Asymmetric synthesis of homochiral differentially protected bis-β-amino acid scaffolds

Article abstract of DOI:10.1016/S0040-4020(02)00369-1

A strategy for the asymmetric synthesis of homochiral [(R,R)- or (S,S)-], or meso-(R,S) bis-β-amino acid scaffolds, formally resulting from the stepwise conjugate addition of two differentially protected homochiral lithium amides to two α,β-unsaturated esters attached to a central arene, is demonstrated. Further manipulation enables the efficient synthesis of orthogonally protected pseudo-meso or pseudo-C₂ symmetric scaffolds via selective N-benzyl or N-allyl deprotection, enabling regio-, stereo- and chemoselective functionalisation.

Full text of DOI:10.1016/S0040-4020(02)00369-1

TETRAHEDRON
Pergamon
Tetrahedron 58 )2002) 4629±4642
Asymmetric synthesis of homochiral differentially protected
bis-b-amino acid scaffolds
Steven D. Bull, Stephen G. Davies,p Paul M. Roberts, Edward D. Savory and Andrew D. Smith
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 19December 2001; accepted 19February 2002
AbstractÐA strategy for the asymmetric synthesis of homochiral [)R,R)- or )S,S)-], or meso-)R,S) bis-b-amino acid scaffolds, formally
resulting from the stepwise conjugate addition of two differentially protected homochiral lithium amides to two a,b-unsaturated esters
attached to a central arene, is demonstrated. Further manipulation enables the ef®cient synthesis of orthogonally protected pseudo-meso or
pseudo-C2 symmetric scaffolds via selective N-benzyl or N-allyl deprotection, enabling regio-, stereo- and chemoselective functionalisation.
q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
N,N-protected b-amino esters arising from conjugate addi-
tion of lithium amides 3±5 offer the facility for selective
mono- or bis-N-deprotection, enabling the asymmetric
synthesis of a variety of homochiral b-amino acid deriva-
tives as demonstrated in Scheme 1.14
Chiral lithium amides have been extensively used and
studied1 within organic synthesis as effective reagents for
a range of transformations including enantioselective
reduction,2 alkylation,3 deprotonation,4 desymmetrisation5
and kinetic resolution.6 While these procedures typically
use the powerful basic properties of lithium amides, their
propensity to take part in nucleophilic reactions, particularly
conjugate addition, has also been widely investigated. This
reaction manifold was ®rst recognised by Schlessinger, who
reported that LDA added in a conjugate fashion to ethyl
crotonate.7 Yamamoto later introduced lithium N-benzyl-
N-trimethylsilyl amide )LSA) for conjugate addition,8 and
showed the versatility of this process for a range of trans-
formations.9 The preparation of a homochiral ammonia
equivalent for the asymmetric synthesis of b-amino acid
derivatives was ®rst demonstrated by Hawkins et al. with
the diastereoselective addition of homochiral lithium amide
3,5-dihydro-4H-dinaphth[2,1-c:10,10-e]azepine 1 to methyl
crotonate,10 and Bovy11 and Sewald12 investigated the use of
lithium N-trimethylsilyl-N-a-methylbenzylamide 2 toward
the same aim. While powerful, these methodologies show
limited versatility, either due to the extreme conditions
required for N-deprotection or limited substrate applicabil-
ity. Concurrently within this area, we have developed a
range of homochiral lithium amides 3±513 derived from
a-methylbenzylamines which undergo highly diastereo-
selective conjugate addition to a wide range of a,b-
unsaturated esters and amides )Fig. 1).
The high and predictable levels of diastereoselectivity
observed using this conjugate addition protocol15 has been
widely applied to a variety of synthetic targets,16 including
the total syntheses of negamycin,17 sperabillin C18 and
andrimid.19 While b-amino acids are an integral part of
many biologically active species, much recent interest in
this structural motif has been due to the propensity of
pseudopeptide sequences containing this functionality
to generate novel secondary and tertiary structures.20 Simi-
larly, advances in the understanding of the factors
which promote peptide folding have led to the use of topo-
logical templates21 that constrain the conformational free-
dom of attached peptides and help to nucleate structural
Keywords: conjugate addition; lithium amides; asymmetric synthesis;
differential deprotection.
p
Corresponding author. Tel.: 144-1865-275646; fax: 144-1865-275633;
e-mail: steve.davies@chem.ox.ac.uk
Figure 1. Homochiral ammonia equivalents for conjugate addition.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)02)00369-1

