A ring-closing metathesis approach to cyclic α,β-dehydroamino acids

Article abstract of DOI:10.1002/adsc.200700308

A comprehensive study on the synthesis and ring-closing metathesis (RCM) of α,β-dehydroamino acids is described. This sequence has led to the formation of a range of biologically relevant functionalized nitrogen heterocycles. The incorporation of chiral b

Full text of DOI:10.1002/adsc.200700308

FULL PAPERS
DOI: 10.1002/adsc.200700308
A Ring-Closing Metathesis Approach to Cyclic a,b-Dehydro-
amino Acids
Koen F. W. Hekking,a Dennis C. J. Waalboer,a Marcel A. H. Moelands,a
Floris L. van Delft,a and Floris P. J. T. Rutjesa,*
a
Institute for Molecules and Materials, Radboud University Nijmegen, Toernooiveld 1, 6525 ED Nijmegen,
The Netherlands
Fax : (+31)-24-365-3393; e-mail: F.Rutjes@science.ru.nl
Received: September 9, 2007; Published online: November 23, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A comprehensive study on the synthesis dition, olefin isomerization under metathesis condi-
and ring-closing metathesis (RCM) of a,b-dehydro- tions was observed for a number of compounds,
amino acids is described. This sequence has led to which could be successfully inhibited either by the
the formation of a range of biologically relevant introduction of allylic substituents or by the addition
functionalized nitrogen heterocycles. The incorpora- of a ruthenium hydride scavenger.
tion of chiral building blocks in the RCM precursors
eventually resulted in the formation of optically Keywords: 1,4-benzoquinone; enamides; isomeriza-
active 4-substituted cyclic dehydroamino acids. In ad- tion; nitrogen heterocycles; olefin metathesis
Introduction
Non-proteinogenic a,b-dehydroamino acids are en-
countered in a range of natural products with impor-
tant biological activities.[1] Their occurrence in nature,
in combination with their interesting and diverse reac-
tivity, has inspired many chemists to develop method-
ology to synthesize dehydroamino acids and study
their behaviour.[2] Conceptually, a dehydroalanine
fragment consists of a double bond substituted with
both an electron-donating and an electron-withdraw-
ing group, similar to the a-alkoxyacrylate systems that
have previously been reported by us.[3] Since ring-clos- Scheme 1. Ring-closing metathesis of dehydroamino acids.
ing metathesis (RCM) of the latter systems appeared
to be a particularly versatile process and successful
RCM of regular enamides had already been devel- hydrogenation leads to the corresponding pipecolic
oped by our group,[4] we also set out to investigate the acid derivatives, which are key structural elements in
metathesis behaviour of dehydroamino acids.[5] Initial- a range of natural products and pharmaceutically
ly, our efforts were focused on the generation of ni- active compounds.[6] One of the most relevant classes
trogen heterocycles 1 from the corresponding precur- is the family of 4-substituted pipecolic acids, which
sors 2 via RCM. If the formation of such model sys- constitute key structural elements in a number of
tems would be successful, this methodology could be pharmaceutically relevant compounds (Figure 1). For
applied to more complex systems, eventually resulting instance, 4-alkyl-substituted pipecolic acids are con-
in functionalized cyclic dehydroamino acids
(Scheme 1).
3
stituents of Argatroban, a potent inhibitor of the
enzyme thrombin,[7] and the selective trypsin inhibitor
Besides the introduction of R substituents, building MNAPPA.[8] Moreover, 4-O-substituted pipecolic
blocks of type 3 possess a double bond representing a acids have been applied in a number of biologically
useful handle for further functionalization. First of all, active compounds, such as the potent HIV-1 protease
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Figure 1. Therapeutically relevant agents incorporating a 4-substituted pipecolic acid moiety.
inhibitors Palinavir[9] and analogues thereof.[10] Finally, pared to regular protected amines. Reacting 4 with 4-
dehydroamino acids are reasonably reactive in, for in- bromo-1-butene (6a) and 5-bromo-1-pentene (6b) re-
stance, Michael additions, radical additions and cyclo- sulted in the formation of RCM precursors 7a and 7b
additions, opening up possibilities for further func- in yields of 49 and 59%, respectively. Alkylation of
tionalization at the 2- and 3-positions.[2]
Boc-protected 5 with 6b proceeded slightly better and
the corresponding product 8 was isolated in 74%
yield. In addition, the aromatic iodide 9[13] was cou-
pled with 4, resulting in precursor 10 (Scheme 2).
With four precursors in hand, the stage was set for
Results and Discussion
We envisaged that the preparation of dehydroamino investigation of the behaviour of these systems under
acid-based RCM precursors could in principle be car- metathesis conditions. The RCM reactions were per-
ried out using a protected dehydroalanine fragment formed in toluene at 808C, using 10 mol% of the 2nd
as building block. Conversion into an RCM precursor generation Grubbs catalyst (A, Scheme 3). Gratifying-
is then performed through N-alkylation of the dehy- ly, cyclization of 7a proceeded smoothly, resulting in
droalanine with, for instance, an alkyl halide. Regard- the formation of five-membered heterocycle 11 in a
ing the dehydroalanine building blocks, we focused yield of 78%. In contrast, in the reaction of 7b and 8
our attention on a Ts- as well as a Boc-protected scaf- under identical conditions multiple products were
fold (i.e., 4[11] and 5,[12] Scheme 2). The N-alkylations formed, none of which could be separated by column
of 4 and 5 were performed at room temperature in chromatography. According to LC-MS measurements
DMF, using NaH as a base. Reactions with K2CO3/ on the crude mixture the desired six-membered rings
acetone and Et3N/DMF did not show any conversion, had not been formed. The analyses did, however,
illustrating the somewhat reduced nucleophilicity of show masses corresponding to dimeric species of dif-
the nitrogen in these dehydroamino acids, as com- ferent lengths, as well as masses that corresponded to
Scheme 2. Synthesis of RCM precursors via alkylation of
protected dehydroalanine methyl esters.
