Asymmetric aza-[2,3]-Wittig sigmatropic rearrangements: Chiral auxiliary control and formal asymmetric synthesis of (2S, 3R, 4R)-4-hydroxy-3- methylproline and (-)-kainic acid

Article abstract of DOI:10.1039/b506198a

A survey of 16 different chiral auxiliaries and a variety of strategies found that an (-)-8-phenylmenthol ester of a glycine derived migrating group can control the absolute stereochemistry of aza-[2,3]-Wittig sigmatropic rearrangements with diastereoselectivities of ca. 3 : 1 with respect to the auxiliary. In two specific examples, ca. 50% yields of enantiomerically pure products were obtained after chromatographic purification. These were synthetically manipulated with no erosion of stereochemistry into intermediates that completed formal asymmetric syntheses of (+)-HyMePro and (-)-kainic acid. The Royal Society of Chemisrry 2005.

Full text of DOI:10.1039/b506198a

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A R T I C L E
Asymmetric aza-[2,3]-Wittig sigmatropic rearrangements: chiral
auxiliary control and formal asymmetric synthesis of (2S, 3R,
4R)-4-hydroxy-3-methylproline and (−)-kainic acid†
James C. Anderson,*a Julian M. A. O’Loughlina and James A. Tornosb
a School of Chemistry, University of Nottingham, Nottingham, UK NG7 2RD.
E-mail: j.anderson@nottingham.ac.uk; Fax: +44(0)115 9513564; Tel: +44(0)115 9514194
b AstraZeneca, Process Research and Development Charnwood, Bakewell Road, Loughborough,
UK LE11 5RH
Received 4th May 2005, Accepted 6th June 2005
First published as an Advance Article on the web 30th June 2005
A survey of 16 different chiral auxiliaries and a variety of strategies found that an (−)-8-phenylmenthol ester of a
glycine derived migrating group can control the absolute stereochemistry of aza-[2,3]-Wittig sigmatropic
rearrangements with diastereoselectivities of ca. 3 : 1 with respect to the auxiliary. In two specific examples, ca. 50%
yields of enantiomerically pure products were obtained after chromatographic purification. These were synthetically
manipulated with no erosion of stereochemistry into intermediates that completed formal asymmetric syntheses of
(+)-HyMePro and (−)-kainic acid.
carbanion dictating stereocontrol in our silicon assisted aza-
Introduction
[2,3]-Wittig sigmatropic rearrangements. Analogous attempts
We have previously developed the aza-[2,3]-Wittig sigmatropic
to use chiral bases to generate chiral anions in oxy-[2,3]-Wittig
rearrangement as a synthetic method for the synthesis of
systems has only been possible in isolated cases and with only
unnatural amino acids (eqn. 1).1 In addition, we have defined the
moderate enantioselectivity (<30–60%).12 The configurational
limits of activation and control of diastereoselectivity imparted
stability of carbanions adjacent to nitrogen atoms can be
by the dimethylphenylsilyl group.2 However, all our studies to
stabilised by the Boc dipole,13 enabling even the configurational
date have been racemic, and we wish to report in this paper
out first attempts at achieving asymmetric rearrangements,
culminating in the use of a chiral auxiliary.
stability of tertiary benzylic anions at −78 ◦C.14 Accordingly, we
synthesised the structurally similar and enantiomerically pure
aza-[2,3]-Wittig precursors 1a and 1b (Rꢀ = Me) and subjected
them to anionic rearrangement (eqn. 2). The rearrangements
were successful at just under −40 ◦C to give rearranged
products with significant optical rotations.15 Measurement of
the enantioselectivity proved very difficult. Separation of a
number of derivatives by chiral HPLC proved impossible, and
derivatisation with a number of chiral groups was low yielding
(1)
and despite giving very favourable results was thought to be
ambiguous. However, these experiments led us to tentatively
assign the major enantiomer as shown, which is that expected
from inversion at the lithium-bearing chiral centre.16
For the more common oxy-[2,3]-Wittig rearrangement, there
exists a number of successful strategies to control the asymmetry
of the [2,3]-sigmatropic process. These include: asymmetric
transmission from an enantiomerically enriched allylic ether,3
asymmetric induction from an auxiliary attached to the an-
ionic migrating group4 or the terminus of the allyl group,5
an enantioselective ring contraction of a chiral cyclic ether,6
and the rearrangement of chiral boron ester enolates.7 In
comparison, there are only a few isolated and specific examples
of the control of absolute stereochemistry in the aza-[2,3]-Wittig
rearrangement. Good enantioselectivities were obtained from
the rearrangement of enantiomerically enriched vinylaziridines
that were independently reported by the groups of Somfai8 and
Coldham.9 The use of configurationally defined lithio carban-
ions derived from enantiomerically enriched tributylstannyl-N-
tert-butoxycarbonyl pyrrolidine gave complicated results, due to
epimerisation of the chiral lithio carbanion and also a mixture of
competing [1,2] and [2,3] rearrangement pathways.10 This work,
from Gawley et al., verified that the [2,3] rearrangement pro-
ceeded with complete inversion of configuration at the lithium-
bearing carbanion centre, in accord with precedent in the
oxygen series.11 We were intrigued by the possibilities of a chiral
(2)
Encouraged by a hint of success from this strategy, we
attempted to deprotonate the achiral aza-[2,3]-Wittig precursor
3 (R3 = PhMe2, Rꢀ = H) by using chiral base systems.
Examples of very similar a-(N-Boc)amino benzylic chiral anions
have been generated in the literature with varying degrees of
configurational stability.17 Many attempts using sparteine/BuLi
and chiral amide bases18 were wholly unsuccessful. From our
experiments, rearrangement of the less substituted benzylic
anion of 3 occurs at temperatures above −40 ◦C, and we
conclude that at this temperature, the rate of epimerisation is
faster than the rate of sigmatropic rearrangement. Disappointed
that the natural character of this molecular system had defeated
our endeavours, we contemplated the more straightforward but
synthetically less appealing strategy of using a chiral auxiliary.
† Electronic supplementary information (ESI) available: Synthesis and
characterisation of chiral auxiliary rearrangement precursors. See
http://dx.doi.org/10.1039/b506198a
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 , 2 7 4 1 – 2 7 4 9
2 7 4 1
©

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protocols.21 Quaternisation was eventually achieved by warming
Results and discussion
9 in neat methyl p-toluenesulfonate, the salt then readily
In parallel with studies investigating a chiral auxiliary at-
tached to the migrating group, we also explored the possibility
of a chiral protecting group on nitrogen in our aza-[2,3]-
Wittig systems. We inferred, from our studies to determine
the scope and limitations of the aza-[2,3]-Wittig sigmatropic
rearrangement,2 that the nature of the nitrogen protecting
group had a profound effect on the success of the reac-
tion. We synthesised (+)-N-menthyloxycarbonyl-N-but-2(E)-
enylbenzylamine 4 from benzylamine by protection with (+)-
menthyl chloroformate followed by crotylation, and synthesised
the chiralN-sulfinamide 5 bycrotylation ofthe known N-benzyl-
4-methylbenzenesulfinamide 6 (Scheme 1).19 Rearrangement of
the menthyl precursor 4 gave a 62% yield of the rearranged
product, but the complexity of the 1H NMR thwarted any mea-
surement of stereoinduction. Reductive removal of the menthyl
=
hydrolysed by stirring in aqueous base to give 10 (R H) in good
yield, but with an erosion in anti-stereochemistry (Scheme 2).22
Analysis of the quaternised material revealed epimerisation at
the C-1 stereocentre before any hydroxide ion had been added.
Due to the configurational instability of 9 imparted by the
oxazoline functional group, it was decided to investigate other
chiral auxiliaries.
Nakai had gone on to show that (−)-8-phenylmenthyl esters
as a migrating group in the oxy-[2,3]-Wittig rearrangement were
more effective than chiral oxazolines.4c Accordingly we synthe-
sised the aza-[2,3]-Wittig precursor 12. The most convergent
route to 12 was the alkylation of the N-anion of N-Boc-glycine
(−)-8-phenylmenthol ester23 with 13, but this gave a complex
mixture of products and after laborious separation only gave
low yields of 12 under a variety of different conditions. An
alternative route involved the N-alkylation of N-Boc glycine
methyl ester with 13, which gave 14 in 97% yield. Standard
saponification gave the corresponding acid (98%), which was
esterified with (−)-8-phenylmenthol24 to give the rearrangement
precursor 12 in 93% yield (Scheme 3). This route not only
gave access to gram quantities of 12, but also allowed the
screening of other chiral auxiliaries which could be attached
as the final step (vide supra). Rearrangement of 12 under our
R
carabamate with Red-Alꢀ, followed by Boc reprotection, gave
7, our very first aza-[2,3]-Wittig rearrangement product.20 This
had an identical diastereoselectivity of 3 : 2 as observed before20
and exhibited no optical rotation. Rearrangement of 5 did not
occur under a variety of standard rearrangement conditions and
in that respect was similar to the sulfonamide analogue.2
◦
general conditions (1.9 equiv. LDA, THF–HMPA, −78 C to
rt)2 gave a 57% yield of rearranged product with a diastereomeric
ratio of 4 : 1.25 Optimisation of the rearrangement conditions
led to the use of KHMDS in THF with DMPU (9%) as
co-solvent, at rt for 2 h, and quenching with aq. NH4Cl.
These conditions gave a much higher 87% yield of 15 : 16,
dr = 3 : 1, with only the anti distereoisomer detectable by
1H NMR. This optimised rearrangement gave the highest
isolated yield of diastereomerically pure 15. The two isomers
had a small separation on silica tlc, but could be efficiently
R
separated by two purifications using Biotageꢀ medium pressure
chromatography to give a 55% yield of diastereomerically pure
(>95% by 1H NMR) 15 along with the pure minor isomer 16 in
20% yield.