4630
S. D. Bull et al. / Tetrahedron 58 -2002) 4629±4642
Scheme 1. Reagents and conditions: )i) )S)-3 )1.6 equiv.), THF, 2788C; )ii) )S)-4 )1.6 equiv.), THF, 2788C; )iii) Pd)OH)2 on C, MeOH, AcOH, H2 )5 atm)
then TFA/DCM )1:1) and ion exchange; )iv) )S)-5 )1.6 equiv.), THF, 2788C and recrystallisation; )v) Rh)PPh3)3Cl, MeCN/H2O )8.5:1.5), D; )vi) CAN
)6 equiv.), MeCN/H2O )5:1), rt then HCl )1 M)aq, rt and ion exchange; )vii) CAN )2.1 equiv.), MeCN/H2O )5:1), rt; )viii) MeOH, HCl then MeMgBr, Et2O,
08C; )ix) TFA/DCM )1:1) then )PyS)2±PPh3, MeCN then CAN )3.0 equiv.), MeCN/H2O )5:1).
interactions, enabling progress in the area of synthetic
protein design.22 The potential combination of these two
concepts has led to the proposed use of b-amino based
scaffolds for speci®c sidechain attachments in an attempt
to understand the factors that control peptide folding. For
instance, Gellman et al. have prepared )R,R,R)-2,5-diamino-
cyclohexanecarboxylic acid derivative 6 and proposed its
use as a template to direct functional groups in speci®c
arrangements,23 while we have recently reported the
synthesis of a range of C2-symmetric bis-b-amino acid
templates for probing the secondary structure of attached
a- and b-pseudopeptidic fragments.24 For example, )R,R)-
bis-b-amino ester 9 can be ef®ciently prepared in 95% de
and .99% ee using the double conjugate addition of homo-
chiral lithium )S)-N-benzyl-N-a-methylbenzylamide 3 to
bis-functionalised a,b-unsaturated acceptor 7 to furnish N-
protected diamine )3R,aS,30R,a0S)-8, followed by hydro-
genolytic debenzylation )Scheme 2).
The potential utility of these bis-b-amino acid derivatives
could be extended if a ¯exible approach could be developed
that would allow for the preparation of not only the C2
symmetric )R,R)- or )S,S)- diastereoisomers,25 as previously
demonstrated by Frejd et al. for poly-a-amino acid deriva-
tives,26 but also a suitably protected variant of either the
)R,S)-meso, )R,R)- or )S,S)- diastereoisomers. Our synthetic
strategy toward this aim relied upon the supposition that the
dominant stereocontrol offered by homochiral lithium
amides would allow the construction of either the C2 or
meso bis-b-amino acid diastereoisomers 11 and 12, respec-
tively from an a,b-unsaturated ester 10. a,b-Unsaturated
ester 10 may in turn be constructed using Horner±
Wadsworth±Emmons methodology from aldehyde 13, or
via palladium mediated Heck methodology from halide 14
)Fig. 2).
While the generation of C2 symmetric or meso bis-b-amino
Scheme 2.

