Stereoselective β-hydroxy-α-amino acid synthesis via an ether-directed, palladium-catalysed aza-Claisen rearrangement

Article abstract of DOI:10.1039/b510808j

A highly diastereoselective synthesis of (2S,3S)-β-hydroxy-α- amino acids has been developed from enantiopure α-hydroxy acids using a MOM-ether-directed, palladium(II)-catalysed, aza-Claisen rearrangement of allylic acetimidates to effect the key step. This highly stereoselective process gave allylic amides in diastereomeric ratios of up to 14 : 1. Problems associated with the isolation of 1,3-products (anti-Claisen) from sterically demanding substrates via an in situ palladium(0)-catalysed rearrangement process were overcome by the addition of a re-oxidant, p-benzoquinone, leading to cleaner reactions and improved yields of the 3,3-products (Claisen). The target β-hydroxy-α-amino acids are an important class of natural products that are also components of more complex organic compounds with significant biological properties. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b510808j

View Online / Journal Homepage / Table of Contents for this issue
A R T I C L E
Stereoselective b-hydroxy-a-amino acid synthesis via an
ether-directed, palladium-catalysed aza-Claisen rearrangement
Kate N. Fanning, Andrew G. Jamieson and Andrew Sutherland*
WestChem, Department of Chemistry, The Joseph Black Building, University of Glasgow,
Glasgow, UK G12 8QQ. E-mail: andrews@chem.gla.ac.uk; Fax: 0141 330 4888;
Tel: 0141 330 5936
Received 1st August 2005, Accepted 18th August 2005
First published as an Advance Article on the web 9th September 2005
A highly diastereoselective synthesis of (2S,3S)-b-hydroxy-a-amino acids has been developed from enantiopure
a-hydroxy acids using a MOM-ether-directed, palladium(II)-catalysed, aza-Claisen rearrangement of allylic
acetimidates to effect the key step. This highly stereoselective process gave allylic amides in diastereomeric ratios of
up to 14 : 1. Problems associated with the isolation of 1,3-products (anti-Claisen) from sterically demanding
substrates via an in situ palladium(0)-catalysed rearrangement process were overcome by the addition of a re-oxidant,
p-benzoquinone, leading to cleaner reactions and improved yields of the 3,3-products (Claisen). The target
b-hydroxy-a-amino acids are an important class of natural products that are also components of more complex
organic compounds with significant biological properties.
modified, monomeric cobalt oxazoline palladacycle which can
Introduction
catalyse the rearrangement of allylic trichloroacetimidates in
Thermally promoted [3,3]-sigmatropic rearrangements of allylic
good yield and with high asymmetric induction.6
imidates to allylic amides has found widespread application
We have made our own contribution to this field, utilising a
in organic chemistry due to the ease of transformation of
substrate-directed aza-Claisen rearrangement for the stereose-
readily available allylic alcohols under mild conditions to less
lective synthesis of allylic amides.7 Substrate-directed reactions
available allylic amines and derivatives.1 The reaction pathway
for this transformation proceeds via a highly ordered chair-like
transition state allowing excellent transfer of chirality to the final
involve the pre-association of reagents with chiral functional
groups in the vicinity of the reacting centre resulting in a
stereoselective process.8 Using a series of allylic trichloroace-
product.1b This conservation of stereochemistry has led to the
timidates with various ether groups, it was shown that the
use of the reaction for the asymmetric synthesis of a number of
methoxymethyl (MOM) ether is the most effective at directing
natural products.2
the facial coordination of the palladium(II) catalyst, yielding the
The metal-catalysed version of this reaction (aza-Claisen) first
major stereoisomer in 82% de (Scheme 2).7 Further evidence
reported by Overman1 using Hg(II) salts and then by Ikariya3
for this directing effect was achieved by the rearrangement
using Pd(II) salts can be carried out at room temperature, giving
of a carbon analogue of the MOM ether substrate, which
the desired allylic amides cleanly in high yields. The reaction
produced the corresponding amide in only 33% de. Following
pathway for the palladium(II)-catalysed aza-Claisen reaction
on from this work, we decided to explore the versatility of
has been shown to follow a cyclisation-induced rearrangement
this MOM-ether-directing effect for the general preparation of
mechanism involving intramolecular aminopalladation of the
chiral allylic amides and to utilise these compounds for the
alkene followed by reductive elimination to generate the amide
stereoselective synthesis of biologically important b-hydroxy-
products (Scheme 1).4
a-amino acids.9 We now describe this work in full, as well as
the unexpected isolation of 1,3-products (anti-Claisen) from
these rearrangements via a Pd(0)-catalysed allylic substitution
reaction.
Scheme 1 Pd(II)-catalysed rearrangement of allylic imidates via a
cyclisation-induced mechanism.
Work on the development of asymmetric metal-catalysed aza-
Claisen rearrangements has focused on the preparation of chiral
Pd(II) catalysts.5 While many of these catalysts are complex in
Scheme
2
Stereoselective
rearrangement.
MOM-ether-directed
aza-Claisen
structure, Overman and co-workers have recently reported a
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 4 9 – 3 7 5 6
3 7 4 9
©

View Online
Table 1 Aza-Claisen rearrangement of E-allylic trichloroacetimidates
25–29
Results and discussion
Our initial aim in this project was the development of a flexible,
efficient route for the synthesis of a series of E-allylic alcohols
(Scheme 3). Commercially available a-hydroxy acids10 were con-
verted to MOM-protected a-hydroxy esters 5–9 by esterification
using hydrochloric acid and methanol followed by reaction with
bromomethyl methyl ether and Hu¨nig’s base. In previous work
we have found it difficult to handle certain 2-methoxymethoxy
aldehydes due to the volatility and easy decomposition of these
compounds.7 Therefore, the MOM-protected a-hydroxy esters
5–9 were reduced directly to the corresponding alcohols 10–14
using DIBAL-H.7 These were converted to E-allylic esters 15–
19 in good yields using a one-pot, Swern oxidation/Horner–
Wadsworth–Emmons (HWE) reaction, thereby avoiding iso-
lation of the volatile and unstable aldehyde intermediates.11
Finally, reduction, again using DIBAL-H, gave the desired E-
allylic alcohols 20–24.
Entry
R
Yielda
Ratiob (a : b : c)
1
2
3
4
5
Me (30)
64%
58%
60%
54%
65%
10 : 1 : 0
0 : 1 : 2
14 : 1 : 1
12 : 1 : 0
9 : 1 : 4
iPr (31)
iBu (32)
PhCH2 (33)
PhCH2CH2 (34)
a Isolated combined yields of a, b and c from E-allylic alcohol. b Ratio
in crude reaction mixture.
using sodium hydride as a base.13 However, in our hands, the use
of DBU is more reliable, giving the allylic trichloroacetimidates
in higher yields. Allylic trichloroacetimidates are known to be
relatively unstable14 and thus, the work-up and purification of
these compounds involves simply washing the reaction mixture
through a small dry flash column of silica gel followed by
removal of the solvent in vacuo.
The aza-Claisen rearrangement of E-allylic trichloroace-
timidates 25–29 was carried out at room temperature using
bis(acetonitrile)palladium(II) chloride as the catalyst (Scheme 4,
Table 1). As previously reported, rearrangement of substrate
25 (R = Me) is essentially complete after 4 hours to give
an excellent 10 : 1 ratio of diastereomers 30a and 30b (3,3-
Claisen products) in 64% yield.7 Surprisingly, similar treatment
i
of substrate 26 (R = Pr) with the Pd(II) catalyst required
48 hours for completion of the reaction and yielded none of the
usual (3R,4S)-diastereomer 31a. Instead, the major products
from this reaction are the (3S,4S)-diastereomer 31b and the
1,3-product (anti-Claisen) 31c in a 1 : 2 ratio. The groups
of Ikariya and Bosnich have investigated the metal-catalysed
rearrangement of allylic imidates using both Pd(II) and Pd(0)
complexes.3,4b These studies clearly demonstrated that the use of
Pd(II) gives exclusively the 3,3-product (Claisen) while Pd(0), via
a non-concerted ionisation pathway, produces predominantly
the 1,3-product (anti-Claisen). Overman and co-workers have
also reported the isolation of 1,3-products via an ionisation
pathway.5c,15 MOM-ether-directed rearrangement of substrate
26 is obviously suppressed by the combined steric bulk of the
isopropyl group and the MOM ether. This steric hindrance also
slows the formation of the other products, including the (3S,4S)-
diastereomer 31b, which is produced by direct coordination
of the Pd(II) catalyst to the least hindered face of the alkene,
followed by a concerted, cyclisation-induced rearrangement
mechanism to give this specific stereoisomer.7 Based on the
work of Ikariya and Bosnich described above,3,4b it is proposed
that 1,3-product 31c is formed via a Pd(0)-catalysed allylic
substitution reaction (Scheme 5) and that the Pd(0) likely arises
by a competing b-elimination process during the slow Pd(II)-
catalysed rearrangement of allylic imidate 26.
Scheme 3 Reagents and conditions: i. conc. HCl, MeOH, toluene, D; ii.
MOMBr, EtN(iPr)2, CH2Cl2, D; iii. DIBAL-H (2.2 equiv.), Et2O, −78 ◦C
to RT; iv. DMSO, (COCl)2, NEt3, CH2Cl2, −78 ◦C to RT, then triethyl
phosphonoacetate, LiCl, DBU, MeCN.
