A straightforward approach towards glycoamino acids and glycopeptides via Pd-catalysed allylic alkylation

Article abstract of DOI:10.1039/b813978d

Chelated enolates are versatile nucleophiles for palladium-catalysed allylic alkylations. Even with complex allylic substrates the reaction proceed without significant isomerisation. This allows the stereoselective introduction of polyhydroxylated allylic sidechains into amino acids and peptides with retention of the olefin geometry.

Full text of DOI:10.1039/b813978d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A straightforward approach towards glycoamino acids and glycopeptides via
Pd-catalysed allylic alkylation†
Katja Kra¨mer, Jan Deska, Christina Hebach and Uli Kazmaier*
Received 12th August 2008, Accepted 24th September 2008
First published as an Advance Article on the web 31st October 2008
DOI: 10.1039/b813978d
Chelated enolates are versatile nucleophiles for palladium-catalysed allylic alkylations. Even with
complex allylic substrates the reaction proceed without significant isomerisation. This allows the
stereoselective introduction of polyhydroxylated allylic sidechains into amino acids and peptides with
retention of the olefin geometry.
The major problem was the formation of homocoupling products
Introduction
in the metathesis step.
Glycopeptides play a central role in intercellular processes such
In principle, the double bond obtained can be subjected to
as cell-cell recognition or ligand-receptor interaction.1 Biosyn-
other addition reactions to generate modified glycosyl amino acids.
thetically these glycopeptides and -proteins are the result of
Therefore, it would be important to generate the double bond in a
post-translational peptide modifications, managed by numerous
glycosyltransferases.2 In general, the sugar moieties are connected
highly stereoselective fashion (E or Z), which is not a trivial issue
under the metathesis conditions.
Based on our interest in the synthesis of azasugars12 and
polyhydroxylated amino acids,13 we developed an alternative
protocol towards these unsaturated amino acids, taking advantage
of a chelate-enolate Claisen rearrangement.14 If ester of chiral
allyl alcohols15 are subjected to this version of the Claisen
rearrangement, an excellent chirality transfer is observed towards
the a-position of the amino acid (Scheme 2). Based on the chair-
like transition state, the (E)-configured double bond is formed
to the peptide chain via N- or O-acetals, preferentially towards
serines or threonines. The acetal linkage is easily to realize for
the enzymes involved, but on the other hand is also sensitive
towards hydrolytic cleavage. With respect, that the building blocks
of glycopeptides, the glyco amino acids are also interesting drug
candidates, this lability is a significant limitation.3 Replacing the
connecting oxygen by a methylene unit offers a great deal of
stability without changing the steric properties of this so-called
C-glycosides. Not surprisingly, a lot of different synthetic ap-
proaches have been developed in recent years,4 using electrophilic,5
nucleophilic6 or radical glycal precursors.7 Recently, several ap-
proaches also used ruthenium-catalysed olefin cross-metathesis to
generate unsaturated glycosyl amino acids or derivatives thereof.8
For example, Nolan et al. reported on the coupling of sugar-
derived allyl alcohols with protected allyl glycine giving rise to
the g,d-unsaturated polyhydroxylated amino acid,9 which could
by cyclized to the C-linked glycosyl amino acid in the presence of
Hg-salts (Scheme 1).10 Best results were obtained with the second
generation Grubbs-catalyst (G2)11 which gave yields around 50%.
Scheme 1 Synthesis of glycosylamino acids via cross-metathesis.
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
† Electronic supplementary information (ESI) available: 1H-NMR and
Scheme
rearrangements.
2
Synthesis of glycosyl amino acids via chelate-Claisen
13C-NMR spectra of compounds 5–12. See DOI: 10.1039/b813978d
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exclusively in high yield.14 The free carboxylic acid obtained can
be coupled directly with other amino acids and peptides, giving
rise to glycopeptide-type structures.
Interestingly, incorporation of the allylic alcohol into a dipep-
tide and attempts to rearrange these peptide esters were unsuccess-
ful, although unfunctionalized allylic esters gave rise to modified
peptides in high yield.16 In principle, also chirality transfer from the
peptide chain towards the newly formed amino acid is possible,17
but with these rather complex substrates only isomerisation of the
double bond was observed.
used.21 If chelated enolates of TFA-protected glycinates (generated
in situ via deprotonation/transmetallation) are subjected to Pd-
catalysed allylic alkylations,22 the reaction proceeds under very
mild conditions, even at -78 ◦C. A wide range of allylic substrates
can be used, also highly functionalized ones such as 5.23 Therefore,
this approach is also suitable for the synthesis of polyhydroxylated
amino acids. Also here, the (E)-double bond is formed nearly
exclusively, what can be explained by a reaction of the thermo-
dynamically more stable syn-p-allyl complex. In general, p-allyl
complexes can undergo fast p–s–p-isomerisation, what makes it
difficult to transfer the olefin geometry from the allylic substrate
into the product.24 This is a major issue especially with (Z)-allyl
compounds, which also give rise to the (E)-product under standard
conditions for allylic alkylations.
Results and discussion
To figure out if this Claisen protocol is also suitable to introduce
not only a polyhydroxylated side chain, but also a glycoside unit
directly, we synthesized an allylic alcohol derived from the
protected furanoside aldehyde 1 (Scheme 3).18 Vinyl magnesium
bromide addition gave rise to the required allyl alcohols (S)-2
and (R)-2, which could be separated by flash chromatography.6
Coupling of (S)-2 with Z-glycine gave rise to ester (S)-3 as
monoclinic crystals, which allowed the determination of the newly
formed stereogenic center via X-ray structure analysis. Subsequent
chelate-enolate Claisen rearrangement under standard conditions
gave disappointing results. Only 10% of the rearrangement product
(R)-4 could be obtained, together with unreacted allylic ester
(S)-3 (40%) and (S)-2, resulting from decomposition of the
enolate. Obviously, with this sterically demanding allylic ester,
the rearrangement is getting very slow and side reactions (such
as elimination) have to be considered to an increased extent. By
prolonging the reaction time the yield could be increased to 32%,
but still, with these highly functionalized substrates the chelate-
Claisen rearrangement gets to its bounds.
Based on the high reactivity of the chelated enolates this isomeri-
sation can be suppressed almost completely for 1,3-disubstituted
allylic substrates,25 and to some extend also for terminal p-allyl
complexes.26 In many cases, (Z)-allylic substrates reacted more
selectively than the (E)-analogues. Therefore, we were interested
to see, if we can use the higher selectivity of (Z)-substrates
also for the synthesis of polyhydroxylated and glycosyl amino
acids, preferentially those containing a (Z)-double bond. The
synthesis of several (Z)-allylic substrates, especially phosphates is
summarized in Scheme 4. Phosphates showed a higher reactivity
compared to the commonly used acetates and carbonates, not only
in Pd- but also Rh-catalysed reactions.22
Scheme 4 Synthesis of carbohydrate-derived allylic substrates.
