Preparation and reactions of stannylated amino, acids

Article abstract of DOI:10.1002/1521-3765(20010119)7:2<456::AID-CHEM456>3.0.CO;2-A

Hydrostannations of propargylic glycine esters with the new hydrostannation catalyst [Mo(CO)₃(CNtBu)₃] (MoBI₃) gave rise to α-stannylated allylic esters in good yield and with high regioselectivity. The chelate Claisen rearrangements of these esters allow the syntheses of γ,δ-unsaturated amino acids with a vinylstannane moiety in the side chain. The amino acids obtained can be further modified by cross-coupling with various types of electrophiles.

Full text of DOI:10.1002/1521-3765(20010119)7:2<456::AID-CHEM456>3.0.CO;2-A

FULL PAPER
Preparation and Reactions of Stannylated Amino Acids
Uli Kazmaier,* Dagmar Schauû, Stefan Raddatz, and Matthias Pohlman[a]
Dedicated to Prof. R. Neidlein on the occasion of his 70th birthday
Abstract: Hydrostannations of propargylic glycine esters with the new hydrostan-
nation catalyst [Mo(CO)3(CNtBu)3] (MoBI3) gave rise to a-stannylated allylic esters
in good yield and with high regioselectivity. The chelate Claisen rearrangements of
these esters allow the syntheses of g,d-unsaturated amino acids with a vinylstannane
moiety in the side chain. The amino acids obtained can be further modified by cross-
coupling with various types of electrophiles.
Keywords: amino acids ´ cross-cou-
pling ´ hydrostannation ´ molybde-
num ´ rearrangement
syn-selectivity independent of the protecting group (PG)
used. This protocol is suitable for various types of allylic and
even propargylic esters.[6] Furthermore, chiral amino acids can
be obtained through rearrangement and chirality transfer
from enantiomerically pure allylic esters,[7] or in the presence
of chiral ligands.[8]
Very recently we developed an alternative approach
towards this class of unsaturated amino acids through
palladium-catalyzed allylic alkylation. We have observed that
such chelated ester enolates of amino acids are efficient
nucleophiles in palladium-catalyzed allylations (Scheme 2).[9]
Introduction
g,d-Unsaturated amino acids are of great interest, not only as
naturally occurring nonproteinogenic amino acids, such as the
isoleucine antagonist cyclopentenylglycine[1] and the anti-
biotic furanomycine,[2] but also as important intermediates for
the synthesis of complex amino acids.[3] Therefore, various
approaches to the synthesis of this class of amino acids have
been described.[4]
During our studies towards the syntheses of unnatural
amino acids we were able to develop a new variation of the
ester enolate Claisen rearrangement which is especially
suitable for allylic esters of amino acids. Deprotonation of
N-protected amino acid allylic esters with lithium diisopro-
pylamide (LDA) at ꢀ788C, and subsequent addition of a
metal salt (MXn), presumably results in the formation of a
chelated metal enolate (Scheme 1), which undergoes Claisen
Scheme 2. a) 2.5 equiv LHMDS, 1.1 equiv ZnCl2, 1 mol% [allylPdCl]2,
4.5 mol% PPh3, THF, ꢀ788C ! RT.
Besides the generally used soft nucleophiles, such as malo-
nates, only a few examples using nonstabilized enolates, such
as those of ketones[10] or esters,[11] are described in the
literature so far. Therefore, these chelated enolates consid-
erably enlarge the spectrum of potential nucleophiles. If
optically active allylic carbonates are used as substrates, the
chirality is transferred completely into the amino acid
obtained.[12] The anti-products are obtained in a highly
diastereoselective fashion, and therefore these two protocols
complement each other in an ideal way.
Scheme 1. a) 2.2 equiv LDA, 1.2 equiv MXn.
rearrangement upon warming to room temperature, giving
rise to unsaturated amino acids.[5] Due to the fixed enolate
geometry the rearrangement proceeds with a high degree of
[a] Priv.-Doz. Dr. U. Kazmaier, Dipl.-Chem. D. Schauû,
Dipl.-Chem. S. Raddatz, Dipl.-Chem. M. Pohlman
Organisch-Chemisches Institut der Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (‡ 49)6221-544205
A slight drawback of these procedures results from the fact,
that each side chain introduced requires the corresponding
allylic alcohol, which has to be prepared first. Therefore, we
are interested in developing suitable reactions to allow further
E-mail: ck1@popix.urz.uni-heidelberg.de
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456±464
modification of the allylic side chain. Besides heterofunction-
Results and Discussion
alizations,[13] C C couplings are especially interesting from
ꢀ
this point of view. Several examples are reported in the
literature so far, in particular, modifications of terminal
double bonds. Besides inter-[14] and intramolecular[15] meta-
theses, Heck-type couplings can also be carried out.[16]
Applying this reaction to our rearrangement products, we
obtained good results, especially with a-alkylated amino
acids.[17] However, optically active allylglycine derivatives
showed partial racemization depending on the protecting
group used. This epimerization is evidently due to the
relatively drastic conditions of the Heck reaction.[18] These
couplings are also limited to substitutions on the sterically
least hindered side of terminal double bonds.
Synthesis of stannylated allylic esters: Our studies on the
synthesis of the required stannylated allylic esters began with
the hydrostannation of propargylic alcohol (1) under different
reaction conditions (Scheme 4). Two differing procedures are
For these reasons, we focused our investigations on another
valuable approach, the Stille coupling reactions.[19] Since these
reactions take place under rather mild conditions and are
tolerant of a wide variety of functional groups this method-
ology is especially suitable for side chain modifications.[20] The
required amino acids, bearing a vinylstannane side chain,
should be accessible through a Claisen rearrangement from
the corresponding a-stannylated esters. In turn, these could be
obtained by esterification of the amino acids with the
stannylated allylic alcohols, or through hydrostannation of
propargylic esters (Scheme 3). Alternatively the stannylated
Scheme 4. a) 1.2 equiv DCC, 10 mol% DMAP, CH2Cl2, ꢀ208C ! RT
(82%).
common for this purpose: the radical and the catalytic
pathway. Following the pioneering work of Leusink et al.,[21]
radical tin hydride additions to acetylenic bonds have been
extensively used.[22] Applying this procedure to the hydro-
stannation of propargylic alcohols provides a mixture of all
three possible isomers. In this case the product distribution
depends not only on the substrate but also on the reaction
conditions used.[23] Unfortunately, the desired a-substituted
compound 2 was only obtained as a minor product, the b-
stannylated allylic alcohol 3a was obtained preferentially, as
an E/Z-isomeric mixture.[24]
The regioisomers were separated by flash column chroma-
tography, giving pure (E)-3 and an inseparable mixture of 2
and (Z)-3.[25] Therefore, we also examined the metal-catalyzed
version using [Pd(COD)Cl2] as a catalyst. The catalytically
active Pd0-complex is probably formed in situ through
reduction of the palladium(ii) species by the tin hydride.[26]
In accordance with the reaction mechanism, the hydrostan-
nation proceeded with clean syn-addition,[27] giving rise to 2
and (E)-3 with a slight preference for the required a-product
2. Flash chromatography furnished the pure regioisomers,
which were coupled with benzyloxycarbonyl (Cbz)-glycine,
using the Steglich protocol,[28] to give rise to the stannylated
allylic esters 4a and 6a, respectively, in high yields. The
regioselectivity in the hydrostannation step towards the a-
product was acceptable in this case, although the selectivities
obtained with other, sterically more hindered propargylic
alcohols, such as 3-butyn-2-ol, are worse.[27] Therefore, from a
synthetic point of view, only the hydrostannation of 1 is useful
for this purpose, especially because the purification of the
stannylated products is often not a trivial issue.[29]
Scheme 3. Retrosynthetic approach.
amino acid should also be accessible through palladium-
catalyzed allylation directly from a stannylated allylic carbo-
nate (or acetate). This building block, bearing two reactive
centers, can be extremely useful. The vinylstannane subunit
should allow coupling with electrophiles under Stille condi-
tions, and the allyl ester moiety should be suitable for Pd-
catalyzed allylic alkylations, allowing nucleophilic substitu-
tions at the terminal allylic position. The stannylated sub-
strates should be accessible through hydrostannation, and
therefore this transformation plays a significant role in the
whole reaction sequence. This is especially true because the
regioselectivity of the tin hydride addition to the triple bond is
the product determining step. For our approach, only the a-
stannylated allylic alcohols or esters are interesting as only
they give rise to the desired vinylstannane side chain.
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For these reasons we also investigated the hydrostannation
of propargylic esters 5 (Scheme 5). This approach should give
direct access to the required esters 4, and should reduce the
Scheme 6. a) 3 equiv Bu3SnH, 2 mol% MoBI3, THF, 508C, 4 h.
a-stannylated products 9 in very high yields as single
regioisomers.[34] Fortunately, these compounds are stable
towards protodestannylation, which allows purification by
flash column chromatography without decomposition, and
explains the high yields obtained.
Syntheses of stannylated amino acid esters: With the stanny-
lated allylic esters in hand, we firstly investigated the chelate
Claisen rearrangement[35] of the a-stannylated esters 4a and
4b (Scheme 7). Deprotonation of these esters with excess
Scheme 5. Hydrostannation of propargylic esters.
number of stannylated intermediates. Again, under radical
reaction conditions, a mixture of all possible isomers was
formed, containing (Z)-isomer 7 as the major product
(Table 1). Because only a small amount of the desired ester
Table 1. Hydrostannation of propargylic esters 5.