Scheme 1 Reagents and conditions: (i) (+)-menthyl chloroformate,
◦
=
Et3N, CH2Cl2, 91%; (ii) KH, THF, 0 C; trans-CH3CH CHCH2Br,
0
◦C to rt, 91%; (iii) n-BuLi, Et2O–HMPA (4 : 1), −78 to −40 ◦C,
14 h, 62%; (iv) Red-AlꢀR , PhMe, rt; (v) Boc2O, CH2Cl2, 94% (2 steps);
Hydrolysis of the bulky (−)-8-phenylmenthyl auxiliary was
not possible,26 and instead ester 15 was reduced with LiAlH4
to alcohol 17 in a reproducible 79% yield (99% recovery of
(−)-8-phenylmenthol), as long as a non-aqueous work up was
used (Scheme 4).27 The 1H NMR of 17, both as a crude
sample and after purification, showed only one diastereoisomer.
Rearrangment of achiral 14 at 0 ◦C instead of the optimal
−40 ◦C gave a 3 : 1 (anti : syn) mixture of rearranged methyl
esters, which were reduced with LiAlH4 as above to give a
corresponding 3 : 1 diastereomeric mixture of 17. The 1H NMR
of this sample showed the major diastereoisomer was identical
to that obtained from the rearrangement of 12. The major
diastereoisomer from the rearrangement of 14 has been inferred
as anti by us previously.2 Therefore rearrangement of (−)-8-
phenylmenthyl ester 12 gives only the anti-2,3-diastereoisomer,
(vi) KH, THF, 13, 59%.
In the oxy-[2,3]-Wittig sigmatropic rearrangement Nakia
had shown that a migrating chiral amide derived from
Meyers’ oxazoline led to reasonable levels (up to 84%) of
diastereoselectivity.4a,b Preliminary studies by us using an achiral
oxazoline in an aza-[2,3]-Wittig precursor (8) revealed that
although the rearrangement gave 9 in good conversion (75%
with 25% unreacted starting material) and excellent anti-
stereocontrol, the compound was not configurationally stable
(Scheme 2). Attempts at purification of 9 from residual starting
material by column chromatography led to degradation and
erosion of the anti-stereochemistry. Removal of the oxazoline
in the presence of the N-Boc group necessitated hydrolysis with
aqueous base. The oxazoline of 9 was resistant to quaternisation
with MeI, the first step of many basic hydrolytic deprotection
1
with the observed diastereoisomeric ratio by H NMR being
equal to the diastereoselectivity exerted by the chiral auxiliary
(3 : 1).
To determine the level of asymmetric induction from the
rearrangement, protodesilylation of 17 was performed in an
attempt to correlate the enantioenriched material to known
N-Boc-isoleucinol. In the event, treatment with TBAF in
refluxing DMSO28,29 caused incomplete protodesilylation, but
cyclisation to the oxazolidinones 18 and 19 (Scheme 4). Desi-
lylated material 19, upon hydrogenation over platinum, gave
the known compound 20 (99%). Unfortunately the reported
optical rotation of enantiomerically pure 20 is small [lit.30
[a]D + 2.6 (c 1.3 CHCl3)], which made our value [[a]D + 1.6
(c 1.3 CHCl3)] ambiguous within error limits. We therefore
synthesised authentic samples of racemic- and (+)-20 according
to the literature route,30 from DL- and L-isoleucine respectively.
Scheme 2 Reagents and conditions: (i) n-BuLi, Et2O–HMPA (1 : 4),
−78 to −40 ◦C, 14 h, 75% conversion; (ii) p-MePhSO3Me, 80 ◦C;
(iii) 15% aq. NaOH, rt, 99% (2 steps); (iv) CH2N2, CH2Cl2, rt, 83%.
2 7 4 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 1 – 2 7 4 9

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Scheme 3 Reagents and conditions: (i) KH, THF, 0 ◦C to rt, 97%; (ii) NaOH, H2O–THF, rt, 98%; (iii) DCC, DMAP, (−)-8-phenylmenthol, CH2Cl2,
−30 ◦C to rt, 93%; (iv) KHMDS, THF–DMPU (10 : 1), rt, 87%, dr = 3 : 1.
derived from 14; the more hindered examples required the use
of HOBt, and sometimes elevated temperature.
Rearrangements were performed under the optimised con-
ditions found for 12 [KHMDS, THF–DMPU (10 : 1), rt, 2 h].
Quantification of the rearrangements was carried out tentatively
1
by H NMR, with more complicated spectra needing further
2D COSY, HMBC and HMQC experiments. Many of the
rearrangement precursors gave broad and multiple signals due
to Boc- and amide-rotamers. These characteristics, coupled with
the complex mixtures of diastereosiosmers produced from the
rearrangments, made interpretation of the 1H NMR spectra very
difficult and individual assignments of rearrangement products
Scheme 4 Reagents and conditions: (i) LiAlH4, Et2O, 0 ◦C, 79%;
were not possible. However, an indication of the extent of
(ii) TBAF, THF, DMSO, 135 ◦C; (iii) H2, PtO2, EtOAc, 99%.
rearrangement and any diastereoselection could be tentatively
estimated from certain 1H NMR signals (Table 1). We planned
that any promising auxiliaries would be investigated further, but
in the event this was not necessary. The results were recorded on
the criteria of isolated yield, anti/syn diastereoselectivity, and
diastereoselectivity with respect to the auxiliary (Table 1). In
general, rearrangements were tolerant of most of the auxiliaries,
except 23 and 29 which gave recovered starting material despite
several attempts. However, in the worst of these (24, 25, 27, 30
and 33), it was clear that there was no single major product and
Chiral GC analysis confirmed that our synthetic sample of
(+)-20 derived from pure 15 was a single enantiomer, and
therefore that the major enantiomer from the rearrangement of
12 was (2S, 3R)-15.31
Having optimised the rearrangement using the (−)-8-
phenylmenthol auxiliary, we surveyed several other commonly
available chiral auxiliaries that covered a wide range of chiral
pool families (Fig. 1).32 Menthol-like auxiliaries 21 and 22
we concluded these were not suitable auxiliaries to control the
stereochemistry of the rearrangement. The anti-selectivity was
assumed, as all rearrangements of a secondary stabilised anion
were chosen as they were structurally similar to 12. Ephedrine-
like auxiliaries have received widespread use in controlling the
attack of glycine enolates to various electrophiles.33 Proline-
performed to date have given the anti-(2,3)-diastereoisomer as
like auxiliaries have been used as stereocontrol elements in
the major stereoisomer.2 The menthol-like auxiliaries 21 and
a variety of asymmetric reactions.32 Finally, a small selection
22 gave reduced selectivities compared to (−)-8-phenylmenthol.
of structurally diverse and inexpensive auxiliaries were also
These results suggest that the additional phenyl substituent of
screened. The auxiliaries were attached, using DCC, to the acid
(−)-8-phenylmenthol compared to menthol is important for
Table 1 Screening of chiral auxiliaries in the aza-[2,3]-Wittig sigmat-
ropic rearrangement
Substrate Yield/% anti-Selectivity/% Diastereomeric excess/%
21
22
23
24
25
26
27
28
29
30
31
32
33
57
100c
0
10
43
58
69
72
0
50
100c
56
60
95b
>95
—
20b
30d
—
e
>95
—
e
e
—
—
>95
50f
e
e
—
—
>95
70g
—
—
—
e
e
—
>95
20h
35i
0i
70j
—
e
a KHMDS (1.9 equiv.), THF–DMPU (9 : 1), rt, 2 h. b From integration
in 1H NMR of 4 sets of vinylic signals, d 5.47–5.65. c Conversion. d From
integration in 1H NMR of vinylic signals, d 5.71–5.77. e Unidentified
1
complex mixture. f From integration in H NMR of multiplets d 2.42–
2.63. g From integration in 1H NMR of triplets d 4.31–4.43. h From
integration in 1H NMR of vinylic signals, d 5.79–5.82. i From integration
in 1H NMR of 4 sets of vinylic signals, d 5.18–5.64. j From 1H NMR of
reduction product 17.
Fig. 1 Different chiral auxiliaries in rearrangement precursor.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 1 – 2 7 4 9
2 7 4 3

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control of stereoselectivity, and alternative aryl groups34 or
napthyl35 could give better results but at increased cost. The
ephedrine-like auxiliaries that underwent rearrangement (24 and
25) gave complex 1H NMR spectra that showed no single major
product. The miscellaneous auxiliaries investigated (30–33) gave
either complex mixtures, or in the case of 31 only 3 : 2 auxiliary
control. The proline derivatives gave two of the most promising
results. The standard prolinol auxiliary 26 gave 58% yield of rear-
ranged product with 3 : 1 auxiliary control. This is a lower yield,
but identical stereocontrol to the (−)-8-phenylmenthol auxiliary.
The diphenylprolinol auxiliary 28 gave a 72% yield of inseparable
rearranged diastereoisomers, but with a high 85 : 15 auxiliary
control. This result does offer a slight improvement over the
(−)-8-phenylmenthol auxiliary in terms of selectivity and the
availability of either enantiomer. However, the minor isomer
could not be removed from the rearrangement mixture, and the
auxiliary is expensive. Despite investigating a wide range of aux-
iliary structures none offered a significant improvement over the
use of (−)-8-phenylmenthol and were not investigated further.
Having found an auxiliary that allowed an efficient material
throughput of enantiomerically pure rearrangement products,
we investigated the total synthesis of two natural products that
we had previously made using the aza-[2,3]-Wittig sigmatropic
rearrangement as a key step, but which had been completed
in racemic forms. The synthesis of ( )-HyMePro relied upon
the formation of rearrangement product 34 (Scheme 5).1a
We decided to intercept this racemic intermediate with ena-
tiomerically pure material from the rearrangement of 12.
Fortuitously, the major enantiomer 15 contains the correct
absolute stereochemistry for the synthesis of naturally occuring
(+)-HyMePro. Direct amidation of 15 with a dimethyl amide
nucleophile proved unsuccessful due to the necessary basic
reaction conditions. Treatment with Weinreb’s36 Me2NAl(Me)Cl
gave clean conversion to a urea derived from attack of the N-Boc
group (56%). In the event, alcohol 17 was oxidised by a two-step
procedure to the carboxylic acid (+)-10 via the crude aldehyde
by Dess–Martin periodinane oxidation followed by treatment
with buffered sodium chlorite (69% yield over two steps).
