Allylsilane-modified amino acids from the Claisen rearrangement

Article abstract of DOI:10.1002/hlca.200290002

The Claisen rearrangement of the N-protected, silylated allyl glycinates 11 and 12 led to the formation of allyl/silyl-functionalized amino acids 13 and 14 in yields up to 80%. The diastereoisomer ratio varied from 2:1 to 29:1 for 11mb, and from 2:1 to 46:1 (syn/anti) for 12mb, depending on reaction conditions, as shown by X-ray crystallographic analysis of 14mb. The relationship between the size of the alkyl groups on the chlorosilane reagent (Me₂R″SiCl, R″ = Cl, Me, t-Bu, Ph) used as an enolate trap and the observed stereoselectivity was investigated in the case of the Ireland - Claisen variant. Me₃SiCl gave the best results. However, the size of the alkyl groups on the silylated ester (Me₂R″Si, R = Me, t-Bu, Ph, i-Pr) did not exert a significant effect on the diastereoselectivity or yield of the rearrangement.

Full text of DOI:10.1002/hlca.200290002

Helvetica Chimica Acta Vol. 85 (2002)
4165
Allylsilane-Modified Amino Acids from the Claisen Rearrangement
by Mustafa Mohamed1) and Michael A. Brook*
Department of Chemistry, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada, L8S4M1
(e-mail: mabrook@mcmaster.ca; fax: ‡1(905)5222509)
It is an honour to dedicate this paper to Dieter Seebach on the occasion of his 65th birthday. He has been an
exceptionally important presence in my professional life, both through his example of how to be a successful
scientist and by the many doors he has opened for me. I am very gratefulto have had the opportunity to be one
of −die Mitarbeiter×.
The Claisen rearrangement of the N-protected, silylated allyl glycinates 11 and 12 led to the formation of
allyl/silyl-functionalized amino acids 13 and 14 in yields up to 80%. The diastereoisomer ratio varied from 2 :1 to
29 :1 for 11mb, and from 2 :1 to 46 :1 (syn/anti) for 12mb, depending on reaction conditions, as shown by X-ray
crystallographic analysis of 14mb. The relationship between the size of the alkyl groups on the chlorosilane
reagent (Me2R''SiCl, R'' ˆ Cl, Me, t-Bu, Ph) used as an enolate trap and the observed stereoselectivity was
investigated in the case of the Ireland Claisen variant. Me3SiClgave the best results. However, the size of the
alkyl groups on the silylated ester (Me2R''Si, R ˆ Me, t-Bu, Ph, i-Pr) did not exert a significant effect on the
diastereoselectivity or yield of the rearrangement.
Introduction. The Claisen rearrangement [1] and its variants provide a powerful
means to effect stereocontrolled CÀC bond formation. The highly-ordered transition
state guarantees the reliable chirality transfer from starting materials to products. One
of the most successfulimpel mentations of the many variants of the Claisen rearrange-
ment is that of Ireland [2][3].
The Ireland Claisen rearrangement has been used for crucialC ÀC bond-
formation in the synthesis of many natural products and biologically important
molecules, including steroids [4], macrocycles [5], polyether antibiotics [6], C-
glycosides [7], terpenes [8], and iridoids [9]. Some noteworthy examples of stereo-
selective syntheses based on the Ireland Claisen rearrangement include Schreiber×s
preparation of the cyclohexyl moiety of FK-506 (1) [10], Danishefsky×s route to the
C28 C49 unit of rapamycin (2) [11], and Ireland×s preparation of nonactic acid (3) [12]
and the monensin c/d ring assembly (4) (Scheme 1) [6].
The preparation of naturaland unnaturalamino acids and peptides has captured
the interest of the synthetic community. Seebach, among others, has devoted
considerable attention to the stereoselective syntheses of this class of compounds
[13]. g,d-Unsaturated amino acids have become the subject of intense investigation due
to their biological activity [14]. We sought to synthesize such amino acids that, at the
1
)
Current Address: Dr. Mustafa Mohamed, Senior Chemist, Electronics, Dow Corning Corporation, Auburn
MI 48686-0994 USA; phone: (989)496-7024, fax: (989)496-7084, e-mail: mustafa.mohamed@dowcorning.
com

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 1
same time, would possess allylsilane moieties for further functionalization, taking
advantage of the well-documented allylsilane chemistry [15][16].
The Ireland Claisen rearrangement occupies a prominent position among the
available procedures for acyclic CÀC bond-formation in a stereochemically-defined
manner [1][17] and has been used for the preparation of amino acids [18]. We, thus,
surmised that the Ireland Claisen rearrangement with allylsilanes, described by Panek
[19] and others for non-amino acids, might provide a new, generic entry to unnatural
amino acids. To this end, we have investigated methods to facilitate the rearrangement
of (substituted) 3-silylprop-2-enyl glycinates [20].
Results. The silylated alcohols 5 and 6 were prepared according to literature
procedures [21]. Treatment of either propargylalcoholor but-3-yn-2-olwith 2.7 equiv.
of EtMgBr followed by addition of silyl reagent (2.7 equiv.) and workup under acidic
conditions gave 7 and 8, respectively, in moderate to excellent yield, depending on the
size of the silyl group (Table 1). Reduction with sodium bis(methoxyethoxy)aluminum
hydride led to the exclusive formation of the (E)-configured vinylsilane allylic alcohols
5 and 6, respectively.
Alternative methods for the synthesis of vinylsilanes, e.g., hydrosilylation of the
triple bond of a propargyl ester, were less convenient, since mixtures of (Z)- and (E)-
configured products were obtained. The configuration at the double bond was
determined by 1H-NMR (coupling constants), and the presence of a single (E)-isomer
was confirmed by GC.
The silylated allyl glycinate substrates for the Claisen rearrangement were prepared
by esterification of the N-protected amino acids 9 and 10 with the appropriate alcohol
(Table 2). Addition of dicyclohexylcarbodimide (DCC) at 08 to a solution of the
alcohol and 4-(N,N-dimethylamino)pyridine (DMAP) in CH2Cl2 or DMF, depending

Helvetica Chimica Acta Vol. 85 (2002)
4167
Table 1. Preparation of Silylated Vinylsilane Alcohols
R
R'3Si
Product
Yielda) [%]
Product
Yielda) [%]
H
H
H
Me
Me
Me3Si
7m
7b
7a
8m
8p
92
54
70
95
82
5m
5b
5a
6m
6p
77
58
65
72
68
(t-Bu)Me2Si
Me2(Ph)Si
Me3Si
(i-Pr)Me2Si
a) Isolated yield.
Table 2. Esterification of N-Protected Glycine with Alcohols 5 and 6
R'3Si
R
Solvent
PGa)
Product
Yield [%]
Me3Si
Me3Si
(t-Bu)Me2Si
Me2(Ph)Si
Me3Si
Me3Si
Me3Si
Me3Si
(i-Pr)Me2Si
H
H
H
H
H
H
Me
Me
Me
DMF
Boc
Cbz
Boc
Boc
Cbz
Bz
Boc
Cbz
Boc
11mb
11mc
11bb
11ab
11mc
11mz
12mb
12mc
12pb
60
87
77
81
65
60
82
76
80
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
CH2Cl2
DMF
CH2Cl2
a) Protecting groups: Boc ˆ (tert-butoxy)carbonyl, Cbz ˆ benzyloxycarbonyl, Bz ˆ benzoyl.
on the specific amino-acid protecting group, followed by addition of the amino acid,
resulted in formation of the esters 11 or 12 in good yield2).
The use of a zinc-chelated enolate for the Claisen rearrangement [22][23] was first
examined (Scheme 2). Kazmaier et al. reported improved yields and better stereo-
selectivities in the rearrangement of glycinate esters in the presence of chelating salts
such as ZnCl2. The addition of lithium hexamethyldisilazide (LHMDS) to a solution of
11mb at À788, followed by addition of ZnCl2 after 10 min, resulted in a clear yellow
2
)
Designations for 11 14: silyl group (first letter): m ˆ SiMe3 , b ˆ (t-Bu)Me2Si, p ˆ (i-Pr)Me2Si, a ˆ
Me2(Ph)Si; protecting group (second letter): b ˆ Boc, c ˆ Cbz, z ˆ Bz; diastereoisomer (third letter): a ˆ
anti, s ˆ syn. Thus, 13mba is the anti-product 13 with the SiMe3 and the N-Boc groups. For abbreviations,
see Table 2.