Scheme 3. RCM-mediated generation of five- and six-mem-
bered ring heterocycles.
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A Ring-Closing Metathesis Approach to Cyclic a,b-Dehydroamino Acids
FULL PAPERS
the five-membered ring analogues. This suggests that
olefin isomerization had taken place, followed by cy-
clization, resulting in the formation of a smaller ring.
Furthermore, homodimerization/cross-metathesis be-
tween 7b or 8 and their isomerized forms probably
explains the observation of several dimers. In addi-
tion, reaction of 8 with the first generation Grubbs
catalyst [(PCy3)2Cl2Ru=CHPh] yielded exclusively
the corresponding homodimer. This behaviour, in-
cluding the isomerization, is comparable to that ob-
served during earlier work by our group on the RCM
of a-alkoxyacrylates.[3]
Interestingly, ring-closing metathesis of 10 proceed-
ed without problems in a yield of 79%. Apparently,
the impossibility of isomerization of 10 in combina-
tion with a constrained geometry eliminates all side
reactions. Thus, formation of six-membered cyclic de-
hydroamino acids by RCM can indeed occur, if unde-
sired side reactions can be overcome.
Scheme 4. Synthesis of allylically substituted RCM precur-
sors.
During our work on the ring-closing metathesis of
carbohydrate-derived a-alkoxyacrylates, we found
that the presence of allylic substituents in the sub-
strate completely inhibited olefin isomerization.[3] In
Scheme 5. RCM of allylically substituted dehydroamino
view of the disappointing metathesis behaviour of acid-based precursors.
compounds 7b and 8, we decided to investigate the in-
fluence of allylic methyl and phenyl substituents on
the formation of six-membered cyclic dehydroamino
acids via RCM. This required the synthesis of substi- phy – for example, flushing over silica and stirring
tuted halides 15 and 16, which can then be used in the with activated carbon[15] – solved this problem and re-
alkylation of the protected dehydroalanine derivative sulted in the isolation of a stable product.
(Scheme 4).
Since a small allylic substituent is apparently suffi-
Methyl-substituted 15 was prepared from commer- cient to facilitate the ring-closing metathesis of dehy-
cially available carboxylic acid 13 by reduction with droamino acids and to prevent olefin isomerization,
LiAlH4 and subsequent iodination. Ester 14 – ob- we decided to investigate whether the scope of this
tained by Claisen rearrangement of cinnamyl alco- reaction could be extended to O-substituted sub-
hol[14] – was transformed into the corresponding strates. These allylic ethers are notorious for their iso-
iodide 16 by the same reduction/iodination procedure. merization behaviour, because they can easily form
The alkylation of 5 was performed under the same the corresponding enol ether, or, in case of allylic al-
conditions as described earlier, using DMF and NaH. cohols, the ketone or aldehyde.[16] We decided to
Thus, RCM precursors 17 and 18 were synthesized in focus on substrates containing three protected alco-
yields of 77 and 64% (Scheme 4).
hols as substituents, all possessing distinct differences
In sharp contrast to the metathesis behaviour of 7b in steric bulk. The mutual starting point for the three
and 8, the cyclization of substituted precursors 17 and RCM-precursors was hydroxy ester 21.[17] The alcohol
18 proceeded smoothly and six-membered heterocy- function in 21 was transformed into three different
cles 19 and 20 could be isolated in yields of 81 and side groups, using standard procedures, resulting in
85% (Scheme 5). No traces of side products were ob- the MOMO-, TBSO- and MeO-substituted esters 22–
served, which is surprising in both cases. First of all, it 24 (Scheme 6).
is striking that a single methyl substituent in 17 is ap-
Conversion of the esters into the corresponding io-
parently sufficient to prevent side reactions. Further- dides was performed using the same conditions as de-
more, 18 was expected to be prone to olefin isomeri- scribed earlier, involving sequential reduction/iodina-
zation due to the position of the phenyl substituent, tion. The reduction of 23 with LiAlH4 was accompa-
however, this is clearly not the case. Finally, it should nied by removal of the TBS group, which is a known
be mentioned that compound 19 appeared to be fairly problem for TBS-protected b-hydroxy esters.[18] Using
labile. We found that degradation was caused by DIBALH as a reducing agent left the OTBS group
ruthenium residues, which remained in the product, intact, but resulted in a somewhat lower overall yield
even after careful column chromatography. Addition- of 26 (48%), compared to those of 25 (62%) and 27
al work-up procedures prior to column chromatogra- (70%). Finally, the coupling of 25–27 to 5 using NaH/
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Scheme 6. Synthesis of O-substituted RCM precursors;[a] DIBALH was used for the reduction instead of LiAlH4.
DMF proceeded as expected, yielding the RCM pre-
cursors 28–30 in 64–76% (Scheme 6).