Scheme 3 Chelate-Claisen rearrangements of glycosylallylic esters.
Starting from readily available chiral pool materials the (Z)-
configured allylic substrates were prepared from the corresponding
aldehydes via an Ando version of the Horner–Wadsworth–
Emmons reaction.27 Dibal-reduction of the a,b-unsaturated ester
formed and subsequent esterification of the resulting allyl alcohol
with diethyl chlorophosphate gave rise to the (Z)-allyl phosphates
5–8. For analytical purposes and to investigate the difference
between (E)- and (Z)-substrates, the corresponding (E)-substrates
were obtained in an analogous way using a standard phosphonate
During recent years we have developed an independent ap-
proach towards these g,d-unsaturated amino acids based on Pd-
catalysed allylic alkylations.19 We stumbled into this field during
our peptide Claisen rearrangements,20 and nowadays this synthetic
pathway has developed to be a good alternative to the Claisen
rearrangement. Both protocols complement each other, giving rise
to the opposite diastereomers if substituted allylic substrates are
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Table 1 Allylic alkylations using polyhydroxylated allylic substrates
Entry
Subs.
Prod.
Yield (%)
(Z:E)
(Z) (% ds)
(E) (% ds)
1
2
3
4
5
6
7
8
(Z)-5
9
99
79
92
77
93
69
99
98
91:9
1:99
85:15
1:99
98:2
1:99
90:10
1:99
61 (S,S)
99 (R,S)
(E)-5
9
—
90 (R,S)
(Z)-6a
(E)-6b
(Z)-7
(E)-7
(Z)-8a
(E)-8b
10
10
11
11
12
12
76 (R,S)
—
95 (R,S,S)
—
99 (R,R,R,S,R)
—
99 (R,S)
81 (R,S)
—
87 (R,S,S)
65 (R,R,R,S,R)
68 (R,R,R,S,R)
condensation in the first step. The (E)-configured allyl carbonates
(E)-6b and (E)-8b were prepared previously.
Interesting results were obtained in the comparison of the (E)-
and (Z)-phosphates 5 (Table 1, entries 1 and 2). With (E)-5 the
linear product having a (E)-double bond was formed exclusively
with high yield and excellent chiral induction. The chiral center
at the a-position of the amino acid is exclusively controlled by
the stereogenic center in the allyl moiety. With respect, that these
two stereogenic centers are separated by three atoms, an induction
of 90% is remarkable. Even better results were obtained with the
(Z)-substrate. The yield was excellent, and the (Z)-double bond
could be conserved to more than 90%, indicating that p–s–p-
isomerisation could be suppressed efficiently. Surprisingly, the
induction for the (Z)-product was significantly lower compared
to the previous experiment, but the (E)-product (resulting from
the isomerisation) was obtained as a single stereoisomer.
Scheme 5 Allylic alkylations of dipeptide enolates.
To prove the generality of this observation, we also subjected
the other substrate couples to the same reaction conditions.
Comparable results were obtained with substrates 6 (entries 3,
4). Again the yield and the ds for the (E)-product was significantly
better if (Z)-6 was used, although the (Z)-selectivity was slightly
worse than with the first substrate. Interestingly the selectivity
the (Z)-product was formed with increased, probably because
of the increased sterical hindrance of the allylic substituent.
This tendency was confirmed by using the even more hindered
substrates 7 and 8. With (Z)-7 the olefin geometry could be
conserved nearly completely (no isomerisation!) and both, yield
and stereoselectivity were excellent. By far the best results in
this respect were obtained with the glycosidic substrate 8, giving
quantitative yield and stereoselectivity. The stereoisomerically
pure product was obtained by crystallization.
This clearly indicates that, for the synthesis of complex highly
functionalized amino acids, the Pd-catalysed allylic alkylation is
definitely more suitable than the chelate-Claisen rearrangement.
To prove if this methodology can also be used for the synthesis
of glycopeptides by direct introduction of functionalized side
chains into peptides,28 we subjected dipeptide enolates towards
allylic alkylation using 6 and 7 as substrates (Scheme 5). Peptides
are slightly less reactive than the corresponding amino acid
enolates, requiring higher reaction temperatures. Under these
conditions the olefin geometry of the allylic substrates does
not play any role, because the p-allyl complexes formed are in
an equilibrium. The same results are obtained if the branched
allylic substrates with a terminal double bond are used.23 In both
cases the allylated products were obtained in good yield and
excellent diastereoselectivity, while the stereochemical outcome of
the reaction is controlled exclusively by the stereogenic center in
the peptide chain. An (S)-amino acid in the peptide chain induces a
(R)-amino acid at the C-terminus of the chain. The stereochemical
outcome can be explained by the formation of peptide-metal
complexes and the shielding of one face of the enolate formed
by the side chain of the adjacent amino acid.28
Conclusion
In conclusion, we have shown that the Pd-catalysed allylic alkyla-
tion is a powerful tool for the synthesis of complex amino acids.
Even with sterically highly hindered allylic substrates, excellent
yields can be obtained not only with amino acid but also peptide
enolates.
Experimental
General remarks
All the reactions were carried out in oven-dried glassware (100 ◦C)
under nitrogen. All the 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
the eluents. Analysis by TLC was carried out on commercially
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precoated Polygram SIL-G/UV 254 plates (Machery-Nagel,
Dueren). Visualization was accomplished with UV light, KMnO4
solution, or iodine. Melting points were determined on a Bu¨chi
melting-point apparatus and are uncorrected. 1H- and 13C-NMR
spectroscopic analysis was performed on Bruker AC-500 or Bruker
DRX-500 spectrometers. Selected signals for the minor diastere-
omers are extracted from the spectra of the diastereoisomeric
mixture. The values for diastereoisomeric excess were determined
by analytical HPLC using a Trentec Reprosil-100 Chiral-NR
8 mm-column and a Shimadzu UV detector. Optical rotations
were measured on a Perkin-Elmer polarimeter PE 341. Chemical
ionisation (CI) mass spectra were performed on a Finnigan MAT
95, FAB spectra on a Joel JMS-700 mass spectrometer. Elemental
analyses were carried out at the Department of Chemistry at
Saarland University.
General procedure of the preparation of the allyl phosphates 5–8
Pyridine (2.5 eq.), DMAP (5 mol%) and diethyl chlorophosphate
(1.2 eq.) were added to a solution of the corresponding allyl alcohol
in dry dichloromethane (2 mL/mmol) at 0 ◦C and the mixture was
stirred over night. The solution was diluted with dichloromethane
before 1 N KHSO4 was added. The layers were separated, the
aqueous phase was extracted three times with diethyl ether and
the combined organic layers were dried over Na2SO4. After
evaporation of the solvent in vacuo the crude product was purified
by flash chromatography (hexanes/ethyl acetate = 1:1).