Amide coupling with an excess of Me2NH by DCC–HOBt gave
enantiomerically pure amide 34 in 78% yield and with no erosion
of diastereoselectivity along the four steps from 15 (Scheme 5).
The spectral and analytical data of (+)-34 was identical to the
racemic amide that had been prepared earlier1a and represents a
formal enantioselective total synthesis of (+)-HyMePro.
Scheme 6 Reagents and conditions: (i) KH, THF, 0 ◦C to rt, 90%;
(ii) NaOH, H2O–THF, rt, 99%; (iii) DCC, DMAP, (−)-8-phenylmenthol,
CH2Cl2, −30 ◦C to rt, 72%; (iv) KH, 18–C-6, THF, 0 ◦C to rt, 47%;
(v) LiAlH4, Et2O, 0 ◦C, 70%; (vi) Dess–Martin periodinane, CH2Cl2,
rt; (vii) NaO2Cl, (CH3)2C–CHCH3, t-BuOH, pH4 buffer, rt, 75% over 2
steps; (viii) Me2NH (excess), DCC, HOBt, CH2Cl2, −30 ◦C to rt, 76%.
381c gave methyl ester 39 in 90% yield. Standard saponification
gave the corresponding acid (99%), which was esterified with
(−)-8-phenylmenthol37 to give the rearrangement precursor 37
in 72% yield (Scheme 6). Aza-[2,3]-Wittig rearrangement was
◦
initiated with KH and 18-C-6 in THF (0 C to rt, 2 h) to give
a 47% yield of diastereomerically pure 40. The stereochemistry
of this major isomer (reaction dr = 3 : 1 with respect to the
auxiliary) was assumed to be the same as 15 and as a consequence
possessed the absolute stereochemistry required for the synthesis
of (−)-kainic acid. Reductive removal of the auxiliary with
LiAlH4 (41, 70%), two step oxidation to the carboxylic acid
(42, 75%) and DCC–HOBt coupling with Me2NH gave (+)-36
in 76% yield, again with no erosion of diastereoselectivity from
40. The spectral and analytical data of (+)-36 was identical to the
racemic amide that had been prepared earlier,1c and represents
a formal enantioselective total synthesis of (−)-kainic acid.
Summary
After surveying a wide range of structurally diverse, privileged
chiral auxiliaries, and investigating a range of strategies, we
found that an (−)-8-phenylmenthol ester was the most useful
at controlling the absolute stereochemistry of the aza-[2,3]-
Wittig sigmatropic rearrangement of substrates when attached
to a glycine derived migrating group. Although the optimised
diastereoselectivity with respect to the (−)-8-phenylmenthol
auxiliary was only ca. 3 : 1, with complete control of (2,3)-
anti diastereoselectivity, the material throughput of isolated,
pure material was quite high (ca.50%). Enantiomerically pure
material obtained from two different substrates, after reductive
removal of the (−)-8-phenylmenthol auxiliary (17 and 41),
was used to complete the formal asymmetric synthesis of (+)-
HyMePro and (−)-kainic acid. This chiral auxiliary approach
is only moderately successful and we are therefore investigating
alternative strategies to control asymmetry in aza-[2,3]-Wittig
sigmatropic rearrangements.
Scheme 5 Reagents and conditions: (i) Dess–Martin periodinane,
=
CH2Cl2, rt; (ii) NaO2Cl, (CH3)2C CHCH3, t-BuOH, pH 4 buffer, rt,
69% 2 steps; (iii) Me2NH (excess), DCC, HOBt, CH2Cl2, −30 ◦C to rt,
78%.
Our synthesis of ( )-kainic acid relied upon the aza-[2,3]-
Wittig rearrangement product 36.1c We decided to intercept this
intermediate with enantiomerically pure material using the (−)-
8-phenylmenthol auxiliary to complete a formal asymmetric
synthesis of naturally occurring (−)-kainic acid. Rearrangement
precursor 37 was synthesised in an analogous manner to 12
(Scheme 6). The N-alkylation of N-Boc glycine methyl ester with
Experimental
Our general experimental details have been published.38
2 7 4 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 1 – 2 7 4 9

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(+)-N-Menthyloxycarbonyl-N-but-2(E)-enylbenzylamine (4)
with Boc2O (180 mg, 0.84 mmol, 2 eq.). After stirring for 72 h at
rt the reaction mixture was adsorbed onto silica gel and purified
by flash chromatography (silica, 10% EtOAc–light petroleum) to
give 7 (103 mg, 94% over 2 steps). Spectroscopic and analytical
data were identical to those reported in the literature.20
To a stirred solution of benzylamine (0.20 mL, 1.80 mmol)
and Et3N (0.56 mL, 4.00 mmol, 2.2 eq.) in CH2Cl2 (1 mL)
was added (+)-menthyl chloroformate (0.43 mL, 2.00 mmol,
1.1 eq.) dropwise at 0 ◦C. The resulting slurry was stirred for
2 h at rt before being diluted with CH2Cl2 (10 mL) and washed
sequentially with 1 N HCl (10 mL), H2O (10 mL) and saturated
aq. NaCl (10 mL). The organic phase was dried (MgSO4)
and the solvent removed in vacuo to give a white solid which
was recrystallised from light petroleum to give the protected
benzylamine (0.48 g, 91%) as a white fibrous solid mp = 98–99 ◦C
(Found C, 74.6; H, 9.35; N, 4.8. C18H27NO2 requires C, 74.7; H,
9.4; N, 4.8%); [a]D + 50.0 (c 1.1; rt, CHCl3); mmax(film)/cm−1
3408, 2952, 1679, 1522; dH (250 MHz; CDCl3) 0.70–2.10 (18H,
m, menthyl), 4.35 (2H, d, J 5.8, NCH2Ph), 4.60 (1H, td, J 11.0
and 4.6, R2CHOCO), 4.90 (1H, br.s, NH), 7.20–7.40 (5H, m,
ArH); dC (63 MHz; CDCl3) 16.5, 20.8, 22.1, 23.5, 26.3, 31.4, 34.3,
41.5, 45.0, 47.4, 74.8, 127.2, 127.4, 128.6, 138.8, 156.5; m/z (EI)
289.2045 (18%, M+. C18H27NO2 requires 289.02042), 150 (100).
A solution of the protected amine (1.36 g, 4.70 mmol) in THF
(10 mL) was added dropwise, via cannula, to a stirred suspension
of KH (1.2 eq. of a 35% dispersion in mineral oil, washed twice
with hexane) in THF (10 mL) at 0 ◦C. After stirring for 1 h
a solution of trans-CH3CH=CHCH2Br (0.58 mL, 5.6 mmol,
1.2 eq.) in THF (5 mL) was added dropwise, via cannula,
and the reaction stirred for 1 h at 0 ◦C then 14 h at rt. The
reaction was quenched with saturated aq. NH4Cl and the THF
removed in vacuo. The residue was partitioned between Et2O and
saturated aq. NH4Cl, separated and the aqueous phase further
extracted with Et2O (2×). The combined organic layers were
dried (MgSO4) and the solvent removed in vacuo to give an oil
that was purified by flash column chromatography (silica, 5%
EtOAc–light petroleum) to give 4 (1.47 g, 91%) as a colourless
oil (Found C, 76.9; H, 9.8; N, 4.1. C22H33NO2 requires C, 76.9;
H, 9.7; N, 4.1%); [a]D + 44.4 (c 0.9; rt, CHCl3); mmax(film)/cm−1
2955, 1694, 1230; dH (250 MHz; CDCl3) 0.70–2.15 (21H, m,
4-Methylbenzenesulfinic acid benzyl-[2-(dimethylphenylsilanyl)-
but-2(E)-enyl]amide (5)
A solution of 6 (1.31 g, 5.00 mmol) in THF (10 mL) was added
dropwise to a suspension of KH (240 mg, 6.00 mmol, from
a 30% dispersion in mineral oil washed twice with hexane)
in THF (10 mL) at 0 ◦C. After stirring for 1 h, 1-bromo-2-
(dimethylphenylsilanyl)but-2(E)-ene2 (1.41 g, 5.25 mmol, 1.05
eq.) in THF (2 mL) was added, the reaction then stirred for 1 h at
0 ◦C and then warmed to rt for 14 h. After addition of saturated
aq. NaHCO3 (10 mL) the THF was removed in vacuo and the
remainder extracted with Et2O (4 × 20 mL). The combined
organic phases were dried (MgSO4) and concentrated in vacuo
to give a brown oil which was purified by flash chromatography
(silica, 20% EtOAc–h◦exanes) to give 5 (1.27 g, 59%) as a
white solid mp 72–73 C; mmax(film)/cm−1 1068; dH (400 MHz;
CDCl3) 0.33 (3H, s, SiCH3), 0.37 (3H, s, SiCH3), 1.62 (3H, d,
J 6.0, CH3CH=C), 2.41 (3H, s, Ar–CH3), 3.67–3.76 (2H, m,
=
NCH2C C), 3.88 (1H, d J 9.0, NCH2Ph), 4.04 (1H, d, J 9.0,
NCH2Ph), 6.47 (1H, q, J 7.0, CH3CH=C), 7.06–7.53 (14H, m,
Ar). dC (67.5 MHz; CDCl3) − 0.3(q), 0.0(q), 19.4(q), 22.5(q),
51.9(t), 56.7(t), 140.0(s), 127.4–142.3(Ar), 145.1(d); m/z (FAB)
434 (MH+).