Fortunately, treatment of allylic imidates 27–29 with the Pd(II)
catalyst gave the desired (3R,4S)-diastereomers 32–34a in good
yield and excellent stereoselectivity (up to 14 : 1) (Table 1). The
sterically encumbered tertiary centres contained within the side
chains of these substrates are now further away from the reacting
sp2 centre of the alkene, allowing the MOM-ether-directed
Treatment of E-allylic alcohols 20–24 with DBU and
trichloroacetonitrile provided E-allylic trichloroacetimidates
25–29,12 the substrates required for the directed aza-Claisen re-
arrangement (Scheme 4). This transformation can be carried out
Scheme 4 Reagents and conditions: i. Cl3CCN, DBU, CH2Cl2, 0 ◦C to RT; ii. PdCl2(MeCN)2, THF, RT.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 4 9 – 3 7 5 6
3 7 5 0

View Online
Scheme 5 Pd(0)-catalysed formation of 1,3-products (anti-Claisen).
process to take effect. Nevertheless, significant amounts of the
1,3-products were still isolated from these reactions, resulting in
slightly lower than expected yields for the 3,3-products. Thus,
while these substrates are able to undergo the MOM-ether-
directed rearrangement, the reactions are still slow enough to
produce trace amounts of Pd(0), which catalyses formation of
the 1,3-products.
In an effort to optimise the yield of the 3,3-products and
also provide evidence for the Pd(0)-catalysed formation of the
1,3-products, a suitably mild reagent was sought which could
rapidly re-oxidise Pd(0) back to Pd(II). p-Benzoquinone is widely
used for such a purpose in the Pd(II)-catalysed oxidation of
alkenes.16,17 Therefore, we were gratified to note that treatment of
allylic imidates 27–29 with the Pd(II) catalyst and 2 equivalents
of p-benzoquinone gave only the 3,3-products with improved
yields from the corresponding allylic alcohol and again, in
excellent stereoselectivity (Table 2). These experiments clearly
demonstrate both the presence of Pd(0) during the Pd(II)-
catalysed aza-Claisen rearrangement of allylic imidates 27–29
and also the effective suppression of this competing Pd(0)-
catalysed pathway using p-benzoquinone as a re-oxidant.
The (3R,4S)-allylic amides produced using the MOM-ether-
directed aza-Claisen rearrangement were then converted to the
corresponding (2S,3S)-b-hydroxy-a-amino acids (Scheme 6).
Oxidation of the allylic amides was carried out according to
the Sharpless protocol using catalytic ruthenium(III) trichloride
hydrate and sodium metaperiodate.18 Deprotection of the result-
ing carboxylic acids 35–38 under acidic conditions followed by
purification with ion exchange chromatography gave the target
compounds in good yields. Spectroscopic data for the (2S,3S)-
b-hydroxy-a-amino acids were entirely consistent with literature
reports,19,20 thereby confirming our previous stereochemical
assignment of the rearrangement products using oxazolidin-2-
one derivatives and NOE experiments.7
Scheme 6 Reagents and conditions: i. RuCl3·xH2O, NaIO4, H2O, CCl4,
MeCN; ii. 6 M HCl, D.
In summary, we have developed a novel approach for the
diastereoselective synthesis of b-hydroxy-a-amino acids from
enantiopure a-hydroxy acids. These target compounds are an
important class of natural products that are also components
of more complex organic compounds with interesting biolog-
ical properties.9 While the key step, the MOM-ether-directed
palladium-catalysed aza-Claisen rearrangement does provide
the desired 3,3-products in good yields and excellent diastereos-
electivity, 1,3-products were also isolated via a competing Pd(0)
pathway. However, this pathway was effectively inhibited using
p-benzoquinone as an oxidant of Pd(0), resulting in the isolation
of only the 3,3-products in greater yields and again with excellent
stereoselectivity. Catalytic ruthenium oxidation of the resulting
allylic amides and deprotection under acid conditions completed
the synthesis of the b-hydroxy-a-amino acids.
Experimental
All reactions were performed under a nitrogen atmosphere
unless otherwise noted. Reagents and starting materials were
obtained from commercial sources and used as received. THF
and diethyl ether were distilled from sodium and benzophenone.
Lithium chloride was oven dried (100 ◦C) for at least 12 h before
use. Brine refers to a saturated solution of sodium chloride.
Flash column chromatography was carried out using Fisher
Matrex silica 60. Macherey–Nagel aluminium-backed plates
pre-coated with silica gel 60 (UV254) were used for thin layer
chromatography and were visualised by staining with KMnO4.
1H NMR and 13C NMR spectra were recorded on a Bruker DPX
400 spectrometer with chemical shift values in ppm relative to
residual chloroform (dH 7.28 and dC 77.2) as standard. Infrared
spectra were recorded using Golden Gate apparatus on a JASCO
FTIR 410 spectrometer and mass spectra were obtained using a
JEOL JMS-700 spectrometer. Optical rotations were determined
as solutions irradiating with the sodium D line (k = 589 nm)
using a AA series Automatic polarimeter. [a]D values are given
in units 10−1 deg cm2 g−1.
Table 2 Treatment of allylic imidates 27–29 with the Pd(II) catalyst and
p-benzoquinone
Entry
R
Yielda
Ratiob (a : b)
1
2
3
iBu (32)
PhCH2 (33)
PhCH2CH2 (34)
73%
70%
69%
14 : 1
12 : 1
9 : 1
Esterification of a-hydroxy acids
The a-hydroxy acid (5 mmol) was dissolved in toluene (40 mL)
and methanol (25 mL). Concentrated hydrochloric acid (1 mL)
was added and the reaction mixture was heated under reflux
overnight. The reaction mixture was cooled to room temperature
a Isolated combined yields of a and b from E-allylic alcohol. b Ratio in
crude reaction mixture.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 4 9 – 3 7 5 6
3 7 5 1

View Online
and concentrated in vacuo. The resulting residue was neutralised
with saturated sodium hydrogen carbonate solution (50 mL)
and extracted with ethyl acetate (3 × 50 mL). The combined
organic layers were dried (MgSO4), filtered and concentrated.
Purification by Kugelrohr distillation gave the a-hydroxy esters
as colourless oils. Hydroxy ester 3 became a white solid on
standing.
(1H, d, J 7.2 Hz, OCHHO); dC (100 MHz, CDCl3) 17.7 (CH3),
18.8 (CH3), 31.5 (CH), 51.7 (CH3), 56.1 (CH3), 80.7 (CH), 96.5
(CH2), 172.9 (C); m/z (CI) 177.1126 (MH+. C8H17O4 requires
177.1127), 145 (100%), 117 (34) and 79 (38).
Methyl (2S)-2-methoxymethoxy-4-methylpentanoate (7).
71% yield; mmax/cm−1 (neat) 2956 (CH), 1750 (CO), 1203, 1158,
1026, 917; [a]2D0 −66.0 (c 1.0, CHCl3); dH (400 MHz, CDCl3)
0.95 (3H, d, J 6.4 Hz, 5-H3), 0.96 (3H, d, J 6.4 Hz, 4-CH3),
1.50–1.57 (1H, m, 3-HH), 1.67–1.76 (1H, m, 3-HH), 1.78–1.87
(1H, m, 4-H), 3.40 (3H, s, OMe), 3.75 (3H, s, CO2Me), 4.16
(1H, dd, J 9.2, 4.4 Hz, 2-H), 4.66 (1H, d, J 6.8 Hz, OCHHO),
4.69 (1H, d, J 6.8 Hz, OCHHO); dC (100 MHz, CDCl3) 21.5
(CH3), 23.2 (CH), 24.4 (CH3), 41.8 (CH2), 51.9 (CH3), 56.1
(CH3), 74.3 (CH), 96.4 (CH2), 173.7 (C); m/z (CI) 191.1289
(MH+. C9H19O4 requires 191.1283) and 159 (100%).
Methyl (2S)-2-hydroxy-3-methylbutanoate (1). 84% yield;
[a]2D1 +24.3 (c 1.0, CHCl3); lit.21 [a]2D5 +23.1 (c 2.5, CHCl3); dH
(400 MHz, CDCl3) 0.87 (3H, d, J 6.8 Hz, 3-CH3), 1.03 (3H, d,
J 6.8 Hz, 4-H3), 2.02 (1H, sept of d, J 6.8, 3.6 Hz, 3-H), 2.66
(1H, d, J 6.4 Hz, OH), 3.80 (3H, s, CO2Me), 4.05 (1H, dd, J
6.4, 3.6 Hz, 2-H); dC (100 MHz, CDCl3) 16.0 (CH3), 18.8 (CH3),
32.2 (CH), 52.4 (CH3), 75.0 (CH), 175.4 (C); m/z (CI) 133.0872
(MH+. C6H13O3 requires 133.0865), 105 (8%) and 73 (7).
Methyl (2S)-2-methoxymethoxy-3-phenylpropanoate (8).