S. D. Bull et al. / Tetrahedron 58 -2002) 4629±4642
4631
Scheme 3. Reagents and conditions: )i) CH)OMe)3, MeOH, HCl, D; )ii)
)S)-3 )1.6 equiv.), THF, 2788C; )iii) Amberlyst 15, Me2CO/H2O )10:1), rt.
The propensity of lithium amide )S)-3 to act as an in situ
protecting group for the aldehyde functionality, whilst
undergoing conjugate addition, was next investigated.31
Thus, conjugate addition of an excess of lithium amide
)S)-3 to tert-butyl 3-)4-formylphenyl)prop-2-enoate 15
gave the required b-amino aldehyde 21 in 97% de and in
81% isolated yield, presumably via the intermediate a-
amino alkoxides 19 and 20. Subsequent Horner±
Wadsworth±Emmons reaction of aldehyde 21 with the
lithium anion of tert-butyl diethylphosphonoacetate gave
a,b-unsaturated acceptor 22 in 89% yield and 97% de
after chromatographic puri®cation )Scheme 4). The differ-
ence in diastereoselectivity observed upon conjugate addi-
tion of )S)-3 to 16 )82% de) and 15 )97% de) is presumably
due to the chelating ability of the acetal functionality of 16
which may serve to disrupt the normal chelation controlled
lithium amide transition state.15
Figure 2.
esters 10 and 11 is of interest, it would not be possible to
elaborate selectively peptide chains onto either of the nitro-
gen or carboxylate fragments due to the equivalent protect-
ing groups employed in their synthesis. However, it was
envisaged that differentially protected bis-b-amino acid
esters could be regio-, stereo- and chemoselectively elabor-
ated at either of the nitrogen or carboxylate functionality,
and would therefore be the most appropriate targets. We
now report herein our progress in this area, part of which
have been communicated previously.27
2. Results and discussion
An alternative synthesis of acceptor 22 involving Heck
coupling was also evaluated. Thus, conjugate addition of
lithium amide )S)-3 to )E)-tert-butyl 3-)4-bromophenyl)-
prop-2-enoate32 gave )3R,aS)-23 in 92% yield and 97% de
after puri®cation. Further treatment of )3R,aS)-23 under
Heck coupling conditions with tert-butyl acrylate gave
a,b-unsaturated acceptor 22 in 91% yield and 97% de
)Scheme 5).
Initial investigations were directed towards the preparation
of non-racemic chiral aldehyde 18 )Scheme 3). a,b-
Unsaturated acetal 16 was therefore prepared in two steps
via palladium mediated Heck coupling of 4-bromobenzal-
dehyde with tert-butyl acrylate to give a,b-unsaturated
acceptor 15 in 91% yield,28 with subsequent protection of
the aldehyde functionality through treatment with trimethyl-
orthoformate in a saturated solution of HCl in MeOH in
96% yield. Conjugate addition of lithium amide )S)-3
gave a crude reaction mixture containing the required acetal
protected b-amino ester 17 in 82% de,29 which gave 17 in
58% yield and 82% de after puri®cation. While deprotection
of acetal 17 with amberlyst 15 in acetone30 furnished the
required aldehyde 18 in 87% isolated yield )82% de),
neither acetal 17 nor aldehyde 18 could be puri®ed to homo-
geneity. An alternative protection strategy was therefore
sought for the synthesis of the required aldehyde in high
diastereoisomeric purity.
With two viable synthetic routes toward acceptor 22 in
hand, conjugate addition of both enantiomers of lithium
amide 3 was examined. Addition of lithium amide )S)-3 to
a,b-unsaturated acceptor 22 proceeded in 96% de,29
furnishing the known C2 symmetric bis-b-amino ester
)3R,aS,30R,a0S)-8 in 82% yield and in 96% de after puri®-
cation, with spectroscopic properties consistent with those
previously reported.24 Conjugate addition of lithium amide
)R)-3 to acceptor 22 proceeded in 97% de,29 furnishing

4632
S. D. Bull et al. / Tetrahedron 58 -2002) 4629±4642
Scheme 5. Reagents and conditions: )i) )S)-3 )1.6 equiv.), THF, 2788C; )ii)
Pd)OAc)2 )5 mol%), NEt3, tert-butyl acrylate )1.5 equiv.), tri-)o-tolyl)-
phosphine )20 mol%).
Scheme 4. Reagents and conditions: )i) )S)-3 )3 equiv.), THF, 2788C; )ii)
tert-butyl diethylphosphonoacetate )1.15 equiv.), n-BuLi )1.1 equiv.),
THF, 2788C to rt.
meso-bis-b-amino ester )3R,aS,30S,a0R)-24 in 89% yield
and in 97% de. The )3R,aS,30S,a0R)-meso stereochemistry
of 24 was unambiguously proven by X-ray crystallographic
analysis, consistent with the model developed previously to
explain the observed stereoselectivity during addition of
Scheme 6. Reagents and conditions: )i) )S)-3 )3 equiv.), THF, 2788C; )ii) )R)-3 )3 equiv.), THF, 2788C; )iii) Pd)OH)2, MeOH, AcOH, H2 )5 atm).