Scheme 7. a) 3.5 equiv LDA, 1.2 equiv ZnCl2, THF, ꢀ788C ! RT.
Reaction conditions
substrate
yield [%]
4:6:7
b) CH2N2.
AIBN, CCl4, 608C, 15 h
[Pd(COD)Cl2], THF, RT, 1 h
[Rh(PPh3)3Cl], THF, 608C, 15 h
MoBI3, THF, 508C, 5 h
5a
5a
5a
5a
5b
67
±
57
70
85
12:26:62
±
81:19:0
95:5:0
92:8:0
LDA at ꢀ788C in the presence of ZnCl2, resulted in a clean
rearrangement when the reaction mixture was warmed to
room temperature. In the rearrangement of 4b, the product with
(E)-olefin geometry (10b) was obtained nearly exclusively
(less than 5% of (Z)-olefin); this can be explained by the
rearrangement occurring via a chairlike transition state.[36]
The reaction mixture was quenched with 1n KHSO4 solution
(no protodestannylation was observed during this workup
procedure) and the crude amino acids were converted into the
corresponding methyl esters 10 with diazomethane. In gen-
eral, these esters can be used directly for further modifications
without purification. In contrast to the stannylated allylic
acetates and carbonates 9, these stannylated amino acids (and
esters) are sensitive toward protodestannylation, and decom-
pose during flash chromatography, even in the presence of
triethylamine. Although the crude product was obtained nearly
quantitatively, the yield, especially of the substituted deriva-
tive 10b, dropped to around 50% after chromatography.
In the alternative approach towards these stannylated
amino acid derivatives we investigated the palladium-cata-
lyzed allylic alkylation of two different protected glycine
esters 11 using the carbonate 9b as an allylic substrate
(Scheme 8).[37] Both derivatives gave the desired products in a
MoBI3, THF, 508C, 6 h
4 was obtained, we also applied the palladium-catalyzed
methodology to these substrates. However, no hydrostannat-
ed products were obtained, and cleavage of the ester moiety
was the only reaction observed. Fortunately, besides palla-
dium complexes, other transitions metals can also be used as
catalysts; for example rhodium[30] or molybdenum com-
plexes.[26] Indeed, hydrostannation of ester 5a in the presence
of Wilkinsonꢁs catalyst (1 mol%) gave the required ester 4a
with acceptable yield and selectivity. Even better results were
obtained with a new hydrostannation catalyst,[31] developed in
our laboratory. [Mo(CO)3(CNtBu)3] (MoBI3), easily obtained
by ligand exchange from [Mo(CO)6],[32] proved to be a highly
efficient catalyst for regioselective hydrostannations for
various types of alkynes. In all examples investigated so far,
the tin moiety was transferred preferentially to the sterically
more hindered position of the triple bond. With this catalyst,
we observed excellent a-regioselectivity in the reaction of 5a,
and the sterically more hindered derivative 5b as well.[33] With
the last substrate an even higher yield was obtained. When
traces of hydroquinone were added to the reaction mixture
(to suppress competitive radical reactions) the syn-addition
products were formed exclusively.
After we successfully applied our methodolody to glycine
esters, we transferred the optimized reaction conditions
towards the hydrostannation of propargylic acetate (8a) and
carbonate (8b) (Scheme 6). Both substrates gave the desired
Scheme 8. a 1) 2.5 equiv LDA, 1.1 equiv ZnCl2, THF, ꢀ788C; 2) 0.8 equiv
9b, 1% [allylPdCl]2, 4.5% PPh3, ꢀ788C ! RT.
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very clean reaction and reasonable to good isolated yields.
Best results were obtained if the chelated enolates were used,
and the allylic carbonate 9b was consumed completely. In
these cases, the highly unpolar amino acid esters were
separated from the starting materials 11 by rapid column
chromatography (silica gel, 2% triethylamine added to the
solvent).
Stille couplings with stannylated amino acid esters: The
stannylated amino acid esters 10 were subjected to cross-
coupling reactions with various types of electrophiles
(Scheme 9 and Scheme 10). In those cases, where the crude
rearrangement product was used, the yields (in brackets) are
overall yields for both steps: Claisen rearrangement and
cross-coupling reaction.
We began our investigations with the coupling of ester 10a
with bromobenzene (Scheme 9). Instead of [Pd(PPh3)4],
which was originally used as catalyst by Stille et al., we chose
[Pd2(dba)3] ´ CHCl3 as a palladium source and AsPh3 as ligand.
Scheme 10. a) 3 equiv BnBr, 2.5 mol% [Pd2(dba)3] ´ CHCl3, 20 mol%
AsPh3, THF, 20 h. b) 3 equiv allylBr, 2.5 mol% [Pd2(dba)3] ´ CHCl3,
20 mol% AsPh3, toluene, 608C, 20 h. c) o-Br-BnBr, 2.5 mol%
[Pd2(dba)3] ´ CHCl3, 20 mol% AsPh3, 20 h. d) 1.05 equiv BzCl, 2.5 mol%
[allylPdCl]2, MeCN. e) 1.05 equiv AcCl, 2.5 mol% [allylPdCl]2, MeCN, RT,
10 min. f) 1.1 equiv ClCOOAll, 2.5 mol% [allylPdCl]2, MeCN, RT, 10 min.
compounds in the reaction mixture. The three isomers were
easily characterized by the vinylic proton signals in their
1H NMR spectra. In the major isomer 13a the terminal
olefinic protons gave two singlets at d ˆ 5.30 and 5.35. For the
(E)-isomer a doublet of triplets (d ˆ 6.06, J ˆ 15.8, 7.3Hz) and
a doublet (d ˆ 6.47, J ˆ 15.8 Hz) were observed, whilst the
(Z)-isomer gave a multiplet (d ˆ 5.60) for the g-proton and a
doublet (d ˆ 6.61, J ˆ 11.4 Hz) for the d-proton.
Scheme 9. a) 3 equiv PhBr, 2.5 mol% [Pd2(dba)3] ´ CHCl3, 20 mol%
AsPh3, THF, 658C, 20 h (59%). b) 3 equiv PhBr, 2.5 mol% [Pd2(dba)3] ´
CHCl3, 20 mol% AsPh3, toluene, 908C, 20 h.
As shown by Farina et al., this combination is significantly
superior in cross-coupling reactions, in comparison to phos-
phine containing catalysts.[38] It is proposed that a p-complex,
between the metal and the stannylated double bond, is
involved in the transmetallation, the rate determining step of
the catalytic cycle. Ligands such as AsPh3, which readily
dissociate from PdII and allow ready formation of this p-
complex, are those which produce the fastest coupling rates.
However, even with this reactive catalyst, the reaction was
rather sluggish. After 20 h at 658C, the coupling product was
obtained as a mixture of three regioisomers. Besides the
expected ipso substitution product 13a, the d-regioisomers
(E)-14a and (Z)-14a, resulting from cine substitution, were
also obtained. This is in good agreement with the observations
made by Crisp and Glink with similar substrates.[20] Unfortu-
nately, the regioisomers could not be separated by chroma-
tography. The product ratio was determined by HPLC and
NMR spectroscopy, which was also used to identify the
cine Substitution of vinyl stannanes during Stille couplings
is a general problem of this reaction, and occurs preferentially
during aryl couplings, especially if sterically hindered stan-
nanes are used. In this cases, the rate of transmetallation
might be rather slow. The formation of the cine product
probably results from a Heck reaction between the terminal
alkene position of 10a and the electrophile, followed by a
palladium-catalyzed loss of tributyltin bromide.[39] If this is
true, one might expect that these side reactions should be
suppressed if substituted derivatives such as 10b are subjected
to the same conditions. In this case, the competitive Heck
coupling should also be retarded for steric reasons. Indeed, no
cine products were obtained in the reaction of this substrate,
but in addition, the desired ipso substitution was noticeably
retarded, and therefore the reaction was carried out in toluene
at higher temperature. The product was obtained in about
50% yield from the purified ester 10b, and in 31% (overall
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yield for both steps) if the crude rearrangement product was
used directly.
Significantly higher reactivities and selectivities (no cine
products at all) were obtained with allyl and benzyl bromides.
For example, ester 10a reacted readily with benzyl bromide at
room temperature, and after stirring overnight the coupling
product 15a was obtained in high yield (Scheme 10). In the
coupling of ester 10b the reaction mixture was warmed to
608C to ensure completion. The same reaction conditions
were used for the reaction with allyl bromide as well, and the
allylated product 16b was obtained in comparable yield.
Because of the higher reactivity of the benzylic halides in
comparison to the aryl halides, we also investigated the
reaction of o-bromobenzyl bromide with our stannylated
esters. In principle this substrate has two reactive centers, but,
as expected, reaction occurred exclusively at the more
reactive benzylic position, giving rise to the brominated
products 17. Subsequent Heck reaction was not observed
under the reaction conditions used.