2-[N-Boc-N-(2-phenyldimethylsilanylbut-2(Z)-enyl)-
aminomethyl]-4,4-dimethyl-1,3-oxazoline (8)
Alkylation of 2-tert-butoxycarbonylaminomethyl-4,4-dimethyl-
1,3-oxazoline40 (1.44 g, 6.31 mmol) with 1-bromo-2-(dimethyl-
phenylsilanyl)-but-2(E)-ene2 (1 eq.) in an identical manner to the
preparation of 5 gave 8 (2.09 g, 79%) as a colourless oil (Found
C, 66.0; H, 8.7; N, 6.75. C23H36N2O3Si requires C, 66.3; H, 8.7;
N, 6.7%); mmax(film)/cm−1 2972, 1704, 1682, 1365, 1249, 732,
702; dH (250 MHz; CDCl3) 0.38 (6H, s, (CH3)2Si), 1.25 (6H, s,
=
=
menthyl & CH3CH ), 3.65–3.95 (2H, br.m, NCH2CH ), 4.43
(2H, br.s, NCH2Ph), 4.63 (1H, m, R2CHOCO), 5.30–5.70 (2H,
m, CH=CH), 7.10–7.40 (5H, m, ArH); dC (63 MHz; CDCl3)
12.9, 16.3, 17.7, 20.9, 22.1, 23.4, 26.2, 31.4, 34.4, 41.5, 47.4, 49.2,
75.3, 126.3, 127.1, 128.0, 128.4, 138.3, 156.3; m/z (EI) 343.2508
(16%, M+. C22H33NO2 requires 343.2511), 205 (100), 91 (31).
=
NC(CH3)2CH2O-), 1.43 (9H, s, (CH3)3C), 1.65 (3H, d, J 7.0,
=
=
=
CH3CH ), 3.70–4.10 (6H, m, NC(CH3)2CH2O-, NCH2C N,
=
=
NCH2C ), 6.18 (1H, br.m, CH3CH ), 7.25–7.55 (5H, m, ArH);
dC (63 MHz; CDCl3) − 1.6, 17.8, 28.3, 42.1, 53.6, 67.2, 79.2, 79.9,
127.8, 128.8, 133.6, 134.2, 139.0, 141.3, 155.4, 162.5; m/z (EI)
416.2482 (51%, M+. C23H36N2O3Si requires 416.2495), 360 (36),
316 (24), 304 (14), 135 (62), 57 (57).
(1R*, 2S*)-N-Boc-2-methyl-1-phenylbut-3-enylamine (7) and
the (1S*, 2S*) diastereoisomer (3 : 2)
Precursor 4 (1.09 g, 3.18 mmol) was treated with n-BuLi under
standard conditions39 to give the [2,3]-Wittig rearranged product
as an inseparable ca. 3 : 2 mixture of diastereoisomers (0.68 g,
62%) as a white amorphous solid mp = 78–79 ◦C (Found C, 77.2;
H, 9.5; N, 4.2. C22H33NO2 requires C, 76.9; H, 9.7; N, 4.1%); [a]D
+ 33.0 (c 1.0; rt, CHCl3); mmax(film)/cm−1 3336, 2956, 1704, 1496;
2-[(1S*, 2R*)-1-N-Boc-amino-2-methyl-3-phenyldimethyl-
silanylbut-3-enyl]-4,4-dimethyl-1,2-oxazoline (9)
Precursor 8 (2.03 g, 4.84 mmol) was treated with n-BuLi under
standard conditions28 to give a 1 : 3 mixture of recovered 8 and
the [2,3]-Wittig rearranged product 9 (dr = 19 : 1, anti : syn)
(2.03 g, 100% crude) that was not purified further; spectroscopic
and analytical data were identical to those reported earlier.2
=
dH (250 MHz; CDCl3) 0.45–1.95 (21H, m, menthyl & CH3CH ),
2.40 (1H, m, CH3CHCH=CH2), 4.20–5.60 (6H, m, NCHPh,
R2CHOCO, CH3CHCH=CH2, CH3CHCH=CH2 and NH by
D2O exchange), 6.95–7.20 (5H, m, ArH); dC (63 MHz; CDCl3)
(major diastereoisomer) 16.1, 17.1, 20.8, 22.0, 23.5, 26.3, 31.4,
34.3, 41.5, 43.1, 47.4, 58.7, 74.6, 116.0, 126.7, 127.2, 128.1, 139.5,
(2S*, 3R*)-2-N-Boc-amino-3-methyl-4-phenyldimethyl-
silanylpent-4-enoic acid (10)
140.3, 156.0; m/z (CI) 361 (41, MNH4 ), 344.2601 (100%, MH+.
+
C22H34NO2 requires 344.2590), 288 (54).
A stirred mixture of crude 1 : 3 mixture of recovered 8 and
aza-[2,3]-Wittig product 9 (dr = 19 : 1, anti : syn) (585 mg, 1.40
mmol) and methyl p-toluenesulfonate (261 mg, 1.40 mmol, 1
eq.) was heated at 80 ◦C (oil bath temperature) for 2 h, after
which time stirring became difficult. The reaction was cooled,
treated with 15% aq. NaOH (2.5 mL) and stirred for 14 h. The
resulting yellow homogeneous solution was acidified to pH 1–3
and extracted with EtOAc. The combined organics were dried
(MgSO4) and concentrated in vacuo to give a crude mixture of
carboxylic acids as a yellow oil (525 mg, >100% mass balance).
The material was esterified as below to aid analytical analysis.
To a stirred solution of the rearranged product (143 mg,
0.42 mmol) in PhH (20 mL) at rt was added dropwise Red-
R
Alꢀ (1.30 mL, 4.16 mmol, 10.0 eq.). After stirring for 14 h the
reaction was cooled to 0 ◦C, quenched by the dropwise addition
of saturated aq. NH4Cl (1 mL) and then extracted with 0.1 N
HCl (4 × 10 mL). The combined aqueous phases were adjusted
to pH 12–14 by the addition of 6 N NaOH before being extracted
with CH2Cl2 (4 × 10 mL). The combined organics were dried
(MgSO4) and concentrated in vacuo to give a crude yellow oil
that was immediately dissolved in CH2Cl2 (0.5 mL) and treated
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 1 – 2 7 4 9
2 7 4 5

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Methyl (2S*, 3R*)-2-N-Boc-amino-3-methyl-4-
phenyldimethylsilanylpent-4-enoate (11)
removed in vacuo to furnish the crude product as a cloudy
oil. Purification by flash column chromatography (5% EtOAc–
petroleum ether) gave 12 (14.9 g, 25.7 mmol, 93%) as a
thick colourless oil (Found C, 72.75; H, 9.05; N, 2.34.
C35H51NO4Si requires C, 72.75; H, 8.90; N, 2.42); [a]D + 14.7
(c 2.0 in EtOH);. mmax(film)/cm−1 3074, 2824, 1746, 1694; dH
(400 MHz; CDCl3) 0.50 (6H, s, SiMe2), 0.92–2.21 (29H, m,
R
Diazomethane, prepared from the reaction of Diazaldꢀ (218 mg,
1.02 mmol, 2 eq.) with 20% aq. KOH (0.4 mL) in EtOH (5 mL),
was carried by a stream of N2 and bubbled through a stirred
solution of the crude mixture from above (185 mg, 0.51 mmol)
in CH2Cl2 (5 mL) at rt. Stirring was continued with N2 bubbling,
until 30 min after the yellow colour had faded. Removal of the
solvent in vacuo gave a crude yellow oil (180 mg) which was
purified by flash column chromatography (silica, 10% EtOAc–
light petroleum) to give (2S*, 3R*)-11, (2R*, 3R*)-11 and the
methyl ester of the parent acid of 9 as an inseparable 3 : 1 :
1 ratio (159 mg, 83%). Spectroscopic and analytical data for
(2S*, 3R*)-11 was identical to that already reported;2 (2R*,
3R*)-11: dH (250 MHz; CDCl3) 0.42 (6H, s, (CH3)2Si), 0.95
CH2CH(C)OR + CH(CH3)CH2CH2 + CH(CH3)CH2CH2
+
=
CH3CH + Me2C(C)Ph + CH3CH + CHCMe2Ph + C CHCH3
+ Boc), 3.26–4.19 (4H, m, CH2NCH2), 4.90–4.94 (1H, m,
=
CO2CH), 6.17–6.24 (1H, m, C CHCH3), 7.19–7.64 (5H, m,
CHAr); dC (100 MHz; CDCl3) − 1.6, −1.5, 17.8, 17.9, 21.8, 22.0,
26.3, 26.5, 26.7, 26.8, 27.1, 28.3, 31.3, 31.5, 31.9, 34.5, 34.9, 39.8,
41.8, 41.9, 46.7, 47.0, 50.4, 50.5, 54.2, 75.1, 79.9, 125.1, 125.4,
125.5, 125.8, 127.9, 127.9, 128.4, 128.8, 129.0, 133.2, 133.6,
133.7, 138.7, 139.0, 140.0, 140.6, 140.9, 151.3, 155.2, 155.7,
169.3; m/z (ES+) 578.3644 (4%, MH+ C35H52NO4Si requires
578.3666) 478 (MH+-Boc, 38%), 135 (51, PhMe2Si+), 105 (100,
PhSi+), 119 (60, PhSiMe+), 57 (37, tBu+).