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Helvetica Chimica Acta Vol. 85 (2002)
solution. The rearrangement reaction was monitored by TLC. The formation of the
product was observed after 4 h, at which point the temperature had reached À208. The
mixture was allowed to warm to room temperature overnight. Workup under acidic
conditions furnished 13mbs/13mba in a syn/anti ratio of 25 :1 (Entry 1, Table 3).
However, a substantialamount of decomposition of the starting ester was associated
with this procedure, and the combined yield of the two isomeric amino acids was only
30%. The yield could be improved to 50% when the reaction time was reduced and
when the workup was performed at 58 (Table 3, Entry 2). However, the stereo-
selectivity was unaffected. Similar reaction conditions were used for the rearrangement
of 12mb. Addition of lithium diisopropyl amide (LDA) to a solution of the glycinate,
followed by addition of ZnCl2, led to 14mbs/14mba in a syn/anti ratio of 28 :1 in 57%
yield (Entry 3). When MgBr2 was employed as the enolate trap, only the syn-isomer
was observed by GC. Unfortunately, the yield was relatively low at 46%. Thus,
attractive diastereoselectivities were observed with the chelating Lewis acids ZnCl2 and
MgBr2, but, in both cases, the yields were much lower than with the traditional
Ireland Claisen procedure [20].
Scheme 2
Table 3. Claisen Rearrangement under Chelating Conditions
a
Entry Starting materialCondition
)
Temp. [8]
Time [h] Product Yield [%] syn/anti
1
2
3
4
11mb
11mb
12mb
12mb
LHMDS/ZnCl2 À 78 ! r.t. 24
13mb
13mb
14mb
14mb
30
50
57
46
25 : 1
25 : 1
28 : 1
single isomer
LHMDS/ZnCl2 À 78 ! 5
LDA/ZnCl2
10
LDA/MgBr2
a) LHMDS ˆ lithium hexamethyldisilazide, LDA ˆ lithium diisopropyl amide.
The Ireland Claisen rearrangement of a series of glycinate esters with different
silyl substituents and amine protecting groups was examined next. In general, good
diastereoisomer selectivity (19 :1) and high yields (e.g., Entry 7, Table 4) were observed

Helvetica Chimica Acta Vol. 85 (2002)
4169
under standard conditions (sequentialaddition of the ester to LHMDS and quenching
with Me3SiCl) [6]. The resulting carboxylic acids were directly converted to the
corresponding methylesters by treatment with Me 3SiCHN2 [24] to facilitate character-
ization. The major isomer in each case was purified by flash chromatography (FC). The
products were formed in moderate to high stereoselectivity (3 :1 29 :1) and good yield
(28 85%). Stereoselectivity and yield increased when Et3N was used together with
LDA (29 :1, 85%) (Entry 1, Table 4), or upon reverse addition of the base to the ester
(29 :1, 82%) (Entry 8, Table 4).
Table 4. Claisen Rearrangement of 11mb to 13mb (syn and anti)
Entry
Conditions
Yield [%]
syn/anti (yield [%])
1
2
3
4
5
LDA (2.5 equiv.), Me3SiCl(3 equiv.), Et N
85
29 : 1
3
a
LDA (3.5 equiv.), Me3SiCl(3.5 equiv.)
LDA (2.5 equiv.), (t-Bu)Me2SiCl55
LDA, Ph2SiCl2
LDA, Cl3SiH
LDA, PhSiCl3
50
)
5 : 1
42
3 : 1
5 : 1
3 : 1
40
34
6
7
8
LHMDS (2.5 equiv.), Me3SiCl79
inverse addition
19 : 1
82
29 : 1
9
DMAP, TMSCl9 : 1
10
11
PhMe2SiCl, Et3N
(t-Bu)Me2SiCl, Et3N
15 : 1
2.6 : 1
28
a) Plus 20% of 15 (Scheme 3).
Attempts to improve the reaction by changing the base/ester ratio in the enolization
process proved to be difficult. Increasing the quantity of base led to severely diminished
yields. In the case of 11mb, excess base led to the formation of compound 15 in 20%
yield (Entry 2, Table 4), which results from double deprotonation and silylation of
11mb followed by rearrangement (Scheme 3). Compounds like 15 are not common side
products in the Ireland Claisen rearrangement; usually, silylation of the enolate
carbon occurs, a process that was not observed in our reactions. Additionalbase
(3.5 equiv.) led not only to 15, but also to decomposition of the enolate intermediate via
b-elimination (Entry 2, Table 4) [25]. Elimination of the allylic ether moiety has been
reported to compete in certain cases with the rearrangement [26]. By using 2.5 equiv. of
either LDA or LHMDS in the enolization process (Entries 1 and 7, Table 4), the formation
of 15 could be suppressed. Under these conditions, the rearrangement took place at ca.
À208, and the yields of the esterified products were moderate to excellent (55 85%).
Next, we tried more-electrophilic dichloro- or trichlorosilanes as trapping agents to
controlproduct selctivity through N ÀSiÀO cyclization. Alternatively, bulkier
monochlorosilanes were tested to determine whether more steric congestion in the
transition state would improve the stereoselectivity of the process. In neither case were
these approaches successful with respect to yield or diastereoselectivity (Entries 4 6,
Table 4).
The effect of different silyl groups (Me3Si, (i-Pr)Me2Si, Me2(Ph)Si, (t-Bu)Me2Si) on
the starting allylic ester was studied next. It was expected that greater steric bulk on the
silane would lead to an enhanced stereoselectivity due to fewer degrees of freedom in

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 3
the transition state of the Claisen rearrangement (see below). In all cases examined, the
reaction of Me3Si-substituted 11mb gave rise to both the highest stereoselectivity and
yield. In general, the use of other silyl groups led either to lower yield or selectivity, or
both. As the size of the silyl group increased, there was a dramatic decrease in yield,
with the following trend: Me3Si > Me2(Ph)Si > (t-Bu)Me2Si. A slight decrease in
selectivity was noted, thus, with the larger silyl groups (Table 5).
Table 5. Effect of the Silyl Group of 11 on the Stereoselectivity of the Rearrangement
Entry
Compound
R'3Si
Product
Yield [%]
syn/anti
1
2
3
11mb
11bb
11ab
Me3Si
(t-Bu)Me2Si
Me2(Ph)Si
13mbs/13mba
13bbs/13bba
13abs/13aba
85
40
62
29 : 1
16 : 1
5.5 : 1
The optimized reaction conditions for 11mb were used for the rearrangement of
12mb and 12pb, which bear an additionalstereogenic center ( Table 6). In the case of
12mb, a notable increase in selectivity and yield resulted from introduction of the
a-methyl substituent into the allylic system.
The N-protecting group had a significant impact on the stereoselectivity, Boc-
protected esters performing much better than Bz- or Cbz-protected esters, as shown in
the rearrangement of 12mb (Table 7). Bartlett and co-workers reported similar results
[18]. When more than 3 equiv. of base were employed in the enolization process,
deprotection of the Boc group was observed at room temperature.
The configurations of the methylgyl cinates were determined by two independent
methods. First, the structure of the major isomer of 14mb (Figure) was solved by X-ray
crystallography (Table 9 and 10), which confirmed the assumed stereochemistry of the
favored isomer. Second, the diastereoisomer ratios were determined by GC, and
1H-NMR analyses were performed, correlating the coupling constants of the C(2) and
C(3) protons (Table 8) [27]. For the remaining compounds, stereochemicalassignment
was based on 1H-NMR chemicalshifts of the C(3) methine proton, which distinguishes
the syn and anti diastereoisomers (Table 8). In most cases, the vicinalcoupinl g
constants for the 2,3-syn diastereoisomer (zigzag conformation in Scheme 2) are larger
than for those of the 2,3-anti counterpart and show a downfield shift. The resonance of
the C(2) methine proton is not useful in this respect, since it overlaps with the signals of
the vinylic protons.

