:
C, 66.75; H, 7.08; N, 4.35.
To a solution of amine 12 (1.64 g, 3.3 mmol), Z-L-Glu-OBn
(1.22, 3.3 mmol) and DMAP (40 mg, 0.33 mmol) in dry CH2Cl2
(20 mL), DCC (0.75 g, 3.63 mmol) was added at 0 ◦C. The reaction
was stirred at this temperature for 15 min and was allowed to
warm to room temperature. After 3 h the solvent was removed by
evaporation, and the crude product was dissolved in Et2O. The
white precipitate formed was filtered off and the filtrate was
washed with 1 N HCl, followed by sat. NaHCO3. The organic
layer was dried over Na2SO4, concentrated in vacuo and purified
by flash chromatography (hexanes–EtOAc, 75 : 25), giving rise to
the desired dipeptide 13 (2.41 g, 2.75 mmol, 86%). 1H-NMR
(400 MHz, CDCl3): d = 7.67–7.27 (m, 20H), 5.93 (d, J = 7.4,
1H), 5.72 (d, J = 7.8 Hz, 1H), 5.47 (dd, J = 15.3, 6.4 Hz, 1H),
5.21–5.05 (m, 5H), 4.50–4.30 (m, 2H), 4.15–4.07 (m, 1H), 2.45–
2.28 (m, 2H), 2.24–1.90 (m, 4H), 1.53–1.31 (m, 2H), 1.41 (s, 9H),
1.23–1.09 (m, 4H), 1.04 (s, 9H), 0.78 (t, J = 6.6 Hz, 3H); 13C-NMR
(100 MHz, CDCl3): d = 171.7, 171.1, 170.7, 156.1, 137.5, 136.2,
135.9 (2C), 135.8 (2C) 135.2, 134.3, 134.2, 129.5, 129.4, 129.3,
128.6 (2C), 128.5 (2C), 128.4 (2C), 128.3, 128.1, 128.0, 127.4 (2C),
127.3 (2C), 123.5, 82.1, 73.7, 62.2, 67.0, 53.6, 52.2, 37.3, 34.6, 31.9,
27.9 (3C), 27.8, 27.0 (3C), 26.7, 22.5, 19.3, 14.0. HRMS (EI) calcd
for C50H64N2O8Si [M]+: 848.4432. Found; 848.4454.
c-Glutamyl boletine TFA-salt (5·TFA). A solution of com-
pound 15 (304 mg, 0.5 mmol) in MeOH (10 mL) was continuously
stirred in the presence of 10 mol% Pd/C (30 mg) at room
temperature, under an atmosphere of hydrogen overnight. The
reaction mixture was filtered through a pad of Celite, which was
washed with methanol (20 mL). The solvent was evaporated in
vacuo, and the crude product obtained was dissolved in CH2Cl2
(10 mL) and treated with trifluoroacetic acid (57 mg, 2.5 mmol).
After stirring the reaction mixture for 12 h the solvent was removed
in vacuo, and the TFA ◦salt of 5 (217 mg, 98%) was obtained in
1
excellent yield, mp. 72 C. H-NMR (500 MHz, CD3OD): d =
4.15 (sbr, 1H), 3.98 (sbr, 1H), 2.66–2.35 (m, 4H), 2.32–2.03 (m, 2H),
1.95–1.24 (m, 10H), 0.91 (t, J = 7.3 Hz, 3H); 13C-NMR (125 MHz;
CD3OD): d = 212.7, 174.2, 173.5, 171.2, 162.1, 117.13, 53.0, 52.4,
42.2, 41.1, 31.4, 30.6, 26.2, 25.7, 22.1, 19.7, 13.0.
c-Glutamyl boletine (5)12. The free natural product 5 was
obtained in an analogous manner from 11. 1H-NMR (500 MHz,
CD3OD): d = 4.38 (1H, br s, CHNH), 4.24 (1H, br s, CHNH),
2.49–2.39 (2H, m, COCH2), 2.34 (2H, t, J 7.4, COCH2), 2.32–
2.21 (2H, m, COCH2), 2.20–1.81 (2H, m, CH2), 1.79–1.47 (4H, m,
2 ¥ CH2), 1.52 (2H, quint., J 7.1, CH2CH2CH2), 1.36–1.25 (2H,
m, CH3CH2), 0.90 (3H, t, J 7.3, CH3CH2); 13C-NMR (125 MHz;
CD3OD): d = 212.4, 175.1, 174.0, 173.5, 52.4, 50.8, 41.6, 40.9,
31.2, 30.3, 27.4, 25.4, 21.7, 19.4, 12.6.
Dipeptide 14. Dipeptide 13 (2.12 g, 2.5 mmol) in CH2Cl2
(5 mL) was added to a solution of HF·pyridine (65–75%) (2.47 g,
3.8 mL, 2.5 mmol) and pyridine (1.9 mL) in CH2Cl2 (20 mL) at
0 ◦C. After stirring the reaction mixture at room temperature for
24 h, the solvent was evaporated in vacuo. The residue was dis-
solved in CH2Cl2 and washed with sat. NaHCO3, H2O and brine,
and dried over Na2SO4. The solvent was removed in vacuo and the
crude product was purified by flash chromatography (hexanes–
EtOAc, 6 : 4) to provide allyl alcohol 14 (1.25 g, 2.05 mmol, 82%)
as a colorless oil. 1H-NMR (400 MHz, CDCl3): d = 7.58–7.08 (m,
10H), 6.24 (d, J = 6.8 Hz, 1H), 5.8 (d, J = 7.6 Hz, 1H), 5.61–5.45
(m, 2H), 5.21–5.02 (m, 4H), 4.53 (q, J = 6.7 Hz, 1H), 4.40 (tbr, J =
7.8 Hz, 1H), 4.06–3.92 (m, 1H), 2.64–2.32 (m, 2H), 2.30–1.87 (m,
4H), 1.54–1.21 (m, 6H), 1.45 (s, 9H), 0.88 (t, J = 6.9 Hz, 3H); 13C-
NMR (100 MHz, CDCl3): d = 171.8, 171.3, 170.8, 156.3, 137.7,
136.1, 135.2, 128.6 (2C), 128.4 (2C), 128.3 (2C), 128.2 (2C), 128.1,
128.0, 124.5, 82.2, 72.2, 67.3, 67.1, 53.4, 52.3, 36.7, 35.1, 31.9, 28.2,
28.0 (3C), 27.6, 22.6, 14.0. HRMS (EI) calcd for C34H46N2O8 [M]+:
610.3254. Found; 610.3222.
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft as
well as the Fonds der Chemischen Industie is gratefully acknowl-
edged.
References
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Dipeptide 15. MnO2 (1.56 g, 18.0 mmol) was added to a
solution of alcohol 14 (1.10 g, 1.8 mmol) in CH2Cl2 (20 mL).
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1
white solid, mp. 58 C. H-NMR (400 MHz, CDCl3): d = 7.44–
7.24 (m, 10H), 6.72–6.63 (m, 1H2), 6.36 (sbr, 1H), 6.10 (d, J =
15.8 Hz, 1H), 5.70 (sbr, 1H), 5.24–5.06 (m, 4H), 4.65–4.33 (m, 2H),
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