(4S)-Benzyloxy-5-methoxy-2-(Z)-pentenyl diethyl phosphate
((Z)-5). According to the general procedure for the preparation
of allyl phosphates, (Z)-5 was obtained from (4S)-Benzyloxy-
5-methoxy-2-(Z)-penten-1-ol (120 mg, 0.54 mmol) and diethyl
chlorophosphate (112 mg, 0.65 mmol) in 66% yield (128 mg,
N-Benzyloxycarbonylglycine (S)-[(3aR,5R,6S,6aR)-1-(6-benzy-
loxy-2,2-dimethyl-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-prop-2-
enyl]ester (S)-3. To a solution of (S)-229 (1.28 g, 4.1 mmol)
and N-benzyloxycarbonylglycine (875 mg, 4.1 mmol) in CH2Cl2
(50 mL) DMAP (50 mg, 0.4 mmol) and DCC (930 mg, 4.5 mmol)
0.36 mmol, 99% Z) as a colourless oil; [a]D +23.9◦ (c 1.0 in
20
CHCl3); 1H NMR (500 MHz): d 7.31–7.22 (m, 5H), 5.79 (m, 1H),
5.55 (ddt, J = 11.3, 8.8, 1.6 Hz, 1H), 4.62–4.57 (m, 2H), 4.51
(dddd, J = 12.8, 8.3, 5.9, 1.6 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H),
4.29 (dddd, J = 8.8, 6.2, 4.7, 0.8, 1H), 4.08 (m, 4H), 3.49 (dd, J =
10.2, 6.2 Hz, 1H), 3.36 (dd, J = 10.2, 4.7 Hz, 1H), 3.33 (s, 3H), 1.30
(t, J = 6.9 Hz, 6H); 13C NMR (125 MHz): d 138.0, 131.9, 128.9
(d, J = 7.4 Hz), 128.3, 127.7, 127.6, 75.0, 73.4, 70.6, 63.8 (d, J =
5.9 Hz), 63.0 (d, J = 5.5 Hz), 59.3, 16.1 (d, J = 6.7 Hz); HRMS
(CI) calcd for C17H27O6P [M]+: 358.1545. Found: 358.1524.
◦
were added at 0 C. The mixture was allowed to warm to room
temperature overnight. After filtration of the precipitated urea
and extracting the organic layer with NaHCO3 and 1 N KHSO4,
the solvent was dried (Na2SO4) and evaporated in vacuo. Flash
chromatography of the crude product gave rise to (S)-3 (1.51 g,
3.0 mmol, 74%) as monoclinic crystals, mp. 109–112 ◦C. 1H-NMR
(300 MHz, CDCl3): d 7.33–7.24 (m, 10H), 5.93 (d, J2 = 3.7 Hz,
1H), 5.86–5.55 (m, 2H), 5.30–5.23 (m, 3H), 5.12 (d, J = 12.4 Hz,
1H), 5.08 (d, J = 12.2 Hz, 1H), 4.63 (d, J = 11.9 Hz, 1H), 4.61
(d, J = 4.0 Hz, 1H), 4.40 (d, J = 11.7 Hz, 1H), 4.17 (dd, J = 8.4,
3.1 Hz, 1H), 4.25 (dd, J = 17.7, 5.0 Hz, 1H), 3.93 (dd, J = 17.7,
5.3 Hz, 1H), 3.88 (d, J = 3.2 Hz, 1H), 1.30 (s, 3H), 1.43 (s, 3H);
13C-NMR (75 MHz, CDCl3): d 169.0, 156.1, 136.8, 136.3, 131.6,
128.3, 128.5, 128.1, 128.0, 127.8, 119.5, 111.9, 105.2, 81.9, 81.6,
81.0, 73.8, 71.8, 66.9, 42.9, 26.8, 26.2; HRMS (FAB) calcd for
C27H32O8N [M + H]+: 498.2128. Found: 498.2128; Anal. calcd for
C27H31O8N (497.55): C, 65.18; H, 6.28; N, 2.82. Found: C, 64.75;
H, 6.44; N, 2.71.
(4S)-Benzyloxy-5-methoxy-2-(E)-pentenyl diethyl phosphate
((E)-5). According to the general procedure for the preparation
of allyl phosphates, (E)-5 was obtained from (4S)-Benzyloxy-
5-methoxy-2-(Z)-penten-1-ol (197 mg, 0.87 mmol) and diethyl
chlorophosphate (184 mg, 1.06 mmol) in 55% yield (173 mg,
0.48 mmol) as a colourless oil; [a]D +36.7◦ (c 0.9 in CHCl3);
20
1H NMR (500 MHz): d 7.32–7.22 (m, 5H), 5.87 (m, 1H), 5.76 (dd,
J = 15.6, 7.0 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.54 (m, 2H),
4.45 (d, J = 12.0 Hz, 1H), 4.10 (dq, J = 7.2, 7.1 Hz, 4H), 4.01 (m,
1H), 3.47 (dd, J = 10.2, 6.2 Hz, 1H), 3.41 (dd, J = 10.2, 4.4 Hz,
1H), 3.34 (s, 3H), 1.32 (t, J = 7.1 Hz, 6H); 13C NMR (125 MHz):
d 138.2, 131.6, 128.3, 128.3 (d, J = 7.4 Hz), 127.7, 127.5, 77.7,
75.3, 70.7, 66.9 (d, J = 5.6 Hz), 63.8 (d, J = 5.8 Hz), 59.2, 16.1 (d,
J = 6.7 Hz); HRMS (CI) calcd for C17H28O6P [M + H]+: 359.1624.
Found: 359.1586. Anal. calcd for C17H27O6P (358.37): C 56.98; H
7.59. Found: C 57.35; H 7.70.
5-((3aR,5R,6S,6aR)-6-Benzyloxy-2,2-dimethyl-tetrahydrofuro-
[2,3-d][1,3]-dioxol-5-yl)-(2R)-(benzyloxacarbonyl)amino-4-(E)-
pentenoic acid methyllester (R)-4. A fresh prepared solution of
LDA (1.5 mmol) in THF (5 mL) was added to a solution of
ester (S)-3 (300 mg, 0.6 mmol) and ZnCl2 (100 mg, 0.7 mmol) in
(Z)-3-((4S)-2,2-Dimethyl-[1,3]-dioxolan-4-yl)-allyl diethyl phos-
phate ((Z)-6a). NaH (55–65%, 220 mg, 5.00 mmol) and NaI
(749 mg, 5.00 mmol) were added to a solution of (diphenylphos-
phono)acetic acid tert-butylester (1.74 g, 5.00 mmol) in dry THF
(60 mL) at 0 ◦C. The solution was stirred for 30 min and was then
cooled to -78 ◦C before 2,3-O-Isopropyliden-(S)-glyceraldehyd
(846 mg, 6.50 mol) dissolved in dry THF was added slowly. The
reaction mixture was allowed to warm to room temperature over
night. 1 N KHSO4 was added and the layers were separated.