Good reactivities were also observed with acyl halides such
as benzoyl chloride or acetyl chloride.[40] These reactions can
be carried out in acetone or, even better, acetonitrile without
additional ligands. Probably these polar solvents can coor-
dinate to the palladium complexes formed during the reaction,
keeping them in solution.[41] Surprisingly, the reaction of 10a
with benzoyl chloride (Scheme 10) gave comparable yields in
both solvents, while the same reaction with acetyl chloride
proceeded only in acetonitrile. In the reactions of 10a, the
products were formed in a few minutes. After this time the
reaction had to be complete, otherwise it stopped, because
palladium(0) precipitated from the reaction mixture. Obvi-
ously, the coordinating effects of the solvents are not very
strong. This fact might explain the somewhat lower yields
obtained with substrate 10b, which generally reacted more
slowly in comparison to 10a. The amino acids 18 and 19
obtained in these acylation reactions are interesting substrates
for further modifications, for example through Michael addi-
tions. In contrast, the analogous reaction with allyl chlorofor-
mate does not provide the expected allylic ester, but the
allylated product 16b by decarboxylation. The yield obtained
was comparable to that from the reaction with allyl bromide,
which was discussed earlier. This reaction probably proceeds
via a p-allyl palladium intermediate, formed from the chloro-
formate.
Scheme 11. a) 1.1 equiv I2, CHCl3, RT. b) (E)-3, [(MeCN)2PdCl2], DMF,
808C, 2 h.
Conclusion
In summary, we have shown that MoBI3 is an efficient catalyst
for the regioselective hydrostannation of propargylic esters
and carbonates. a-Stannylated amino acid allyl esters ob-
tained by this protocol can be subjected to chelate Claisen
rearrangements, giving rise to the corresponding amino acids.
These amino acids, bearing a ªvinylstannaneº side chain are
suitable substrates for subsequent Stille couplings. Therefore,
this sequence provides a flexible strategy for the synthesis of
unnatural, highly functionalized amino acids. Further appli-
cations are currently under investigation.
Experimental Section
General remarks: All reactions were carried out in oven-dried glassware
(808C) under argon. All solvents were dried before use. THF and toluene
were distilled from sodium/benzophenone, dichloromethane, acetonitrile,
and diisopropylamine from calcium hydride. LDA solutions were prepared
from freshly distilled diisopropylamine and commercially available n-
butyllithium solution (15% in hexane) in THF at ꢀ208C directly before
use. The starting materials and the products were purified by flash column
chromatography on silica gel (32 ± 63 mm). Mixtures of ethyl acetate and
petrol ether (40 ± 608C) were generally used as eluents. 1% Triethylamine
was added to the solvent if stannylated compounds were subjected towards
flash chromatography. TLC: commercially precoated Polygram SIL-G/UV
254 plates (Macherey ± Nagel). Visualization was accomplished with UV
light, iodine, and potassium permanganate solution. 1H and 13C NMR
spectroscopy: Bruker AC300 spectrometer. Isomeric ratios were deter-
mined by NMR and/or analytical HPLC using a Knauer Eurosphere
column (250 Â 4 mm, Si80, 5 mm, flow: 2 mlminꢀ1) and a Knauer UV
detector. Bu3SnH, [Pd(MeCN)2Cl2] and [allylPdCl]2 were purchased from
Fluka, [Rh(PPh3)3Cl] from Aldrich, [Pd2(dba)3] ´ CHCl3,[42] [Pd(COD)-
Cl2][43] and were prepared according to the literature.
General procedure for esterifications: Dicyclohexylcarbodiimide (DCC)
(2.46 g, 12 mmol) and 4-dimethylaminopyridine (DMAP) (125 mg,
1 mmol) were added to a solution of the alcohol (10 mmol) in methylene
chloride (30 mL) at 08C. The clear solution was cooled to ꢀ208C, before
Cbz-glycine (2.10 g, 10 mmol) was added after 5 min. The mixture was
allowed to warm to room temperature overnight. After filtration of the
precipitate, the organic phase was extracted with 1n KHSO4 solution, sat.
NaHCO3 solution and brine. The organic layer was dried over Na2SO4 and
evaporation of the solvent gave crude ester which was purified by flash
chromatography.
In all reactions described so far, the stannylated amino acid
esters reacted as nucleophiles with several types of electro-
philic coupling partners. However, this concept for side chain
modification is not limited to this approach; it can also be
carried out vice versa. Thus, when ester 10a was subjected to a
metal halogen exchange with iodine,[25] the corresponding
amino acid 20, with a ªvinyliodideº side chain, was obtained in
nearly quantitative yield (Scheme 11). By this procedure, the
original nucleophile is converted into an electrophile, which
can now be coupled with, for example, other vinylstannanes.
Unfortunately we were not able to couple our two amino acid
esters 10a and 20 to afford the corresponding dimer, probably
for steric reasons. Pleasingly, however, with the terminal
stannane (E)-3, the coupling product 21 was obtained in good
yield.
Radical hydrostannations: The alkyne (1 mmol) was dissolved in a Schlenk
tube under argon in CCl4 (1 mL). Bu3SnH (0.8 mL 3 mmol) and AIBN
(20 mg) were added and the mixture was warmed to 608C for 15 h. After
cooling to room temperature, the reaction mixture was subjected to flash
chromatography. Excess of Bu3SnH was removed using hexane as an
eluent. The stannylated products were obtained using hexanes/ethyl
acetate containing 1% triethylamine as eluent. The isomeric ratios
observed are given in Table 1.
Palladium-catalyzed hydrostannation: Propargyl alcohol (1) (1.58 g,
28.2 mmol), [Pd(COD)Cl2] (14 mg, 50 mmol), and triphenylphosphine
(26 mg, 0.1 mmol) were dissolved in THF (2.5 mL) in a Schlenk tube
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under argon. Bu3SnH (9 g, 33.2 mmol) was added slowly during 30 min at
08C. The mixture was allowed to warm to room temperature after further
10 min and was subjected to flash chromatography.
92% yield. Ester 6a was also formed as the minor product in the rhodium-
(1 mmol) and molybdenum (5 mmol) catalyzed reaction. Rf: 0.31 (hexanes/
ethyl acetate 85:15); 1H NMR (300 MHz, CDCl3): d ˆ 7.35 (m, 5H; Har),
ˆ
6.29 (d, J ˆ 18.8 Hz, 1H; C CHSn, J(Sn,H) ˆ 57 Hz), 6.02 (dt, J ˆ 19.2,
Rhodium-catalyzed hydrostannations: The alkyne (1 mmol) was dissolved
in a Schlenk tube under argon in THF (1 mL). Bu3SnH (0.8 mL, 3 mmol)
and [Rh(PPh3)3Cl] (9 mg, 10 mmol) were added and the mixture was
warmed to 608C for 15 h. After cooling to room temperature, the reaction
mixture was subjected to flash chromatography.
ˆ
5.3 Hz, 1H; CH CH, J(Sn,H) ˆ 72 Hz), 5.26 (brs, 1H; NH), 5.11 (s, 2H;
PhCH2), 4.66 (d, J ˆ 4.9 Hz, 2H; OCH2), 3.94 (d, J ˆ 4.9 Hz, 2H; NCH2),
1.55 ± 1.44 (m, 6H; SnCH2), 1.39 ± 1.26 (m, 6H; CH2CH3), 0.96 ± 0.87 (m,
15H; CH2, CH3); 13C NMR (75 MHz, CDCl3): d ˆ 171.7 (CO), 158.3
ˆ
ˆ
(NCO), 148.9 (C C), 142.6 (C C), 138.3, 130.6, 130.3, 130.2 (Car), 74.0
(OCH2), 68.9 (PhCH2), 45.5 (NCH2), 31.1 (CH2CH3, J(Sn,C) ˆ 20 Hz), 29.1
(CH2, J(Sn,C) ˆ 59 Hz), 15.8 (CH3), 11.7 (SnCH2, J(Sn,C) ˆ 332 Hz);
elemental analysis calcd (%) for C25H41NO4Sn (538.3): C 55.78, H 7.68, N
2.60; found C 55.87, H 7.76, N 2.56.
MoBI3-catalyzed hydrostannations: The alkyne (1 mmol), hydroquinone
(10 mg), and [Mo(CO)3(CNtBu)3] (MoBI3) (8.6 mg, 20 mmol) were dis-
solved in a Schlenk tube under argon in THF (1 mL). Bu3SnH (0.8 mL,
3 mmol) was added slowly and the mixture was warmed to 558C until all
starting material was consumed. After cooling to room temperature, the
reaction mixture was subjected to flash chromatography.