Helvetica Chimica Acta Vol. 85 (2002)
4171
Table 6. Rearrangement Conditions for 12mb and 12pb
Entry
Substrate
Conditiona)
Product
Yield [%]
syn/anti
1
2
3
4
5
6
12mb
12mb
12mb
12mb
12pb
12pb
A (reverse)
B
C
THF/HMPA (23%)
THF/HMPA (23%)
(reverse addition)
14mb
14mb
14mb
14mb
14pb
14pb
92
65
50
72
65
78
single isomer
46 : 1
46 : 1
23 : 1
2 : 1
25 : 1
a) For conditions A C, see Exper. Part (Sect. 4).
Table 7. Rearrangement of Differently N-Protected 12
Entry
Substrate
Condition
PGa)
Boc
Product
Yield [%]
syn/anti
1
2
3
12mb
12mc
12mz
LDA, Me3SiCl, Et3N
LDA, Me3SiClCbz
LDA, Me3SiClBz
14mb
14mc
14mz
92
80
71
32 : 1
12 : 1
9 : 1
a) Protecting group.
Figure. a) Thermal ellipsoids (50% probability) of 14mb. b) Dimer in cell.

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Helvetica Chimica Acta Vol. 85 (2002)
Table 8. Vicinal 1H-NMR Coupling Constants (J [Hz]) and Chemical Shifts (d [ppm]) of Selected Compounds
Compound
R3Si
PGa)
Product
d(syn)
d(anti)
J2,3(syn)
J2,3(anti)
11mb
11bb
11ab
12mb
12mc
12mz
12pb
Me3Si
Boc
Boc
Boc
Boc
Cbz
Bz
13mb
13bb
13ab
14mb
14mc
14mz
14pb
1.95
2.16
2.18
1.83
1.81
1.98
1.88
2.03
2.41
2.29
5.86
6.87
6.37
5.65
5.34
5.37
6.94
4.59
4.40
5.28
(t-Bu)Me2Si
Me2(Ph)Si
Me3Si
Me3Si
Me3Si
2.07
1.79
5.16
5.33
(i-Pr)Me2Si
Boc
a) Protecting group.
Table 9. Bond Lengths [ä] and Angles [8] for 14mb
Bond lengths
Si(1)ÀC(14)
Si(1)ÀC(15)
Si(1)ÀC(13)
Si(1)ÀC(8)
O(1)ÀC(9)
O(1)ÀC(12)
O(2)ÀC(7)
O(2)ÀC(16)
N(3)ÀC(9)
N(3)ÀC(5)
1.857(3)
1.857(3)
1.856(2)
1.905(2)
1.345(2)
1.467(2)
1.3292(19)
1.452(3)
1.341(2)
1.446(2)
O(4)ÀC(9)
C(5)ÀC(7)
1.2084(19)
1.512(3)
1.544(2)
1.198(2)
1.505(3)
1.300(3)
1.490(3)
1.509(4)
1.511(3)
1.511(4)
C(5)ÀC(8)
O(6)ÀC(7)
C(8)ÀC(10)
C(10)ÀC(11)
C(11)ÀC(17)
C(12)ÀC(19)
C(12)ÀC(18)
C(12)ÀC(20)
Bond angles
C(14)ÀSi(1)ÀC(15)
C(14)ÀSi(1)ÀC(13)
C(15)ÀSi(1)ÀC(13)
C(14)ÀSi(1)ÀC(8)
C(15)ÀSi(1)ÀC(8)
C(13)ÀSi(1)ÀC(8)
C(9)ÀO(1)ÀC(12)
C(7)ÀO(2)ÀC(16)
C(9)ÀN(3)ÀC(5)
N(3)ÀC(5)ÀC(7)
N(3)ÀC(5)ÀC(8)
C(7)ÀC(5)ÀC(8)
O(6)ÀC(7)ÀO(2)
O(6)ÀC(7)ÀC(5)
O(2)ÀC(7)ÀC(5)
108.74(15)
109.29(16)
110.15(16)
107.77(13)
111.91(11)
108.92(11)
120.60(14)
115.93(18)
122.99(15)
109.15(14)
110.90(13)
110.76(15)
123.45(17)
124.61(15)
111.94(15)
C(10)ÀC(8)ÀC(5)
C(10)ÀC(8)ÀSi(1)
C(5)ÀC(8)ÀSi(1)
O(4)ÀC(9)ÀN(3)
O(4)ÀC(9)ÀO(1)
N(3)ÀC(9)ÀO(1)
C(11)ÀC(10)ÀC(8)
C(10)ÀC(11)ÀC(17)
O(1)ÀC(12)ÀC(19)
O(1)ÀC(12)ÀC(18)
C(19)ÀC(12)ÀC(18)
O(1)ÀC(12)ÀC(20)
C(19)ÀC(12)ÀC(20)
C(18)ÀC(12)ÀC(20)
110.89(13)
111.39(13)
113.09(13)
124.50(18)
125.84(17)
109.65(14)
125.81(19)
126.6(2)
108.3(2)
110.6(2)
112.8(3)
102.0(2)
112.3(3)
110.3(3)
Discussion.
There are three structural elements that mainly determine the
stereoselectivity of the ester enolate Claisen rearrangement: 1) the chair or boat-like
nature of the transition state, 2) the geometry about the vinylic CˆC bond, and 3) the
geometry about the allylic CˆC bond.
In the case of simple allyl esters, the geometry of the silyl enolate formed during the
first step of the Ireland Claisen rearrangement can be controlled by the reaction