S. D. Bull et al. / Tetrahedron 58 -2002) 4629±4642
4633
Figure 3. Possible differentially protected bis-b-amino acids.
lithium amide )R)-3 to a,b-unsaturated acceptors.15 Subse-
quent N-benzyl deprotection via hydrogenolysis, a process
known to proceed without loss of stereochemical integrity,24
furnished meso-diamine )3R,30S)-25 in 81% yield
)Scheme 6).
With synthetic routes established for the preparation of
either C2 symmetric [)R,R)- or )S,S)-] diastereoisomers or
meso-)R,S) diastereoisomers of bis-b-amino acids, investi-
gations were directed towards the preparation of second
generation templates incorporating differentially protected
amino and carboxylate functionality. This concept has
previously been applied by Mutter et al. for protein de
novo design, with regioselectively addressable functional-
ised templates )RAFTs) proposed for the preparation
of complex protein architectures.22 For this purpose, the
synthesis of model differentially protected bis-b-diamino
Scheme 8. Reagents and conditions: )i) )R)-3 )1.6 equiv.), THF, 2788C;
)ii) Pd)OAc)2 )5 mol%), NEt3, tert-butyl acrylate )1.5 equiv.), tri)o-tolyl)-
phosphine )20 mol%).
esters, in which either the pseudo-C2 or pseudo-meso
symmetry of the molecule is determined by the chirality
of the lithium amide, was investigated )Fig. 3).
The ready availability of lithium N-benzyl-N-a-methyl-
benzylamide 3 and lithium N-allyl-N-a-methylbenzylamide
4 in either homochiral form seemed ideally suited for differ-
entiation of the N-protecting groups. It was envisaged
that the ability to deprotect the N-allyl functionality using
Wilkinson's catalyst,33 coupled with the ability of N-benzyl
tertiary amines to be chemoselectively debenzylated upon
treatment with CAN,34 would allow selective deprotection
and subsequent elaboration at nitrogen. The relative acid
and base lability of tert-butyl and iso-propyl esters would
allow selective access to the carboxylate functionality.35
Thus, following the aldehyde self protection protocol
developed previously, inverse addition of lithium )S)-N-
allyl-N-a-methylbenzylamide 4 to aldehyde 15 gave
)3R,aS)-26 in 92% de,29 and in 63% yield and in 92% de
after puri®cation. Wadsworth±Emmons extension using
iso-propyl diethylphosphonoacetate furnished the required
a,b-unsaturated ester 27 in 91% de,29 and in 87% yield and
91% de after puri®cation. Conjugate addition of lithium
amide )R)-3 to acceptor 27 furnished the required pseudo-
meso scaffold 28 in 82% yield and 90% de after puri®cation
)Scheme 7).
While this route provides an ef®cient synthesis of template
28, attempts to increase the levels of diastereoselectivity of
28 from 90% by further puri®cation proved impossible, so
an alternative synthesis of 28 was developed, using a Heck
coupling approach. Thus, conjugate addition of lithium
amide )R)-3 to )E)-iso-propyl 3-)4-bromophenyl)prop-2-
enoate gave b-amino ester )3S,aR)-29 in 95% de,29 and in
Scheme 7. Reagents and conditions: )i) )S)-4 )3 equiv.), THF, 2788C; )ii)
iso-propyl diethylphosphonoacetate )1.15 equiv.), nBuLi )1.1 equiv.),
THF, 2788C to rt; )iii) )R)-3 )3 equiv.), THF, 2788C.