=
(3H, d, J 7.0, CH3CHC ), 1.34–1.45 (9H, m, (CH3)3C), 2.77
(1H, quin., J 6.7, CH3CHC ), 3.64 (3H, s, CO2CH3), 4.36
=
(1H, dd, J 9.5, 5.8, NCHCO2CH3), 4.86 (1H, d, J 8.2, NH),
=
=
5.50 (1H, m, CH3CHC CH2), 5.78 (1H, m, CH3CHC CH2),
7.30–7.55 (5H, m, ArH); 13C NMR not decipherable; m/z (EI)
377.2007 (10%, M+. C20H31NO4Si requires 377.2007), 321 (19),
300 (24), 277 (11), 189 (12), 135 (99), 57 (100). Spectroscopic
and analytical data for the methyl ester of the parent acid of 9
was identical to those already reported.2
[2S,3R]-2-N-Boc-amino-4-(dimethylphenylsilanyl)-3-
methylpent-4-enoic acid [1R,2S,5R]-8-phenylmenthol ester (15)
and [2R,3S]-2-N-Boc-amino-4-(dimethylphenylsilanyl)-3-
methylpent-4-enoic acid [1R,2S,5R]-8-phenylmenthol ester (16)
A solution of rearrangement precursor 12 (665 mg, 1.15 mmol)
in THF (5.8 mL) and DMPU (0.58 mL) at rt was treated with
KHMDS (4.37 mL of a 2 M solution in PhMe, 2.19 mmol,
1.90 eq.), and the resultant yellow solution was stirred at rt for
2 h. The reaction was quenched with saturated aq. NH4Cl (5 mL)
and diluted with Et2O (10 mL). The mixture was separated, and
the aqueous phase re-extracted with Et2O (5 mL). The combined
organics were dried (MgSO4) and the solvent removed in vacuo
to give the crude product as a colourless oil. Purification twice by
N-Boc-glycine (−)-8-phenylmenthol ester
A solution of Boc-glycine (180 mg, 1.03 mmol), DCC (255 mg,
1.24 mmol) and DMAP (6 mg, 50 lmol) in CH2Cl2 (10 mL)
was stirred at −30 ◦C for 10 min. (−)-8-phenyl menthol (1.19 g,
5.13 mmol) in CH2Cl2 (6 mL) was then added, and the mixture
was slowly warmed to rt. The reaction was then refluxed for
20 h. The solvent was removed in vacuo and Et2O (25 mL)
was added. The reaction mixture was filtered through Celite,
washed sequentially with saturated aq. NaHCO3 (10 mL), H2O
(10 mL) and brine (10 mL) before being dried (MgSO4) and the
solvent removed in vacuo. The excess auxiliary was recovered
R
flash column chromatography (Biotageꢀ, 5% EtOAc–petroleum
ether) gave 15 (366 mg, 55%). as a colourless oil followed by
the minor diastereoisomer 16 (133 mg, 20%) as a colourless
oil. 15: [a]D + 6.7 (c 2.0 in CHCl3); mmax(film)/cm−1 3444, 3052,
2962, 2927, 1719; dH (400 MHz; CDCl3) 0.42 (6H, s, SiMe2),
◦
via Kugelro¨hr distillation (bp 132 C @ 1 mmHg) to leave the
product as a colourless oil (402 mg, 96%, lit.23 yield 93%). dH
(400 MHz; CDCl3) 0.90 (3H, d, J 6.5, CH3CH), 1.20 (3H, s,
CMe2Ph), 1.27 (3H, s, CMe2Ph), 1.45 (9H, s, Boc), 0.94–2.19
(8H, m, c-hexyl), 3.07 (1H, dd, J 18.3, 5.9, CHNH), 3.29 (1H,
dd, J 18.0, 5.2, CHNH), 4.38 (1H, br. m, NH), 4.89 (1H, td,
J 10.8, 4.5, CHOR), 7.12–7.34 (5H, m, Ar). All other spectral
data were in agreement with literature.23
0.73–1.97 (20H, m, CH2CH(C)OR + CH(CH3)CH2CH2
+
CH(CH3)CH2CH2 + CH3CH + Me2C(C)Ph + CH3CH +
CHCMe2Ph + CHCH3), 1.44 (9H, s, Boc), 2.42 (1H, m,
=
C CCHCH3), 3.94 (1H, t, J 8.8, NHCH), 4.53 (1H, br d, J 8.7,
=
NH), 4.76 (1H, td, J 10.7, 4.3, CO2CH), 5.50 (1H, s, C CH2),
=
5.74 (1H, s, C CH2), 7.15–7.53 (10H, m, CHAr). dC (100 MHz;
CDCl3) −2.3, −2.2, 18.5, 21.8, 26.1, 27.0, 27.7, 28.4, 31.4,
34.6, 40.1, 41.7, 41.9, 50.7, 57.7, 76.2, 79.3, 120.8, 125.4, 125.7,
127.9, 128.1, 129.2, 134.1, 138.0, 150.9, 171.9; m/z (ES+) 601
(MNa+, 5%), 578.3664 (MH+ C35H52NO4Si requires 578.3666)
478 (MH+-Boc, 4%), 135 (PhMe2Si+, 100%), 105 (PhSi+, 42%).
16: [a]D + 3.1 (c 1.6 in CH2Cl2); mmax(film)/cm−1 2955, 2916, 2866,
1720. dH (400 MHz; CDCl3) 0.43 (6H, s, SiMe2), 0.74–2.01 (20H,
m, CH2CH(C)OR + CH(CH3)CH2CH2 + CH(CH3)CH2CH2 +
CH3CH + Me2C(C)Ph + CH3CH + CHCMe2Ph + CHCH3),
N-Boc-N-[2-(dimethylphenylsilanyl)but-2(Z)-enyl]glycine
methyl ester (14)2
N-Boc-N-[2-(dimethylphenylsilanyl)but-2(Z)-enyl]glycine. A
solution of NaOH (60 mg, 1.7 mmol, 3.0 eq.) in water (2 mL)
was added to a solution of 14 (212 mg, 0.563 mmol) in THF (2
mL) at rt and was stirred for 21 h. The reaction was acidified
with citric acid to pH 3, diluted with Et2O (10 mL) and
separated. The aqueous was re-extracted with Et2O (10 mL)
and the combined organics dried (MgSO4) before the solvents
were removed in vacuo to afford the title acid as a colourless oil
(198 mg, 0.546 mmol, 97%) which was judged >95% pure by
1H NMR. Spectroscopic and analytical data were identical to
those already reported.2
=
1.43 (9H, s, Boc), 2.45 (1H, m, C CCHCH3), 4.07 (1H, t, J 9.0,
NHCH), 4.32 (1H, br.d, J 8.8, NH), 4.78 (1H, td, J 10.6, 4.2,
=
=
CO2CH), 5.55 (1H, d, J 1.9, C CH2), 5.80 (1H, s, C CH2),
7.13–7.56 (10H, m, CHAr). dC (100 MHz; CDCl3); −2.4, −1.4,
18.0, 18.9, 21.8, 22.1, 24.2, 24.3, 26.5, 27.4, 28.4, 28.8, 29.3, 29.8,
31.4, 31.6, 34.5, 34.9, 39.8, 40.3, 41.3, 41.9, 45.4, 50.3, 54.2, 58.6,
73.0, 76.3, 79.5, 125.1, 125.4, 125.7, 125.8, 128.0, 128.1, 128.3,
128.5, 129.0, 129.3, 133.7, 134.1, 137.9, 150.8, 151.1, 151.4,
154.7, 170.6. MS (ES+): m/z 600 (28%, MNa+), 578.3694 (100%,
MH+ C35H52NO4Si requires 578.3666), 478 (18%, MH+-Boc).
N-Boc-N-[2-(dimethylphenylsilanyl)but-2(Z)-enyl]glycine-(1R,
2R, 5R)-8-phenylmenthol ester (12)
A solution of the above acid (10.0 g, 27.6 mmol) in CH2Cl2
(135 mL) was cooled to −30 ◦C, and DCC (5.69 g, 27.6 mmol,
1.00 eq.) and DMAP (330 mg, 2.76 mmol, 0.10 eq.) were added.
A solution of (−)-8-phenyl menthol24 (6.41 g, 27.6 mmol, 1.00
eq.) in CH2Cl2 (5 mL) was then added and the resultant yellow
solution allowed to warm to rt over 14 h. The solvent was
then removed in vacuo and replaced with EtOAc (100 mL).
[1S,2R]-[3-(Dimethylphenylsilanyl)-1-hydroxymethyl-2-
methylbut-3-enyl]carbamic acid tert-butyl ester (17)
A suspension of LiAlH4 (90 mg, 2.4 mmol, 3.0 eq.) in Et2O
(3.5 mL) was refluxed for 30 min and cooled to 0 ◦C. A
solution of rearrangement product 15 (460 mg, 0.79 mmol) in
R
The resulting suspension was filtered (Celiteꢀ) and the solvent
2 7 4 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 1 – 2 7 4 9

View Article Online
Et2O (0.5 mL) was then added via cannula, and the resultant
suspension stirred at 0 ◦C for 90 min. The reaction was
quenched sequentially with H2O (90 lL), 15% aq. NaOH (90
lL) and H2O (270 lL). The resulting suspension was diluted
with Et2O (15 mL) and dried (MgSO4) before removal of the
solvent in vacuo. Purification of the crude product by flash
column chromatography (30% EtOAc–petroleum ether) gave 17
(195 mg, 79%) as a colourless oil; [a]D + 15.3 (c 2.0 in CHCl3);
mmax(film)/cm−1 3624, 3435, 2956, 2879, 1692; dH (400 MHz;
CDCl3) 0.44 (3H, s, SiMe2), 0.46 (3H, s, SiMe2), 1.02 (3H,
d, J 6.9, CH3CH), 1.42 (9H, s, Boc), 2.51 (1H, quin., J 7.0,
CHCH3), 2.64 (1H, br s, OH), 3.46–3.58 (2H, m, CH2OH),
3.69–3.72 (1H, m, NHCH), 4.36 (1H, d, J 5.5, NH), 5.60 (1H,
d, J 2.3, C CH2), 5.84 (1H, d, J 2.2, C CH2), 7.38–7.40 (3H,
m, CHAr), 7.54–7.57 (2H, m, CHAr); dC (100 MHz; CDCl3);
−2.7, −2.3, 18.8, 28.6, 40.1, 56.5, 64.1, 79.4, 126.7, 128.0,
129.2, 134.0, 137.9, 152.7, 156.5; m/z (ES+) 372 (16%, MNa+),
350.2144 (31, MH+ C19H32NO3Si requires 350.2151), 216 (61,
MH+-PhMe2Si), 135 (81, PhMe2Si+), 57 (100, tBu+).