Stannylated ester 7a: Ester 7a was obtained in a 5 mmol scale as the major
product through radical hydrostannation of ester 5a. Flash chromatog-
raphy (hexanes/ethyl acetate/NEt3 84:15:1) gave a inseparable mixture of
4a and 7a (total 50%). Rf: 0.39 (hexanes/ethyl acetate 85:15); 1H NMR
(300 MHz, CDCl3): d ˆ 7.37 (m, 5H; Har), 6.60 (dt, J ˆ 12.9, 6.6 Hz, 1H;
Stannylated ester 4a: Ester 4a was obtained in a 20 mmol scale from the
stannylated alcohol 2[23] using the general procedure for esterifications in
82% yield. The MoBI3-catalyzed hydrostannation of propargylic ester 5a
was carried out in a 5 mmol scale. The crude product was purified by flash
column chromatography (hexanes/ethyl acetate/NEt3 84:15:1) giving rise
to ester 4a as a pale yellow oil (70%). Rf: 0.39 (hexanes/ethyl acetate
85:15); 1H NMR (300 MHz, CDCl3): d ˆ 7.34 (m, 5H; Har), 5.86 (d, J ˆ
ˆ
ˆ
CH2CH C), 6.27 (d, J ˆ 12.9 Hz, C CHSn), 5.32 (brs, 1H, NH), 5.14 (s,
2H; PhCH2), 4.59 (d, J ˆ 6.6 Hz, 2H; OCH2), 4.01 (d, J ˆ 5.5 Hz, 2H;
NCH2), 1.55 ± 1.43 (m, 6H; SnCH2), 1.39 ± 1.26 (m, 6H; CH2CH3), 0.99 ±
0.88 (m, 15H; CH2, CH3); 13C NMR (75 MHz, CDCl3): d ˆ 169.7 (CO),
ˆ
ˆ
1.8 Hz, 1H; C CHtrans, J(Sn,H) ˆ 120 Hz), 5.29 (d, J ˆ 1.9 Hz, 1H; C CHcis,
J(Sn,H) ˆ 59 Hz), 5.27 (brs, 1H; NH), 5.12 (s, 2H; PhCH2), 4.79 (s, 2H;
OCH2, J(Sn,H) ˆ 28 Hz), 4.00 (d, J ˆ 5.2 Hz, 2H; NCH2), 1.53 ± 1.43 (m,
ˆ
ˆ
156.2 (NCO), 140.8 (C C), 136.5 (C C), 136.2, 128.5, 128.2, 128.1 (Car), 68.2
(OCH2), 67.1 (PhCH2), 42.8 (NCH2), 30.0 (CH2CH3, J(Sn,C) ˆ 21 Hz), 27.3
(CH2, J(Sn,C) ˆ 55 Hz), 13.6 (CH3), 10.4 (SnCH2, J(Sn,C) ˆ 337 Hz);
elemental analysis calcd (%) for C25H41NO4Sn (538.3) (mixture 4a/7a): C
55.78, H 7.68, N 2.60; found C 55.60, H 7.55, N 2.53.
6H; SnCH2), 1.36 ± 1.26 (m, 6H; CH2CH3), 0.97 ± 0.85 (m, 15H; CH2, CH3);
13
ˆ
C NMR (75 MHz, CDCl3): d ˆ 169.5 (CO), 156.1 (NCO), 148.2 (C CSn),
ˆ
136.2, 128.5, 128.2, 128.1 (Car), 126.0 (C C), 71.9 (OCH2), 67.1 (PhCH2),
2-Tributylstannyl-allyl acetate (9a): Ester 9a was obtained through MoBI3-
catalyzed hydrostannation of ester 8a (617 mg, 6.30 mmol). Flash chroma-
tography (hexanes/ethyl acetate/NEt3 95:4:1) provided ester 9a (2.225 g,
5.72 mmol, 91%). Rf: 0.46 (hexanes/ethyl acetate 95:5); 1H NMR
42.8 (NCH2), 28.9 (CH2CH3, J(Sn,C) ˆ 20 Hz), 27.3 (CH2, J(Sn,C) ˆ
58 Hz), 13.6 (CH3), 9.6 (SnCH2, J(Sn,C) ˆ 335 Hz); elemental analysis
calcd (%) for C25H41NO4Sn (538.3): C 55.78, H 7.68, N 2.60; found C 55.71,
H 7.73, N 2.51.
ˆ
(300 MHz, CDCl3): d ˆ 5.85 (m, 1H; C CHtrans, J(Sn,H) ˆ 121 Hz), 5.28
Stannylated ester 4b: Ester 4b was obtained in a 10 mmol scale from ester
5b through MoBI3-catalyzed hydrostannation as a pale yellow oil (85%).
Rf: 0.44 (hexanes/ethyl acetate 85:15); 1H NMR (300 MHz, CDCl3): d ˆ
ˆ
(m, 1H; C CHcis, J(Sn,H) ˆ 60 Hz), 4.69 (m, 2H; OCH2, J(Sn,H) ˆ 31 Hz),
2.05 (s, 3H; COCH3), 1.63 ± 1.40 (m, 6H; SnCH2), 1.35 ± 1.23 (m, 6H;
CH2CH3), 1.10 ± 0.84 (m, 15H; CH2, CH3); 13C NMR (75 MHz, CDCl3):
d ˆ 170.3 (CO), 148.9 (C CSn), 125.5 (C CSn), 71.0 (OCH2), 28.9
(CH2CH3), 27.1 (CH2), 20.7 (COCH3), 13.4 (CH3), 9.3 (SnCH2); elemental
analysis calcd (%) for C17H34O2Sn (389.1): C 52.48, H 8.74; found C 52.23,
H 8.78.
ˆ
7.33 (m, 5H; Har), 5.80 (s, 1H; C CHtrans, J(Sn,H) ˆ 125 Hz), 5.51 (q, J ˆ
ˆ
ˆ
ˆ
7.0 Hz, 1H; OCH), 5.26 (brs, 1H; NH), 5.22 (s, 1H; C CHcis, J(Sn,H) ˆ
75 Hz), 5.11 (s, 2H; PhCH2), 3.97 (dd, J ˆ 12.8, 5.5 Hz, 1H; NCH), 3.93 (dd,
J ˆ 12.9, 5.3 Hz, 1H; NCH), 1.50 ± 1.43 (m, 6H; SnCH2), 1.36 ± 1.24 (m, 6H;
CH2CH3), 0.92 ± 0.85 (m, 18H; CH2, CH3); 13C NMR (75 MHz, CDCl3):
ˆ
d ˆ 169.0 (CO), 156.1 (NCO), 154.3 (C CSn), 136.2, 128.5, 128.15, 128.07
Methyl (2-tributylstannyl-allyl) carbonate (9b): Ester 9b was obtained
through MoBI3-catalyzed hydrostannation of ester 8b (250 mg,
2.19 mmol). Flash chromatography (hexanes/ethyl acetate/NEt3 98:1:1)
provided ester 9b (750 mg, 1.86 mmol, 85%). Rf: 0.36 (hexanes/ethyl
ˆ
(Car), 125.1 (C C J(Sn,C) ˆ 19 Hz), 79.0 (OCH), 67.0 (PhCH2), 43.0
(NCH2), 29.0 (CH2CH3, J(Sn,C) ˆ 20 Hz), 27.3 (CH2, J(Sn,C) ˆ 44 Hz),
21.5 (CH3), 13.6 (CH3), 10.1 (SnCH2, J(Sn,C) ˆ 334 Hz); elemental analysis
calcd (%) for C26H43NO4Sn (552.3): C 56.54, H 7.85, N 2.54; found C 56.59,
H 7.92, N 2.52.
1
ˆ
acetate 98:2); H NMR (300 MHz, CDCl3): d ˆ 5.89 (m, 1H; C CHtrans
,
ˆ
J(Sn,H) ˆ 112 Hz), 5.29 (m, 1H; C CHcis, J(Sn,H) ˆ 59 Hz), 4.75 (m, 2H;
OCH2, J(Sn,H) ˆ 28 Hz), 3.76 (s, 3H; OCH3), 1.57 ± 1.39 (m, 6H; SnCH2),
Propargyl N-(benzyloxycarbonyl)glycinate (5a): Ester 5a was obtained in a
40 mmol scale from propargylic alcohol and Cbz-glycine using the general
procedure for esterifications in 87% yield. Crystallization from ether/
petrol ether gave colorless crystals. M.p. 78 ± 798C; Rf: 0.54 (hexanes/ethyl
acetate 1:1); 1H NMR (300 MHz, CDCl3): d ˆ 7.33 (m, 5H; Har), 5.35 (brs,
1H; NH), 5.11 (s, 2H; PhCH2), 4.73 (d, J ˆ 2.2 Hz, 2H; OCH2), 4.00 (d, J ˆ
1.34 ± 1.22 (m, 6H; CH2CH3), 1.08 ± 0.81 (m, 15H; CH2, CH3); 13C NMR
ˆ
ˆ
(75 MHz, CDCl3): d ˆ 155.4 (CO), 148.5 (C CSn), 125.5 (C CSn), 74.1
(OCH2), 54.4 (OCH3), 28.7 (CH2CH3), 27.0 (CH2), 13.4 (CH3), 9.4 (SnCH2);
elemental analysis calcd (%) for C17H34O3Sn (405.1): C 50.40, H 8.45; found
C 50.35, H 8.46.
5.7 Hz, 2H; NCH2), 2.49 (t, J ˆ 2.4 Hz, 1H; C CH); 13C NMR (75 MHz,
ꢁ
General procedure for chelate Claisen rearrangements: A freshly prepared
LDA solution (2.5 mmol) in THF (7 mL) was added under argon to a
stirred solution of the stannylated allylic ester 4 (1 mmol) and ZnCl2
(1.1 mmol) in dry THF at ꢀ788C. The mixture was allowed to warm to
room temperature overnight. The resulting clear solution was diluted with
ether and hydrolyzed with 1n KHSO4 solution. After separation of the
aqueous layer, the organic layer was dried (Na2SO4) and the solvent was
removed in vacuo. The crude product was treated with a solution of
diazomethane in ether. The esters 10 obtained were purified by flash
chromatography on silica gel (hexanes/ethyl acetate/NEt3 90:9:1). In
general, they can directly be used for subsequent cross-coupling reactions.