4634
S. D. Bull et al. / Tetrahedron 58 -2002) 4629±4642
Conjugate addition of lithium )S)-N-allyl-N-a-methyl-
benzylamide 4 gave pseudo-meso scaffold 28 in 95% de
and in 82% yield, while conjugate addition of lithium )R)-
N-allyl-N-a-methylbenzylamide 4 furnished the pseudo-C2
symmetric scaffold 31 in 87% yield and in 95% de after
puri®cation )Scheme 9).
With the required diamino esters 28 and 31 in hand,
differentiation between the N-protecting groups was
next investigated to allow for the selective functionali-
sation of either )R)- or )S)-b-amino acid containing
fragment in either template. Thus, treatment of either
pseudo-meso diamino or pseudo-C2 diamino esters 28
and 31 with Wilkinson's catalyst in re¯uxing aqueous
acetonitrile gave selective deallylation, furnishing
diamines 32 and 34 in 82 and 92% yield respectively,
and in 95% de. Alternatively, treatment of pseudo-meso
28 or pseudo-C2 31 with CAN gave selective mono
N-debenzylation, furnishing diamines 33 and 35 in 79
yield and 87% yield respectively, and in 95% de
)Scheme 10).
Having demonstrated that either )R)- or )S)-b-amino acid
containing fragments can be selectively accessed, this
methodology was used as a model for selective peptide
elaboration. Thus, simulation of the formation of a peptide
bond with the secondary amine functionality of diamines 32
and 34 through protection as their Z-carbamates gave
amides 36 and 37 in 70 and 72% yields respectively.
Subsequent treatment of amides 36 and 37 with formic
acid under re¯ux36 gave acids 38 and 39 in 75 and 71%
yield respectively, in which differential deprotection of
both the ester and N-protecting fragments of the pseudo-
meso and pseudo-C2 templates 27 and 31 has been achieved
)Scheme 11).
Scheme 9. Reagents and conditions: )i) )S)-4 )3 equiv.), THF, 2788C; )ii)
)R)-4 )3 equiv.), THF, 2788C.
86% yield and 95% de after puri®cation. Subsequent palla-
dium mediated Heck reaction of )3S,aR)-bromide 29 with
tert-butyl acrylate furnished a,b-unsaturated ester )3S,aR)-
30 in 82% yield and in 95% de )Scheme 8).
Scheme 10. Reagents and conditions: )i) Rh)PPh3)3Cl )0.1 equiv.), MeCN/H2O )8.5:1.5), D; )ii) CAN )2.1 equiv.), MeCN/H2O )5:1), rt.