and Et2O (15 mL), separated and the aqueous re-extracted
with Et2O (15 mL). The combined organics were washed with
saturated aq. NaHCO3 (10 mL), dried (MgSO4) and the solvents
removed in vacuo to leave the aldehyde as a cloudy oil. The
t
crude aldehyde was then dissolved in BuOH (6.3 mL), pH 4
buffer solution (1.7 mL), and 2-methyl-2-butene (2 M in THF,
1.3 mL). The resulting pink solution was treated with NaO2Cl
(29 mg, 0.33 mmol, 1.25 eq.) and the solution stirred for 2 h,
during which time the solution became yellow. The reaction was
diluted with water (10 mL) and Et2O (10 mL) and separated. The
aqueous was re-extracted with Et2O (5 mL) and the combined
organics dried (MgSO4) and the solvents removed in vacuo to
give a cloudy oil. Purification by flash column chromatography
(1% AcOH, 49% EtOAc–petroleum ether) gave (+)-10 (65 mg,
69% over 2 steps) as a colourless oil; dH (400 MHz; CDCl3) 0.43
(6H, s, SiMe2), 1.05 (3H, d, J 6.9, CH3CH), 1.44 (9H, s, Boc),
2.64 (1H, m, CHCH3), 4.18 (1H, t, J 8.2, NHCH), 4.62 (1H, d, J
=
=
=
=
7.8, NH), 5.60 (1H, d, J 1.6, C CH2), 5.81 (1H, br s, C CH2),
7.37–7.39 (3H, m, CHAr), 7.54–7.57 (2H, m, CHAr). All other
spectral data were in agreement with literature.2
[1S,4S]-4-[2-(Dimethylphenylsilanyl)-1-methylallyl]oxazolidin-
2-one (18) and [1S,4S]-4-(1-methylallyl)oxazolidin-2-one (19)
[1-Dimethylcarbamoyl-3-(dimethylphenylsilanyl)-2-methylbut-3-
enyl]carbamic acid tert-butyl ester (34)
A solution of alcohol 17 (92 mg, 0.27 mmol) in DMSO (1 mL)
was treated with a solution of TBAF (0.8 mL of a 1.0 M solution
in THF, 0.8 mmol, 3 eq.) and stirred for 30 min. The solution
was then heated to 135 ◦C and stirred for 14 h. The reaction
was cooled, quenched with H2O (1 mL) and extracted into
EtOAc (5 mL). The organics were dried (MgSO4) and solvent
removed in vacuo to furnish the crude product. Purification by
flash column chromatography (30% EtOAc–petroleum ether)
gave 18 (10.4 mg, 14%) as a colourless oil and the major product
19 (20.1 mg, 53%) as a colourless oil. 18: mmax(film)/cm−1 3273,
2959, 1755; dH (500 MHz; CDCl3) 0.43 (3H, s, SiMe2Ph), 0.44
(3H, s, SiMe2Ph), 0.90 (3H, d, J 6.9, CH3CH), 2.42 (1H, dq,
J 9.0, 6.9, CH3CH), 3.73 (1H, q, J 8.5, CHNH), 4.00 (1H,
dd, J 8.7, 6.6, CH2O), 4.33 (1H, t, J 8.5, CH2O), 5.06 (1H,
br s, NH), 5.65 (1H, d, J 1.9, CH2=C), 5.80 (1H, d, J 1.7,
CH2=C), 7.38–7.39 (3H, m, CHAr), 7.50–7.52 (2H, m, CHAr);
dC (125 MHz; CDCl3) − 2.8, −2.6, 16.7, 44.1, 56.0, 68.7, 127.9,
128.2, 129.6, 133.9, 137.2, 152.5, 159.0; m/z (EI+) 275.1342
(1%, M+ C15H21NO2Si requires 275.1322), 260 (68, M+-CH3),
135 (100, PhMe2Si+). 19: mmax(film)/cm−1 3286, 2970, 2920, 1748;
dH (400 MHz; CDCl3) 1.02 (3H, d, J 6.8, CH3CH), 2.28 (1H,
sext, J 7.2, CH3CH), 3.69 (1H, q, J 7.8, CHNH), 4.14 (1H, dd,
J 8.8, 6.1, CH2O), 4.46 (1H, t, J 8.6, CH2O), 5.16 (1H, d, J 10.5,
CH2=CH), 5.17 (1H, dt, J 17.4, 1.2), 5.65 (1H, ddd, J 16.9, 10.6,
8.1, CH2=CH), 5.67 (1H, br.s, NH); dC (100 MHz; CDCl3) 15.4,
42.9, 56.4, 68.3, 117.7, 138.4, 159.3; m/z (EI+) 141.0793 (4%, M+
C7H11NO2 requires 141.0790), 86 (100, M+–C4H7).
A commercially available solution of HNMe2 (2.0 M in THF)
◦
was cooled to −190 C and a stream of N2 passed over it into
◦
a flame-dried flask, cooled to −78 C, via cannula. The frozen
liquid was slowly allowed to warm to rt with a continuous flow
of N2 passing any vapour through to the second flask. This
process was continued until the smell of amine ceased from
the former flask. The now concentrated solution of amine was
maintained at −78 ◦C until required. A solution of acid (+)-10
(65 mg, 0.18 mmol) in CH2Cl2 (1 mL) was cooled to −30 ◦C
and HOBt (27 mg, 0.20 mmol, 1.1 eq.) and DCC (41 mg,
0.20 mmol, 1.1 eq.) were added. This solution was then treated
with dimethylamine (1 mL of concentrated solution from above)
and allowed to warm to rt over 2 h. The excess amine and
solvent were removed in vacuo and replaced with EtOAc (10
R
mL). The resultant suspension was filtered via Celiteꢀ and the
solvent removed in vacuo to furnish the crude product as a cloudy
suspension. Purification by flash column chromatography (30%
EtOAc– petroleum ether) gave 34 (54 mg, 78%) as a colourless
oil; [a]D + 26.4 (c 2.7 in CHCl3); dH (400 MHz, CDCl3) 0.44
(3H, s, SiMe2), 0.46 (3H, s, SiMe2), 0.90 (3H, d, J 7.0, CH3CH),
1.41 (9H, s, Boc), 2.66 (1H, m, CHCH3), 2.92 (3H, s, NMe2),
3.10 (3H, s, NMe2), 4.62 (1H, t, J 9.4, NHCH), 4.77 (1H, d,
=
J 9.0, NH), 5.62 (1H, d, J 2.3, C CH2), 5.85 (1H, d, J 1.6,
C CH2), 7.34–7.37 (3H, m, CHAr), 7.54–7.57 (2H, m, CHAr);
=
dC (100 MHz; CDCl3) − 2.1, −2.0, 14.5, 18.8, 28.8, 36.1, 37.9,
43.4, 53.2, 79.6, 128.3, 128.5, 129.5, 134.6, 151.7, 155.2, 172.9.
All other spectral data were in agreement with literature.2
[4S]-4-((S)-sec-Butyloxazolidin-2-one (20)
[N-Boc-[5-tert-butoxy-2-(dimethylphenylsilanyl)-pent-2-
enyl]amino]acetic acid methyl ester (39)
A solution of oxazolidinone 19 (20.1 mg, 0.143 mmol) in EtOAc
(1 mL) was treated with PtO2 (5.0 mg, 22 lmol, 15 mol%) and
stirred under a positive atmosphere of H2 (balloon) for 4 h.
The reaction was filtered through a plug of cotton wool, and the
solvent was removed in vacuo to give 20 (20.1 mg, 98%) as a clear
oil; [a]D + 1.6 (c 1.3 in CHCl3) [lit30 [a]D + 2.6 (c 1.3 CHCl3)];
dH (400 MHz; CDCl3) 0.88 (3H, d, J 6.8, CH3CH), 0.93 (3H, t,
J 7.4, CH3CH2), 1.15 (1H, m, CH2CH3), 1.53 (2H, m, CHCH3
+ CH2CH3), 3.70 (1H, q, J 6.9, CHNH), 4.11 (1H, dd, J 8.6,
6.5, CH2O), 4.46 (1H, t, J 8.6, CH2O), 6.22 (1H, br s, NH). All
other spectral data were in agreement with literature.30
To a suspension of KH (1.70 g of a 30% suspension in mineral
oil, washed twice with petroleum ether, 12.7 mmol, 1.26 eq.) in
THF (50 mL) at 0 ◦C, Boc–Gly–OMe (2.00 g, 10.6 mmol, 1.05
eq.) was added dropwise, and the resultant yellow suspension
stirred for 1 h. Bromide 381c was then added dropwise, the
resultant solution then warmed to rt over 3 h and stirred
for 14 h, by which point the solution had turned red. The
reaction was cautiously quenched with saturated aq. NaHCO3
(30 mL), diluted with Et2O (50 mL) and separated. The aqueous
layer was re-extracted with Et2O (30 mL) and the combined
organics washed with brine (30 mL) and then dried (MgSO4)
before the solvents were removed in vacuo. Purification by flash
column chromatography (10% EtOAc–petroleum ether) gave 39
(4.19 g, 90%) as a colourless oil; mmax(film)/cm−1 3069, 3006,
2955, 2870, 1748, 1694; dH (400 MHz; CDCl3) 0.41 (6H, s,
SiMe2), 1.11 (9H, s, CH2OtBu), 1.43 (9H, m, Boc), 2.24–2.29
[2S,3R]-2-N-Boc-amino-4-(dimethylphenylsilanyl)-3-
methylpent-4-enoic acid (10)
To a solution of alcohol 17 (90 mg, 0.26 mmol) in CH2Cl2 (1.1
mL) was added Dess–Martin periodinane (120 mg, 0.28 mmol,
1.1 eq.) and the reaction stirred at rt. After 2 h the reac-
tion was partitioned between saturated aq. NaHCO3 (5 mL)
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 1 – 2 7 4 9
2 7 4 7

View Article Online
(2H, m, CH2CH2OtBu), 3.20 (2H, m, CH2CH2OtBu), 3.70
(3H, s, OMe), 3.70 (1H, s, NCH2), 3.87 (1H, s, NCH2), 4.03
(1H, s, NCH2), 4.09 (1H, s, NCH2), 6.06–6.14 (1H, m, C CH),
7.33–7.34 (3H, m, CHAr), 7.49–7.52 (2H, m, CHAr); dC (100 MHz;
CDCl3) −1.4, −1.3, 27.5, 28.3, 33.3, 46.3, 46.5, 51.8, 54.3, 54.6,
60.9, 72.6, 80.1, 80.3, 127.9, 128.9, 129.0, 133.7, 133.9, 134.4,
138.8, 139.0, 143.7, 145.0, 155.1, 155.9, 170.7, 170.8; m/z (FAB)
486 (4%, MNa+), 464 (7, MH+), 463.2740 (M+ C25H41NO5Si
requires 463.2754), 386 (4, MNa+-Boc), 364 (10, MH+-Boc),
330 (18, MH+-PhMe2Si), 135 (75, PhMe2Si+), 57 (100, tBu+).
the solvent removed in vacuo. The residue was redissolved in
THF (1 mL) and 18-C-6 (37 mg, 0.14 mmol, 1.0 eq.) was
added. This solution was then added to KH (47 mg of a ca.