The ring-closing metathesis was again carried out in
toluene at 808C, using 10 mol% of catalyst A. In all
cases the expected cyclic products (31–33) were
formed in yields of 27–59%, however, together with
significant amounts of non-cyclic isomerized starting
material (34–36, Scheme 7). The resulting enol ethers
are apparently not cyclized by the catalyst, judging
from the absence of smaller ring products. Although
the isolated amount of isomerized product was com-
parable (31–45%) for all three substrates, the yield of
cyclized product varied considerably. The TBSO-func-
tionalized heterocycle 32 was isolated in an accepta-
ble yield of 59%, whereas 31 and 33 were formed in
yields of 27 and 43%, respectively.
Figure 2. Conditions: 30 in C6D6 (5 mm), A (10 mol%),
708C. Values are based on H NMR.
1
In order to gain more insight into the underlying
mechanism for the observed isomerization of allylic
ethers, we decided to monitor the conversion in time
Figure 2 clearly shows that the formation of the in-
1
by H NMR. A 5.0 mM solution of the MeO-substitut- tended product 33 stops at a certain point in time,
ed precursor 30 and catalyst A (10 mol%) in C6D6 while the formation of 36 continues until all starting
was heated to 708C and a sample was measured every material has been consumed. This observation clearly
20 min (Figure 2).
points to a hydride-based mechanism, suggesting that
the metathesis catalyst decomposes quickly, resulting
in a ruthenium hydride species.[16a,c,19] This compound
is presumably responsible for converting the remain-
ing starting material into the isomerized side-product.
Furthermore, it is important to note that the isomeri-
zation is apparently more favoured in deuterated ben-
zene than in toluene. The final ratio between 33 and
36 was 1:5.7 in benzene-d6, whereas it was only 1:0.7
in toluene. This is not completely unexpected, since it
is known that the generation of a ruthenium hydride
species from catalyst A occurs readily in benzene.[19]
The use of a number of different solvents and addi-
tives that have been reported to influence isomeriza-
tion during olefin metathesis[20] was not particularly
[21b]
successful. THF[21a] and CHCl3
as a solvent com-
pletely inhibited metathesis, as did adding Ph3P=O[22a]
Scheme 7. RCM and isomerization of allylic ether frag-
ments;[a] mixture of E/Z-isomers.
and (PhO)P(O)(OH)2.[22b] Ring-closing metathesis in
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A Ring-Closing Metathesis Approach to Cyclic a,b-Dehydroamino Acids
Table 1. RCM in the presence of 1,4-benzoquinone.
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Entry Substrate
R
Cyclized product Yield [%][a] Isomerized product Yield [%][a] Starting material [%][a]
1
2
3
4
28
29
30
8[c]
OMOM 31
75
58
34[b]
35[b]
36[b]
n.a.
3
1
0
n.a.
22
41
38
2
OTBS
OMe
H
32
33
37
62
98[d]
[a]
[b]
[c]
[d]
1
Yields based on H NMR.
Mixture of E/Z-isomers.
Reaction time was 1 h.
Isolated yield was 94%.
(i-OPr)4[23] did proceed, but unfortu- (Scheme 3). Although a complex mixture of products
the presence of TiACHTREUNG
nately the outcome was not influenced in a positive was formed in that original attempt, the current re-
manner: 33 and 36 were formed in yields of 37 and sults suggest that the cause for those observations is
42%, respectively.
probably hydride-based.
Very recently, Grubbs and co-workers reported that
As already pointed out in the introduction, cyclic
the addition of certain metal hydride scavengers can dehydroamino acids substituted at the allylic position
prevent isomerization during olefin metathesis. For in- may represent valuable intermediates en route to 4-
stance, catalytic amounts of benzoquinones or organic substituted pipecolic acid derivatives. While the heter-
acids completely inhibited olefin isomerization during ocyclic products prepared so far are racemic, the
the RCM of diallyl ether in CD2Cl2 at 408C.[24] De- enantiomerically pure analogues would be more
spite the fact that the RCM of dehydroamino acids is useful as synthetic building blocks. If a similar RCM-
typically carried out in toluene and at elevated tem- based retrosynthetic approach to these compounds is
peratures, we decided to investigate the influence of to be followed – that is, alkylation of a protected de-
1,4-benzoquinone on the isomerization of the allylic hydroalanine and subsequent cyclization by RCM – a
ether moieties under these circumstances.
general procedure for the synthesis of enantiomeri-
Entries 1–3 in Table 1 clearly show that the addition cally pure iodides 38 is required. We envisioned that
of 20 mol% of 1,4-benzoquinone almost completely carboxylic acids 40 are useful precursors for these io-
inhibited isomerization of the allylic ether fragments dides. Because carboxylic acids can be selectively re-
of all three substrates. Cyclic products 31–33 were duced in the presence of esters, it should be possible
1
formed in yields of 58–75%, according to H NMR. It to convert the carboxylic acid function of 40 into a
should be noted that the addition of the quinone does double bond prior to transforming the methyl ester
not necessarily increase the absolute yield, as is illus- into the corresponding iodide 38 (Scheme 8).
trated by the yield of 58% for 32, compared to 59%
The carboxylic acids 40 were available via asym-
in the absence of the quinone (Scheme 7). This can be metric hydrogenation of functionalized itaconic acid
explained by the fact that the additive scavenges the monoesters 41. Four carboxylic acids (40a–d; R=H,
decomposition product (e.g., the ruthenium hydride), Et, Ph, p-MeOC6H4) were synthesized on a prepara-
but does not inhibit catalyst decomposition itself. Pos- tive scale via this method, details on these investiga-
sibly, both cyclization and catalyst decomposition are tions are reported separately in the preceding paper
relatively fast for the reaction of 29, meaning that a in this issue.[25] The selected route from the monoacids
certain amount of substrate is rapidly cyclized 40a–d to the corresponding olefinic iodides 38a–d in-
anyway, before isomerization gets the upper hand.