100% yield; [a]2D1 −56.6 (c 1.0, CHCl3); lit.25 (opposite
enantiomer) [a]D +55.7 (c 0.8, CHCl3); dH (400 MHz, CDCl3)
3.01 (1H, dd, J 14.0, 9.2 Hz, 3-HH), 3.09 (3H, s, OMe), 3.13
(1H, dd, J 14.0, 4.4 Hz, 3-HH), 3.76 (3H, s, CO2Me), 4.37
(1H, dd, J 9.2, 4.4 Hz, 2-H), 4.54 (1H, d, J 6.8 Hz, OCHHO),
4.66 (1H, d, J 6.8 Hz, OCHHO), 7.24–7.37 (5H, m, Ph); dC
(100 MHz, CDCl3) 39.2 (CH2), 52.1 (CH3), 55.7 (CH3), 76.3
(CH), 96.0 (CH2), 126.8 (CH), 128.4 (CH), 129.5 (CH), 137.0
(C), 172.6 (C); m/z (CI) 225.1124 (MH+. C12H17O4 requires
225.1127), 193 (100%), 162 (12), 133 (39) and 85 (22).
Methyl (2S)-2-hydroxy-4-methylpentanoate (2). 81% yield;
[a]2D0 +3.9 (c 1.0, CHCl3); lit.21 [a]2D5 +2.2 (c 2.2, CHCl3); dH
(400 MHz, CDCl3) 0.95 (3H, d, J 6.8 Hz, 5-H3), 0.94 (3H, d,
J 6.8 Hz, 4-CH3), 1.54–1.60 (2H, m, 3-H2), 1.83 (1H, m, 4-H),
2.63 (1H, d, J 6.0 Hz, OH), 3.79 (3H, s, CO2Me), 4.19 (1H, dt, J
7.6, 6.0 Hz, 2-H); dC (100 MHz, CDCl3) 21.6 (CH3), 23.3 (CH),
24.4 (CH3), 43.5 (CH2), 52.5 (CH3), 69.1 (CH), 176.4 (C); m/z
(CI) 147.1023 (MH+. C7H15O3 requires 147.1021), 143 (8%) and
119 (11).
Methyl (2S)-2-hydroxy-3-phenylpropanoate (3). 92% yield;
[a]2D1 −5.9 (c 1.0, CHCl3); lit.22 [a]2D0 −7.3 (c 1.0, CHCl3); dH
(400 MHz, CDCl3) 2.74 (1H, br s, OH), 3.00 (1H, dd, J 14.0,
6.8 Hz, 3-HH), 3.17 (1H, dd, J 14.0, 4.4 Hz, 3-HH), 3.81 (3H, s,
CO2Me), 4.49 (1H, dd, J 4.4, 2.4 Hz, 2-H), 7.23–7.36 (5H, m,
Ph); dC (100 MHz, CDCl3) 40.6 (CH2), 52.5 (CH3), 71.3 (CH),
126.9 (CH), 128.5 (CH), 129.5 (CH), 136.3 (CH), 174.6 (C); m/z
(EI) 180.0786 (M+. C10H12O3 requires 180.0786), 162 (34%), 150
(7), 121 (16) and 91 (100).
Methyl (2S)-2-methoxymethoxy-4-phenylbutanoate (9). 86%
yield; mmax/cm−1 (neat) 2949 (CH), 1749 (CO), 1655 (C C), 1644,
=
1028; [a]1D8 −28.6 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 2.10 (2H,
td, J 8.4, 6.4 Hz, 3-H2), 2.68–2.84 (2H, m, 4-H2), 3.42 (3H, s,
OMe), 3.74 (3H, s, CO2Me), 4.15 (1H, t, J 6.4 Hz, 2-H), 4.68
(1H, d, J 6.8 Hz, OCHHO), 4.72 (1H, d, J 6.8 Hz, OCHHO),
7.18–7.31 (5H, m, Ph); dC (100 MHz, CDCl3) 31.4 (CH2), 34.5
(CH2), 52.0 (CH3), 56.2 (CH), 75.1 (CH3), 96.5 (CH2), 126.1
(CH), 128.5 (CH), 128.5 (CH), 141.0 (C), 173.1 (C); m/z (CI)
207.1015 (MH+ − CH3OH. C12H15O3 requires 207.1021), 189
(89), 147 (52) and 105 (23).
Methyl (2S)-2-hydroxy-4-phenylbutanoate (4). 75% yield;
[a]1D9 +23.7 (c 1.0, CHCl3); lit.23 [a]2D5 +30.9 (c 2.1, CHCl3); dH
(400 MHz, CDCl3) 1.94–2.04 (1H, m, 3-HH), 2.11–2.21 (1H, m,
3-HH), 2.76–2.81 (2H, m, 4-H2), 2.84 (1H, d, J 5.6 Hz, OH), 3.79
(1H, s, CO2Me), 4.20 (1H, ddd, J 9.2, 5.6, 4.4 Hz, 2-H), 7.21–
7.35 (5H, m, Ph); m/z (EI) 194.0941 (M+. C11H14O3 requires
194.0943), 176 (8%), 117 (20), 105 (58) and 90 (100).
DIBAL-H reduction to alcohols 10–14
The ester (5 mmol) was dissolved in diethyl ether (30 mL) and
◦
cooled to −78 C. DIBAL-H (1 M in hexane) (2.2 equiv.) was
added dropwise and the reaction mixture was allowed to stir at
−78 ◦C for 1 h then overnight at room temperature. The reaction
mixture was cooled to 0 ◦C before being quenched by the
addition of a saturated solution of ammonium chloride (20 mL)
and being warmed to room temperature, producing a white
precipitate. The reaction mixture was filtered through a pad of
Preparation of methoxymethyl ethers (5–9)
N,N-Diisopropylethylamine (1.5 equiv.) and bromomethyl
methyl ether (1.5 equiv.) were added to a solution of the
a-hydroxy ester (5 mmol) in dichloromethane (20 mL). The
reaction mixture was then heated under reflux for 12 h before
being diluted with dichloromethane (50 mL) and washed with
2 M hydrochloric acid solution (25 mL). The organic layer
was dried (MgSO4) and concentrated in vacuo. Purification was
carried out by flash column chromatography using diethyl ether–
petroleum ether to give the desired compounds as colourless oils.
R
Celiteꢀ and washed with diethyl ether (3 × 100 mL). The filtrate
was then dried (MgSO4) and concentrated in vacuo. Purification
by flash column chromatography using diethyl ether–petroleum
gave the desired compounds as colourless oils.
(2S)-2-Methoxymethoxypropan-1-ol
(10). 71%
yield;
mmax/cm−1 (neat) 3409 (OH), 2930 (CH), 1454, 1377, 1141,
1101, 1025; [a]2D5 −80.0 (c 1.0, CHCl3); dH (400 MHz, CDCl3)
1.18 (3H, d, J 6.4 Hz, 3-H3), 2.60 (1H, br s, OH), 3.43 (3H, s,
OMe), 3.46 (1H, dd, J 11.8, 7.3 Hz, 1-HH), 3.57 (1H, dd, J
11.8, 2.8 Hz, 1-HH), 3.70 (1H, m, 2-H), 4.71 (1H, d, J 6.9 Hz,
OCHHO), 4.76 (1H, d, J 6.9 Hz, OCHHO); dC (100 MHz,
CDCl3) 17.4 (CH3), 55.9 (CH3), 67.4 (CH2), 77.3 (CH), 96.5
(CH2); m/z (CI) 121.0866 (MH+. C5H13O3 requires 121.0865),
119 (8%), 89 (100) and 87 (19).
Ethyl (2S)-2-methoxymethoxypropanoate (5). 82% yield;
[a]2D0 −92.3 (c 1.0, CHCl3); lit.24 [a]2D2 −88.1 (c 2.9, CHCl3); dH
(400 MHz, CDCl3) 1.29 (3H, t, J 7.0, OCH2CH3), 1.43 (3H, d,
J 7.0, 3-H3), 3.39 (3H, s, OMe), 4.21 (2H, q, J 7.0, OCH2CH3),
4.24 (1H, q, J 7.0, 2-H), 4.69 (1H, d, J 7.0, OCHHO), 4.72
(1H, d, J 7.0, OCHHO); dC (100 MHz, CDCl3) 14.9 (CH3), 18.5
(CH3), 55.9 (CH3), 60.9 (CH2), 71.5 (CH), 95.9 (CH2), 173.1
(C); m/z (CI) 163.0969 (MH+. C7H15O4 requires 163.0970), 131
(100%) and 119 (5).
Methyl
(2S)-2-methoxymethoxy-3-methylbutanoate
(6).
(2S)-2-Methoxymethoxy-3-methylbutan-1-ol
(11). 62%
60% yield; mmax/cm−1 (neat) 2965 (CH), 1748 (CO), 1201, 1152,
1041, 916; [a]2D0 −76.0 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 0.97
(3H, d, J 6.8 Hz, 3-CH3), 0.99 (3H, d, J 6.8 Hz, 4-H3), 2.04–2.15
(1H, m, 3-H), 3.39 (3H, s, OMe), 3.75 (3H, s, CO2Me), 3.89
(1H, d, J 5.6 Hz, 2-H), 4.66 (1H, d, J 7.2 Hz, OCHHO), 4.68
yield; mmax/cm−1 (neat) 3423 (OH), 2957 (CH), 1152, 1095, 1027,
916; [a]1D9 +80.3 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 0.94 (3H,
d, J 6.8 Hz, 3-CH3), 0.95 (3H, d, J 6.8 Hz, 4-H3), 1.78–1.90
(1H, m, 3-H), 3.17 (1H, dd, J 9.2, 3.2 Hz, OH), 3.29 (1H, m,
2-H), 3.45 (3H, s, OMe), 3.61 (1H, m, 1-HH), 3.61 (1H, ddd, J
3 7 5 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 4 9 – 3 7 5 6

View Online
12.0, 9.2, 2.4 Hz, 1-HH), 4.66 (1H, d, J 6.8 Hz, OCHHO), 4.76
(1H, d, J 6.8 Hz, OCHHO); dC (100 MHz, CDCl3) 18.2 (CH3),
18.9 (CH3), 30.3 (CH), 55.7 (CH3), 63.9 (CH2), 88.2 (CH), 97.8
(CH2); m/z (CI) 149.1174 (MH+. C7H17O3 requires 149.1178),
117 (100%), 87 (20) and 71 (18).