The aqueous phase was extracted three times with diethyl ether
and the combined organic layers were dried over MgSO4. After
evaporation of the solvent in vacuo the crude product was purified
by flash chromatography (hexanes/ethyl acetate = 8:2). After
carefully concentration, the ester obtained was dissolved in dry
THF and the solution was cooled to -78 ◦C followed by the
addition of Dibah (1M in hexanes, 10 ml, 10.0 mmol). The reaction
◦
THF (6 mL) at -78 C. The cooling bath was removed and the
resulting clear solution was allowed to warm to room temperature.
Et2O (20 mL) and 1 N KHSO4 was added and the emulsion was
stirred until the layers became clear and colourless. The layers
were separated and after drying the organic layer (Na2SO4) and
evaporationof thesolvent the crudeacid was esterifiedwithCH2N2
and purified by flash chromatography giving rise to (R)-4 as a pale
yellow oil (92 mg, 0.18 mmol, 32%).1H-NMR (300 MHz, CDCl3):
d 7.33–7.22 (m, 10H), 5.91–5.72 (m, 2H), 5.73 (d, J = 2.9 Hz,
1H), 5.42 (d, J = 8.1 Hz,1H), 5.10–5.05 (m, 3H), 4.67–4.43 (m,
5H), 3.82 (s, 3H), 2.61–2.67 (m, 2H), 1.39 (s, 3H), 1.28 (s, 3H);
13C-NMR (75 MHz, CDCl3): d 168.1, 156.7, 137.2, 135.9, 128.3,
127.8, 127.2, 126.8, 126.6, 126.4, 126.1, 111.3, 104.5, 83.1, 82.6,
80.4, 71.9, 66.8, 53.1, 52.2, 35.0, 26.8, 26.0. HRMS (FAB) calcd
for C28H34O8N [M + H]+: 512.2306.
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mixture was allowed to warm to room temperature over night.
After diluting with diethyl ether, the mixture was quenched by the
addition of 8.3 mL of water. The mixture was stirred 30 min, the
gel-like precipitate formed was removed by filtration and washed
with dichloromethane. The filtrate was dried over MgSO4 and
concentrated under reduced pressure. The residue was subjected
to the general procedure for the preparation of allyl phosphates
with diethyl chlorophosphate (1.04 g, 6.00 mmol) and (Z)-6a was
phosphates, (Z)-8a was obtained from 3-((3aR,5R,6S,6aR)-6-
Benzyloxy-2,2-dimethyl-tetrahydro-duro[2,3-d][1,3]-dioxol-5-yl)-
2-(Z)-penten-1-ol (864 mg, 2.82 mmol) and diethyl chlorophos-
phate (583 mg, 3.38 mmol) in 90% yield (1.12 g, 2.54 mmol, 99%
Z) as a colourless oil; [a]D -70.3◦ (c 1.1 in CHCl3); H-NMR
(500 MHz, CDCl3): d 7.33–7.25 (m, 5H,), 5.93 (d, J = 3.8 Hz,
1H), 5.84–5.82 (m, 2H), 4.88 (dd, J = 5.8, 3.4 Hz, 1H), 4.63–4.60
(m, 4H), 4.50 (d, J = 12.1 Hz, 1H), 4.08 (dq, J = 7.2, 7.1 Hz, 4H),
3.86 (d, J = 3.1 Hz, 1H), 1.48 (s, 3H), 1.32–1.28 (m, 9H); 13C NMR
(125 MHz): d 137.8, 128.7 (d, J4 = 7.0 Hz), 128.4, 127.9, 127.8,
127.5, 111.6, 104.8, 83.4, 82.7, 76.0, 72.1, 63.8 (d, J = 5.8 Hz), 63.2
(d, J = 5.4 Hz), 26.7, 26.1, 16.1 (d, J = 6.7 Hz); HRMS (CI) calcd
for C21H32O8P [M + H]+: 443.1835. Found: 443.1857. Anal. calcd
for C21H31O8P (442.45): C 57.01; H 7.06. Found: C 56.98; 7.01.
20
1
obtained in 37% yield (514 mg, 1.83 mmol, 99% Z) as a colourless
◦
oil; [a]D -1.5 (c 1.0 in CHCl3); 1H-NMR (500 MHz, CDCl3):d
20
5.75 (dddd, J = 11.2, 6.7, 4.6, 1.0 Hz, 1H), 5.62 (ddt, J = 11.2,
8.2, 1.4 Hz, 1H), 4.79 (m, 1H), 4.62 (m, 2H), 4.10–4.04 (m, 5H),
3.53 (dd, J = 7.9, 7.9 Hz, 1H), 1.38 (s, 3H), 1.34 (s, 3H), 1.30
(t, J = 7.0 Hz, 6H); 13C NMR (125 MHz): d 131.9, 128.1 (d, J =
6.9 Hz), 109.6, 71.8, 69.3, 63.8 (d, J = 5.8 Hz), 62.7 (d, J = 5.6 Hz),
26.6, 25.8, 16.1 (d, J = 6.7 Hz); HRMS (CI) calcd for C12H24O6P
[M + H]+: 295.1311. Found: 295.1258. Anal. calcd for C12H23O6P
(294.28): C 48.98; H 7.88. Found: C 48.49; 7.89.
(E)-3-((3aR,5R,6S,6aR)-6-Benzyloxy-2,2-dimethyl-tetrahydro-
furo[2,3-d][1,3]-dioxol-5-yl)-allyl methyl carbonate ((E)-8b). 3-
((3aR,5R,6S,6aR)-6-Benzyloxy-2,2-dimethyl-tetrahydro-duro-
[2,3-d][1,3]-dioxol-5-yl)-2-(E)-penten-1-ol (744 mg, 2.43 mmol)
was dissolved in dichloromethane (5 mL) before pyridine (0.49 mL,
6.08 mmol) and methyl chloroformate (345 mg, 3.65 mmol)
(Z)-3-((4S,5S)-5-Benzyloxymethyl-2,2-dimethyl-[1,3]-dioxolan-
4-yl)-allyl diethyl phosphate ((Z)-7). According to the general
procedure for the preparation of allyl phosphates, (Z)-7 was
obtained from 3-((4S,5S)-5-Benzyloxymethyl-2,2-dimethyl-[1,3]-
dioxolan-4-yl)-2-(Z)-penten-1-ol (502 mg, 1.80 mmol) and diethyl
chlorophosphate (373 g, 2.16 mmol) in 92% yield (690 mg,
◦
were added at 0 C. After complete consumption of the starting
material (TLC control), the reaction mixture was diluted with
diethyl ether, 1 N KHSO4 was added, the layers were separated
and the aqueous phase was extracted three times with diethyl
ether. The combined organic layers were dried over MgSO4 and
concentrated in vacuo. The crude product was purified by column
chromatography (hexanes/ethyl acetate= 8:2) to afford (E)-8b in
1.66 mmol, 99% Z) as a colourless oil; [a]D +5.8◦ (c 1.0 in
20
CHCl3); 1H-NMR (500 MHz, CDCl3): d 7.33–7.23 (m, 5H), 5.79
(dddd, J = 11.2, 7.0, 5.4, 0.8 Hz, 1H), 5.62 (ddt, J = 11.2, 8.4,
1.3 Hz, 1H), 4.67 (m, 1H), 4.59–4.51 (m, 4H), 4.06 (dq, J = 8.0,
7.1 Hz, 4H), 3.85 (m, 1H), 3.57 (dd, J = 10.6, 3.9 Hz, 1H), 3.53
(dd, J = 10.6, 4.9 Hz, 1H), 1.40 (s, 6H), 1.29 (td, J = 7.1, 0.6 Hz,
6H); 13C NMR (125 MHz): d 137.8, 130.3, 129.4 (d, J = 7.1 Hz),
128.3, 127.6, 127.6, 109.7, 80.0, 73.8, 73.6, 69.1, 63.7 (d, J =
5.8 Hz), 62.9 (d, J = 5.2 Hz), 27.0, 26.9, 16.0 (d, J = 6.7 Hz);
HRMS (CI) calcd for C20H32O7P [M + H]+: 415.1886. Found:
415.1907. Anal. calcd for C20H31O7P (414.44): C 57.96; H 7.54.
Found: C 57.79; 7.41.
◦
20
87% yield (807 mg, 2.12 mmol) as a colourless oil; [a]D -53.5 (c
1.0 in CHCl3); 1H-NMR (500 MHz, CDCl3): d 7.34–7.25 (m, 5H),
5.96–5.93 (m, 3H), 4.72–4.59 (m, 5H), 4.50 (d, J = 12.2 Hz, 1H),
3.96 (d, J = 3.1 Hz, 1H), 3.75 (s, 3H), 1.47 (s, 3H), 1.30 (s, 3H); 13
C
NMR (125 MHz): d 155.5, 137.4, 128.9, 128.4, 127.9, 127.7, 127.6,
111.6, 104.8, 83.2, 82.9, 80.2, 72.1, 67.4, 54.8, 26.7, 26.2; HRMS
(CI) calcd for C19H26O7 [M + 2H]+: 366.1679. Found: 366.1664.
Anal. calcd for C19H24O7 (364.40): C 62.63; H 6.64. Found: C
62.66; 6.59.
(E)-3-((4S,5S)-5-Benzyloxymethyl-2,2-dimethyl-[1,3]-dioxolan-
4-yl)-allyl diethyl phosphate ((E)-7). According to the general
procedure for the preparation of allyl phosphates, (E)-7 was
obtained from 3-((4S,5S)-5-Benzyloxymethyl-2,2-dimethyl-[1,3]-
dioxolan-4-yl)-2-(E)-penten-1-ol (228 mg, 0.82 mmol) and diethyl
chlorophosphate (170 mg, 0.98 mmol) in 85% yield (290 mg,
General procedure for the allylic alkylation using polyhydroxylated
allylic substrates
In a Schlenk flask hexamethyldisilazane (222 mg, 1.38 mmol)
was dissolved in dry THF (2 mL) under argon. After cooling
the solution to -78 ◦C, n-BuLi (1.6 M in hexanes, 0.78 mL,
1.25 mmol) was added slowly. The cooling bath was removed, and
the solution was stirred 10 min. In a second Schlenk flask ZnCl2
(76 mg, 0.55 mmol) was carefully dried in vacuo. After cooling
to room temperature, TFA-Gly-OtBu (114 mg, 0.50 mmol) was
added dissolved in dry THF (1 mL). The solution was cooled
to -78 ◦C, before the freshly prepared LHMDS solution was
added and stirring was continued for 20 min. In a third flask,
[allylPdCl]2 (1 mg, 0.0025 mmol) and PPh3 (3 mg, 0.0113 mmol)
were dissolved in dry THF (0.5 mL). After stirring for 15 min
at room temperature, this solution was added to the chelated
0.70 mmol) as a colourless oil; [a]D -11.9◦ (c 1.0 in CHCl3);
20
1H-NMR (500 MHz, CDCl3): d 7.33–7.25 (m, 5H), 5.86 (dt, J =
15.5, 5.3 Hz, 1H), 5.78 (dd, J = 15.5, 6.6 Hz, 1H), 4.56 (s, 2H),
4.50 (m, 2H), 4.25 (dd, J = 8.7, 5.1 Hz, 1H), 4.08 (m, 4H), 3.87
(ddd, J = 8.7, 5.1, 3.7 Hz, 1H), 3.58 (dd, J = 10.4, 3.7 Hz, 1H),
3.53 (dd, J = 10.4, 5.1 Hz, 1H), 1.41 (s, 3H), 1.40 (s, 3H), 1.30
(t, J = 7.1 Hz, 6H); 13C NMR (125 MHz): d 137.9, 130.6, 128.4
(d, J = 7.5 Hz), 128.3, 127.7, 127.6, 109.6, 80.0, 78.0, 73.6, 69.3,
66.6 (d, J = 5.1 Hz), 63.8 (d, J = 5.9 Hz), 26.9, 26.9, 16.1 (d, J =
6.7 Hz); HRMS (CI) calcd for C20H32O7P [M + H]+: 415.1886.
Found: 415.1874. Anal. calcd for C20H31O7P (414.44): C 57.96; H
7.54. Found: C 57.71; 7.20.
◦
enolate at -78 C. At the same temperature the allylic substrate
(0.25 mmol) was added drop wise in THF (1 mL). Excess of
dry ice was added to the cooling bath, before the mixture was
allowed to warm to room temperature overnight. The solution
was diluted with diethyl ether and then quenched by the addition
of 1 N KHSO4. The layers were separated, the aqueous layer was
(Z)-3-((3aR,5R,6S,6aR)-6-Benzyloxy-2,2-dimethyl-tetrahydro-
furo[2,3-d][1,3]-dioxol-5-yl)-allyl diethyl phosphate ((Z)-8a). Ac-
cording to the general procedure for the preparation of allyl
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extracted three times with diethyl ether and the combined organic
layers were dried over MgSO4. The solvent was evaporated under
vacuum and the residue was purified by flash-chromatography.
1.47 (s, 9H), 1.38 (s, 3H), 1.36 (s, 3H); 13C NMR (125 MHz): d
168.8, 131.7, 128.0, 109.6, 83.5, 71.2, 69.4, 52.6, 29.6, 26.6, 25.8;
HRMS (CI) calcd for C12H15F3NO5 [M–C4H9]+: 310.0902. Found:
310.0930; HPLC (Reprosil 100 Chiral-NR 8 mm, hexane/iPrOH
99.5:0.5, 0.5 mL/min): tR(R,S) = 26.72 min; tR(S,S) = 28.47 min.