volved selective reduction of the carboxylic acids with
The encouraging results of these experiments BH3·SMe2, followed by oxidation to the aldehyde
prompted us to test the unsubstituted precursor 8 using trichloroisocyanuric acid (TCCA) and
under the same conditions. Surprisingly, reaction of 8 TEMPO.[26] Subsequent Wittig reaction of the crude
with A in the presence of 1,4-benzoquinone resulted aldehydes resulted in the olefinic esters 39, which
in a nearly quantitative conversion into the desired were purified by column chromatography. Next, the
six-membered ring 37 (entry 4), whereas without 1,4- ester groups were converted into the corresponding
benzoquinone no trace of this product was observed iodides by subsequent reduction with LiAlH4 and io-
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and 60% yields over three steps (Scheme 9). Howev-
er, a setback was that the ee dropped to 75 and 85%
for 39a and b, respectively. This partial racemization
possibly occurs in the Wittig reaction, due to the ba-
sicity of the phosphonium ylide. Finally, 39a and b
were reduced with LiAlH4 in THF followed by iodi-
nation with I2/PPh3, resulting in iodides 38a and b in
yields of 86 and 78% over two steps.
The synthesis of 39c from 40c proceeded in a simi-
lar yield as observed for 39a and b (61% over 3
steps), however, application of this synthetic route to
40d proved to be problematic (Scheme 10). After re-
duction of the carboxylic acid function of 40d, oxida-
tion of the alcohol to the corresponding aldehyde
with TCCA/TEMPO resulted in multiple products,
presumably due to overoxidation at, for instance, the
benzylic position. Thus, we were forced to apply a dif-
ferent oxidation method. Reaction of the alcohol with
TPAP/NMO in acetone produced a single aldehyde
and subsequent Wittig olefination resulted in 39d in
an overall yield of 58%. Moreover, a small amount of
racemization was again observed for both 39c and d
and the compounds were isolated with ees of 84 and
83%, respectively. Finally, transformation of 39c and
d into the corresponding olefinic iodides proceeded as
expected, resulting in the isolation of 38c and d in 80
and 88% yields over two steps.
Scheme 8. Retrosynthetic approach to optically active iodide
building blocks.
With the four desired unsaturated iodides in hand,
the stage was set for the synthesis of the correspond-
ing RCM precursors. Similar to the synthesis of the
racemic precursors (see above) 42a–d were prepared
Scheme 9. Transformation of hydrogenation products into
unsaturated iodides.
dination of the crude alcohol with I2/PPh3/imidazole. by alkylation of protected dehydroalanine
5
The syntheses of 39a and b via this route proceeded (Scheme 11).
well, resulting in isolation of the two products in 56
Scheme 10. Synthesis of aryl-substituted iodides.
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Conclusions
Ring-closing metathesis of dehydroamino acids was
found to proceed readily and therefore represents a
suitable method for the preparation of a range of
five- and six-membered nitrogen heterocycles. Olefin
isomerization of allylic ether fragments in the starting
materials initially gave considerable problems in the
formation of 4-O-substituted cyclic dehydroamino
acids. However, the addition of a catalytic amount of
1,4-benzoquinone as a hydride scavenger almost com-
pletely inhibited this side reaction. Even an attempted
cyclization in which a complex mixture of products
was formed could be optimized by the addition of 1,4-
benzoquinone, suggesting that ruthenium hydrides are
indeed responsible for most, if not all of the observed
side products.
Scheme 11. Preparation of optically active RCM precursors.
Finally, the use of enantiomerically enriched build-
ing blocks – obtained by asymmetric hydrogenation
The alkylations were performed using the opti- of itaconic acid monoesters – resulted in the forma-
mized conditions described above. Deprotonation of 5 tion of optically active 4-substituted cyclic dehydro-
at room temperature in DMF using NaH as a base amino acids. These substituted heterocycles present a
and subsequent addition of the appropriate iodide re- useful class of synthetic building blocks, given that the
sulted in the formation of RCM precursors 42a–d in dehydroamino acid double bond opens up possibilities
satisfactory yields of 58–77%.
for further functionalization and thereby the genera-
Finally, we were pleased to find that ring-closing tion of highly functionalized, biologically relevant
metathesis of olefins 42a–d proceeded readily. Reac- products.
tion of these compounds with the second generation
Grubbs catalyst (A) in toluene at 808C for 4 h result-
ed in the formation of the functionalized cyclic dehy-
droamino acids 43a–d in excellent yields of 81–90%
(Scheme 12). Determination of the ees of the hetero-
cyclic products by chiral HPLC led to the conclusion
Experimental Section
that no significant racemization had taken place in
the four-step conversions of 39a–d to 43a–d.