2-H), 6.87 (1H, dd, J 15.7, 6.3 Hz, 3-H); dC (100 MHz, CDCl3)
14.6 (CH3), 20.9 (CH3), 55.8 (CH3), 60.8 (CH2), 71.4 (CH), 94.8
(CH2), 121.4 (CH), 149.1 (CH), 166.7 (C); m/z (CI) 189.1125
(MH+. C9H17O4 requires 189.1127), 159 (39%), 143 (46), 127 (58)
and 101 (12).
(2S)-Methoxymethoxy-4-methylpentan-1-ol (12). 86% yield;
mmax/cm−1 (neat) 3402 (OH), 2951 (CH), 1469, 1099, 1029, 917;
[a]1D9 +57.1 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 0.90 (3H,
d, J 6.8 Hz, 5-H3), 0.92 (3H, d, J 6.8 Hz, 4-CH3), 1.20 (1H,
ddd, J 14.0, 8.4, 5.2 Hz, 3-HH), 1.47 (1H, ddd, J 14.0, 8.4,
5.6 Hz, 3-HH), 1.68–1.77 (1H, m, 4-H), 3.26 (1H, dd, J 9.2,
3.6 Hz, OH), 3.44 (3H, s, OMe), 3.47 (1H, m, 2-H), 3.55–3.65
(2H, m, 1-H2), 4.68 (1H, d, J 6.8 Hz, OCHHO), 4.73 (1H, d, J
6.8 Hz, OCHHO); dC (100 MHz, CDCl3) 22.2 (CH3), 23.2 (CH),
24.4 (CH3), 40.7 (CH2), 55.7 (CH3), 66.2 (CH2), 81.0 (CH), 97.1
(CH2); m/z (CI) 163.1333 (MH+. C8H19O3 requires 163.1334),
131 (100%), 101 (29), 83 (21).
Ethyl (2E,4S)-4-methoxymethoxy-5-methylhex-2-enoate (16).
79% yield for two steps; mmax/cm−1 (neat) 2965 (CH), 1718 (CO),
19
=
1656 (C C), 1249, 1153, 1029, 986, 920; [a]D −96.2 (c 1.0,
CHCl3); dH (400 MHz, CDCl3) 0.93 (3H, d, J 6.8 Hz, 5-CH3),
0.98 (3H, d, J 6.8 Hz, 6-H3), 1.31 (3H, t, J 7.2 Hz, OCH2CH3),
1.82–1.93 (1H, m, 5-H), 3.38 (3H, s, OMe), 3.95 (1H, m, 4-
H), 4.18 (2H, q, J 7.2 Hz, OCH2CH3), 4.58 (1H, d, J 6.8 Hz,
OCHHO), 4.63 (1H, d, J 6.8 Hz, OCHHO), 5.98 (1H, dd, J 15.6,
1.2 Hz, 2-H), 6.82 (1H, dd, J 15.6, 6.8 Hz, 3-H); dC (100 MHz,
CDCl3) 14.2 (CH3), 18.2 (CH3), 18.3 (CH3), 32.6 (CH), 55.7
(CH3), 60.5 (CH2), 80.2 (CH), 94.7 (CH2), 123.0 (CH), 146.5
(CH), 166.2 (C); m/z (CI) 217.1441 (MH+. C11H21O4 requires
217.1440), 187 (17%), 155 (100) and 127 (5).
(2S)-2-Methoxymethoxy-3-phenylpropan-1-ol (13). 70%
yield; mmax/cm−1 (neat) 3386 (OH), 2930 (CH), 1495, 1454, 1146,
1104, 1029, 913, 699; [a]2D1 +20.7 (c 1.0, CHCl3); dH (400 MHz,
CDCl3) 2.79–2.94 (3H, m, 3-H2 and OH), 3.37 (3H, s, OMe), 3.55
(1H, m, 1-HH), 3.67 (1H, m, 1-HH), 3.87 (1H, m, 2-H), 4.59
(1H, d, J 7.2 Hz, OCHHO), 4.70 (1H, d, J 7.2 Hz, OCHHO),
7.24–7.38 (5H, m, Ph); dC (100 MHz, CDCl3) 38.2 (CH2), 55.6
(CH3), 64.9 (CH2), 82.1 (CH), 96.7 (CH2), 126.4 (CH), 128.4
(CH), 129.4 (CH), 138.0 (C); m/z (CI) 197.1179 (MH+. C11H17O3
requires 197.1178), 165 (76%), 147 (100), 136 (12), 117 (15) and
105 (12).
Ethyl (2E,4S)-4-methoxymethoxy-6-methylhept-2-enoate (17).
83% yield over two steps; mmax/cm−1 (neat) 2954 (CH), 1718 (CO),
21
=
1659 (C C), 1266, 1161, 984, 919; [a]D −125.6 (c 1.0, CHCl3); dH
(400 MHz, CDCl3) 0.94 (3H, d, J 6.4 Hz, 6-CH3), 0.95 (3H, d, J
6.4 Hz, 7-H3), 1.30 (3H, t, J 7.2 Hz, OCH2CH3), 1.34 (1H, m, 5-
HH), 1.58 (1H, ddd, J 14.0, 8.4, 6.0 Hz, 5-HH), 1.73–1.84 (1H,
m, 6-H), 3.39 (3H, s, OMe), 4.20 (2H, q, J 7.2 Hz, OCH2CH3),
4.27 (1H, m, 4-H), 4.57 (1H, d, J 6.8 Hz, OCHHO), 4.64 (1H,
d, J 6.8 Hz, OCHHO), 5.97 (1H, dd, J 15.6, 1.2 Hz, 2-H), 6.81
(1H, dd, J 15.6, 6.8 Hz, 3-H); dC (100 MHz, CDCl3) 14.3 (CH3),
22.1 (CH3), 23.1 (CH3), 24.3 (CH), 44.2 (CH2), 55.7 (CH3), 60.5
(CH2), 73.6 (CH), 94.6 (CH2), 121.7 (CH), 148.2 (CH), 166.3
(C); m/z (CI) 231.1594 (MH+. C12H23O4 requires 231.1596), 201
(63%), 169 (100) and 129 (6).
(2S )-2-Methoxymethoxy-4-phenylbutan-1-ol (14). 79%
yield; mmax/cm−1 (neat) 3421 (OH), 2934 (CH), 1146, 1101, 1024,
916; [a]1D8 +47.5 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 1.78–1.94
(2H, m, 3-H2), 2.68 (1H, ddd, J 14.0, 9.6, 7.2 Hz, 4-HH), 2.80
(1H, ddd, J 14.0, 9.6, 5.6 Hz, 4-HH), 3.48 (3H, s, OMe), 3.54–
3.65 (3H, m, 2-H and 1-H2), 4.70 (1H, d, J 6.8 Hz, OCHHO),
4.80 (1H, d, J 6.8 Hz, OCHHO), 7.20–7.35 (5H, m, Ph); dC
(100 MHz, CDCl3) 31.7 (CH2), 33.3 (CH2), 55.8 (CH3), 65.8
(CH2), 81.9 (CH), 97.2 (CH2), 126.0 (CH), 128.4 (CH), 128.5
(CH), 141.7 (C); m/z (CI) 211 (MH+, 7%), 179 (92), 161 (100),
131 (55) and 105 (17); (Found: C, 68.4; H, 8.6. C12H18O3 requires
C, 68.5; H, 8.6%).
Ethyl (2E,4S)-4-methoxymethoxy-5-phenylpent-2-enoate (18).
81% yield over two steps; mmax/cm−1 (neat) 2925 (CH), 1716 (CO),
1268, 1149, 1016, 699; [a]2D1 −56.6 (c 1.0, CHCl3); dH (400 MHz,
CDCl3) 1.32 (3H, t, J 7.2 Hz, OCH2CH3), 2.92 (2H, d, J 6.8 Hz,
5-H2), 3.08 (3H, s, OMe), 4.23 (2H, q, J 7.2 Hz, OCH2CH3),
4.43–4.49 (2H, m, 4-H and OCHHO), 4.61 (2H, d, J 6.8 Hz,
OCHHO), 6.01 (1H, dd, J 15.6, 1.2 Hz, 2-H), 6.90 (1H, dd, J
15.6, 6.0 Hz, 3-H), 7.23–7.35 (5H, m, Ph); dC (100 MHz, CDCl3)
14.3 (CH3), 41.6 (CH2), 55.4 (CH3), 60.6 (CH2), 75.9 (CH), 94.5
(CH2), 122.1 (CH), 126.6 (CH), 128.4 (CH), 129.6 (CH), 137.4
(C), 147.1 (CH), 166.2 (C); m/z (EI) 264.1363 (M+. C15H20O4
requires 264.1362), 203 (2%), 173 (21), 136 (12), 129 (11), 85
(63) and 83 (100).