30% weight solution in mineral oil, washed with dry petroleum
ether, 2.5 eq.) in THF (0.5 mL) at 0 ◦C via cannula over
5 min. The resultant suspension was stirred at rt for 3 h before
being cautiously quenched with saturated aq. NH4Cl (1 mL),
and stirred for 5 min. The biphasic solution was partitioned
between Et2O (5 mL) and H2O (5 mL), the organics separated,
dried (MgSO4) and the solvents removed in vacuo. The crude
product was purified twice by flash column chromatography
=
R
(Biotageꢀ, 8% EtOAc–petroleum ether) to give 40 (45 mg, 47%)
[N-Boc-[5-tert-butoxy-2-(dimethylphenylsilanyl)-pent-2-enyl]-
amino]-acetic acid
as a colourless oil; [a]D + 1.9 (c 1.2 in CHCl3); mmax(film)/cm−1
3437, 2954, 2927, 2872, 1713; dH (400 MHz, CDCl3) 0.42 (3H, s,
SiMe2), 0.43 (3H, s, SiMe2), 0.73–1.73 (8H, m, CH2CH(C)OR +
CH(CH3)CH2CH2 + CH(CH3)CH2CH2 +CH2CH2OtBu), 0.83
(3H, d, J 6.5, CHCH3), 1.10 (9H, s, CH2OtBu), 1.26 (3H, s,
C(Ph)Me2), 1.33 (3H, s, C(Ph)Me2), 1.44 (9H, s, Boc), 1.87–
A solution of NaOH (340 mg, 8.5 mmol, 3.5 eq.) in H2O (5.5 mL)
was added to a solution of 39 (1.13 g, 2.43 mmol) in THF
(5.5 mL) at rt and was stirred for 23 h. The reaction was acidified
with citric acid to pH 3, diluted with Et2O (10 mL) and then
separated. The aqueous was re-extracted with Et2O (10 mL) and
the combined organics dried (MgSO4) before the solvents were
removed in vacuo to give the acid (1.08 g, 99%) as a colourless
oil, which was used without further purification; mmax(film)/cm−1
1.96 (2H, m, CHCH3 + CHCMe2Ph), 2.55–2.66 (1H, m,
t
=
CHC CH2), 2.92–3.02 (1H, m, CH2CH2O Bu), 3.10–3.16 (1H,
m, CH2CH2OtBu), 3.94 (1H, t, J 8.4, NHC(C)HCO2R), 4.70–
4.78 (1H, m, NH + CO2CH), 5.57 (1H, d, J 1.9, C CH2),
5.75 (1H, d, J 1.3, C CH2), 7.20–7.55 (10H, m, CHAr); dC
(100 MHz, CDCl3) −2.0, −1.7, 21.8, 25.8, 27.1, 27.6, 28.1, 28.4,
29.8, 31.4, 31.9, 34.6, 40.1, 41.7, 45.2, 50.7, 56.8, 59.4, 72.6, 76.3,
79.3, 125.4, 125.8, 127.9, 128.1, 129.2, 130.2, 134.2, 138.2, 149.2,
150.8, 154.9, 171.6; m/z (ES+) 687 (38%, MNa+), 664.4337 (100,
MH+ C40H62NO5Si required 664.4397), 564 (69, MH+-Boc).
=
=
2974, 2930, 2871, 1726, 1694 (C OBoc); dH (400 MHz, DMSO,
=
95 ◦C) 0.40 (6H, s, SiMe2), 1.09 (9H, s, CH2OtBu), 1.41 (9H, s,
Boc), 2.17 (2H, q, J 6.9, CH2CH2OtBu), 3.22 (2H, t, J 6.7,
CH2CH2OtBu), 3.58 (2H, br s, NCH2), 3.98 (2H, br s, NCH2),
=
6.07 (1H, t, J 7.3, C CH), 7.34–7.36 (3H, m, CHAr), 7.51–7.53
(2H, m, CHAr); dC (100 MHz, DMSO-d6, 95 ◦C) −0.5, 28.2, 29.0,
33.8, 49.1, 53.9, 61.5, 72.8, 79.1, 128.5, 129.6, 134.3, 138.2, 139.8,
156.0, 175.7; m/z (FAB) 472.2519 (5%, MNa+ C24H39NNaO5Si
requires 472.2495), 135 (37, PhMe2Si+), 57 (100, tBu+).
[1S,2R]-[2-(2-tert-Butoxyethyl)-3-(dimethylphenylsilanyl)-1-
hydroxymethylbut-3-enyl]carbamic acid tert-butyl ester (41)
A suspension of LiAlH4 (54 mg, 1.4 mmol, 3 eq.) in Et2O (2 mL)
was refluxed for 30 min and cooled to 0 ◦C. A solution of rear-
rangement product 40 (317 mg, 0.477 mmol) in Et2O (0.5 mL)
was then added via cannula, and the resultant suspension stirred
at 0 ◦C for 90 min. The reaction was quenched sequentially
with H2O (54 lL), 15% aq. NaOH (54 lL), and H2O (162 lL).
The resultant suspension was diluted with Et2O (10 mL), dried
(MgSO4) before removal of the solvent in vacuo. Purification
of the crude product by flash column chromatography (30%
EtOAc–petroleum ether) gave 41 (143 mg, 70%) as a colourless
oil; [a]D + 21.5 (c 2.0 in CHCl3); mmax(film)/cm−1 3439, 2975,
1701; dH (270 MHz, CDCl3) 0.43 (6H, s, SiMe2), 1.11 (9H, s,
CH2OtBu), 1.42 (9H, s, Boc), 1.57–71 (2H, m, CH2CH2OtBu),
[N-Boc-[5-tert-butoxy-2-(dimethylphenylsilanyl)pent-2-
enyl]amino]acetic acid [1R,2S,5R]-8-phenylmenthol ester (37)
A solution of the acid derived from 39 (2.73 g, 6.07 mmol,
1.05 eq.) in CH2Cl2 (30 mL) was cooled to −30 ◦C and treated
sequentially with DCC (1.79 g, 8.67 mmol, 1.5 eq.), DMAP
(70 mg, 0.58 mmol, 0.1 eq.) and (−)-8-phenyl menthol (1.34 g,
5.78 mmol, 1 eq.). The resultant solution was allowed to warm to
rt over 14 h, by which point the solution had turned yellow. The
solvent was removed in vacuo and replaced with EtOAc (40 mL).
R
Filtration through Celiteꢀ and evaporation of the solvent
in vacuo afforded the crude product, which was purified by flash
column chromatography (8% EtOAc–petroleum ether) to give
37 (2.75 g, 72%) as a thick colourless oil; [a]D − 2.2 (c 0.6 in
=
2.49 (1H, dt, J 7.9, 4.5, CHC CH2), 3.02 (1H, dt, J 8.2, 6.4,
CHCl3); mmax(film)/cm−1 2972, 2925, 2869, 1744, 1701 (C OBoc);
CH2CH2OtBu), 3.10–3.25 (2H, m, CH2CH2OtBu + OH), 3.51–
3.60 (3H, m, CH2OH + CHNH), 4.82 (1H, d, J 6.3, NH), 5.59
=
dH (400 MHz, CDCl3) 0.44 (3H, s, SiMe2), 0.45 (3H, s, SiMe2),
0.89 (3H, d, J 2.8, CHCH3), 1.14 (9H, s, CH2OtBu), 1.26 (3H, s,
C(Ph)Me2), 1.33 (3H, s, C(Ph)Me2), 1.45 (9H, m, Boc), 0.83–1.64
(6H, m, CHCH3 + CH(CH3)CH2CH2 + CH(CH3)CH2CH2 +
CHCMe2Ph), 1.96–2.01 (2H, m, CH2CH(C)OR), 2.29–2.31
(2H, m, CH2CH2OtBu), 3.22 (2H, t, J 6.9, CH2CH2OtBu), 3.26–
3.63 (2H, m, NCH2), 3.94–4.16 (2H, m, NCH2), 4.83–4.91 (1H,
=
=
(1H, d, J 2.0, C CH2), 5.80 (1H, d, J 1.9, C CH2), 7.32–
7.35 (3H, m, CHAr), 7.51–7.55 (2H, m, CHAr); dC (68 MHz,
CDCl3) −2.3, −2.2, 27.4, 28.3, 31.8, 55.1, 59.8, 63.6, 73.0,
79.1, 127.8, 129.1, 129.2, 133.9, 137.9, 151.4, 156.1; m/z (ES+)
458.2735 (78%, MNa+ C24H41NO4SiNa required 458.2703), 436
(34, MH+), 336 (77, MH+-Boc).
=
m, CO2CH), 6.01 (1H, t, J 7.1, C CHminor rot.), 6.08 (1H, t, J
7.3, C CHmajor rot.), 7.12–7.16 (1H, m, CHAr), 7.26–7.29 (4H, m,
=
[2S,3R]-2-N-Boc-amino-3-(2-tert-butoxyethyl)-4-
(dimethylphenylsilanyl)pent-4-enoic acid (42)
CHAr), 7.36–7.37 (3H, m, CHAr), 7.53–7.55 (2H, m, CHAr); dC
(100 MHz, CDCl3) −1.5, −1.4, −1.3, 21.8, 26.4, 26.8, 26.9, 27.5,
28.3, 31.3, 33.3, 34.5, 34.9, 39.9, 41.8, 41.9, 46.8, 47.2, 50.4, 50.5,
54.1, 54.3, 60.9, 72.6, 75.2, 79.9, 125.1, 125.2, 125.4, 127.5, 127.8,
127.9, 128.9, 133.7, 134.2, 138.7, 139.0, 141.4, 143.2, 151.2,
155.2, 155.7, 169.3; m/z (FAB) 687 (3%, MNa+), 664.4375 (4,
MH+ C40H62NO5Si requires 664.4397), 135 (45, PhMe2Si+), 105
(100, PhSi+), 119 (67, PhSiMe+), 57 (75, tBu+).