General
All reactions were carried out under an atmosphere of dry
argon, unless stated otherwise. Argon was dried over SICA-
PENTꢁ, CaCl2 and KOH. Infrared (IR) spectra were ob-
tained using an ATI Mattison Genesis Series FTIR spec-
trometer and wavelengths (n) are reported in cmꢀ1. Optical
rotations were measured on a Perkin–Elmer 241 polarime-
ter, using concentrations (c) in g/100 mL in the indicated
solvents. 1H and 13C nuclear magnetic resonance (NMR)
spectra were determined in CDCl3, unless indicated other-
wise, using a Bruker DMX200 (200 MHz) or a Bruker
DMX300 (300 MHz) spectrometer. Chemical shifts (d) are
given in ppm downfield from tetramethylsilane. HR-MS
measurements were carried out using a Fisons (VG) Micro-
mass 7070E or a Finnigan MAT900S instrument. Column
chromatography was performed with Acros Organics silica
gel (0.035ꢁ0.070 nm) or Merck silica gel 60 (0.040–
0.063 mm). THF and Et2O were distilled over sodium. Tolu-
ene was distilled before use and deoxygenated using the
freeze-pump-thaw method. Et3N was distilled and stored
over KOH. Unless stated otherwise, all commercially avail-
able reagents were used as received. Compounds 4,[11] 5,[12]
9,[13] 16[14] and 21[17] were synthesized according to literature
Scheme 12. Ring-closing metathesis of optically active dehy-
procedures. Analytical and spectroscopic data can be found
droamino acids.
in the Supporting Information.
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General Procedure A for the Alkylation of N-Ts-
5-Iodo-3-methylpent-1-ene (15)
Protected Dehydroalanine Methyl Ester 4
To a cooled (08C) suspension of LiAlH4 (1.00 g, 26,3 mmol)
in Et2O (60 mL), was added a solution of methyl 3-methyl-
pent-4-enoic acid (13) in Et2O (15 mL). After stirring at
room temperature for 24 h, the reaction mixture was poured
over ice and the remaining salts were dissolved with H2SO4
(5M, 15 mL). The layers were separated and the organic
layer washed with H2O (15 mL). The combined aqueous
layers were washed with Et2O (2”20 mL). The solvents
were evaporated, yielding the corresponding alcohol as a
colorless liquid; yield: 1.20 g (90%). Analytical data were
agreement with reported values.[27]
A solution of 4 in DMF (~0.03M) was cooled to 08C and
NaH (60% dispersion in mineral oil, 1.5 equivs.) was added.
The resulting solution was stirred at 08C for 15 min. Next,
the alkyl halide (2 equivs.) was added, the solution was
warmed to 608C and stirred for 3 h. Saturated NH4Cl was
added and the mixture was extracted with pentane (3”).
The organic layers were dried (MgSO4) and concentrated
under vacuum. The product was purified by column chroma-
tography (EtOAc/heptane/Et3N, 10:90:1).
Next, the reaction mixture was cooled to 08C and a solu-
tion of iodine (2.64 g, 10.4 mmol) in CH2Cl2 (60 mL) was
added. The reaction mixture was stirred at room tempera-
ture for 45 min. The mixture was washed with a 10%
Na2SO3 solution (3”20 mL), H2O (20 mL) and brine
(20 mL). The organic layer was dried with Na2SO4 and the
solvents were removed under vacuum. The crude product
was purified by column chromatography (100% pentane) to
give 15 as a colorless liquid; yield: 1.38 g (82%). Analytical
data agreed with those reported in the literature.[28]
Methyl 2-[tert-butoxycarbonyl(3-methylpent-4-enyl)ami-
no]acrylate (17): This compound was synthesized from 5
and 15, following general procedure B; colorless oil; yield:
553 mg (77%).
General Procedure B for the Alkylation of N-Boc-
Protected Dehydroalanine Methyl Ester 5
A solution of 5 in DMF (~0.1M) was cooled to 08C and
NaH (60% dispersion in mineral oil, 1.3 equivs.) was added.
The resulting solution was stirred at 08C for 15 min and at
room temperature for 30 min. Next, the reaction was cooled
to 08C, followed by addition of the alkyl halide (2 equivs.).
The solution was allowed to warm to room temperature and
stirred for 2 h. Saturated NH4Cl was added and the mixture
was extracted with pentane (3”). The organic layers were
dried (Na2SO4) and concentrated under vacuum. The crude
product was purified by column chromatography (EtOAc/
heptane, 1:10).
Methyl
2-[N-(but-3-enyl)-4-methylphenylsulfonamido]-
Methyl 2-[tert-butoxycarbonyl(3-phenylpent-4-enyl)ami-
no]acrylate (18): This compound was synthesized from 5
and 16, following general procedure B; colorless oil; yield:
281 mg (64%).
acrylate (7a): This compound was synthesized from 4 and
bromo-1-butene, following general procedure A; yield:
29.4 mg (49%).
Methyl 2-[4-methyl-N-(pent-4-enyl)phenylsulfonamido]-
acrylate (7b): This compound was synthesized from 4 and 5-
bromo-1-pentene, following general procedure A; yield:
37.5 mg (59%).
Methyl 2-[tert-butoxycarbonyl(pent-4-enyl)amino]acrylate
(8): This compound was synthesized from 5 and 5-bromo-1-
pentene, following general procedure C. A catalytic amount
of LiI (5 mg, 0.037 mmol) was used as an additive; pale
yellow oil; yield: 122 mg (74%).
1-tert-Butyl
2-methyl
4-methyl-5,6-dihydropyridine-
1,2(4H)-dicarboxylate (19): This compound was prepared
from 17, following general procedure C, at 608C; yield:
22.2 mg (81%). Additional work-up was required in order
to prevent degradation of the product over time. The prod-
uct was stirred overnight with activated carbon to remove
any ruthenium residues, after which the solvent was evapo-
rated and the product purified by column chromatography
(EtOAc/heptane, 1:40) to give 19; yield: 18.4 mg (67%).
Methyl
2-[4-methyl-N-(2-vinylbenzyl)phenylsulfonami-
1-tert-Butyl
2-methyl
4-phenyl-5,6-dihydropyridine-
do]acrylate (10): This compound was synthesized from 4
and 9, following general procedure A; yield: 13.8 mg (22%).