Synthesis of allylic esters 15–19 using the one-pot
Swern/Horner–Wadsworth–Emmons reaction
Methyl sulfoxide (2.4 equiv.) was added to a stirred solution
of oxalyl chloride (1.2 equiv.) in dichloromethane (20 mL) at
◦
−78 C. This mixture was stirred for 0.25 h before the alcohol
Ethyl (2E,4S)-4-methoxymethoxy-6-phenylhex-2-enoate (19).
(5 mmol) in dichloromethane (30 mL) was added. The mixture
was stirred for a further 0.25 h before triethylamine (5 equiv.) was
added. This reaction mixture was then allowed to stir for 2 h. In
a second flask, a solution of lithium chloride (1.5 equiv.), triethyl
phosphonoacetate (1.5 equiv.) and 1,8-diazabicyclo[5.4.0]undec-
7-ene (1.5 equiv.) in acetonitrile (30 mL) was prepared and stirred
for 0.5 h. The contents of the second flask were then added to
the Swern solution and the reaction mixture was allowed to
stir at room temperature overnight. The reaction was quenched
with brine (50 mL) and then concentrated in vacuo. This residue
was extracted with diethyl ether (5 × 50 mL) and the organic
layers were combined, dried (MgSO4) and concentrated to give
an orange liquid. Purification was carried out by flash column
chromatography using diethyl ether–petroleum ether to give the
desired compounds as colourless oils.
55% yield over two steps; mmax/cm−1 (neat) 2944 (CH), 1717
19
=
(CO), 1658 (C C), 1265, 1147, 1020; [a]D −52.0 (c 1.0, CHCl3);
dH (400 MHz, CDCl3) 1.31 (3H, t, J 7.2 Hz, OCH2CH3), 1.86–
2.02 (2H, m, 5-H2), 2.67–2.82 (2H, m, 6-H2), 3.41 (3H, s, OMe),
4.21 (2H, q, J 7.2 Hz, OCH2CH3), 4.25 (1H, m, 4-H), 4.62 (1H,
d, J 6.8 Hz, OCHHO), 4.67 (1H, d, J 6.8 Hz, OCHHO), 6.01
(1H, dd, J 15.6, 1.6 Hz, 2-H), 6.86 (1H, dd, J 15.6, 6.0 Hz,
3-H), 7.18–7.32 (5H, m, Ph); dC (100 MHz, CDCl3) 14.3 (CH3),
31.4 (CH2), 36.6 (CH2), 55.8 (CH3), 60.6 (CH2), 74.9 (CH), 94.8
(CH2), 122.2 (CH), 126.0 (CH), 128.4 (CH), 128.5 (CH), 141.5
(C), 147.6 (CH), 166.2 (C); m/z 279 (MH+, 52%), 247 (50), 217
(100), 216 (7) and 173 (6); (Found: C, 68.8; H, 8.0. C16H22O4
requires C, 69.0; H, 8.0%).
DIBAL-H reduction to allylic alcohols 20–24
Ethyl (2E,4S)-4-methoxymethoxypent-2-enoate (15). 58%
The allylic ester (4 mmol) was dissolved in diethyl ether
(20 mL) and cooled to −78 ◦C. DIBAL-H (1 M in hexane)
(2.2 equiv.) was added dropwise and the reaction mixture was
allowed to stir at −78 ◦C for 2 h then overnight at room
temperature. The reaction was cooled to 0 ◦C, quenched by
the addition of a saturated solution of ammonium chloride
yield for two steps; mmax/cm−1 (neat) 2981 (CH), 1720 (CO), 1660
21
=
(C C), 1271, 1032; [a]D −80.0 (c 1.0, CHCl3); dH (400 MHz,
CDCl3) 1.30 (6H, m, OCH2CH3 and 5-H3), 3.37 (3H, s, OMe),
4.20 (2H, q, J 7.1 Hz, OCH2CH3), 4.35 (1H, quin of d, J 6.6,
1.3 Hz, 4-H), 4.62 (2H, s, OCH2O), 5.99 (1H, dd, J 15.7, 2.1 Hz,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 4 9 – 3 7 5 6
3 7 5 3

View Online
(20 mL) and warmed to room temperature. The precipitate
(C); m/z (CI) 219 (MH+ − H2O, 12%), 199 (15), 175 (96), 157
R
was filtered through a pad of Celiteꢀ and washed with diethyl
(100) and 131 (86).
ether (3 × 100 mL). The filtrate was then dried (MgSO4) and
concentrated in vacuo. Purification was carried out by flash
column chromatography using diethyl ether–petroleum ether to
give the desired compounds as colourless oils.
Allylic trichloroacetimidate synthesis and subsequent
rearrangement with bis(acetonitrile)palladium(II) chloride
The allyic alcohol (2 mmol) was dissolved in dichloromethane
(20 mL) and cooled to 0 ◦C. 1,8-Diazabicyclo[5.4.0]undec-7-ene
(1.2 equiv.) and trichloroacetonitrile (1.5 equiv.) were then added
and the mixture was allowed to warm to room temperature and
stirred for 2 h. The reaction mixture was then filtered through
a dry silica plug and the filtrate was concentrated in vacuo to
give an orange liquid. The product was used without further
purification. The allylic trichloroacetimidate was dissolved in
THF (10 mL). Bis(acetonitrile)palladium(II) chloride (10 mol%)
was then added and the reaction mixture stirred for 24–48 h.
Concentration in vacuo followed by purification by flash column
chromatography eluting with diethyl ether–petroleum ether gave
all products as colourless oils.
(2E,4S)-4-Methoxymethoxypent-2-en-1-ol (20). 84% yield;
mmax/cm−1 (neat) 3404 (OH), 2931 (CH), 1446, 1373, 1217, 1026;
[a]2D3 −117.9 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 1.27 (3H, d, J
6.4 Hz, 5-H3), 2.21 (1H, br s, OH), 3.37 (3H, s, OMe), 4.14 (2H,
dd, J 5.1, 1.6 Hz, 1-H2), 4.16 (1H, quin, J 6.4 Hz, 4-H), 4.57
(1H, d, J 6.7 Hz, OCHHO), 4.66 (1H, d, J 6.7 Hz, OCHHO),
5.63 (1H, ddt, J 15.0, 7.0, 1.6 Hz, 3-H), 5.81 (1H, dt, J 15.0,
5.1 Hz, 2-H); dC (100 MHz, CDCl3) 21.3 (CH3), 55.3 (CH3),
63.0 (CH2), 72.0 (CH), 93.8 (CH2), 130.9 (CH), 132.8 (CH); m/z
(CI) 129.0910 (MH+ − H2O. C7H13O2 requires 129.0916), 117
(63) and 85 (100%).
(2E,4S)-4-Methoxymethoxy-5-methylhex-2-en-1-ol (21).
77% yield; mmax/cm−1 (neat) 3386 (OH), 2958 (CH), 1469, 1152,
1089, 1030, 973, 920; [a]D20 −124.3 (c 1.0, CHCl3); dH (400 MHz,
CDCl3) 0.89 (3H, d, J 6.8 Hz, 5-CH3), 0.96 (3H, d, J 6.8 Hz,
6-H3), 1.71 (1H, sept, J 6.8 Hz, 5-H), 1.86 (1H, t, J 5.6 Hz,
OH), 3.37 (3H, s, OMe), 3.73 (1H, br t, J 6.8 Hz, 4-H), 4.16
(2H, br t, J 5.6 Hz, 1-H2), 4.51 (1H, d, J 6.8 Hz, OCHHO), 4.69
(1H, d, J 6.8 Hz, OCHHO), 5.54 (1H, ddt, J 15.6, 8.0, 1.6 Hz,
3-H), 5.79 (1H, dt, J 15.6, 5.6 Hz, 2-H); dC (100 MHz, CDCl3)
18.5 (CH3), 18.6 (CH3), 32.7 (CH), 55.5 (CH3), 62.9 (CH2), 81.5
(CH), 93.7 (CH2), 129.6 (CH), 133.3 (CH); m/z (CI) 145.1227
(MH+ − CH2O. C8H17O2 requires 145.1229), 125 (8%), 113 (38),
95 (100) and 85 (110).
(3R,4S)-3-(Trichloromethylcarbonylamino)-4-(methoxymeth-
oxy)penta-1-ene (30a). 64% yield; mmax/cm−1 (neat) 3302 (NH),
2935 (CH), 1713 (CO), 1643 (C C), 1511, 1148, 1028, 819; dH
=
(400 MHz, CDCl3) 1.27 (3H, d, J 6.4 Hz, 5-H3), 3.44 (3H, s,
OMe), 3.87 (1H, qd, J 6.4, 2.4 Hz, 4-H), 4.37 (1H, m, 3-H),
4.70 (1H, d, J 6.8, OCHHO), 4.73 (1H, d, J 6.8 Hz, OCHHO),
5.36 (2H, m, 1-H2), 5.89 (1H, m, 2-H), 7.89 (1H, br s, NH);
dC (100 MHz, CDCl3) 18.4 (CH3), 56.2 (CH3), 58.1 (CH), 77.7
(CH), 92.1 (C), 97.0 (CH2), 119.6 (CH2), 131.8 (CH), 161.7 (C);
m/z (CI) 290.0127 (MH+. C9H15O3NCl3 requires 290.0118), 258
(76%), 246 (21), 214 (28), 196 (62) and 162 (29).