Helvetica Chimica Acta Vol. 85 (2002)
4173
Table 10. Selected Crystallographic Data for 14mb
Identification code
Empiricalformual
Formula weight
Temperature
Wavelength
Crystalsystem
CCDC-186958
C
15H29NO4Si
315.48
299(2) K
0.71073 ä
Tricilnic
≈
Space group
P1
Unit cell dimensions
a ˆ 8.6830(8) ä
b ˆ 10.3930(10) ä
c ˆ 11.9048(12) ä
965.25(16) ä3
a ˆ 97.131(2)8
b ˆ 94.114(2)8
g ˆ 113.962(2)8
Volume
Z
2
Density (calc.)
Absorption coefficient
F(000)
1.085 Mg/m3
0.135 mmÀ1
344
Crystalsize
Theta range for data collection
Index ranges
0.08 Â 0.22 Â 0.36 mm
1.74 to 27.528
À 11 ꢀ h ꢀ 9, À13 ꢀ k ꢀ 13, À14 ꢀ l ꢀ 15
8800
Reflections collected
Independent reflections
Completeness to theta
Absorption correction
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2s(I)]
R indices (all data)
Extinction coefficient
Largest diff. peak and hole
4333 [R(int) ˆ 0.0294]
97.0%
None
Full-matrix least-squares on F2
4333/0/307
0.986
R1 ˆ 0.0455, wR2 ˆ 0.1051
R1 ˆ 0.0882, wR2 ˆ 0.1206
0.009(3)
0.190 and À0.157 e äÀ3
conditions. The (Z)-configured ester enolate 16 was preferentially formed under
kinetic control by LDA in THF and led, after silylation [28], to (E)-configured 17
(Scheme 4) [3]. The structures of such enolates have been established by X-ray crystal
‡
analysis [29]. In contrast, in the presence of solvents or additives that coordinate Li ,
e.g., TMEDA, DMPU [30] or HMPA, the (E)-configured enolate 19 is preferentially
formed and converted to the (Z)-oriented silyl ketene acetal 203)4). Note that the
specific nature and concentration of the chelating molecules can strongly affect the
degree of stereocontrol of enolates [31]. The ratio of the isomeric silyl ketene acetals
can also be affected by the ratio of substrate to base. Higher mole ratios of base/ester
slightly favor the formation of the (E)-configured silyl ketene acetal, whereas the (Z)-
intermediate can be increased with a lower base/ester ratio. Deviations from a 1:1 base/
ester ratio can, however, have a negative impact on isolated yields [31]. There is
considerable discussion in the literature regarding the origin of this observation,
3
)
)
The (E)/(Z) notation is adopted from the definition of the geometries of silyl ketene acetal as well as metal
enolates; the configurations are opposite due to the priority of Si over Li [3].
Note that, because of CIP priorities, the a-heteroatom-substituted, (Z)-configured silyl ketene acetals
(Scheme 5,a) have the same relative configuration during the bond-forming process as 19 (Scheme 4), but
the addition is ul in this case (see Footnote 5), while, with two heteroatom substituents (Scheme 5,b), it
returns to lk addition.
4

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Helvetica Chimica Acta Vol. 85 (2002)
including formation of the thermodynamically more stable enolate, change of
transition-state geometry after deprotonation, and kinetic resolution of the intervening
lithium enolates. The situation is somewhat different with a-heteroatom-substituted
esters, where internalchealtion constrains the deprotonation geometry. Preferential
formation of the (E)-configured ester enolate 22 has been observed by Bartlett [32],
Fujisawa [33], Burke [34], Panek [27], and Kazmaier [23] (Scheme 5,a).
Scheme 4
The Ireland Claisen rearrangement is predetermined by the pericyclic transition
state. In our case, the starting allylic esters 11 and 12 are (E)-configured vinylsial nes
and, thus, the impact on stereoselectivity should be the same for both types of
compound (the distalstereogenic center bearing the Me group in 12 is considered
separately below). Thus, much of the battle for stereoselectivity in the rearrangement
rides on the ability to control the enolate geometry. With (E)-allyl groups, (E)-
configured silyl ketene acetals preferentially undergo ul addition5) to the anti product
18, and (Z)-configured silyl ketene acetals lk addition to the syn product 21 a typical
trend in many related addition reactions6).
The preferred stereochemicaloutcome of the rearrangement of 11 can be explained
by invoking the generally favored chair-like over the boat-like transition state [37]. The
selectivity in the Claisen rearrangement of esters containing a-heteroatom substituents
has been attributed to the formation of five-membered chelates, which lead to the
5
)
)
For a definition of the stereodescriptors lk (−like×) and ul (−unlike×) for bond-forming reactions between
trigonalcenters, see [35].
6
There is a disconnect between the syn and anti stereochemicaldescriptors used here and those more
generally used for aldol condensations. In the latter, the nucleofuge is found on the side chain, thus ul aldol
addition gives a syn-adduct. In the case of the Claisen rearrangement, however, the alignment of the C
chain puts the nucleofugal allyl group on the chain end, such that lk-addition produces the syn-adduct. In
both cases, however, the relative stereochemistry of the addition process is the same:
Note that Lewis acid catalyzed addition frequently favor ul-additions irrespective of the enolate geometry [36].

Helvetica Chimica Acta Vol. 85 (2002)
4175
Scheme 5
(Z)-configured silyl ketene acetal and, finally, to the syn-isomer 13 as the major
product (Scheme 5) [38]. The low stereoselectivity observed with the Cbz- and Bz-
protected compounds 11mc and 11mz may have its origin in the presence of the
aromatic ring in the protecting groups, which may simply adopt a conformation that
prevents chelation. Alternatively, it is conceivable that the ring affects the nucleophi-
licity of the N-atom, reducing its ability to coordinate to the Si. Similarly, it is well-
known that certain amines coordinate to tetravalent Si to produce hypervalent silane
species [39][40]. A SiÀN interaction cannot be excluded as an additional (unhelpful)
stereocontroleel ment in the rearrangement.
The best yields and stereoselectivities in the rearrangement of 11 occurred with an
excess of 2 equiv. of both base and chlorosilane. The active silyl enolate that undergoes
the Ireland Claisen rearrangement should, thus, be silylated on N as well as O.
Multifunctional silanes were used in the hope that the resulting cyclic 5-ring, analogous
to 22 (M ˆ Si; Scheme 5), would cooperatively direct the rearrangement, thereby
improving selectivity. Alternatively, larger chlorosilanes were used as trapping agents,
but did not prove helpful. The structures of the silylated enolates were apparently
distorted away from the transition state that leads to the syn diastereoisomer (Table 4).
Attempts were also made to bias the relative formation of the (E)- and (Z)-
configured silyl enolates by adding larger silyl moieties to the allyl group, which,
however, decreased the selectivity. Simple molecular modelling [41] of the transition
state (lengthening of the CÀO bond, shortening of the ˆC ¥¥¥ Cˆ distance: dotted
line ˆ 1.9 ä, bold line ˆ 2.2 ä in Scheme 6), following the work of Houk and co-
workers [42], showed that, first, the silyl group is somewhat remote from the
reaction centre and, second, that the large group R can avoid the reaction centre by
simple rotation. This suggests that size may not be the only significant factor in
controlling the stereoselectivity of the reaction. Irrespective, this simple expedient

4176
Helvetica Chimica Acta Vol. 85 (2002)
Scheme 6
could not be productively exploited to improve the stereoselectivity of the rearrange-
ment.
Finally, we found that another stereoelement, the additional Me group in 12, gave
rise to both higher yields and stereoselectivities in the formation of 14 compared to 13.
The stereotransfer of the allyl group was extremely efficient. We were unable to detect
any (Z)-alkene at all [38]. It remains to be established whether the (Z)-crotylanalogue
of 12 will behave similarly and what the stereochemical outcome in these systems
would be. Similarly, the utility of allylsilanes as nucleophiles for the preparation of new,
unnaturalamino acids must be examined and willform the basis of future reports.
Conclusions. The Ireland Claisen rearrangement of silylated allyl glycinates
provides allyl/silyl-functionalized glycines in good yield with moderate to high
stereoselectivity, favoring the syn-diastereoisomer. Replacing the intermediate Me3Si
enolate with either bulkier or more electrophilic silanes did not improve the outcome in
terms of selectivity or yield. The stereochemical outcome was mainly determined by the
size of the silyl substituent of the substrate. Thereby, best results were obtained with the
smallest substituent, i.e., the Me3Si group.
We gratefully acknowledge the financial support of the Natural Sciences and Engineering Research Council
of Canada and thank Jim Britten (McMaster) for obtaining the X-ray structure.
Experimental Part
1. General. 1H- and 13C-NMR Spectra were recorded on a Bruker AC-200 spectrometer in CDCl3 or C6D6, d
in ppm, J in Hz. IR Spectra were recorded on a Biorad spectrometer; in cmÀ1. Electron-impact (EI) and
chemical-ionization (CI) mass spectra were recorded at 70 eV with a source temp. of 2008 on a VG Instruments
analytical ZAB-R mass spectrometer equipped with a VG 11-250 data system; m/z (rel. [%]). Gas
chromatographic (GC) analyses were run on a Hewlett-Packard 5890A gas chromatograph equipped with a
conventionalheated injector, a falme ionization detector, a Hewlett-Packard 3393A integrator, and a DB-1
megabore capillary column (30 m  0.54 mm) from Chromatographic Specialties, Inc. GC/MS Analyses were
recorded on a Hewlett-Packard 5890II gas chromatograph equipped with a HP-5971A mass selective detector
and a DB-5 fused-silica capillary column (30 m  0.25 mm; Chromatographic Specialties, Inc.).