1,2(4H)-dicarboxylate (20): This compound was prepared
from 18, following general procedure C, at 808C; colorless
oil; yield: 11.3 mg (85%).
General Procedure C for Ring-Closing Metathesis of
Dehydroamino Acids
Ethyl 3-(Methoxymethoxy)pent-4-enoate (22)
DIPEA (4.8 mL, 27.6 mmol) was added to a solution of
21[17] (0.197 g, 1.37 mmol), chloromethyl methyl ether
(1.06 mL, 13.96 mmol) and TBAI (51 mg, 0.14 mmol) in
CH2Cl2 (35 mL) at 08C. The reaction mixture was protected
from light and allowed to warm to room temperature. After
stirring for 18 h, saturated NaHCO3 (10 mL) and Et2O
(5 mL) were added. The organic layer was washed with
brine (10 mL) and the aqueous layers were washed with
CH2Cl2 (2”10 mL). The combined organic layers were dried
with NaSO4 and the solvents were evaporated under
vacuum. Column chromatography (EtOAc/heptane, 1:10) af-
forded 22 as a pale yellow liquid; yield: 249 mg (97%).
A solution of the substrate in toluene (~5 mM) was stirred
under an inert atmosphere. Catalyst A (10 mol%) was
added and the reaction mixture was stirred at the specified
temperature. When TLC indicated that the reaction was
complete, the mixture was concentrated under vacuum. The
product was purified by column chromatography (EtOAc/
heptane, 1:10).
Methyl 1-tosyl-4,5-dihydro-1H-pyrrole-2-carboxylate (11):
This compound was prepared from 7a, following general
procedure B, at 808C; yield: 20.7 mg (78%).
Methyl 2-tosyl-1,2-dihydroisoquinoline-3-carboxylate (12):
This compound was prepared from 10, following general
procedure B, at 808C; yield: 7.3 mg (79%).
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FULL PAPERS
5-Iodo-3-methoxypent-1-ene (27): This compound was
prepared from 24, following general procedure D; colorless
liquid; yield: 586 mg (70% over 2 steps).
Methyl 2-{tert-butoxycarbonyl[3-(methoxymethoxy)pent-
4-enyl]amino}acrylate (28): This compound was synthesized
from 5 and 25, following general procedure B; colorless oil;
yield: 157 mg (76%).
Methyl 2-{tert-butoxycarbonyl[3-(tert-butyldimethylsilyl-
oxy)pent-4-enyl]amino}acrylate (29): This compound was
synthesized from 5 and 26, following general procedure B;
colorless oil; yield: 131 mg (66%).
Methyl 2-[tert-butoxycarbonyl(3-methoxypent-4-enyl)ami-
no]acrylate (30): This compound was synthesized from 5
and 27, following general procedure B; colorless oil; yield:
394 mg (64%).
Ethyl 3-(tert-Butyldimethylsilyloxy)pent-4-enoate (23)
To a stirred solution of 21[17] (1.00 g, 3.87 mmol) and imida-
zole (527 mg, 7.74 mmol) in CH2Cl2 (20 mL) at 08C was
added TBSCl (1.17 g, 7.74 mmol). After 15 min the reaction
mixture was warmed to room temperature and stirred over-
night. Saturated NaHCO3 (5 mL) was added and the organic
layer was extracted with H2O (10 mL) and brine (10 mL).
After removing the solvent under vacuum, the crude prod-
uct was purified by Kugelrohr distillation to afford 23 as a
colorless liquid; yield: 1.79 g (99%). Analytical data agreed
with those reported in literature.[29]
Ethyl 3-Methoxypent-4-enoate (24)
Powdered NaOH (0.613 g, 15.3 mmol) was added to a solu-
tion of 21[17] (1.49 g, 10.4 mmol) and MeI (1.3 mL,
20.9 mmol) in DMSO (5 mL) at 08C. After stirring for 2 h
an additional amount of NaOH (0.330 g, 8.45 mmol) and
MeI (1.3 mL, 20.9 mmol) were added an the reaction mix-
ture was allowed to warm to room temperature. After 2 h
the reaction mixture was diluted with H2O (20 mL), and ex-
tracted with pentane (4”10 mL). The organic layer was
dried (Na2SO4) and the solvents removed under vacuum.
The crude product was purified by column chromatography
(100% pentane!Et2O/pentane, 1:20) to give 24 as a color-
less liquid; yield: 692 mg (42%).
General Procedure E for Ring-Closing Metathesis of
8, 28–30
A solution of the substrate in toluene (~3 mm) was stirred
under an inert atmosphere at 808C. Catalyst A (5 mol%)
was added and the reaction mixtuire was stirred at 808C for
1 h. Next, a second portion of A (5 mol%) was added and
the reaction mixture was stirred overnight at 808C. The sol-
vent was evaporated and the crude product purified by
column chromatography (EtOAc/heptane, 1:20).
1-tert-Butyl 2-methyl 4-(methoxymethoxy)-5,6-dihydro-
pyridine-1,2(4H)-dicarboxylate (31): This compound was
prepared from 28, following general procedure E. Product
31 was isolated as a colorless oil; yield: 24.4 mg (27%).
Compound 34 (1.4:1) was isolated as a side product; yield:
44.5 mg (45%).