CDCl3): d ˆ 169.2 (CO), 156.1 (NCO), 135.9, 128.3, 128.1, 127.9 (Car), 76.7
ꢁ
ꢁ
(C CH), 75.4 (C CH), 67.0 (PhCH2), 52.6 (OCH2), 42.4 (NCH2);
elemental analysis calcd (%) for C13H13NO4 (247.2): C 63.15, H 5.30, N
5.67; found C 63.22, H 5.28, N 5.66.
Ester 5b: Ester 5b was obtained in a 40 mmol scale from 3-butyne-2-ol and
Cbz-glycine using the general procedure for esterifications in 81% yield.
The crude product was purified by flash chromatography (hexanes/ethyl
acetate 8:2) giving rise to a pale yellow oil. Rf: 0.49 (hexanes/ethyl acetate
1: 1); 1H NMR (300 MHz, CDCl3): d ˆ 7.33 (m, 5H; Har), 5.46 (qd, J ˆ 6.7,
2.0 Hz, 1H; OCH), 5.31 (brs, 1H; NH), 5.11 (s, 2H; PhCH2), 3.99 (dd, J ˆ
13.0, 5.8 Hz, 1H; NCH), 3.96 (dd, J ˆ 12.9, 5.5 Hz, 1H; NCH), 2.46 (d, J ˆ
General procedure for palladium-catalyzed allylic alkylations: The pro-
tected amino acid ester 11 (1 mmol) was dissolved in THF (4 mL). At
ꢀ788C a freshly prepared solution of lithium 1,1,1,3,3,3-hexamethyldisila-
zane (LHMDS) (2.5 mmol) in THF (2 mL) was added. After 30 min at
ꢀ788C, a solution of ZnCl2 (1.1 mmol) in THF (5 mL) was added under
2.1 Hz, 1H; C CH), 1.50 (d, J ˆ 6.7 Hz, 3H; CH3); 13C NMR (75 MHz,
ꢁ
CDCl3): d ˆ 168.8 (CO), 156.0 (NCO), 136.0, 128.3, 128.0, 127.9 (Car), 81.2
ꢁ
ꢁ
(C CH), 73.4 (C CH), 66.9 (PhCH2), 61.0 (OCH), 42.6 (NCH2), 20.9
(CH3); elemental analysis calcd (%) for C14H15NO4 (261.3): C 64.35, H 5.79,
N 5.36; found C 64.25, H 5.60, N 5.33.
vigorous stirring. After additional 30 min
a solution of [allylPdCl]2
Stannylated ester 6a: Ester 6a was obtained in a 10 mmol scale from the
stannylated alcohol (E)-3 using the general procedure for esterifications in
(1 mol%), PPh3 (4.5 mol%), and the corresponding allylic ester
(0.80 mmol) in THF (3 mL) was added. The solution was stirred and
Chem. Eur. J. 2001, 7, No. 2
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0702-0461 $ 17.50+.50/0
461

U. Kazmaier et al.
FULL PAPER
warmed up to room temperature overnight. Subsequently, the solution was
diluted with diethyl ether and hydrolyzed with 1n KHSO4 solution. The
aqueous phase was extracted twice with diethyl ether, and the combined
organic phases were dried over anhydrous Na2SO4. After evaporation of
the solvent the crude product was purified by silica gel column chromatog-
raphy (hexanes/ethyl acetate/NEt3 90:9:1).
bromobenzene (32 mL, 0.3 mmol) following the general procedure for
[Pd2(dba)3] ´ CHCl3 catalyzed reactions at 608C using THF as solvent. The
crude product was purified by flash chromatography (hexanes/ethyl acetate
9:1) giving rise to a pale yellow oil (20 mg, 59 mmol, 59%), which was a
inseparable mixture of 13a and the isomers 14a. Rf: 0.49 (hexanes/ethyl
acetate 8:2). 13a: 1H NMR (300 MHz, CDCl3): d ˆ 7.40 ± 7.20 (m, 10H;
ˆ
ˆ
Har), 5.35 (s, 1H; C CH), 5.30 (s, 1H; C CH), 5.22 (d, J ˆ 8.5 Hz, 1H;
Stannylated amino acid ester 10a: Ester 10a was obtained from 4a (3.23 g,
6.0 mmol) following the general procedure for chelate Claisen rearrange-
ments (2.32 g, 4.2 mmol, 70%) after flash chromatography (hexanes/ethyl
acetate/NEt3 90:8:2). Alternatively, ester 10a was also prepared from 9b
(86 mg, 0.21 mmol) according to the general procedure for palladium-
catalyzed allylic alkylations (49 mg, 0.089 mmol, 42%). Rf: 0.34 (hexanes/
ethyl acetate 85:15); 1H NMR (300 MHz, CDCl3): d ˆ 7.34 (m, 5H; Har),
NH), 5.10 (s, 2H; PhCH2), 4.47 (m, 1H; NCH), 3.55 (s, 3H; OCH3), 3.07,
(dd, J ˆ 14.0, 4.4 Hz, 1H; CH2), 2.98 (dd, J ˆ 14.0, 7.0 Hz, 1H; CH2);
13
ˆ
C NMR (75 MHz, CDCl3): d ˆ 172.1 (CO), 155.5 (NCO), 143.7 (C C),
ˆ
140.4, 136.3, 128.5, 128.4, 128.13, 128.08, 127.9, 126.3 (Car), 116.6 (C C), 66.9
(PhCH2), 53.0 (NCH), 52.0 (OCH3), 38.1 (CH2). (E)-14a: 1H NMR
ˆ
(selected signals): d ˆ 6.47 (d, J ˆ 15.8 Hz, 1H; PhCH C), 6.06 (dt, J ˆ 15.8,
1
ˆ
7.3 Hz, 1H; CH2CH C); (Z)-14a: H NMR (selected signals): d ˆ 6.61 (d,
ˆ
ˆ
5.72 (s, 1H; C CHtrans, J(Sn,H) ˆ 119 Hz), 5.24 (s, 1H; C CHcis, J(Sn,H) ˆ
57 Hz), 5.06 (m, 1H; NH), 5.09 (s, 2H; PhCH2), 4.34 (dd, J ˆ 8.3, 4.9 Hz,
1H; NCH), 3.74 (s, 3H; OCH3), 2.80 (dd, J ˆ 14.3, 4.5 Hz, 1H; CH2CSn),
2.50 (dd, J ˆ 14.0, 9.0 Hz, 1H; CH2CSn), 1.51 ± 1.43 (m, 6H; SnCH2), 1.34 ±
1.27 (m, 6H; CH2CH3), 0.96 ± 0.86 (m, 15H; CH2, CH3); 13C NMR
ˆ
ˆ
J ˆ 11.4 Hz, 1H; PhCH C), 5.60 (m, 1H; CH2CH C); HRMS (FAB):
‡
C20H21NO4 [M] (mixture 13a/14a): calcd 339.1471; found 339.1473; MS
(FAB): m/z (%): 339 (2.5), 280 (3.3), 188 (20.3).
Methyl 2-(benzyloxycarbonyl)amino-4-phenyl-4(Z)-hexenoate (13b):
Coupling product 13b was obtained from purified (or crude) 10b
(283 mg, 0.5 mmol) and bromobenzene (0.16 mL, 1.5 mmol) following the
general procedure for [Pd2(dba)3] ´ CHCl3 catalyzed reactions at 908C using
toluene as a solvent. The crude product was purified by flash chromatog-
raphy (hexanes/ethyl acetate 8:2) giving rise to 13b (86 mg, 0.245 mmol,
49%) (55 mg, 1.55 mmol, 31% from the crude product) as a pale yellow oil.
Rf: 0.32 (hexanes/ethyl acetate 8: 2); 1H NMR (300 MHz, CDCl3): d ˆ 7.34
(m, 9H; Har), 7.09 (d, J ˆ 7.5 Hz, 1H; Har), 5.50 (q, J ˆ 6.3 Hz, 1H;
ˆ
(75 MHz, CDCl3): d ˆ 170.9 (CO), 153.9 (NCO), 148.0 (C CSn), 134.4
ˆ
(Car), 127.5 (C CH2), 126.7, 126.3 (Car), 65.2 (PhCH2), 51.9 (NCH), 50.4
(OCH3), 41.7 (CH2), 27.2 (CH2CH3, J(Sn,C) ˆ 20 Hz), 25.6 (CH2,
J(Sn,C) ˆ 57 Hz), 11.9 (CH3), 7.9 (SnCH2, J(Sn,C) ˆ 332 Hz); elemental
analysis calcd (%) for C26H43NO4Sn (552.3): C 56.54, H 7.85, N 2.54; found
C 56.52, H 7.85, N 2.51.