Helvetica Chimica Acta Vol. 85 (2002)
4177
All reactions were performed with dried glassware under an atmosphere of anh. N2. The following reagents
were purchased from Aldrich and used without further purification: N-protected glycines, sodium bis(2-
methoxyethoxy)aluminum hydride (SMEAH), dicyclohexylcarbodiimide (DCC), 4-(N,N-dimethylamino)pyr-
idine (DMAP), ZnCl2, MgBr2. Et3N and hexamethylphosphortriamide (HMPA) were distilled from CaH2.
Diisopropylamine was distilled from NaOH. Propargyl alcohol and but-3-yn-2-ol were distilled from flame-
dried glass ware prior to use. Tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl under N2
just before use. Silica-coated aluminium TLC plates (60 F254) were purchased from Merck.
Crystallographic data (excluding structure factors) for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as depositon No. CCDC-186958. Copies of the data
can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
‡ 44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).
2. Synthesis of Silylated Alcohols [21]. 2.1. 3-(Trimethylsilyl)prop-2-yn-1-ol (7m). A three-neck, round-
bottomed flask equipped with a magnetic stirring bar and dry N2 inlet was fitted with a reflux condenser, a
thermometer, and a septum. The apparatus was flushed with N2 and charged with Mg turnings (12.2 g, 50 mmol)
and dry THF (50 ml). To the stirred suspension was added dropwise bromoethane (37.3 ml, 50 mmol) over 1 h
via a syringe, while the temp. was kept at 37 478. After complete addition, the grey suspension was heated at 508
for 1 h and then cooled to 58. A soln. of propargyl alcohol (10.47 ml, 18.50 mmol) in THF (20 ml) was cautiously
added dropwise to the grey suspension over 1 h at a const. temp. of 108. When the grey suspension became very
viscous, an additional 60 ml of THF was added and the mixture was stirred overnight. The resulting soln. was
cooled to 58, and 1.0 equiv. of Me3SiCl(6.35 ml, 50 mmol) was added dropwise over 1 h at 25 8 or less (external
cooling with ice). The mixture was heated to reflux for 2 h, the suspension was cooled to r.t. and carefully
quenched with H2SO4 (300 ml, 1.4m) over 1 h and below 408. The resulting soln. was stirred for 5 min, the org.
layer was extracted with Et2O (3 Â 100 ml), the etheral layer was washed with 2 Â 100 mlof H 2O. The combined
org. extracts were dried over MgSO4, and the solvent was removed in vacuo. The yellow-brown residue was
purified by short-path distillation to afford a colourless oil (21.5 g, 16.8 mmol, 90%). IR: 3331 (br., OH), 2961,
2866, 2177, 1446, 1413, 1252, 1045, 983, 844, 761. 1H-NMR (200 MHz, CDCl3): 4.23 (s, 2 HÀC(1)); 1.97 (s, OH);
0.14 (s, Me3Si).
2.2. 3-[(tert-Butyl)dimethylsilyl]prop-2-yn-1-ol (7b). Prepared according to 2.1. Yield: 54%. IR: 3331 (br.,
OH), 2961, 2866, 2177. 1H-NMR (200 MHz, CDCl3): 4.4 (s, 2 H); 1.2 (s, 1 H); 0.98 (s, 9 H); 0.20 (s, 6 H).
13C-NMR (50 MHz, CDCl3): 108.3; 87.0; 58.8; 16.3; 13.9; À3.8.
2.3. 3-[(Dimethyl)phenylsilyl]prop-2-yn-1-ol (7a). Prepared according to 2.1. Yield: 70%. IR: 3331 (br.,
OH), 2961, 2866, 2177, 1720, 740. 1H-NMR (200 MHz, CDCl3): 7.66 (m, 2 H); 7.41 (m, 3 H); 4.28 (s, 2 H); 2.48
(br. s, 1 H); 0.46 (s, 6 H). 13C-NMR (50 MHz, CDCl3): 133.6; 133.3; 129.0; 128.8; 127.9; 107.9; 88.4; 58.90; À4.1.
2.4. 4-(Trimethylsilyl)but-3-yn-2-ol (8m). Prepared according to 2.1. Yield: 95%. IR: 3330 (br., OH), 2961,
1
2866, 2177. H-NMR (200 MHz, CDCl3): 4.38 (q, J ˆ 6.6, HÀC(2)); 3.79 (s, OH); 1.30 (d, J ˆ 6.6, 3 HÀC(1));
0.02 (s, 9 H). 13C-NMR (50 MHz, CDCl3): 107.1; 87.5; 58.1; 24.0; À0.3.
2.5. 3-[(Isopropyl)dimethylsilyl]but-3-yn-2-ol (8p). Prepared according to 2.1. Yield: 80% 1H-NMR
(200 MHz, CDCl3): 4.51 (q, J ˆ 6.6, 1 H); 2.08 (s, 1 H); 1.44 (d, J ˆ 6.6, 3 H); 0.98 (d, J ˆ 6.6, 6 H); 0.90
(m, 1 H); 0.09 (s, 6 H, SiMe3). 13C-NMR (50 MHz, CDCl3): 108.50; 86.92; 58.86; 24.47; 16.94; 13.91; À3.78.
2.6. (E)-3-(Trimethylsilyl)prop-2-en-1-ol (5m). A two-neck, 500 mlround-bottomed falsk fitted with a
thermometer, septum, N2 inlet, and magnetic stirring bar was charged with SMEAH (47 ml, 3.4m soln.,
160 mmol) and Et2O (65 ml). The soln. was cooled to 08 and treated dropwise via syringe with a soln. of 3-
(trimethylsilyl)prop-2-yn-1-ol (12.78 g, 100 mmol) in Et2O (60 ml) over 30 min at 58 or less. After complete
addition, the cooling bath was removed. The reaction was complete within 1 h. The mixture was cooled to 08 and
quenched with aq. H2SO4 (200 ml, 3.6m). The org. layer was extracted with Et2O (2 Â 100 ml). The org. extract
was dried over MgSO4, the solvent was removed in vacuo, and the remaining yellow oil was purified by FC
(SiO2; AcOEt/pentane 1 :3) to afford a colorless oil (9.1 g, 70 mmol, 77%). 1H-NMR (200 MHz, CDCl3): 6.12
(dt, J ˆ 4, 18, 1 H); 5.86 (d, J ˆ 18, 1 H); 4.12 (dd, J ˆ 4, 6, 2 H); 0.18 (s, 9 H). 13C-NMR (50 MHz, CDCl3): 144.8;
129.2; 65.1; À1.45.
2.7. (E)-3-[(tert-Butyl)dimethylsilyl]prop-2-en-1-ol (5b). Prepared according to 2.6. Yield: 58%. IR: 3335
1
(br., OH), 1645, 1120, 750. H-NMR (200 MHz, CDCl3): 5.9 (dt, J ˆ 12.2, 3.2, 1 H); 5.8 (d, J ˆ 12.2, 1 H); 3.9
(d, J ˆ 5.4, 2 H); 1.3 (s, 1 H); 0.9 (s, 9 H); 0.2 (s, 6 H). 13C-NMR (50 MHz, CDCl3): 139.3; 131.6; 67.5; 26.41;
17.23; À6.4.
2.8. (E)-3-[(Dimethyl)phenylsilyl]prop-2-en-1-ol (5a). Prepared according to 2.6. Yield: 65%. IR: 3335
(br., OH), 1645. 1H-NMR (200 MHz, CDCl3): 7.4 (m, 3 H); 7.3 (m, 2 H); 6.1 (dt, J ˆ 18.1, 3.9, 1 H); 5.9 (d,