(6S)-Benzyloxy-7-methoxy-(2S)-(trifluoroacetyl)amino-4-(Z)-
heptenoic acid tert-butylester ((S,S)-(Z)-9). According to the
general procedure for allylic alkylation using polyhydroxylated al-
lylic substrates, (Z)-9 was obtained from TFA-Gly-OtBu (114 mg,
0.50 mmol) and allyl phosphate (Z)-5 (90 mg, 0.25 mmol) in 96%
yield (104 mg, 0.24 mmol, 91% Z, 61% ds) as a colourless oil;
major diastereomer: 1H-NMR (500 MHz, CDCl3): d 7.39 (d, J =
6.0 Hz, 1H), 7.33–7.24 (m, 5H), 5.60–5.55 (m, 2H), 4.58 (d, J =
11.8 Hz, 1H), 4.49 (m, 1H), 4.41 (d, J = 11.8 Hz, 1H), 4.22 (m, 1H),
3.55 (dd, J = 9.6, 5.5 Hz, 1H), 3.37–3.33 (m, 4H), 2.67 (m, 1H),
2.59 (m, 1H), 1.46 (s, 9H); 13C NMR (125 MHz): d 168.8, 157.0
(q, J = 37.5 Hz), 137.9, 133.0, 128.4, 127.8, 127.7, 127.4, 115.7 (q,
J = 288 Hz), 83.2, 74.7, 72.6, 70.5, 59.3, 52.4, 29.7, 27.9; minor
5-[(4S,5S)-5-Benzyloxymethyl-2,2-dimethyl-[1,3]dioxolan-4-
yl)]-(2R)-(trifluoroacetyl) amino-4-(Z)-pentenoic acid tert-butyl-
ester ((R,S,S)-(Z)-11). According to the general procedure for
allylic alkylation using polyhydroxylated allylic substrates, (Z)-
11 was obtained from TFA-Gly-OtBu (114 mg, 0.50 mmol) and
allyl phosphate (Z)-7 (104 mg, 0.25 mmol) in 93% yield (113 mg,
0.23 mmol, 98% Z, 95% ds) as a colourless oil; major diastereomer:
1H-NMR (500 MHz, CDCl3): d 7.36 (d, J = 7.1 Hz, 1H), 7.35–
7.26 (m, 5H), 5.66 (dd, J = 11.0, 8.1 Hz, 1H), 5.53 (m, 1H), 4.58
(s, 2H), 4.49 (dd, J = 8.3, 8.1 Hz, 1H), 4.43 (m, 1H), 3.89 (dt, J =
8.3 Hz, 4.6 Hz, 1H), 3.57 (dd, J = 10.4, 4.6 Hz, 1H), 3.59–3.52 (m,
1
diastereomer (selected signals): H-NMR (500 MHz, CDCl3): d
2H), 2.74–2.58 (m, 2H), 1.45 (s, 9-H), 1.42 (s, 3H), 1.38 (s, 3H); 13
C
4.28 (m, 1H), 3.50 (dd, J = 9.5, 4.9 Hz, 1H), 3.41 (dd, J = 9.5,
6.7 Hz, 1H), 3.36 (s, 3H), 1.45 (s, 9H); 13C NMR (125 MHz): d
169.2, 137.9, 133.3, 75.1, 73.0, 70.6, 59.2, 52.6, 29.8; HRMS (CI)
calcd for C17H19F3NO5 [M–C4H9]+: 374.1215. Found: 374.1240;
Anal. calcd for C21H28F3NO5 (431.45): C 58.46; H 6.54; N, 3.25.
Found: 58.83; H, 6.59; N, 3.54; HPLC (Reprosil 100 Chiral-NR
8 mm, hexane/iPrOH 99.5:0.5, 0.5 mL/min): tR(R,S) = 37.54 min;
tR(S,S) = 42.03 min.
NMR (125 MHz): d 168.8, 157.0 (q, J = 37.5 Hz), 137.6, 131.1,
128.5, 128.4, 127.8, 127.8, 115.7 (q, J19,F = 288 Hz), 109.7, 83.2,
80.3, 73.8, 73.7, 69.3, 52.4, 29.6, 27.9, 27.0, 26.7; HRMS (CI)
calcd for C20H23F3NO6 [M–C4H9]+: 430.1477. Found: 430.1532;
Anal. calcd for C24H32F3NO6 (487.52): 59.13; H, 6.62; N, 2.87.
Found: C 59.19; H, 6.56; N, 3.28; HPLC (Reprosil 100 Chiral-NR
8 mm, hexane/iPrOH 99.5:0.5, 1.0 mL/min): tR(R,S,S) = 22.13 min;
tR(S,S,S) = 24.93 min.
(6S)-Benzyloxy-7-methoxy-(2R)-(trifluoroacetyl)amino-4-(E)-
heptenoic acid tert-butylester ((R,S)-(E)-9). According to the
general procedure for allylic alkylation using polyhydroxylated al-
lylic substrates, (E)-9 was obtained from TFA-Gly-OtBu (114 mg,
0.50 mmol) and allyl phosphate (E)-5 (90 mg, 0.25 mmol) in 7◦9%
0.8 in CHCl3); major diastereomer: 1H-NMR (500 MHz, CDCl3):
d 7.33–7.23 (m, 5H), 6.96 (d, J = 7.1 Hz, 1H), 5.57–5.50 (m, 2H),
4.59–4.55 (m, 2H), 4.39 (d, J = 12.1 Hz, 1H), 3.93 (m, 1H), 3.44
(dd, J = 10.0, 6.0 Hz, 1H), 3.37 (dd, J = 10.0, 5.2 Hz, 1H), 3.33 (s,
3H), 2.68 (m, 1H), 2.60 (m, 1H), 1.47 (s, 9H); 13C NMR (125 MHz):
d 169.1, 156.5 (q, J = 37.6 Hz), 138.2, 133.7, 128.3, 127.7, 127.6,
126.8, 115.7 (q, J = 288 Hz), 83.5, 77.9, 75.1, 70.5, 59.2, 52.4, 34.5,
28.0; minor diastereomer (selected signals): 1H-NMR (500 MHz,
CDCl3): d 4.40 (d, J = 12.1 Hz, 1H), 3.33 (s, 3H), 2.75 (m,
1H), 2.54 (m, 1H); 13C NMR (125 MHz): d 133.2, 126.6, 83.6,
75.3, 52.5; HPLC (Reprosil 100 Chiral-NR 8 mm, hexane/iPrOH
99.5:0.5, 0.5 mL/min): tR(R,S) = 46.58 min; tR(S,S) = 49.36 min.