General Procedure D for the Transformation of Ethyl
Esters in Iodides 25–27
To a suspension of LiAlH4 (1.3 equivꢂs.) in Et2O at 08C was
added a solution of the ethyl ester in Et2O. The reaction
mixture was warmed to room temperature and stirred for
15 min, after which it was cooled to 08C and H2O was
added. To dissolve the remaining salts H2SO4 (1M) was
added and the mixture was stirred for 30 min. The organic
layer was separated and the water layer exhaustively ex-
tracted with Et2O. The organic layer was dried with MgSO4
and concentrated under vacuum. The resulting alcohol was
purified by column chromatography (Et2O/pentane). The al-
cohol was dissolved in CH2Cl2 and PPh3 (1.3 equivs.) and
imidazole (1.5 equivs.) were added. The reaction mixture
was cooled to 08C and a solution of iodine (1.3 equivs.) in
CH2Cl2 was added. After 30 min the reaction mixture was
warmed to room temperature and stirred for 1.5 h. Next, the
mixture was extracted with a 10% Na2SO3 solution (3”),
H2O and brine. The organic layer was dried with Na2SO4
and the solvents were evaporated under vacuum. The crude
product was purified by column chromatography (Et2O/pen-
tane).
1-tert-Butyl 2-methyl 4-(tert-butyldimethylsilyloxy)-5,6-di-
hydropyridine-1,2(4H)-dicarboxylate (32): This compound
was prepared from 29, following general procedure E. Prod-
uct 32 was isolated as a colorless oil; yield: 6.9 mg (59%).
Compound 35 (2.1:1) was isolated as a side product; yield:
4.3 mg (34%).
1-tert-Butyl 2-methyl 4-methoxy-5,6-dihydropyridine-
1,2(4H)-dicarboxylate (33): This compound was prepared
from 30, following general procedure E. Product 33 was iso-
lated as a colorless oil; yield: 13.1 mg (43%). Compound 36
(3.1:1) was isolated as a side product; yield: 10.4 mg (31%).
1-tert-Butyl 2-Methyl 5,6-dihydropyridine-1,2(4H)-
dicarboxylate (37)
To a solution of 8 (10.1 mg, 37.5 mmol) in toluene (8 mL)
and 1,4-benzoquinone (0.8 mg, 20 mol%) was added A
(3.2 mg, 10 mol%). The reaction mixture was stirred at
808C for 1 h, after which 1H NMR of the crude mixture
showed a conversion of 98%. Next, the solvent was evapo-
rated and the product was purified by column chromatogra-
phy (EtOAc/heptane, 1:10); colorless oil; yield: 8.5 mg
(94%).
5-Iodo-3-(methoxymethoxy)pent-1-ene (25): This com-
pound was prepared from 22, following general procedure
D; colorless liquid; yield: 469 mg (62% over 2 steps).
tert-Butyl(5-iodopent-1-en-3-yloxy)dimethylsilane
(26):
This compound was prepared from 23, following general
procedure D. DIBALH was used instead of LiAlH4 in the
reduction step. Work-up after this step was carried out by
pouring the mixture into a cold HCl solution, separating the
organic phase, extracting the aqueous phase with Et2O and
concentrating the combined organic phases; colorless liquid;
yield of 26: 205 mg (48% over 2 steps).
General Procedure F for the Preparation of Olefins
39a–d
To a cooled (ꢀ208C) solution of carboxylic acid 40 in THF
was added BH3·Me2S (2 equivs.). The mixture was stirred at
room temperature for 3 h and MeOH was added. The sol-
vents were removed under vacuum and this procedure was
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FULL PAPERS
repeated twice. The resulting crude alcohol was dissolved in
CH2Cl2 and cooled to 08C. Next, trichloroisocyanuric acid
(1 equiv.) and TEMPO (0.01 equiv.) were added and the re-
action mixture was stirred while warming to room tempera-
ture. After 30 min the mixture was filtered over Celite and
washed with H2O and 1N HCl. The organic layer was con-
centrated, yielding the crude aldehyde. Next, Ph3PMeBr
(1.1 equivs.) was suspended in THF and cooled to ꢀ788C.
NaHMDS (2M solution, 1.0 equiv.) was added and the mix-
ture was stirred while warming to room temperature. After
1 h the solution was again cooled to ꢀ788C and a solution
of the aldehyde was added. The reaction mixture was stirred
at room temperature for 18 h, after which saturated NH4Cl
was added. The aqueous layer was extracted with pentane
and the organic layer was dried with NaSO4 and concentrat-
ed. The resulting olefinic product 39 was purified by column
chromatography (Et2O/pentane, 1:20).
(S)-Methyl 3-methylpent-4-enoate (39a): This compound
was prepared from 40a according to general procedure F;
yield: 270 mg (56%). The ee was determined by GC to be
75% (Supelco GammaDEX 120 column; 508C isothermal).
The analytical data agreed with those reported in the litera-
ture.[30]
(S)-Methyl 3-vinylhexanoate (39b): This compound was
prepared from 40b according to general procedure F; yield:
101 mg (60%). The ee was determined by GC to be 85%
(Chiraldex G-TA column; 658C isothermal).
(R)-Methyl 3-benzylpent-4-enoate (39c): This compound
was prepared from 40c according to general procedure F;
yield: 76 mg (61%). The ee was determined by HPLC to be
84% (Chiralcel OD-H column; hexane/2-propanol, 97:3).
The analytical data agreed with those reported in the litera-
ture.[31]
(R)-Methyl 3-(4-methoxybenzyl)pent-4-enoate (39d): This
compound was prepared from 40d according to general pro-
cedure F, using modified oxidation conditions. The crude al-
cohol was dissolved in acetone and NMO (1.1 equivs.) and
TPAP (1 mol%) were added. The reaction mixture was
stirred at room temperature for 2 h, after which it was fil-
tered over Celite and flushed over a short silica column.