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Helvetica Chimica Acta Vol. 85 (2002)
J ˆ 18.1, 1 H); 4.1 (d, J ˆ 4.0, 2 H); 1.6 (s, 1 H); 0.3 (s, 6 H). 13C-NMR (50 MHz, CDCl3): 133.6; 133.4; 129.1;
128.9; 128.0; 126.5; 64.6; À4.0.
2.9. (E)-4-(Trimethylsilyl)but-3-en-2-ol (6m). Prepared according to 2.6. Yield: 95%. IR: 3330 (br., OH).
1H-NMR (200 MHz, CDCl3): 4.38 (dd, J ˆ 4.6, 18.8, 1 H); 5.6 (d, J ˆ 18.6, 1 H); 2.18 (s, 1 H); 1.30 (d, J ˆ 6.7,
3 H); 0.01 (s, 9 H). 13C-NMR (50 MHz, CDCl3): 140; 131.1; 67.1; 19.7; À0.9.
2.10. (E)-4-[(Isopropyl)dimethylsilyl]but-3-en-2-ol (6p). Prepared according to 2.6. Yield: 68%. IR: 3331
(br., OH), 1645. 1H-NMR (200 MHz, CDCl3): 6.0 (dd, J ˆ 6.0, 18.8, 1 H); 5.9 (d, J ˆ 18.8, 1 H); 3.9 (m, J ˆ 5.5,
1 H); 2.0 (s, 1 H); 0.83 (d, J ˆ 6.5, 1 H); 0.78 (d, J ˆ 6.5, 6 H); 0.67 (m, 1 H); 0.3 (s, 6 H). 13C-NMR (50 MHz,
CDCl3): 139.2; 131.4; 67.3; 24.2; 17.3; 13.3.
3. General Procedure for the Synthesis of Silylated Allyl Glycinates. An oven-dried 250 mlround-bottomed
flask, equipped with a magnetic stirring bar, was charged with 5m (2.6 g, 20 mmol) or 6m (2.9 g, 20 mmol) and
DMAP (0.20 g, 2.0 mmol). The flask was sealed with a rubber septum, and anh. CH2Cl2 (20 ml) was added. The
resulting clear soln. was stirred for 15 min at r.t. DCC (4.1 g, 20 mmol) in CH2Cl2 (10 ml) was added via syringe.
The mixture was stirred at 08 for 15 min before the N-protected glycine (20 mmol) in CH2Cl2 (10 ml) was added
via syringe. The mixture was allowed to warm to r.t. overnight. The precipitated urea was filtered off, the
resulting yellow soln. was washed with sat. NaHCO3, dried (MgSO4), and the solvent was removed in vacuo.
3.1. (E)-3-(Trimethylsilyl)prop-2-en-1-yl N-(tert-Butoxycarbonyl)glycinate (11mb). FC (SiO2; AcOEt/
pentane 1 :4) afforded a colorless oil (5.0 g, 17.4 mmol, 87%). IR (neat): 3376, 2967, 1763, 1701, 1625, 1519, 1509,
1
1166. H-NMR (200 MHz, CDCl3): 5.98 5.86 (m, 2 H); 4.99 (br., 1 H); 4.63 (d, J ˆ 3.9, 2 H); 3.92 (d, J ˆ 6.5,
2 H); 1.42 (s,9 H); 0.06 (s, 9 H). 13C-NMR (50.32 MHz, CDCl3): 169.99; 155.58; 138.47; 134.19; 79.96; 67.50;
‡
‡
42.43; 28.28; À1.55. CI-MS (NH3): 305 (M ‡ NH4 ), 288 (M ), 249 (3), 232 (14), 188 (2), 176 (30), 144 (29),
‡
130 (5), 90 (40), 73 (85), 57 (100). HR-MS: 288.163 ([M ‡ 1] , C13H25NO4Si; calc. 288.165).
3.2. (E)-3-[(tert-Butyl)dimethylsilyl]prop-2-en-1-yl N-(tert-Butoxycarbonyl)glycinate (11bb). FC (SiO2;
AcOEt/pentane 1:4) afforded a colorless oil (5.89 g, 18 mmol, 77%). Rf 0.68 (AcOEt/pentane 1 :4). IR: 3385,
1
2955, 2931, 1755, 1722, 1514. H-NMR (200 MHz, CDCl3): 6.01 (td, J ˆ 3.2, 12.5, 1 H); 5.86 (d, J ˆ 12.5, 1 H);
5.14 (br. s, 1 H); 4.60 (d, J ˆ 4.2, 2 H); 3.87 (d, J ˆ 3.2, 2 H); 1.38 (s, 9 H); 0.80 (s, 9 H); À0.38 (s, 6 H). 13C-NMR
(50.32 MHz, CDCl3): 169.97; 155.68; 139.85; 131.27; 79.78; 67.47; 42.32; 27.75; 26.33; 16.25; À6.41. EI-MS: 330
‡
(11, [M ‡ H] ), 289 (5), 274 (20), 216 (40), 116 (4), 73 (60), 57 (100).
3.3. (E)-[(Dimethyl)phenylsilyl]prop-2-en-1-yl N-(tert-Butoxycarbonyl)glycinate (11ab). FC (SiO2 ;
AcOEt/pentane 1:4) afforded a colorless oil (5.90 g, 17 mmol, 81%). IR: 3380, 2977, 1719, 1167. 1H-NMR
(200 MHz, CDCl3): 7.48 (m, 2 H); 7.34 (m, 3 H); 6.10 (dt, J ˆ 3.4, 18.8, 1 H); 5.94 (d, J ˆ 18.8, 1 H); 5.06 (br. s,
1 H); 4.68 (d, J ˆ 2.1, 2 H); 3.93 (d, J ˆ 3.4, 2 H); 1.43 (s, 9 H); 0.32 (s, 6 H). 13C-NMR (50.32 MHz, CDCl3):
169.97; 155.65; 140.31; 137.80; 133.73; 131.68; 129.11; 127.78; 79.93; 67.24; 42.37; 28.24; À2.86. CI-MS (NH3): 350
‡
(12, [M ‡ H] ), 278 (5), 216 (23), 176 (45), 57 (100).
(E)-3-[(Trimethylsilyl)prop-2-en-1-yl N-(Benzyloxycarbonyl)glycinate (11mc). FC (SiO2; AcOEt/pentane
1:4) gave 11mc (6.42 g, 20 mmol, 65%). Rf 0.52 (AcOEt/pentane 3 :7). IR: 3360, 2956, 1777, 1529, 1249, 1193.
1H-NMR (200 MHz, CDCl3): 7.26 (s, 5 H); 5.99 (dt, J ˆ 4.3, 18.8, 1 H); 5.89 (d, J ˆ 18.8, 1 H); 5.33 (br. s, 1 H);
5.06 (s, 2 H); 4.60 (d, J ˆ 4.2, 2 H); 3.94 (d, J ˆ 5.4, 2 H); 0.02 (s, 9 H). 13C-NMR (50.32 MHz, CDCl3): 169.68;
156.27; 138.43; 136.26; 134.37; 128.50; 128.14; 128.06; 67.63; 67.06; 42.76; À1.53. CI-MS: (NH3): 339 (6, [M ‡
‡
H] ), 322 (25), 278 (22), 131 (12), 91 (100).
3.4. (E)-3-(Trimethylsilyl)prop-2-en-1-yl N-(Benzoyl)glycinate (11mz). FC (SiO2; AcOEt/pentane 1:4)
gave 11mz (5.2 g, 18 mmol, 60%). Rf 0.38 (AcOEt/pentane 3 :7). IR: 3343, 2957, 1751, 1651, 1539. 1H-NMR
(200 MHz, CDCl3): 7.36 7.22 (m, 5 H); 7.19 (br., 1 H); 5.94 (dt, J ˆ 4.3, 18.8, 1 H); 5.84 (d, J ˆ 18.8, 1 H); 4.54
(d, J ˆ 4.3, 2 H); 4.10 (d, J ˆ 5.3, 2 H); 0.04 (s, 9 H). 13C-NMR (50.32 MHz, CDCl3): 169.72; 167.66; 138.46;
‡
134.11; 133.66; 131.59; 128.41; 127.11; 67.52; 41.74; À1.58. CI-MS (NH3): 292 (10, [M ‡ H] ), 276 (5), 236 (8),
206 (19), 162 (41), 105 (21), 73 (100).
3.5. (E)-1-Methyl-3-(trimethylsilyl)prop-2-en-1-yl N-(tert-Butoxycarbonyl)glycinate (12mb). FC (SiO2;
AcOEt/pentane 1:4) gave a colorless oil (9.0 g, 30 mmol, 82%). IR: 3375, 2959, 2980, 1753, 1721, 1518, 1170.
1H-NMR (200 MHz, CDCl3): 5.91 (dd, J ˆ 4.3, 18.9, 1 H); 5.77 (d, J ˆ 18.9, 1 H); 5.31 (m, 1 H); 5.18 (br. s, 1 H);
3.84 (d, J ˆ 5.5, 2 H); 1.37 (s, 9 H); 1.24 (d, J ˆ 6.5, 3 H); 0.01 (s, 9 H). 13C-NMR (50.32 MHz, CDCl3): 169.49;
155.61; 143.86; 131.09; 79.70; 73.35; 42.52; 28.19; 19.66; À1.57. CI-MS (NH3): 214 (8), 120 (42), 73 (100), 57
(71).
3.6. (E)-1-Methyl-3-(trimethylsilyl)prop-2-en-1-yl N-(Benzyloxycarbonyl)glycinate (12mc). FC (SiO2;
AcOEt/pentane 1.4) gave a colorless oil (8.71 g, 26 mmol, 76%). 1H-NMR: 7.32 7.24 (5 H); 5.96 (dd, J ˆ
4.8, 18.8, 1 H); 5.83 (d, J ˆ 18.8, 1 H); 5.06 (s, 2 H); 5.3 (br. s, 1 H); 5.38 (m, 1 H); 3.94 (d, J ˆ 5.4, 2 H); 1.28
(d, J ˆ 6.5, 3 H); 0.49 (s, 9 H). 13C-NMR (50.32 MHz, CDCl3): 169.13; 156.20; 143.81; 136.24; 131.33; 128.41;