5-[(4S,5S)-5-Benzyloxymethyl-2,2-dimethyl-[1,3]dioxolan-4-yl)]-
(2R)-(trifluoroacetyl) amino-4-(E)-pentenoic acid tert-butylester
((R,S,S)-(E)-11). According to the general procedure for allylic
alkylation using polyhydroxylated allylic substrates, (E)-11 was
obtained from TFA-Gly-OtBu (114 mg, 0.50 mmol) and allyl
phosphate (E)-7 (104 mg, 0.25 mmol) in 69% yield (85 mg,
0.17 mmol, 87% ds) as a colourless oil; major diastereomer:
1H-NMR (500 MHz, CDCl3): d 7.34–7.25 (m, 5H), 6.91 (d, J =
7.0 Hz, 1H), 5.59–5.56 (m, 2H), 4.57 (s, 2H), 4.53 (m, 1H), 4.17
(dd, J = 8.4, 6.0 Hz, 1H), 3.82 (ddd, J = 8.4, 5.0, 4.3 Hz, 1H),
3.57–3.50 (m, 2H), 2.67 (m, 1H), 2.56 (m, 1H), 1.47 (s, 9H),
1.38 (2 s, 6H); 13C NMR (125 MHz): d 169.0, 156.5 (q, J =
37.5 Hz), 137.8, 133.0, 128.4, 127.8, 127.7, 126.9, 115.6 (q, J =
288 Hz), 109.5, 83.7, 79.9, 78.7, 73.6, 69.4, 52.4, 34.3, 28.0, 26.9,
26.9; minor diastereomer (selected signals): 1H-NMR (500 MHz,
CDCl3): d 6.88 (d, J = 7.2 Hz, 1H), 2.49 (m, 1H), 1.41 (s, 3H),
1.40 (s, 3H); 13C NMR (125 MHz): d 132.6, 80.1, 78.4, 34.7;
HPLC (Reprosil 100 Chiral-NR 8 mm, hexane/iPrOH 99.5:0.5,
1.0 mL/min): tR(R,S,S) = 27.83 min; tR(S,S,S) = 30.76 min.
20
yield (85 mg, 0.20 mmol, 90% ds) as a colourless oil; [a]D -7.1 (c
(6S)-5-(2,2-Dimethyl-[1,3]-dioxolan-4-yl)-(2R)-(trifluoroacetyl)-
amino-4-(Z)-pentenoic acid tert-butylester ((R,S)-(Z)-10).
According to the general procedure for allylic alkylation using
polyhydroxylated allylic substrates, (Z)-9 was obtained from
TFA-Gly-OtBu (114 mg, 0.50 mmol) and allyl phosphate (Z)-6a
(74 mg, 0.25 mmol) in 92% yield (65 mg, 0.22 mmol, 85% Z, 76%
ds) as a colourless oil; major diastereomer: 1H-NMR (500 MHz,
CDCl3): d 7.31 (d, J = 5.6 Hz, 1H), 5.64 (m, 1H), 5.52 (m, 1H),
4.71 (m, 1H), 4.48 (m, 1H), 4.06 (m, 1H), 3.55 (m, 1H), 2.75
(m, 1H), 2.67 (m, 1H), 1.47 (s, 9H), 1.39 (s, 3H), 1.34 (s, 3H);
13C NMR (125 MHz): d 169.1, 157.0 (q, J = 37.4 Hz), 132.0,
127.6, 115.6 (q, J = 287 Hz), 109.6, 83.5, 71.1, 69.3, 52.4, 29.6,
5-((3aR,5R,6S,6aR)-6-Benzyloxy-2,2-dimethyl-tetrahydrofuro-
[2,3-d][1,3]-dioxol-5-yl)-(2R)-(trifluoroacetyl)amino-4-(Z)-pente-
noic acid tert-butylester ((R,R,R,S,R)-(Z)-12). According to the
general procedure for allylic alkylation using polyhydroxylated al-
lylic substrates, (Z)-12 was obtained from TFA-Gly-OtBu (114 mg,
0.50 mmol) and allyl phosphate (Z)-8a (111 mg, 0.25 mmol) in 99%
yield (129 mg, 0.25 mmol, 90% Z, 99% ds) as a colourless solid.
Recrystallisation affords (Z)-12 in 67% yield (86 mg, 0.17 mmol,
99% Z, 99% ds) in stereoisomerically pure form; mp. 86% (from
pentane); [a]D -79.2◦ (c 1.1 in CHCl3); H-NMR (500 MHz,
CDCl3): d 7.48 (d, J = 5.7 Hz, 1H), 7.34–7.26 (m, 5H), 5.92 (d,
J = 3.9 Hz, 1H), 5.89 (dd, J = 11.1, 7.2 Hz, 1H), 5.60 (m, 1H),
4.82 (dd, J = 7.2, 3.1 Hz, 1H), 4.66 (d, J = 12.1 Hz, 1H), 4.62 (d,
20
1
1
28.0, 26.6, 25.5; minor diastereomer (selected signals): H-NMR
(500 MHz, CDCl3): d 7.19 (d, J = 4.3 Hz, 1H), 4.41 (m, 1H),
108 | Org. Biomol. Chem., 2009, 7, 103–110
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J = 3.9 Hz, 1H), 4.50 (d, J = 12.1 Hz, 1H), 4.34 (m, 1H), 3.81
(d, J = 3.1 Hz, 1H), 2.67 (m, 2H), 1.48 (s, 3H), 1.44 (s, 9H), 1.31
(s, 3H); 13C NMR (125 MHz): d 169.1, 156.5 (q, J = 37.5 Hz),
137.3, 128.5, 128.5, 128.0, 127.6, 127.6, 115.7 (q, J = 288 Hz),
111.7, 104.7, 83.2, 82.7, 82.5, 75.4, 72.0, 52.6, 30.0, 27.9, 26.8, 26.2;
HRMS (CI) calcd for C21H23F3NO7 [M–C4H9]+: 458.1427. Found:
458.1428; Anal. calcd for C25H32F3NO7 (515.53): C, 58.25; H, 6.26;
N, 2.72. Found: C, 58.14; H, 6.26; N, 2.78;HPLC (Reprosil 100
in 70% yield (90 mg, 0.175 mmol, 98% ds) as a colourless oil;
1H-NMR (500 MHz, CDCl3): d 7.78 (br s, 1H), 7.24–7.10 (m,
5H), 6.73 (br s, 1H), 5.39–5.30 (m, 2H), 4.79 (ddd, J = 7.1, 7.1,
6.7 Hz, 1H), 4.41 (ddd, J = 7.6, 7.6, 5.6 Hz, 1H), 4.30 (ddd,
J = 7.3, 7.3, 6.4 Hz, 1H), 3.96 (dd, J = 8.1, 6.2 Hz, 1H), 3.44
(dd, J = 8.1, 7.4 Hz, 1H), 3.10 (dd, J = 13.8, 6.7 Hz, 1H), 3.04
(dd, J = 14.0, 7.1 Hz, 1H), 2.30 (m, 2H), 1.34 (s, 9H), 1.31 (s,
3H), 1.27 (s, 3H); 13C NMR (125 MHz): d 169.7, 168.2, 156.8
(q, J = 38.2 Hz), 135.5, 132.2, 129.2, 128.7, 127.8, 127.3, 115.6
(q, J = 286 Hz), 109.2, 82.5, 76.4, 69.1, 54.6, 52.2, 38.3, 35.0,
27.8, 26.5, 25.7; HRMS (CI) calcd for C23H30F3N2O4 [M–C4H9]+:
429.2004. Found: 429.2041; HPLC (Reprosil 100 Chiral-NR
8 mm, hexane/iPrOH 98:2, 0.6 mL/min): tR(S,S,S) = 28.06 min;
tR(S,R,S) = 37.04 min.