(3S,4S)-3-(Trichloromethylcarbonylamino)-4-(methoxymeth-
oxy)-5-methylhexa-1-ene (31b) and (2E,4S)-1-(trichloromethyl-
carbonylamino)-4-(methoxymethoxy)-5-methylhexa-2-ene (31c).
58% combined yield; 31c: mmax/cm−1 (neat) 3422 (NH), 2853
(CH), 1655, 1037, 992, 793; [a]1D8 −89.7 (c 1.0, CHCl3); dH
(400 MHz, CDCl3) 0.90 (3H, d, J 6.8 Hz, 5-CH3), 0.97 (3H, d, J
6.8 Hz, 6-H3), 1.74–1.84 (1H, m, 5-H), 3.38 (3H, s, OMe), 3.76
(1H, t, J 6.8 Hz, 4-H), 4.08 (2H, d, J 6.8 Hz, 1-H2), 4.53 (1H,
d, J 6.8 Hz, OCHHO), 4.69 (1H, d, J 6.8 Hz, OCHHO), 5.64
(1H, dd, J 15.2, 6.8 Hz, 3-H), 5.79 (1H, m, 2-H); dC (100 MHz,
CDCl3) 17.3 (CH3), 17.5 (CH3), 31.6 (CH), 43.3 (CH2), 54.5
(CH3), 76.2 (C), 79.7 (CH), 92.9 (CH2), 128.5 (CH), 132.3
(CH), 161.8 (C); m/z (CI) 276 (MH+ − CH3OCH2, 11%), 240
(11), 204 (5) and 168 (6); 31b: mmax/cm−1 (neat) 3422 (NH), 2862
(CH), 1680, 1041, 995; [a]2D5 +61.8 (c 1.0, CHCl3); dH (400 MHz,
CDCl3) 0.98 (3H, d, J 6.8 Hz, 5-CH3), 1.00 (3H, d, J 6.8 Hz,
6-H3), 1.77–1.86 (1H, m, 5-H), 3.13 (1H, dd, J 10.0, 1.6 Hz,
4-H), 3.44 (3H, s, OMe), 4.56 (1H, m, 3-H), 4.62 (1H, d, J
6.4 Hz, OCHHO), 4.79 (1H, d, J 6.4 Hz, OCHHO), 5.31 (1H,
d, J 10.0 Hz, 1-HH), 5.36 (1H, d, J 17.2 Hz, 1-HH), 5.80 (1H,
ddd, J 17.2, 10.0, 6.8 Hz, 2-H), 8.49 (1H, br d, J 6.8 Hz, NH);
dC (100 MHz, CDCl3) 18.9 (CH3), 19.6 (CH3), 31.0 (CH), 54.7
(CH3), 55.8 (CH), 90.9 (CH), 93.0 (C), 99.3 (CH2), 118.8 (CH2),
131.5 (CH), 161.5 (C); m/z (CI) 276 (MH+ − CH3OCH2, 12%),
240 (5), 204 (3) and 168 (2).
(2E,4S)-4-Methoxymethoxy-6-methylhept-2-en-1-ol (22).
87% yield; mmax/cm−1 (neat) 3332 (OH), 2952 (CH), 1560, 1092,
1029, 971, 916; [a]19 −126.4 (c 1.0, CHCl3); dH (400 MHz, CDCl3)
0.92 (3H, d, J 6.4DHz, 6-CH3), 0.94 (3H, d, J 6.4 Hz, 7-H3), 1.29
(1H, m, 5-HH), 1.56 (1H, m, 5-HH), 1.69–1.81 (1H, m, 6-H),
3.38 (3H, s, OMe), 4.12 (1H, m, 4-H), 4.15 (2H, dt, J 5.2, 1.2 Hz,
1-H2), 4.52 (1H, d, J 6.8 Hz, OCHHO), 4.71 (1H, d, J 6.8 Hz,
OCHHO), 5.55 (1H, ddt, J 15.6, 8.0, 1.2 Hz, 3-H), 5.79 (1H,
dt, J 15.6, 5.2 Hz, 2-H); dC (100 MHz, CDCl3) 22.3 (CH3),
23.0 (CH3), 24.3 (CH), 44.8 (CH2), 55.5 (CH3), 63.0 (CH2), 74.4
(CH), 93.6 (CH2), 131.8 (CH), 131.9 (CH); m/z (CI) 144 (MH+ −
CH3OCH2, 4%), 127 (100), 109 (92) and 85 (42).
(2E,4S)-4-Methoxymethoxy-5-phenylpent-2-en-1-ol (23).
83% yield; mmax/cm−1 (neat) 3370 (OH), 2888 (CH), 1635 (C C),
=
1496, 1453, 1092, 1028; [a]2D1 −86.3 (c 1.0, CHCl3); dH (400 MHz,
CDCl3) 1.42 (1H, s, OH), 2.86 (1H, dd, J 13.6, 5.6 Hz, 5-HH),
2.92 (1H, dd, J 13.6, 8.0 Hz, 5-HH), 3.08 (3H, s, OMe), 4.17 (2H,
m, 1-H2), 4.31 (1H, m, 4-H), 4.46 (1H, d, J 6.8 Hz, OCHHO),
4.68 (1H, d, J 6.8 Hz, OCHHO), 5.67 (1H, ddt, J 15.6, 7.6,
1.2 Hz, 3-H), 5.83 (1H, dt, J 15.6, 5.2 Hz, 2-H), 7.18–7.36 (5H,
m, Ph); dC (100 MHz, CDCl3) 42.3 (CH2), 55.2 (CH3), 62.9
(CH2), 76.8 (CH), 93.6 (CH2), 126.3 (CH), 128.2 (CH), 129.7
(CH), 130.9 (CH), 132.3 (CH), 138.2 (C); m/z (CI) 205 (MH+ −
H2O, 32%), 175 (21), 161 (69), 143 (100) and 129 (8).
(3R,4S)-3-(Trichloromethylcarbonylamino)-4-(methoxymeth-
oxy)-6-methylhepta-1-ene (32a) and (2E,4S)-1-(trichloromethyl-
carbonylamino)-4-(methoxymethoxy)-6-methylhepta-2-ene (32c).
60% combined yield; 32c: mmax/cm−1 (neat) 2594 (CH), 1769
(CO), 1469, 1154, 1096, 1035; [a]2D0 −91.1 (c 1.0, CHCl3); dH
(400 MHz, CDCl3) 0.92 (3H, d, J 6.4 Hz, 6-CH3), 0.93 (3H, d,
J 6.4 Hz, 7-H3), 1.25 (1H, ddd, J 13.6, 8.2, 5.6 Hz, 5-HH), 1.51
(1H, ddd, J 13.6, 8.2, 6.4 Hz, 5-HH), 1.70–1.81 (1H, m, 6-H),
3.37 (3H, s, OMe), 4.05 (2H, d, J 6.8 Hz, 1-H2), 4.11 (1H, m,
4-H), 4.51 (1H, d, J 6.8 Hz, OCHHO), 4.68 (1H, d, J 6.8 Hz,
OCHHO), 5.62 (1H, dd, J 15.2, 7.6 Hz, 3-H), 5.81 (1H, dt, J
15.2, 6.8 Hz, 2-H); dC (100 MHz, CDCl3) 22.2 (CH3), 23.0 (CH),
24.2 (CH3), 44.3 (CH2), 44.6 (CH2), 55.5 (CH3), 73.9 (CH), 93.8
(CH2), 96.2 (C), 128.3 (CH), 135.2 (CH), 161.9 (C); m/z (CI)
(2E,4S)-4-Methoxymethoxy-6-phenylhex-2-en-1-ol (24).
78% yield; (Found: C, 71.0; H, 8.6. C14H20O3 requires C, 71.2;
H, 8.6%); mmax/cm−1 (neat) 3408 (OH), 2927 (CH), 1603 (C C),
=
1146, 1093, 1028, 972, 917, 699; [a]1D6 −93.7 (c 1.0, CHCl3); dH
(400 MHz, CDCl3) 1.41 (1H, br s, OH), 1.80–2.03 (2H, m, 5-
H2), 2.63–2.81 (2H, m, 6-H2), 3.40 (3H, s, OMe), 4.09 (1H, q, J
7.2 Hz, 4-H), 4.17 (2H, dd, J 5.2, 1.6 Hz, 1-H2), 4.57 (1H, d, J
6.8 Hz, OCHHO), 4.72 (1H, d, J 6.8 Hz, OCHHO), 5.61 (1H,
ddt, J 15.6, 7.2, 1.6 Hz, 3-H), 5.84 (1H, dt, J 15.6, 5.2 Hz, 2-H),
7.17–7.32 (5H, m, Ph); dC (100 MHz, CDCl3) 31.7 (CH2), 37.2
(CH2), 55.6 (CH3), 62.9 (CH2), 75.9 (CH), 93.9 (CH2), 125.9
(CH), 128.4 (CH), 128.4 (CH), 131.2 (CH), 132.4 (CH), 142.0
3 7 5 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 4 9 – 3 7 5 6

View Online
288 (MH+ − CH3OCH2, 32%), 279 (11), 254 (10) and 218 (7);
by purification by flash column chromatography eluting with
diethyl ether–petroleum ether gave the target compounds as
colourless oils.