Helvetica Chimica Acta Vol. 85 (2002)
4179
‡
‡
128.04; 127.95; 73.59; 66.92; 42.89; 19.67; À1.57. CI-MS (NH3): 353 (10, [M ‡ NH4] ), 336 (20, [M ‡ H] ), 291
(18), 268 (42), 227 (6), 210 (40), 108 (28), 91 (45), 73.
3.7. (E)-3-[(Isopropyl)dimethylsilyl]prop-2-en-1-yl N-(tert-Butoxycarbonyl)glycinate (12pb). FC (SiO2;
AcOEt/pentane 1:4) gave a colorless oil (7.2 g, 22 mmol, 80%). IR: 3377, 1722, 1514, 1250, 1171. 1H-NMR
(200 MHz, CDCl3): 5.98 (dd, J ˆ 5.0, 18.8, 1 H); 5.82 (d, J ˆ 18.8, 1 H); 5.41 5.33 (m, 1 H); 5.02 (br., 1 H); 3.90
(d, J ˆ 3.4, 2 H); 1.44 (s,9 H); 1.30 (d, J ˆ 6.5, 3 H); 0.92 (d, J ˆ 7.1, 6 H); 0.81 0.72 (m, 1 H); 0.01 (s, 6 H).
13C-NMR (50.32 MHz, CDCl3): 169.79; 155.93; 145.24; 129.39; 80.13; 73.91; 42.91; 28.54; 20.12; 17.67; 13.68;
‡
‡
À5.22. EI-MS: 330 (22, [M ‡ H] ), 274 (11), 230 (95), 176 (78), 73 (30), 57 (100). CI-MS: 347, ([M ‡ NH4] ).
4. Ester Enolate Claisen Rearrangement. Method A. The silylated allyl ester (1 mmol) was added to a freshly
prepared soln. of LDA (2.5 mmol) in THF (5 ml). Me3SiCl(0.38 m,l 3 mmo)l was added after 3 min. The
resulting yellow soln. was diluted with AcOEt and hydrolyzed with 1n aq. HCl soln. The aq. layer was extracted
with AcOEt (2 Â 5 ml), the combined org. layers were dried (MgSO4), and the solvent was removed in vacuo.
Method B. To a soln. of potassium hexamethyldisilazide (KHMDS) in anh. THF (25 ml) at À788 was added
Me3SiCl. After 5 min, a soln. of the ester in THF (2 ml) was added dropwise. The mixture was allowed to warm
to r.t. overnight, mixed with 1n aq. HClsonl ., stirred for 10 min, and extracted with sat. NaHCO soln. (2Â).
3
Method C. A soln. of lithium hexamethyldisilazide (LHMDS) in hexanes (1.0m, 3.3 ml, 3.3 mmol) in anh.
THF (2 ml) at À788 was added to the allyl ester (0.37 g, 1.3 mmol). After 3 min, Me3SiCl(0.49 ml, 0.39 mmol)
was added, followed by Et3N (0.54 ml, 0.39 mmol). The soln. was stirred for 10 min, the cooling bath was
removed, the soln. was diluted with AcOEt (2 ml) and 1n HCl soln. (4 ml), and stirred vigorously for 10 min.
The aq. layer was extracted with AcOEt (2 Â 5 ml). The combined org. layers were dried over MgSO4, and the
solvent was removed in vacuo.
Esterification of Crude Products. To a soln. of the crude carboxylic acid in MeOH (10 ml), obtained by
Methods A C, was slowly added Me3SiCHN2 [24] via syringe until the yellow color persisted and evolution of
N2 gas stopped.
4.1. Methyl (E)-2-[(tert-Butoxycarbonyl)amino]-3-(trimethylsilyl)pent-4-enoate (13mb). FC (SiO2 ;
AcOEt/pentane 1:3 gave a colorless oil (0.35 g, 1.1 mmol, 85%). IR: 3443, 2957, 1741, 1251. 1H-NMR
(300 MHz, CDCl3): 5.55 (m, 1 H); 5.12 (s, 1 H); 4.97 (dd, J ˆ 16.8, 10.7, 2 H); 4.37 (m, 1 H); 3.65 (s, 3 H); 1.91
(dd, J ˆ 8.6, 16.0, 1 H); 1.38 (s, 9 H); 0.03 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 172.68; 154.98; 134.05; 116.79;
‡
79.86; 53.75; 51.77; 39.75; 28.30; À2.54. CI-MS (NH3): 318 (5, [M ‡ NH4 ]), 302 (5), 246 (14), 202 (4), 186 (27),
‡
112 (92), 73 (94), 57 (100). HR-MS: 302.1775 (C14H28NO4Si ; calc. 302.1788).
4.2. Methyl (E)-2-[(tert-Butoxycarbonyl)amino]-3-[(tert-butyl)dimethylsilyl]pent-4-enoate (13bb). FC
(SiO2; AcOEt/pentane 1:3) gave a colorless oil (0.14 g, 0.40 mmol, 40%). IR: 3444, 2957, 1718, 1491, 1366.
1H-NMR (300 MHz, CDCl3): 5.60 (m, 1 H); 5.32 (br., 1 H); 4.77 (m, 3 H); 3.25 (s, 3 H); 2.16 (dd, J ˆ 6.9, 16.8,
1 H); 1.42 (s, 9 H); 0.90 (s, 9 H); 0.12 (s, 3 H); 0.01 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 172.11; 155.11; 135.81;
‡
117.59; 79.44; 54.60; 51.17; 37.16; 27.46; 27.28; 18.56; À6.80; À7.79. EI-MS: 344 ([M ‡ H] ), 287 (2), 270 (3), 230
‡
(32), 170 (21), 154 (16), 118 (44), 81 (53), 73 (100), 57 (89), 41 (33). HR-MS: 344.2257 ([M ‡ H] ,
C17H34NO4Si; calc. 344.1762).
4.3. Methyl (E)-2-[(tert-Butoxycarbonyl)amino]-3-[(dimethyl)phenylsilyl]pent-4-enoate (13ab). FC (SiO2;
AcOEt/pentane) gave a colorless oil (0.62 g, 0.25 mmol, 65%). IR: 3441, 2984, 1742, 1373, 1242. 1H-NMR
(300 MHz, CDCl3): 7.50 (d, J ˆ 3.4, 2 H); 7.19 (m, 3 H); 5.59 (m, 1 H); 5.02 (dd, J ˆ 1.6, 10.1, 1 H); 4.90 (br.,
1 H); 4.90 (dd, J ˆ 1.2, 16.9, 1 H); 4.37 (br. m, 1 H); 3.53 (s, 3 H); 2.18 (dd, J ˆ 6.4, 10.3, 1 H); 0.98 (s, 9 H); 0.04
(s, 6 H). 13C-NMR (75 MHz, CDCl3): 172.54; 154.87; 137.01; 134.07; 129.24; 127.78; 117.04; 79.78; 54.01; 51.64;
‡
39.40; 28.30; À3.85; À4.19. EI-MS: 364 (32, [M ‡ H] ), 308 (26), 264 (54), 230 (100), 186 (15), 170 (66), 135
‡
(142), 81 (17), 69 (9). HR-MS: 364.1944 (C17H33NO4Si ; calc. 364.1589).
4.4. Methyl (E)-2-[(tert-Butoxycarbonyl)amino]-3-(trimethylsilyl)hex-4-enoate (14mb). FC (SiO2; AcOEt/
pentane 1:3) gave a colorless oil (0.43 g, 1.4 mmol, 92%). IR: 3439, 2980, 1710, 1497, 1250, 842. 1H-NMR
(75 MHz, CDCl3): 5.39 (m, 1 H); 5.17 (m, 1 H); 5.02 (br., 1 H); 4.35 (br., 1 H); 3.70 (s, 3 H); 1.83 (dd, J ˆ 5.7,
10.6, 1 H); 1.67 (d, J ˆ 6.3, 3 H); 1.43 (s, 9 H); 0.05 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 169.49; 155.61; 143.85;
‡
131.09; 79.70; 73.35; 51.81; 53.52; 28.20; 19.66; À1.57. EI-MS: 316 (2, [M ‡ H] ), 198 (6), 156 (5), 134 (21), 111
‡
(82), 95, 73 (80), 57 (100). HR-MS: 316.1638 (C15H23NO4Si ; calc. 316.1688).
4.5. Methyl (E)-2-[(tert-Butoxycarbonyl)amino]-3-[(isopropyl)dimethylsilyl)hex-4-enoate (14pb). FC
1
(SiO2; AcOEt/pentane 1.3) gave a colorless oil (0.41 g, 1.2 mmol, 78%). H-NMR (300 MHz, CDCl3): 5.38
2.24 (m, 1 H); 5.17 5.08 (m, 1 H); 5.02 4.49 (m, 1 H); 4.26 (br., 1 H); 3.61 (s, 3 H); 1.88 (dd, J ˆ 6.0, 10.8,
1 H); 1.60 (d, J ˆ 5.1, 3 H); 1.36 (s, 9 H); 0.86 (d, J ˆ 6.5, 6 H); 0.74 (m, 1 H); 0.03 (s, 6 H). 13C-NMR (75 MHz,
CDCl3): 172.79; 154.94; 127.72; 126.36; 79.70; 53.93; 51.59; 35.71; 28.27; 17.62; 17.47; 12.00; À6.64. EI-MS: 344