Stannylated amino acid ester 10b: Ester 10b was obtained from 4b
(630 mg, 1.14 mmol) following the general procedure for chelate Claisen
rearrangements (316 mg, 0.56 mmol, 49%) after flash chromatography. Rf:
0.32 (hexanes/ethyl acetate 85:15); 1H NMR (300 MHz, CDCl3): d ˆ 7.32
ˆ
C CHCH3), 5.24 (d, J ˆ 7.1 Hz, 1H; NH), 5.09 (s, 2H; PhCH2), 4.39 (dt, J ˆ
7.9, 5.8 Hz, 1H; NCH), 3.72 (s, 3H; OCH3), 2.45 (brs, 2H; CH2), 1.64 (d,
J ˆ 6.3 Hz, 3H; CHCH3); 13C NMR (75 MHz, CDCl3): d ˆ 172.1 (CO),
ˆ
(m, 5H; Har), 6.09 (q, J ˆ 6.5 Hz, 1H; C CH, J(Sn,H) ˆ 123 Hz), 5.06 (s,
ˆ
155.5 (NCO), 136.1 (Car), 130.0 (C CH), 128.5, 128.3, 128.1, 127.93, 127.87,
2H; PhCH2), 5.00 (d, J ˆ 7.4 Hz, 1H; NH), 4.21 (ddd, J ˆ 9.2, 7.4, 5.1 Hz,
1H; NCH), 3.70 (s, 3H; OCH3), 2.69 (dd, J ˆ 13.6, 4.8 Hz, 1H; CH2CSn),
2.38 (dd, J ˆ 13.6, 9.2 Hz, 1H; CH2CSn), 1.67 (d, J ˆ 6.4 Hz, 3H;
ˆ
127.5, 125.6 (Car), 124.1 (C CH), 66.7 (PhCH2), 53.4 (NCH), 52.0 (OCH3),
‡
35.3 (CH2), 17.7 (CHCH3); HRMS (FAB): C21H23NO4 [M] : calcd 354.1705;
found 354.1726.
ˆ
C CHCH3), 1.49 ± 1.41 (m, 6H; SnCH2), 1.35 ± 1.18 (m, 6H; CH2CH3),
Methyl 4-benzyl-2-(benzyloxycarbonyl)amino-4-pentenoate (15a): Cou-
pling product 15a was obtained from 10a (359 mg, 0.65 mmol) and benzyl
bromide (0.23 mL, 2 mmol) following the general procedure for
[Pd2(dba)3] ´ CHCl3 catalyzed reactions using THF as a solvent. The
reaction mixture was stirred overnight at room temperature and was
heated 1 h to 608C for completion. The crude product was purified by flash
chromatography (hexanes/ethyl acetate 9:1) giving rise to 15a (186 mg,
0.53 mmol, 81%) as a pale yellow oil. Rf: 0.31 (hexanes/ethyl acetate 8: 2);
1H NMR (300 MHz, CDCl3): d ˆ 7.40 ± 7.14 (m, Har), 5.19 (d, J ˆ 7.7 Hz, 1H;
NH), 5.13 (d, J ˆ 12.4 Hz, 1H; PhCH2O), 5.08 (d, J ˆ 12.3 Hz, 1H; PhCH2),
0.98 ± 0.84 (m, 15H; CH2, CH3); 13C NMR (75 MHz, CDCl3): d ˆ 172.7
ˆ
ˆ
(CO), 155.5 (NCO), 139.0 (C C), 138.8 (C C), 136.1, 128.3, 127.9 (Car), 66.7
(PhCH2), 53.9 (NCH), 51.9 (OCH3), 43.1 (CH2CSn), 28.8 (CH2CH3,
J(Sn,C) ˆ 29 Hz), 27.2 (CH2, J(Sn,C) ˆ 59 Hz), 19.8 (CHCH3), 13.4
(CH2CH3), 9.9 (SnCH2, J(Sn,C)ˆ 326 Hz); elemental analysis calcd (%) for
C27H45NO4Sn (566.4): C 57.26, H 8.01, N 2.47; found C 57.07, H 8.07, N 2.45.
Stannylated amino acid ester 12: Ester 12 was obtained from 9b (83 mg,
0.205 mmol) following the general procedure for palladium-catalyzed allylic
alkylations (100 mg, 0.180 mmol, 88%) after flash chromatography. Rf: 0.26
(hexanes/ethyl acetate 98:2); 1H NMR (300 MHz, CDCl3): d ˆ 6.52 (d, J ˆ
ˆ
ˆ
4.89 (s, 1H; C CH2), 4.85 (s, 1H; C CH2), 4.52 (ddd, J ˆ 8.3, 8.2, 5.6 Hz,
ˆ
6.0 Hz, 1H; NH), 5.70 (s, 1H; C CH, J(Sn,H) ˆ 127 Hz), 5.25 (s, 1H;
1H; NCH), 3.71 (s, 3H; OCH3), 3.34 (s, 2H; PhCH2), 2.51 (dd, J ˆ 14.2,
ˆ
C CH, J(Sn,H) ˆ 57 Hz), 4.36 (m, 1H; NCH), 2.85 (dd, J ˆ 14.2, 9.1 Hz,
5.3 Hz, 1H; CH2C C), 2.32 (dd, J ˆ 14.2, 8.6 Hz, 1H; CH2C C); 13C NMR
(75 MHz, CDCl3): d ˆ 172.4 (CO), 155.5 (NCO), 143.4 (Car), 138.5
ˆ
ˆ
1H; CH2CSn), 2.49 (dd, J ˆ 14.1, 9.4 Hz, 1H; CH2CSn), 1.55 ± 1.42 (m, 6H;
SnCH2), 1.49 (s, 9H; CCH3), 1.36 ± 1.23 (m, 6H; CH2CH3), 0.96 ± 0.81 (m,
15H; CH2, CH3); 13C NMR (75 MHz, CDCl3): d ˆ 169.4 (CO), 156.1 (q,
ˆ
ˆ
(C CH2), 136.1, 128.8, 128.3, 128.2, 127.9, 127.8, 126.1 (Car), 115.4 (C CH2),
66.8 (PhCH2), 52.1 (NCH), 52.0 (OCH3), 42.0, 38.1 (CH2); C21H23NO4
(353.4): calcd C 71.37, H 6.56, N 3.96; found C 70.99, H 6.60, N 3.74; HRMS
ˆ
ˆ
J(Sn,C) ˆ 37 Hz, CF3CO), 149.0 (C CSn), 129.0 (C CH2), 115.5 (q,
J(Sn,C) ˆ 285 Hz, CF3), 82.8 (OCCH3), 52.4 (NCH), 43.5 (CH2CSn), 28.7
(CH2CH3, J(Sn,C) ˆ 20 Hz), 27.7 (CCH3), 27.1 (CH2, J(Sn,C) ˆ 57 Hz), 13.4
(CH2CH3), 9.9 (SnCH2, J(Sn,C) ˆ 327 Hz); elemental analysis calcd (%) for
C23H42F3NO3Sn (555.9): C 49.66, H 7.61, N 2.52; found C 49.94, H 7.72, N 2.62.
‡
(FAB): C21H23NO4 [M‡H] : calcd 354.1705; found 354.1680.
Methyl 4-benzyl-2-(benzyloxycarbonyl)amino-4-hexenoate (15b): Cou-
pling product 15b was obtained from 10b (566 mg, 1 mmol) and benzyl
bromide (0.36 mL, 3 mmol) following the general procedure for
[Pd2(dba)3] ´ CHCl3 catalyzed reactions at 608C in THF. The crude product
was purified by flash chromatography (hexanes/ethyl acetate 8:2) giving
rise to 15b (280 mg, 0.76 mmol, 76%) as a pale yellow oil. Rf: 0.28
(hexanes/ethyl acetate 8:2); 1H NMR (300 MHz, CDCl3): d ˆ 7.34 ± 7.12 (m,
General procedure for Stille coupling reactions using [Pd2(dba)3] ´ CHCl3
as catalyst: The stannylated ester 10 (1 mmol) was placed in a Schlenk tube
under argon, before the corresponding halide (3 mmol) was added in THF
or toluene (5 mL). The catalyst was added as a solution of [Pd2(dba)3] ´
CHCl3 (25 mg, 25 mmol, 5 mol%) and triphenylarsine (68 mg, 226 mmol)
in THF (3 mL) or toluene, respectively. The reaction mixture was heated to
608C (THF) or 908C (toluene) for about 20 h. After cooling to room
temperature, saturated KF solution (5 mL) was added, and the mixture was
stirred for further 15 h, before diethyl ether (30 mL) was added. The
aqueous layer was separated and the organic layer was washed with H2O
(15 mL). The combined aqueous layers were extracted with diethyl ether
(10 mL). The combined organic layers were evaporated to dryness, and the
residue obtained was dissolved in ethyl acetate. The insoluble tributyltin
fluoride was filtered off, the solvent was removed in vacuo, and the crude
product was purified by flash chromatography.
ˆ
Har), 5.46 (q, J ˆ 6.7 Hz, 1H; C CH), 5.07 ± 5.13 (m, 1H; NH), 5.12 (d, J ˆ
12.2 Hz, 1H; PhCH2O), 5.06 (d, J ˆ 12.3 Hz, 1H; PhCH2), 4.41 (ddd, J ˆ
8.3, 8.2, 5.4 Hz, 1H; NCH), 3.68 (s, 3H; OCH3), 3.43 (d, J ˆ 15.2 Hz, 1H;
PhCH2), 3.34 (d, J ˆ 15.1 Hz, 1H; PhCH2), 2.43 (dd, J ˆ 13.9, 5.0 Hz, 1H;
CH2), 2.20 (dd, J ˆ 14.0, 8.8 Hz, 1H; CH2), 1.72 (d, J ˆ 6.7 Hz, 3H; CH3);
13C NMR (75 MHz, CDCl3): d ˆ 172.6 (CO), 155.5 (NCO), 139.0, 136.1
ˆ
(Car), 133.4 (C CH), 128.3, 128.2, 128.2, 127.93, 127.86, 125.9 (Car), 124.9
ˆ
(C CH), 66.7 (PhCH2), 52.3 (NCH), 51.9 (OCH3), 39.1, 34.8 (CH2), 13.6
(CH3); elemental analysis calcd (%) for C22H25O4N (367.4): C 71.91, H 6.86,
N 3.81; found C 71.81, H 6.86, N 3.76.