Chiral-NR 8 mm, hexane/iPrOH 98:2, 1.5 mL/min): tR(R,R,R,S,R)
10.83 min; tR(S,R,R,S,R) = 13.05 min.
=
5-((3aR,5R,6S,6aR)-6-Benzyloxy-2,2-dimethyl-tetrahydro-furo-
[2,3-d][1,3]-dioxol-5-yl)-(2R)-(trifluoroacetyl)amino-4-(E)-pente-
noic acid tert-butylester ((R,R,R,S,R)-(E)-12). According to the
general procedure for allylic alkylation using polyhydroxylated
allylic substrates, (Z)-12 was obtained from TFA-Gly-OtBu
(114 mg, 0.50 mmol) and allyl carbonate (E)-8b (95 mg, 0.25 mmol)
in 98% yield (127 mg, 0.25 mmol, 68% ds) as a colourless oil; major
diastereomer: 1H-NMR (500 MHz, CDCl3): d 7.34–7.27 (m, 5H),
6.85 (d, J = 5.7 Hz, 1H), 5.90 (d, J = 3.7 Hz, 1H), 5.76 (m, 1H),
5.67 (m, 1H), 4.62–4.46 (m, 5H), 3.81 (d, J = 3.2 Hz, 1H), 2.68
(m, 1H), 2.58 (m, 1H), 1.46 (s, 3H), 1.44 (s, 9H), 1.24 (s, 3H);
13C NMR (125 MHz): d 169.0, 156.0 (q, J = 37.9 Hz), 137.5,
129.3, 128.4, 127.9, 127.5, 127.4, 115.6 (q, J = 288 Hz), 111.6,
104.8, 83.6, 83.5, 82.6, 80.6, 71.9, 52.4, 35.0, 27.9, 26.7, 26.1; minor
N-Trifluoroacetyl-(S)-phenylalanyl-(2R,4E)-2-amino-5-[(4S,5S)-
5-benzyloxymethyl-2,2-dimethyldioxolan-4-yl]-4-pentenoic
acid
tert-butylester (15). According to the general procedure for
allylic alkylation of peptides, 15 was obtained from dipeptide
13 (140 mg, 0.375 mmol) and allyl phosphate (Z)-7 (104 mg,
0.25 mmol) in 89% yield (141 mg, 0.223 mmol, 98% ds) as a
colourless oil; 1H-NMR (500 MHz, CDCl3): d 7.30–7.10 (m,
11H), 6.00 (br s, 1H), 5.34–5.32 (m, 2H), 4.55–4.50 (m, 3H), 4.41
(ddd, J = 7.8, 5.5, 5.5 Hz, 1H), 4.04 (dd, J = 8.4, 6.3 Hz, 1H), 3.73
(ddd, J = 8.4, 5.0, 4.3 Hz, 1H), 3.50 (dd, J = 10.3, 5.3 Hz, 1H),
3.46 (dd, J = 10.3, 4.3 Hz, 1H), 3.04 (dd, J = 13.6, 5.9 Hz, 1H),
2.95 (dd, J = 13.6, 8.4 Hz, 1H), 2.35 (ddd, J = 14.4, 5.5, 5.5 Hz,
1H), 2.24 (ddd, J = 14.4, 5.8, 5.8 Hz, 1H), 1.36 (s, 9H) 1.33 (s,
3H) 1.32 (s, 3H); 13C NMR (125 MHz): d 169.5, 168.5, 156.5
(q, J = 37.8 Hz), 137.7, 135.3, 132.1, 129.2, 128.9, 128.4, 128.1,
127.8, 127.7, 127.5, 115.6 (q, J = 287 Hz), 109.3, 82.8, 79.7, 79.0,
73.6, 69.6, 54.8, 52.1, 38.7, 35.0, 27.9, 27.0, 26.9; HRMS (CI)
calcd for C23H30F3N2O4 [M–C4H9]+: 577.2162. Found: 577.2191;
HPLC (Reprosil 100 Chiral-NR 8 mm, hexane/iPrOH 98:2,
1.0 mL/min): tR(S,S,S,S) = 12.17 min; tR(S,R,S,S) = 15.09 min.
1
diastereomer (selected signals): H-NMR (500 MHz, CDCl3): d
6.89 (d, J = 6.9 Hz, 1H), 5.90 (d, J = 3.5 Hz, 1H), 3.82 (dd,
J = 3.2, 3.2 Hz, 1H); 13C NMR (125 MHz): d 137.4, 129.7, 111.5,
83.7, 83.5, 82.8, 80.5, 72.2, 52.6, 34.4, 28.0; HPLC (Reprosil 100
Chiral-NR 8 mm, hexane/iPrOH 98:2, 1.5 mL/min): tR(S,R,R,S,R)
15.58 min; tR(R,R,R,S,R) = 16.74 min.
=
General procedure for allylic alkylations of peptides
n-BuLi (1.6M in hexanes, 0.82 mL, 1.31 mmol) was added drop
wise to a solution of hexamethyldisilazane (233 mg, 1.44 mmol) in
dry THF (2 mL) at -78 ◦C. The cooling bath was removed, and the
solution was allowed to warm up to room temperature. In a second
flask, ZnCl2 (57 mg, 0.42 mmol) was carefully dried in vacuo with
a heat gun. After the mixture was cooled to room temperature,
the dipeptide 13 (140 mg, 0.375 mmol) was added dissolved in dry
THF (2 mL). The freshly prepared LHMDS solution was cooled
to -78 ◦C and the ZnCl2/peptide solution was slowly added by
syringe. In a third flask, [allylPdCl]2 (1.8 mg, 5.0 mmol) and PPh3
(5.9 mg, 22.5 mmol) were dissolved in dry THF (0.5 mL), allyl
carbonate (0.25 mmol) was added, and the catalyst/carbonate
solution was transferred to the cold solution of the zinc enolate
by syringe. The excess dry ice was removed from the cooling bath,
and the reaction mixture was allowed to warm up. After diluting
with diethyl ether, the mixture was quenched by the addition of
1 N HCl. The aqueous layer was extracted twice with diethyl ether
and the combined organic layers were dried over Na2SO4. The
solvent was evaporated and the residue was purified by column
chromatography.
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft as
well as the Fonds der Chemischen Industie is gratefully acknowl-
edged.
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