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‡
(6, [M ‡ H] ), 288 (22), 270 (7), 244 (24), 126 (43), 95 (100), 73 (70), 57 (100). HR-MS: 344.225
‡
([M ‡ H] , C17H34NO4Si; calc. 344.224).
4.6. Methyl (E)-2-[Benzyloxycarbonyl)amino]-3-(trimethylsilyl)hex-4-enoate (14mc). FC (SiO2; AcOEt/
pentane 1:3) gave a colorless oil (0.36 g, 1.0 mmol, 80%). IR: 3351, 2955, 1726, 1503, 1250, 842. 1H-NMR
(300 MHz, CDCl3): 7.25 (m, 5 H); 5.36 (m, 2 H); 5.08 (m, 3 H); 4.35 (br., 1 H); 3.64 (s, 3 H); 1.81 (dd, J ˆ 5.4,
10.6, 1 H); 1.61 (dd, J ˆ 1.4, 6.4, 3 H); 0.05 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 172.29; 155.48; 136.29; 128.41;
‡
128.18; 128.07; 125.67; 66.83; 54.29; 51.73; 38.03; 29.60; 16.40; À2.54. EI-MS: 350 (4, M ), 290 (3), 258 (5), 199
(3), 91 (100), 73 (51).
4.7. Methyl (E)-2-[(Benzoyl)amino]-3-(trimethylsilyl)hex-4-enoate (14mz). FC (SiO2; AcOEt/pentane
1:3) gave a colorless oil (0.22 g, 0.71 mmol, 71%). IR: 3351, 2955, 1744, 1652, 1526, 1249. 1H-NMR (300 MHz,
CDCl3): 7.29 (m, 5 H); 5.33 (m, 1 H); 5.23 (m, 1 H); 5.06 (m, 2 H); 4.37 (br. m, 1 H); 3.65 (s, 1 H); 1.80 (dd, J ˆ
5.4, 10.7, 1 H); 1.61 (dd, J ˆ 1.2, 6.3, 3 H); À0.03 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 172.20; 166.39; 133.90;
131.50; 128.44; 128.15; 127.89; 126.88; 125.95; 52.85; 51.78; 37.92; 17.99; À2.52.
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Received June 10, 2002