Methyl 4-allyl-2-(benzyloxycarbonyl)amino-4-hexenoate (16b): Coupling
product 16b was obtained from 10b (283 mg, 0.5 mmol) and allyl bromide
(0.13 mL, 1.5 mmol) following the general procedure for [Pd2(dba)3] ´
Methyl 2-(benzyloxycarbonyl)amino-4-phenyl-4-pentenoate (13a): Cou-
pling product 13a was obtained from 10a (55 mg, 0.1 mmol) and
462
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Chem. Eur. J. 2001, 7, No. 2

Stannylated Amino Acids
456±464
CHCl3 catalyzed reactions at 608C in THF. The crude product was purified
by flash chromatography (hexanes/ethyl acetate 8:2) giving rise to 16b
(114 mg, 0.36 mmol, 72%) as a pale yellow oil. Rf: 0.32 (hexanes/ethyl
acetate 8:2); 1H NMR (300 MHz, CDCl3): d ˆ 7.33 (m, 5H; Har), 5.66 (ddt,
120.1, 128.0 (Car), 66.9 (PhCH2), 53.7 (NCH), 52.4 (OCH3), 34.8 (CH2);
elemental analysis calcd (%) for C21H21NO5 (367.4): C 68.65, H 5.76, N 3.81;
found C 68.47, H 5.85, N 3.69.
Methyl 4-benzoyl-2-(benzyloxycarbonyl)amino-4-hexenoate (18b): The
crude ester 10a (283 mg, 0.5 mmol) and benzoyl chloride (73 mg,
0.52 mmol) were dissolved in acetonitrile (2 mL) under argon. [AllylPdCl]2
(4.0 mg, 11 mmol) was added to the solution, and the reaction mixture was
heated to 608C for 1 h. The solution was cooled to room temperature,
before a saturated solution of KF in H2O (5 mL) was added. After stirring
overnight the workup was carried as described for 18a. Flash chromato-
graphy (hexanes/ethyl acetate 8:2) provided 18b (100 mg, 0.26 mmol,
52%) as a colorless oil. Rf: 0.12 (hexanes/ethyl acetate 8:2); 1H NMR
(300 MHz, CDCl3): d ˆ 7.82 (dd, J ˆ 8.3, 1.4 Hz, 2H; Har), 7.53 (td, J ˆ 7.4,
1.4 Hz, 1H; Har), 7.41 (dd, J ˆ 7.7, 7.3 Hz, 2H; Har), 7.29 (m, 5H; Har), 5.95
ˆ
ˆ
J ˆ 16.3, 9.9, 6.6 Hz, 1H; CH CH2), 5.34 (q, J ˆ 6.7 Hz, 1H; C CHCH3),
5.14 (m, 1H; NH), 5.10 (d, J ˆ 12.4 Hz, 1H; PhCH2), 5.05 (d, J ˆ 12.2 Hz,
ˆ
1H; PhCH2), 5.01 ± 5.10 (m, 2H; CH CH2), 4.39 (ddd, J ˆ 8.3, 8.2, 5.4 Hz,
ˆ
1H; NCH), 3.71 (s, 3H; OCH3), 2.76 (d, J ˆ 6.3 Hz, 2H; CH2CH C), 2.51
(dd, J ˆ 13.8, 5.2 Hz, 1H; CH2), 2.27 (dd, J ˆ 13.9, 8.8 Hz, 1H; CH2), 1.57
(d, J ˆ 6.7 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3): d ˆ 172.68 (CO),
ˆ
ˆ
155.52 (NCO), 136.13 (Car), 134.85 (CH CH2), 132.16 (C CH), 128.28,
ˆ
ˆ
127.92, 127.84 (Car), 124.68 (C CH), 115.61 (CH CH2), 66.70 (PhCH2),
52.29 (NCH), 52.00 (OCH3), 39.52, 33.52 (CH2), 13.16 (CH3); elemental
analysis calcd (%) for C18H23NO4 (317.4): C 68.12, H 7.30, N 4.41; found C
67.71, H 7.32, N 4.35; HRMS (FAB): C18H23NO4 [M‡H] : calcd 318.1705;
‡
ˆ
(q, J ˆ 7.2 Hz, 1H; C CH), 5.64 (d, J ˆ 7.5 Hz, 1H; NH), 5.01 (s, 2H;
found 318.1712.
PhCH2), 4.44 (ddd, J ˆ 7.3, 7.2, 5.7 Hz, 1H; NCH), 3.64 (s, 3H; OCH3), 2.88
(dd, J ˆ 14.1, 5.2 Hz, 1H; CH2), 2.78 (dd, J ˆ 14.5, 7.0 Hz, 1H; CH2), 1.47 (d,
J ˆ 7.2 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3): d ˆ 198.9 (ArCO), 171.6
Methyl
2-(benzyloxycarbonyl)amino-4-(o-bromobenzyl)-4-pentenoate
(17a): Coupling product 17a was obtained from 10a (220 mg, 0.4 mmol)
and o-bromobenzyl bromide (100 mg, 0.4 mmol) following the general
procedure for [Pd2(dba)3] ´ CHCl3 catalyzed reactions in THF. The reaction
mixture was refluxed for 5 h. The crude product was purified by flash
chromatography (hexanes/ethyl acetate 9:1) giving rise to 17a
(101 mg,0.23 mmol, 58%) as a pale yellow oil. Rf: 0.37 (hexanes/ethyl
acetate 8:2); 1H NMR (300 MHz, CDCl3): d ˆ 7.42 ± 7.20 (m, 9H; Har), 5.21
(d, J ˆ 8.1 Hz, 1H; NH), 5.13 (d, J ˆ 12.1 Hz, 1H; PhCH2O), 5.10 (d, J ˆ
ˆ
(CO), 155.5 (NCO), 136.9, 136.1 (Car), 135.2 (C CH), 133.1 (Car), 132.8
ˆ
(C CH), 129.0, 128.5, 128.2, 127.83, 127.76 (Car), 66.6 (PhCH2), 53.8 (NCH),
‡
52.0 (OCH3), 37.1 (CH2), 16.0 (CH3); HRMS (FAB): C22H23NO5 [M‡H] :
calcd 382.1655; found 382.1669.
Methyl 4-acetyl-2-(benzyloxycarbonyl)amino-4-pentenoate (19a): Ester
10a (220 mg, 0.4 mmol) and acetyl chloride (32 mg, 0.42 mmol) were
dissolved in acetonitrile (1 mL) under argon. [AllylPdCl]2 (4.0 mg,
11 mmol) was added to the solution, which turned black after 30 s. Usual
workup and purification of the crude product by flash chromatography
(hexanes/ethyl acetate 8:2) yielded 19a (84 mg, 0.28 mmol, 70%) as a
colorless oil. Rf: 0.08 (hexanes/ethyl acetate 8:2); 1H NMR (300 MHz,
ˆ
ˆ
12.1 Hz, 1H; PhCH2O), 4.90 (s, 1H; C CH2), 4.86 (s, 1H; C CH2), 4.53
(ddd, J ˆ 8.5, 8.1, 5.5 Hz, 1H; NCH), 3.72 (s, 3H; OCH3), 3.35 (s, 2H;
PhCH2), 2.52 (dd, J ˆ 14.3, 5.5 Hz, 1H; CH2), 2.32 (dd, J ˆ 14.3, 8.5 Hz, 1H;
CH2); 13C NMR (75 MHz, CDCl3): d ˆ 172.7 (CO), 155.8 (NCO), 143.6
ˆ
(C CH), 138.7, 136.1 (Car), 129.1, 128.6, 128.5, 128.2, 126.4 (Car), 115.7
ˆ
CDCl3): d ˆ 7.35 ± 7.33 (m, 5H; Har), 6.06 (s, 1H; C CH2), 5.86 (s, 1H;
ˆ
(C CH2), 67.0 (PhCH2), 52.3 (NCH), 52.0 (OCH3), 42.2, 38.4 (CH2);
ˆ
C CH2), 5.50 (d, J ˆ 7.9 Hz, 1H; NH), 5.08 (d, J ˆ 12.2 Hz, 1H; PhCH2),
HRMS (FAB): C21H2381BrNO4 [M‡H] : calcd 434.0790; found 434.0770.