To a solution of alcohol 41 (54 mg, 0.13 mmol) in CH2Cl2
(0.5 mL) was added Dess–Martin periodinane (60 mg,
0.14 mmol, 1.1 eq.). The reaction was stirred at rt for 14 h
before saturated aq. NaHCO3 (2 mL) was added. The mixture
was diluted with Et2O (10 mL), separated and the aqueous
layer re-extracted with Et2O (10 mL). The combined organics
washed with saturated aq. NaHCO3 (10 mL), dried (MgSO4)
and solvents removed in vacuo to leave the aldehyde as a cloudy
oil (51 mg, 92%). The crude aldehyde was then dissolved in
tBuOH (3 mL), pH 4 buffer solution (0.8 mL), and 2-methyl-
2-butene (2 M in THF, 0.6 mL). The resultant pink solution
was treated with NaO2Cl (13 mg, 0.148 mmol, 1.25 eq.) and the
solution stirred for 2 h during which time the solution became
[2S,3R]-2-N-Boc-amino-3-(2-tertbutoxyethyl)-4-
(dimethylphenylsilanyl)pent-4-enoic acid
[1R,2S,5R]-8-phenylmenthol ester (40)
Rearrangement precursor 37 (95 mg, 0.14 mmol) in anhydrous
PhMe (1 mL) was transferred into a flame dried flask and
2 7 4 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 1 – 2 7 4 9

View Article Online
˚
yellow. The reaction was diluted with water (5 mL) and Et2O
(5 mL) and separated. The aqueous layer was re-extracted with
Et2O (5 mL), the combined organics were dried (MgSO4) and the
solvents then removed in vacuo to furnish the product as a cloudy
oil. Purification by flash column chromatography (1% AcOH,
19% EtOAc–petroleum ether) gave 42 (43 mg, 75% over 2 steps)
as a colourless oil; [a]D + 39.5 (c 1.1 in CHCl3); mmax(film)/cm−1
3444, 3324, 2975, 1716, 1667; dH (400 MHz, CDCl3): 0.46 (6H, s,
SiMe2), 1.14 (9H, s, CH2OtBu), 1.44 (9H, s, Boc), 1.59–1.64 (1H,
8 (a) J. Ahman and P. Somfai, J. Am. Chem. Soc., 1994, 116, 9781; (b) J.
˚
Ahman, T. Jareva˚ng and P. Somfai, J. Org. Chem., 1996, 61, 8148,
and references therein.
9 (a) I. Coldham, A. J. Collis, R. J. Mould and R. E. Rathmell,
Tetrahedron Lett., 1995, 36, 3557; (b) I. Coldham, A. J. Collis, R. J.
Mould and R. E. Rathmell, J. Chem. Soc., Perkin Trans. 1, 1995,
2739.
10 R. E. Gawley, Q. Zhang and S. Campagna, J. Am. Chem. Soc., 1995,
117, 11817.
11 (a) E. K. Verner and T. Cohen, J. Am. Chem. Soc., 1992, 114, 375;
(b) R. Hoffmann and R. Bru¨ckner, Angew. Chem., Int. Ed., 1992,
31, 647; (c) K. Tomooka, T. Igarishi, M. Watanabe and T. Nakai,
Tetrahedron Lett., 1992, 33, 5795; (d) K. Tomooka, T. Igarishi, N.
Komine and T. Nakai, Synth. Org. Chem. (Tokyo), 1995, 53, 480.
12 (a) J. A. Marshall and X.-J. Wang, J. Org. Chem., 1992, 57, 2747;
(b) S. Manabe, Chem. Commun., 1997, 737.
m, CH2CH2OtBu), 1.76–1.83 (1H, m, CH2CH2OtBu), 2.70–2.75
t
=
(1H, m, CHC CH2), 3.20–3.26 (1H, m, CH2CH2O Bu), 3.39–
3.44 (1H, m, CH2CH2OtBu), 4.48 (1H, t, J 8.8, NHCH), 4.88
(1H, d, J 8.8, NH), 5.75 (1H, d, J 1.7, C CH2), 5.92 (1H,
br s, C CH2), 7.36–7.39 (3H, m, CHAr), 7.51–7.53 (2H, m,
=
=
13 (a) P. Beak and S. T. Kerrick, J. Am. Chem. Soc., 1991, 113, 9708;
(b) P. Beak, S. T. Kerrick, S. Wu and J. Chu, J. Am. Chem. Soc., 1994,
116, 3231.
14 N. C. Faibish, Y. S. Park, S. Lee and P. Beak, J. Am. Chem. Soc.,
1997, 119, 11561.
CHAr); dC (100 MHz, CDCl3): −2.6, 20.8, 27.5, 28.4, 30.8, 44.0,
55.9, 57.5, 58.7, 74.5, 79.8, 128.0, 129.4, 129.9, 134.0, 137.4,
148.1, 155.4, 175.3, 176.7; MS (ES+): m/z 472.2495 (21%, MNa+
C24H39NO5SiNa required 458.2496).
15 D. C. Siddons, PhD thesis, University of Sheffield, 1998.
16 J. C. Anderson and S. Anguille, unpublished results.
17 (a) Y. S. Park, M. L. Boys and P. Beak, J. Am. Chem. Soc., 1996, 118,
3757; (b) S. Wu, S. Lee and P. Beak, J. Am. Chem. Soc., 1996, 118,
715; (c) M. Schlosser and D. Limat, J. Am. Chem. Soc., 1995, 117,
12342; (d) C. Barberis, N. Voyer, J. Roby, S. Che´nard, M. Tremblay
and P. Labrie, Tetrahedron, 2001, 57, 2065; (e) J. Clayden, C. J. Menet
and D. J. Mansfield, Chem. Commun., 2002, 38.
18 P. O’Brien, J. Chem. Soc., Perkin Trans. 1, 1998, 1439.
19 M. Furukawa and T. Okawara, J. Chem. Soc., Chem. Commun., 1976,
339.
20 J. C. Anderson, D. C. Siddons, S. C. Smith and M. E. Swarbrick,
J. Chem. Soc., Chem. Commun., 1995, 1835.
21 A. I. Meyers, D. L. Temple, R. L. Nolen and E. D. Mihelich, J. Org.
Chem., 1974, 39, 2778, and references therein.
22 The mixture containing acid 10 was esterified with diazomethane
to give a mixture containing methyl esters 11 (83%) in order to aid
purification and verify the stereochemical assignment to the identical
ester prepared previously, ref. 2 and M. E. Swarbrick, PhD thesis,
University of Sheffield, 1997.
[2S.3R]-[2-(2-tert-Butoxyethyl)-1-dimethylcarbamoyl-3-
(dimethylphenylsilanyl)but-3-enyl]carbamic acid tert-butyl
ester (36)
In an identical procedure to the preparation of 34, acid 42
(25 mg, 55 lmol) in CH2Cl2 (0.25 mL) was treated with HOBt
(9.0 mg, 66 lmol, 1.1 eq.), DCC (14 mg, 66 lmol, 1.1 eq.)
and concentrated Me2NH solution in THF (1 mL). The crude
product was isolated as a cloudy suspension. The product was
dissolved in hexane (2 mL), filtered, and evaporated to leave
the product as a cloudy oil, which solidified on standing to a
◦
white solid (20 mg, 76%); mp 102–104 C (lit.,1c 104–6 ◦C);
[a]D + 18.2 (c 1.0 in CHCl3); dH (270 MHz, CDCl3): 0.44 (6H, s,
SiMe2), 1.07 (9H, s, CH2OtBu), 1.41 (9H, s, Boc), 1.51–1.61 (2H,
t
=
m, CH2CH2O Bu), 2.67–2.71 (1H, m, CHC CH2), 2.90 (3H, s,
NMe2), 2.97–3.03 (1H, m, CH2CH2OtBu), 3.01 (3H, s, NMe2),
3.10–3.15 (1H, m, CH2CH2OtBu), 4.55 (1H, t, J 8.9, NHCH),
4.93 (1H, d, J 8.9, NH), 5.63 (1H, d, J 1.6, C CH2), 5.86 (1H,
23 Cited in the literature, but no synthesis: D. P. G. Hamon, R. A.
Massy-Westropp and P. Razzino, Tetrahedron, 1992, 48, 5163.
24 Synthesised in >99.5% optical purity in 5 steps from technical grade
(+)-pulegone: O. Ort, Org. Synth., 1987, 65, 203.
=
=
d, J 1.9, C CH2), 7.34–7.37 (3H, m, CHAr), 7.55–7.59 (2H, m,
CHAr); m/z (ES+) 477.3155 (100, MH+ C26H45N2O4Si required
477.3149). Spectroscopic and analytical data were identical to
that recorded in the literature.1c
25 Diastereomeric ratio determined from alkene region of 1H NMR
spectrum: 14; d 5.50 (1H, s) and 5.74 (1H, s), versus 15; d 5.55 (1H,
d, J 1.9) and 5.80 (1H, s).
26 This has been noted before: T. J. Donohoe, P. M. Guyo and M.
Helliwell, Tetrahedron Lett., 1999, 40, 435.
Acknowledgements
27 V. M. Mic´ovic´ and M. L. Mihailovic´, J. Org. Chem., 1953, 18, 1190.
28 J. C. Anderson, S. C. Smith and M. E. Swarbrick, J. Chem. Soc.,
Perkin Trans. 1, 1997, 1517.
29 H. Oda, M. Sato, Y. Morizawa, K. Oshima and H. Nozaki,
Tetrahedron, 1985, 41, 3257.
This work is part of the PhD Thesis of JMAO We
thank AstraZeneca Charnwood and the EPSRC for funding,
Dr M. E. Swarbrick and D. C. Siddons for preliminary results,
Mr T. Spencer for combustion analyses and Mr T. Hollingworth
and Mr D. Hooper for providing mass spectra.
30 N. Lewis, A. McKillop, R. J. K. Taylor and R. J. Watson, Synth.
Commun., 1995, 24, 561.
31 Astec BDM column (20 m × 250 lm), T = 180 ◦C, Rt (2R, 3R)-20;
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 1 – 2 7 4 9
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