32a; mmax/cm−1 (neat) 3263 (NH), 2951 (CH), 1713 (CO), 1625
19
=
(C C), 1517, 1032, 823, 680; [a]D +37.0 (c 1.0, CHCl3); dH
(400 MHz, CDCl3) 0.90 (3H, d, J 6.4 Hz, 6-CH3), 0.94 (3H, d,
J 6.4 Hz, 7-H3), 1.25 (1H, ddd, J 12.8, 9.2, 4.4 Hz, 5-HH), 1.53
(1H, ddd, J 12.8, 9.2, 5.6 Hz, 5-HH), 1.68–1.80 (1H, m, 6-H),
3.44 (3H, s, OMe), 3.66 (1H, ddd, J 9.2, 4.4, 1.6 Hz, 4-H), 4.37
(1H, m, 3-H), 4.66 (1H, d, J 6.8 Hz, OCHHO), 4.75 (1H, d, J
6.8 Hz, OCHHO), 5.31 (1H, d, J 1.6 Hz, 1-HH), 5.35 (1H, m,
1-HH), 5.78–5.91 (1H, m, 2-H), 8.36 (1H, br d, J 6.8 Hz, NH);
dC (100 MHz, CDCl3) 22.2 (CH3), 23.2 (CH3), 24.4 (CH), 42.0
(CH2), 56.0 (CH), 56.9 (CH3), 82.2 (CH), 93.0 (C), 98.2 (CH2),
118.9 (CH2), 131.7 (CH), 161.5 (C); m/z (CI) 332.0578 (MH+.
C12H21O3NCl3 requires 332.0587), 300 (42%), 262 (100), 238
(18), 202 (21) and 167 (49).
(3R,4S)-3-(Trichloromethylcarbonylamino)-4-(methoxymeth-
oxy)-6-methylhepta-1-ene (32a). 73% yield; spectroscopic data
as described above.
(3R,4S)-3-(Trichloromethylcarbonylamino)-4-(methoxymeth-
oxy)-5-phenylpenta-1-ene (33a). 70% yield; spectroscopic data
as described above.
(3R,4S)-3-(Trichloromethylcarbonylamino)-4-(methoxymeth-
oxy)-6-phenylhexa-1-ene (34a). 69% yield; spectroscopic data
as described above.
Ruthenium trichloride oxidation to carboxylic acids 35–38 and
deprotection to b-hydroxy-a-amino acids 39–42
(3R,4S)-3-(Trichloromethylcarbonylamino)-4-(methoxymeth-
oxy)-5-phenylpenta-1-ene (33a). 54% yield; mmax/cm−1 (neat)
3273 (NH), 2943 (CH), 1711 (CO), 1513, 1143, 1027, 820, 699;
[a]2D1 +59.1 (c 1.7, CH2Cl2); dH (400 MHz, CDCl3) 2.82 (1H, dd,
J 14.0, 5.2 Hz, 5-HH), 2.93 (1H, dd, J 14.0, 8.8 Hz, 5-HH),
3.39 (3H, s, OMe), 3.86 (1H, ddd, J 8.4, 4.8, 2.0 Hz, 4-H), 4.36
(1H, d, J 6.8 Hz, OCHHO), 4.45 (1H, br t, J 7.6 Hz, 3-H), 4.60
(1H, d, J 6.8 Hz, OCHHO), 5.42 (1H, d, J 7.6 Hz, 1-HH), 5.45
(1H, br s, 1-HH), 5.92–6.02 (1H, m, 2-H), 7.21–7.36 (5H, m,
Ph), 8.19 (1H, d, J 7.6 Hz, NH); dC (100 MHz, CDCl3) 39.4
(CH2), 55.8 (CH), 56.7 (CH3), 84.4 (CH), 92.9 (C), 98.1 (CH2),
119.7 (CH2), 126.8 (CH), 128.6 (CH), 129.3 (CH), 131.4 (CH),
137.4 (C), 161.4 (C); m/z (CI) 366.0431 (MH+. C15H19O3NCl3
requires 366.0431), 334 (100%), 300 (25), 272 (26), 236 (19) and
173 (33).
Sodium metaperiodate (4.1 equiv.) was dissolved in water
(21 mL) and added to a solution of the allylic trichloroamide
(1 mmol) in carbon tetrachloride (14 mL) and acetonitrile
(14 mL). Ruthenium trichloride hydrate (5 mol%) was added and
the mixture was stirred vigorously for 6 h before a further portion
of sodium metaperiodate (1 equiv.) was added. The reaction
mixture was stirred vigorously overnight and then extracted
with dichloromethane (3 × 40 mL). The organic layers were
combined, dried (MgSO4) and concentrated to give a viscous
oil. The products were used without further purification. The
carboxylic acid (1 mmol) was dissolved in 6 M hydrochloric
acid (20 mL) and heated under reflux overnight. The reaction
mixture was then cooled before being extracted with diethyl
ether (2 × 10 mL). The aqueous layer was concentrated to
give a brown liquid. Purification was carried out using ion
(3R,4S)-3-(Trichloromethylcarbonylamino)-4-(methoxymeth-
oxy)-6-phenylhexa-1-ene (34a) and (2E,4S)-1-(Trichloromethyl-
carbonylamino)-4-(methoxymethoxy)-6-phenylhexa-2-ene (34c).
65% combined yield; 34a: (Found: C, 50.5; H, 5.3; N, 3.7.
C16H20Cl3NO3 requires C, 50.5; H, 5.3; N, 3.7%); mmax/cm−1
(neat) 3277 (NH), 2939 (CH), 1713 (CO), 1514, 1141, 1031,
821; [a]1D8 +58.8 (c 1.0, CHCl3); dH (400 MHz, CDCl3) 1.81–1.91
(1H, m, 5-HH), 1.95–2.05 (1H, m, 5-HH), 2.63–2.71 (1H, m,
6-HH), 2.79–2.86 (1H, m, 6-HH), 3.48 (3H, s, OMe), 3.59 (1H,
ddd, J 8.6, 4.4, 2.0 Hz, 4-H), 4.43 (1H, br t, J 8.6 Hz, 3-H), 4.65
(1H, d, J 6.8 Hz, OCHHO), 4.81 (1H, d, J 6.8 Hz, OCHHO),
5.34 (1H, d, J 1.2 Hz, 1-HH), 5.38 (1H, br d, J 8.6 Hz, 1-HH),
5.89 (1H, ddd, J 17.2, 10.4, 8.6 Hz, 2-H), 7.19–7.39 (5H, m,
Ph), 8.37 (1H, br d, J 8.6 Hz, NH); dC (100 MHz, CDCl3)
31.9 (CH2), 34.8 (CH2), 56.0 (CH), 56.9 (CH3), 83.5 (CH), 93.0
(C), 98.4 (CH2), 119.2 (CH2), 126.2 (CH), 128.4 (CH), 128.6
(CH), 131.5 (CH), 141.0 (C), 161.5 (C); m/z (CI) 380 (MH+,
100%), 310 (63), 286 (12), 244 (16), 187 (66) and 157 (58);
R
exchange chromatography column on Dowexꢀ 50WX8-100
(20 g per mmol of substrate), eluting with 25% ammonia
solution. Concentration gave the b-hydroxy-a-amino acids as
white solids.
(2S,3S)-2-Amino-3-hydroxybutanoic acid (39). 84% yield for
first step and 80% yield for second step; [a]2D1 +8.0 (c 1.0, H2O);
lit.19 [a]D +8.6 (c 1.0, H2O); dH (400 MHz, D2O) 1.17 (3H, d, J
22
6.8 Hz, 4-H3), 3.98 (1H, d, J 3.6 Hz, 2-H), 4.24 (1H, qd, J 6.8,
3.6 Hz, 3-H); dC (100 MHz, D2O) 16.1 (CH3), 59.6 (CH), 65.3
(CH), 171.9 (C); m/z (CI) 119.0589 (MH+. C4H9O3N requires
119.0582), 117 (11%), 85 (4), 81 (74) and 79 (100).
(2S,3S)-2-Amino-3-hydroxy-5-methylhexanoic acid (40).
78% yield for first step and 62% yield for second step; mmax/cm−1
(neat) 3033 (OH and NH), 2960 (CH), 1667 (CO), 1406, 1339,
1136, 1053; [a]2D0 +13.7 (c 1.0, 1 M HCl); lit.20 [a]D +14.6 (c 1.0,
1 M HCl); dH (400 MHz, D2O) 0.82 (3H, d, J 6.8 Hz, 6-H3), 0.86
(3H, d, J 6.8 Hz, 5-CH3), 1.11 (1H, ddd, J 14.0, 10.0, 2.8 Hz,
4-HH), 1.43 (1H, ddd, J 14.0, 10.0, 4.4 Hz, 4-HH), 1.63–1.71
(1H, m, 5-H), 3.75 (3H, d, J 3.2 Hz, 2-H), 4.12 (1H, dt, J 10.0,
3.2 Hz, 3-H); dC (100 MHz, D2O) 20.3 (CH3), 22.7 (CH3), 23.9
(CH), 39.6 (CH2), 59.8 (CH), 67.5 (CH), 171.7 (C); m/z (CI)
145 (MH+ − NH2, 20%), 131 (50), 117 (49) and 113 (100).