The solvent was evaporated, yielding the crude aldehyde,
which was used in the next step: overall yield of 39d: 62 mg
(58%). The ee was determined by HPLC to be 83% (Chir-
alcel OD-H column; hexane/2-propanol, 99.6:0.4).
vacuum. The product was purified by column chromatogra-
phy (100% pentane).
(S)-5-Iodo-3-methylpent-1-ene (38a): This compound was
prepared from 39a according to general procedure G; yield:
74 mg (86%) The analytical data agreed with those reported
in the literature.[28]
(S)-3-(2-Iodoethyl)hex-1-ene (38b): This compound was
prepared from 39b according to general procedure G; yield:
91 mg (78%).
(R)-[2-(2-Iodoethyl)but-3-enyl]benzene (38c): This com-
pound was prepared from 39c according to general proce-
dure G; yield: 37 mg (80%).
(R)-1-[2-(2-Iodoethyl)but-3-enyl]-4-methoxybenzene
(38d): This compound was prepared from 39d according to
general procedure G; yield: 45 mg (88%).
(S)-Methyl 2-[tert-butoxycarbonyl(3-methylpent-4-enyl)-
amino]acrylate (42a): This compound was prepared from
38a and 5 following general procedure B; yield: 23 mg
(58%).
(S)-Methyl 2-[tert-butoxycarbonyl(3-vinylhexyl)amino]-
acrylate (42b): This compound was prepared from 38b and 5
following general procedure B; yield: 18 mg (67%).
(R)-Methyl 2-[(3-benzylpent-4-enyl)(tert-butoxycarbonyl)-
amino]acrylate (42c): This compound was prepared from
38c and 5 following general procedure B; yield: 16 mg
(61%).
(R)-Methyl 2-[(3-benzylpent-4-enyl)(tert-butoxycarbonyl)-
amino]acrylate (42d): This compound was prepared from
38d and 5 following general procedure B; yield: 24 mg
(77%).
General Procedure H for Ring-Closing Metathesis of
Dehydroamino Acids 42a–d
A solution of 42 in toluene (~2 mM) was stirred under an
inert atmosphere at 808C. Catalyst A (5 mol%) was added
and the reaction mixture was stirred at 808C for 1 h. Next, a
second portion of A (5 mol%) was added and the reaction
mixture was stirred for an additional 3 h. The mixture was
cooled to room temperature and silica gel was added. The
solvent was removed and the crude product, adsorbed to
silica, was purified by column chromatography (EtOAc/hep-
tane, 1:20). The ee of the product was determined by chiral
HPLC.
(S)-1-tert-Butyl 2-methyl 4-methyl-5,6-dihydropyridine-
1,2(4H)-dicarboxylate (43a): This compound was prepared
from 42a following general procedure H; yield: 6.0 mg
(81%). The ee was determined by HPLC to be 73% (Chir-
alcel AD-H column; hexane/2-propanol, 98:2).
General Procedure G for the Preparation of Iodides
38a–d
To a solution of 39 in Et2O at ꢀ788C was added LiAlH4
(1.1 equivs.). The reaction mixture was gradually warmed to
room temperature and stirred for 1 h, after which H2O was
added. To dissolve the remaining salts HCl (1M) was added
and the mixture was extracted with Et2O. The organic layers
were dried (Na2SO4) and concentrated under vacuum. The
crude alcohol was dissolved in CH2Cl2 and PPh3 (1.3 equivs.)
and imidazole (1.5 equivs.) were added. The reaction mix-
ture was cooled to 08C and a solution of iodine (1.3 equivs.)
in CH2Cl2 was added. After 30 min the reaction was warmed
to room temperature and stirred for 2 h. Next, the mixture
was extracted with H2O and brine. The organic layer was
dried (Na2SO4) and the solvents were evaporated under
(S)-1-tert-Butyl 2-methyl 4-propyl-5,6-dihydropyridine-
1,2(4H)-dicarboxylate (43b): This compound was prepared
from 42b following general procedure H; yield: 3.0 mg
(82%). The ee was determined by HPLC to be 83% (Chir-
alcel AD-H column; hexane/2-propanol, 98:2).
(R)-1-tert-Butyl 2-methyl 4-benzyl-5,6-dihydropyridine-
1,2(4H)-dicarboxylate (43c): This compound was prepared
from 42c following general procedure H; yield: 6.5 mg
(89%). The ee was determined by HPLC to be 82% (Chir-
alcel AD-H column; hexane/2-propanol, 98:2).
(R)-1-tert-Butyl 2-methyl 4-(4-methoxybenzyl)-5,6-dihy-
dropyridine-1,2(4H)-dicarboxylate (43d): This compound
was prepared from 42d and following general procedure H;
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A Ring-Closing Metathesis Approach to Cyclic a,b-Dehydroamino Acids
FULL PAPERS
yield: 17.5 mg (90%). The ee was determined by HPLC to
be 81% (Chiralcel AD-H column; hexane/2-propanol,
98:2).
mondon, F. Soucy, S. Valois, D. Wernic, C. Yoakim, J.
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Acknowledgements
This research has been financially supported (in part)by the
Council for Chemical Sciences of the Netherlands Organiza-
tion for Scientific Research (CW-NWO). Christien A. Schor-
tinghuis (Chiralix B.V., Nijmegen, The Netherlands)is kindly
acknowledged for the LC-MS measurements. Kaspar Koch
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