‡
5.06 (d, J ˆ 12.2 Hz, 1H; PhCH2), 4.44 (m, 1H; NCH), 3.72 (s, 3H; OCH3),
2.81 (dd, J ˆ 13.6, 4.9 Hz, 1H; CH2), 2.63 (dd, J ˆ 13.6, 8.2 Hz, 1H; CH2),
2.30 (s, 3H; CH3); 13C NMR (75 MHz, CDCl3): d ˆ 199.5 (CH3CO), 172.1
Methyl 4-allyl-2-(benzyloxycarbonyl)amino-4-hexenoate (17b): Coupling
product 17b was obtained from crude 10b (181 mg, 0.32 mmol) and o-
bromobenzyl bromide (240 mg, 0.96 mmol) following the general proce-
dure for [Pd2(dba)3] ´ CHCl3 catalyzed reactions at 908C in toluene. The
crude product was purified by flash chromatography (hexanes/ethyl acetate
8:2) giving rise to 17b (53 mg, 0.12 mmol, 37%) as a pale yellow oil. Rf: 0.26
ˆ
ˆ
(CO), 155.7 (NCO), 144.1 (C CH2), 136.4 (Car), 128.7 (C CH2), 128.5,
128.1, 128.1 (Car), 66.9 (PhCH2), 53.5 (NCH), 52.4 (OCH3), 33.7 (CH2), 25.5
(CH3); elemental analysis calcd (%) for C16H19NO4 (305.3): C 62.94, H 6.27,
N 4.59; found C 62.66, H 6.29, N 4.47.
1
(hexanes/ethyl acetate 8:2); H NMR (300 MHz, CDCl3): d ˆ 7.53 (d, J ˆ
Methyl 2-(benzyloxycarbonyl)amino-4-iodo-4-pentenoate (20): Iodine (80 mg,
0.31 mmol), dissolved in CHCl3 (1 mL), was added to a solution of 10a
(166 mg, 0.3 mmol) in CHCl3 (0.5 mL). After 1 h saturated KF solution
(2 mL) and ethyl acetate (10 mL) were added. After vigorous stirring for
2 h the aqueous layer was removed and the organic layer was filtrated and
dried (Na2SO4). After evaporation of the solvent, the crude product was
purified by flash chromatography (hexanes/ethyl acetate 9:1). to yield a
pale yellow oil (110 mg, 0.28 mmol, 94%). Rf: 0.32 (hexanes/ethyl acetate
8:2); 1H NMR (300 MHz, CDCl3): d ˆ 7.37 ± 7.33 (m, 5H; Har), 6.10 (d, J ˆ
7.7 Hz, 1H; Har), 7.29 ± 7.40 (m, 5H; Har), 7.22 ± 7.02 (m, 3H; Har), 5.56 (q,
ˆ
J ˆ 6.8 Hz, 1H; C CH), 5.25 (d, J ˆ 7.4 Hz, 1H; NH), 5.12 (d, J ˆ 12.3 Hz,
1H; PhCH2O), 5.06 (d, J ˆ 12.3 Hz, 1H; PhCH2O), 4.42 (ddd, J ˆ 9.2, 8.5,
4.4 Hz, 1H; NCH), 3.73 (s, 1H; PhCH2), 3.68 (s, 3H; OCH3), 3.50 (s, 1H;
PhCH2), 2.44 (dd, J ˆ 13.6, 4.5 Hz, 1H; CH2), 2.21 (dd, J ˆ 14.3, 8.8 Hz, 1H;
CH2), 1.65 (d, J ˆ 6.7 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3): d ˆ 172.7
ˆ
(CO), 155.5 (NCO), 137.9, 136.1, 132.63 (Car), 131.9 (C CH), 129.4, 128.3,
ˆ
127.9, 127.9, 127.6, 127.2, 126.3 (Car), 124.9 (C CH), 66.7 (PhCH2O), 52.5
(NCH), 52.0 (OCH3), 39.4, 35.2 (CH2), 13.6 (CH3); elemental analysis calcd
(%) for C22H24NO4Br (446.34): C 59.20, H 5.42, N 3.14; found C 59.34, H
5.67, N 2.93.
ˆ
ˆ
0.7 Hz, 1H; C CH2), 5.84 (d, J ˆ 0.8 Hz, 1H; C CH2), 5.34 (d, J ˆ 7.7 Hz,
1H; NH), 5.13 (s, 2H; PhCH2), 4.58 (m, 1H; NCH), 3.78 (s, 3H; OCH3),
3.01 (dd, J ˆ 14.6, 4.8 Hz, 1H; CH2), 2.84 (dd, J ˆ 14.6, 7.7 Hz, 1H; CH2);
13C NMR (75 MHz, CDCl3): d ˆ 171.3 (CO), 155.6 (NCO), 136.2 (Car),
Methyl 4-benzoyl-2-(benzyloxycarbonyl)amino-4-pentenoate (18a): Ester
10a (220 mg; 0.4 mmol) and benzoyl chloride (58 mg; 0.42 mmol) were
dissolved in acetonitrile (2 mL) under argon. [AllylPdCl]2 (4.0 mg,
11 mmol) was added to the solution, which immediately turned yellow.
After 30 s the mixture turned black from precipitated palladium(0). TLC
control showed complete consumption of 10a. A saturated solution of KF
in H2O (10 mL) was added, and the mixture was vigorously stirred
overnight. The solution was extracted twice with diethyl ether and the
combined organic layers were washed with H2O. After drying (Na2SO4) and
evaporation of the solvent, the crude product obtained was dissolved in
ethyl acetate. The precipitated tin fluoride was filtered off and the residue
obtained after evaporation of the solvent was purified by flash chromatog-
raphy (hexanes/ethyl acetate 85:15) to yield a colorless oil (130 mg,
0.35 mmol, 88%). Rf: 0.17 (hexanes/ethyl acetate 8:2); 1H NMR (300 MHz,
CDCl3): d ˆ 7.69 (d, J ˆ 7.4 Hz, 2H; Har), 7.53 (m, 1H; Har), 7.43 (t, J ˆ
ˆ
ˆ
129.8 (C CH2), 128.5, 128.2, 128.1 (Car), 102.8 (C CH2), 69.1 (PhCH2), 53.3
(NCH), 52.6 (OCH3), 47.2 (CH2); elemental analysis calcd (%) for
C14H16INO4 (388.2): C 43.21, H 4.14, N 3.60; found C 43.38, H 4.15, N 3.51.
Methyl
2-(benzyloxycarbonyl)amino-7-hydroxy-4-methylene-5-hepte-
noate (21): [(MeCN)2PdCl2] (1.0 mg, 4 mmol, 5 mol%) was added to a
solution of (E)-3 (28 mg, 80 mmol) and 20 (31 mg, 80 mmol) in DMF (1 mL)
under argon. The mixture was heated to 808C for 2 h, followed by the usual
workup. The crude product was purified by flash chromatography
(hexanes/ethyl acetate 1:1) giving rise to 21 (19 mg, 60 mmol, 75%) as a
pale yellow oil. Rf: 0.26 (hexanes/ethyl acetate 1:1); 1H NMR (300 MHz,
ˆ
CDCl3): d ˆ 7.36 ± 7.26 (m, 5H; Har), 6.24 (d, J ˆ 15.8 Hz, 1H; CCH CH),
ˆ
5.92 (dt, J ˆ 15.8, 5.5 Hz, 1H; CH2CH C), 5.24 (d, J ˆ 5.1 Hz, 1H; NH),
ˆ
ˆ
5.11 (s, 1H; C CH2), 5.09 (s, 2H; PhCH2), 4.98 (s, 1H; C CH2), 4.55 (m,
1H; NCH), 4.20 (d, J ˆ 5.5 Hz, 2H; CH2OH), 3.73 (s, 3H; OCH3), 2.78 (dd,
J ˆ 14.0, 5.8 Hz, 1H; CH2), 2.58 (dd, J ˆ 14.0, 7.5 Hz, 1H; CH2), 1.96 (brs,
1H; OH); 13C NMR (75 MHz, CDCl3): d ˆ 172.4 (CO), 155.7 (NCO), 140.1
ˆ
7.4 Hz, 2H; Har), 7.34 ± 7.26 (m, 5H; Har), 5.97 (s, 1H; C CH2), 5.74 (s, 1H;
ˆ
C CH2), 5.71 (d, J ˆ 8.1 Hz, 1H; NH), 5.08 (d, J ˆ 12.1 Hz, 1H; PhCH2),
ˆ
ˆ
ˆ
5.05 (d, J ˆ 12.1 Hz, 1H; PhCH2), 4.53 (m, 1H; NCH), 3.70 (s, 3H; OCH3),
3.02 (dd, J ˆ 13.8, 5.5 Hz, 1H; CH2), 2.90 (dd, J ˆ 13.8, 8.0 Hz, 1H; CH2);
13C NMR (75 MHz, CDCl3): d ˆ 197.4 (ArCO), 172.0 (CO), 155.8 (NCO),
(C CH2), 136.2, 131.9, 128.5, 128.2, 128.1 (Car, CH CH), 119.0 (C CH2),
67.0 (PhCH2), 63.4 (CH2OH), 52.9 (NCH), 52.3 (OCH3), 35.5 (CH2);
elemental analysis calcd (%) for C17H21NO5 (319.4): C 63.94, H 6.63, N
4.39; found C 63.68, H 6.58, N 4.33.
ˆ
ˆ
143.0 (C CH2), 137.2, 136.4, 132.1 (Car), 130.2 (C CH2), 129.6, 128.5, 128.2,
Chem. Eur. J. 2001, 7, No. 2
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463

U. Kazmaier et al.
FULL PAPER
E. E. Yonan, M. E. Scaros, O. J. Goodmonson, D. P. Getman, R. A.
Periana, G. R. Beck, Synthesis 1992, 741 ± 743.
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Â
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Received: May 4, 2000 [F2464]
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