(2S,3S)-2-Amino-3-hydroxy-4-phenylbutanoic acid (41).
69% yield for first step and 80% yield for second step; mmax/cm−1
(neat) 3364 (OH and NH), 2940 (CH), 1717 (CO), 1494, 1224,
1034, 742; [a]2D1 +8.6 (c 1.0, 1 M HCl); lit.20 [a]D +9.1 (c 1.0, 1 M
HCl); dH (400 MHz, D2O) 2.83 (1H, dd, J 14.0, 9.2 Hz, 4-HH),
2.93 (1H, dd, J 14.0, 4.8 Hz, 4-HH), 4.03 (1H, d, J 2.8 Hz,
2-H), 4.22 (1H, ddd, J 9.2, 4.8, 2.8 Hz, 3-H), 7.12–7.31 (5H,
m, Ph); dC (100 MHz, D2O) 38.5 (CH2), 57.0 (CH), 71.0 (CH),
126.9 (CH), 128.7 (CH), 129.3 (CH), 137.3 (C), 169.6 (C); m/z
(CI) 196.0974 (MH+. C10H14O3N requires 196.0974), 167 (16%),
139 (37) and 121 (21).
34c: mmax/cm−1 (neat) 3085 (NH), 2947 (CH), 1718 (CO), 1656
20
=
(C C), 1496, 1148, 1098, 1030, 970; [a]D −82.1 (c 1.0, CHCl3);
dH (400 MHz, CDCl3) 1.83–2.04 (2H, m, 5-H2), 2.73–2.83 (2H,
m, 6-H2), 3.43 (3H, s, OMe), 4.10 (3H, m, 4-H and 1-H2), 4.61
(1H, d, J 6.8 Hz, OCHHO), 4.74 (1H, d, J 6.8 Hz, OCHHO),
5.72 (1H, dd, J 15.2, 7.2 Hz, 3-H), 5.86 (1H, dt, J 15.2, 6.4 Hz,
2-H), 7.23–7.35 (5H, m, Ph); dC (100 MHz, CDCl3) 31.6 (CH2),
37.1 (CH2), 44.3 (CH2), 55.6 (CH3), 75.4 (CH), 94.1 (CH2), 94.1
(C), 126.0 (CH), 128.4 (CH), 128.5 (CH), 128.8 (CH), 134.7
(CH), 141.8 (C), 163.1 (C); m/z (CI) 321 (MH+ − CH3OCH2O,
6%), 284 (11), 225 (12), 193 (62) and 157 (100).
Allylic trichloroacetimidate synthesis and subsequent
rearrangement with bis(acetonitrile)palladium(II) chloride and
p-benzoquinone
Preparation of the trichloroacetimidate was carried out as de-
scribed above. The allylic trichloroacetimidate was dissolved in
THF (10 mL). Bis(acetonitrile)palladium(II) chloride (10 mol%)
and p-benzoquinone (2.0 equiv.) were then added and the reac-
tion mixture stirred for 24 h. Concentration in vacuo followed
(2S,3S)-2-Amino-3-hydroxy-5-phenylpentanoic acid (42)9b.
81% yield for first step and 60% yield for second step; mmax/cm−1
(neat) 3388 (OH and NH), 2913 (CH), 1729 (CO), 1495, 1218,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 4 9 – 3 7 5 6
3 7 5 5

View Online
1036; [a]1D9 +14.7 (c 0.4, 2 M HCl); dH (400 MHz, D2O) 1.73–1.83
(2H, m, 4-CH2), 2.53–2.63 (1H, m, 5-HH), 2.74 (1H, ddd, J 14.0,
8.8, 5.2 Hz, 5-HH), 3.89 (1H, d, J 3.6 Hz, 2-H), 3.93 (1H, dt,
J 8.8, 3.6 Hz, 3-H), 7.09–7.26 (5H, m, Ph); dC (100 MHz, D2O)
31.2 (CH2), 33.2 (CH2), 58.1 (CH), 68.6 (CH), 126.2 (CH), 128.5
(CH), 128.7 (CH), 141.3 (C), 169.9 (C); m/z (CI) 210 (MH+,
12%), 175 (100), 144 (28) and 113 (34).
6 S. F. Kirsch, L. E. Overman and M. P. Watson, J. Org. Chem., 2004,
69, 8101.
7 A. G. Jamieson and A. Sutherland, Org. Biomol. Chem., 2005, 3, 735.
8 A. M. Hoveyda, D. A. Evans and G. C. Fu, Chem. Rev., 1993, 93,
1307.
9 (a) A. Saeed and D. W. Young, Tetrahedron, 1992, 48, 2507, and
references therein; (b) T. Kimura, V. P. Vassilev, G.-J. Shen and C.-H.
Wong, J. Am. Chem. Soc., 1997, 119, 11734.
10 All a-hydroxy acids are commercially available except (2S)-2-
hydroxy-4-phenylbutanoic acid, which was synthesised as described
by Mi and co-workers: W.-Q. Lin, Z. He, Y. Jing, X. Cui, H. Liu and
A.-Q. Mi, Tetrahedron: Asymmetry, 2001, 12, 1583.
11 R. E. Ireland and D. W. Norbeck, J. Org. Chem., 1985, 50, 2198.
12 M. Mehmandoust, Y. Petit and M. Larcheveˆque, Tetrahedron Lett.,
1992, 33, 4313.
Acknowledgements
The authors would like to thank Dr Andrei V. Malkov for helpful
and insightful discussions. Financial support from EPSRC
(DTA award) and the University of Glasgow is gratefully
acknowledged.
13 L. A. Clizbe and L. E. Overman, Org. Synth., 1978, 58, 4.
14 (a) A. M. Doherty, B. E. Kornberg and M. D. Reily, J. Org. Chem.,
1993, 58, 795; (b) J. Gonda, A.-C. Helland, B. Ernst and D. Bellus,
Synthesis, 1993, 729.
References
1 (a) L. E. Overman, J. Am. Chem. Soc., 1974, 96, 597; (b) L. E.
Overman, J. Am. Chem. Soc., 1976, 98, 2901; (c) L. E. Overman,
Acc. Chem. Res., 1980, 13, 218.
2 For recent examples see: (a) A. G. Jamieson, A. Sutherland and C. L.
Willis, Org. Biomol. Chem., 2004, 2, 808; (b) S. Kim, T. Lee, E. Lee, J.
Lee, G.-J. Fan, S. K. Lee and D. Kim, J. Org. Chem., 2004, 69, 3144;
(c) A. E. Lurain and P. J. Walsh, J. Am. Chem. Soc., 2003, 125, 10677;
(d) M. Reilly, D. R. Anthony and C. Gallagher, Tetrahedron Lett.,
2003, 44, 2927.
15 T. K. Hollis and L. E. Overman, Tetrahedron Lett., 1997, 38,
8837.
16 J.-E. Ba¨ckvall, Acc. Chem. Res., 1983, 16, 335.
17 For a recent example see: G. L. J. Bar, G. C. Lloyd-Jones and K. I.
Booker-Milburn, J. Am. Chem. Soc., 2005, 127, 7308.
18 P. H. J. Carlsen, T. Katsuki, V. S. Martin and K. B. Sharpless, J. Org.
Chem., 1981, 46, 3936.
19 J. R. Harding, R. A. Hughes, N. M. Kelly, A. Sutherland and C. L.
Willis, J. Chem. Soc., Perkin Trans. 1, 2000, 3406.
20 S. Blank and D. Seebach, Liebigs Ann. Chem., 1993, 889.
21 R. V. Hoffman and J. Tao, J. Org. Chem., 1997, 62, 2292.
22 W. J. Moree, G. A. van der Marel and R. J. Liskamp, J. Org. Chem.,
1995, 60, 5157.
3 T. Ikariya, Y. Ishikawa, K. Hirai and S. Yoshikawa, Chem. Lett.,
1982, 1815.
4 (a) L. E. Overman, Angew. Chem., Int. Ed. Engl., 1984, 23, 579;
(b) T. G. Schenck and B. Bosnich, J. Am. Chem. Soc., 1985, 107,
2058.
5 (a) C. E. Anderson and L. E. Overman, J. Am. Chem. Soc., 2003,
125, 12412; (b) Y. Uozumi, K. Kato and T. Hayashi, Tetrahedron:
Asymmetry, 1998, 9, 1065; (c) M. Calter, T. K. Hollis, L. E. Overman,
J. Ziller and G. G. Zipp, J. Org. Chem., 1997, 62, 1449.
23 T. Satoh, K. Onda and K. Yamakawa, Tetrahedron Lett., 1990, 31,
3567.
24 H. H. Wasserman and R. J. Gambale, Tetrahedron, 1992, 48, 7059.
25 S. Hanessian, M. Tremblay and J. F. W. Petersen, J. Am. Chem. Soc.,
2004, 126, 6064.
3 7 5 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 4 9 – 3 7 5 6