S. D. Bull et al. / Tetrahedron 58 -2002) 4629±4642
4635
Scheme 11. Reagents and conditions: )i) dibenzyl dicarbonate, vacuum, rt; )ii) HCO2H, 608C.
3. Conclusion
13C: 100.6 MHz) or Bruker AMX 500 )1H: 500 MHz
and 13C: 125 MHz) spectrometer in the deuterated solvent
stated. All chemical shifts )d) are quoted in ppm and
coupling constants )J) in Hz. Coupling constants are quoted
twice, each being recorded as observed in the spectrum
without averaging. Residual signals from the solvents
were used as an internal reference. 13C multiplicities were
assigned using a DEPT sequence. Infrared spectra were
recorded on a Perkin±Elmer 1750 IR Fourier Transform
spectrophotometer using either thin ®lms on NaCl plates
)®lm) or KBr discs )KBr) as stated. Only the characteristic
peaks are quoted in cm21. Low resolution mass spectra )m/z)
were recorded on VG MassLab 20±250 or Micromass Plat-
form 1 spectrometers and high resolution mass spectra
)HRMS) on a Micromass Autospec 500 OAT spectrometer
or on a Waters 2790 Micromass LCT Exact Mass Electro-
spray Ionisation Mass Spectrometer. Techniques used were
chemical ionisation )CI, NH3), atmospheric pressure chemi-
cal ionisation )APCI) or electrospray ionisation )ESI) using
partial puri®cation by HPLC with methanol/acetonitrile/
water )40:40:20) as eluent. Optical rotations were recorded
on a Perkin±Elmer 241 polarimeter with a path length of
1 dm. Concentrations are quoted in g/100 mL. Elemental
analyses were performed by the microanalysis service of
the Inorganic Chemistry Laboratory, Oxford.
In conclusion, the unambiguous preparation of either C2
symmetric [)R,R)- or )S,S)-] or meso-)R,S)-diastereoisomers
of bis-b-amino acid templates has been achieved. Extension
of this methodology allows for the synthesis and selective
deprotection of both pseudo-meso and pseudo-C2 symmetric
bis-b-amino acid templates using a matrix of protecting
groups. This strategy shows potential for the attachment
of a- and b-pseudopeptidic fragments for secondary struc-
tural investigations. Further investigations within this area
are currently underway.
4. Experimental
4.1. General
All reactions involving organometallic or other moisture
sensitive reagents were performed under an atmosphere of
nitrogen via standard vacuum line techniques. All glassware
was ¯ame-dried and allowed to cool under vacuum. In all
cases, the reaction diastereoselectivity was assessed by peak
1
integration of the H NMR spectrum of the crude reaction
mixture. Tetrahydrofuran was distilled under an atmosphere
of dry nitrogen from sodium benzophenone ketyl. All other
solvents were used as supplied )Analytical or HPLC grade),
without prior puri®cation. Thin layer chromatography
)TLC) was performed on aluminium or plastic sheets coated
with 60 F254 silica. Sheets were visualised using iodine, UV
light or 1% aqueous KMnO4 solution. Flash chromato-
graphy was performed on Kieselgel 60 silica. Melting points
were recorded on a Gallenkamp hot stage apparatus and are
uncorrected. Nuclear magnetic resonance )NMR) spectra
were recorded on a Bruker AC 200 )1H: 200 MHz and
13C: 50.3 MHz) or Bruker DPX 400 )1H: 400 MHz and
4.2. Representative procedure 1a and 1b for lithium
amide addition
n-BuLi )1.55 equiv.) was added dropwise to a stirred solu-
tion of amine )1.6 equiv.) in anhydrous THF at 2788C and
stirred for 30 min under nitrogen. A solution of the a,b-
unsaturated ester )1.0 equiv.) in anhydrous THF was
added dropwise via cannula and stirred at 2788C for )a)
2 h and )b) 12 h before the addition of saturated aqueous
ammonium chloride. The resultant solution was partitioned

4636
S. D. Bull et al. / Tetrahedron 58 -2002) 4629±4642
between brine and 1:1 DCM/Et2O, and the combined
organic extracts dried )MgSO4), ®ltered and concentrated
in vacuo before being partitioned between 10% aqueous
citric acid and DCM, dried and concentrated in vacuo before
puri®cation by column chromatography.
)6H, s, CH)OMe)2), 3.82 )3H, s, CO2Me), 5.41 )1H, s,
CH)OMe)2), 6.45 )1H, d, Jˆ16.0 Hz, ArCHvCH), 7.45±
7.56 )4H, m, Ph), 7.70 )1H, d, Jˆ16.0 Hz, ArCHvCH); dC
)50 MHz, CDCl3) 51.4, 52.2, 102.2, 118.0, 127.3, 127.9,
134.5, 140.4, 144.4, 167.3; m/z )APCI1) 237.0 )MH1,
30%), 205.0 )MH12MeOH, 100%); nmax )®lm) 2950,
2830 )C±H), 1721 )CvO), 1637 )CvC).
4.3. Representative procedure 2 for lithium amide
inverse addition
4.4.3. /3R,aS)-Methyl 3-/N-benzyl-N-a-methylbenzyl-
amino)-3-/4-dimethoxymethyl-phenyl)propanoate 17.
Following representative procedure 1a, n-BuLi )2.5 M,
1.0 mL, 2.55 mmol), )S)-N-benzyl-N-a-methylbenzylamine
)614 mg, 2.6 mmol, 1.6 equiv.) in THF )5 mL) and 16
)236 mg, 1.0 mmol, 1.0 equiv.) in THF )5 mL) gave,
after puri®cation by column chromatography on silica
gel )hexane/Et2O 2:1), 17 )260 mg, 58%) as a colourless
oil in 82% de; dH )400 MHz, CDCl3) 1.21 )3H, d,
Jˆ6.8 Hz, C)a)Me), 2.57 )1H, dd, J2A,2Bˆ14.9Hz,
J2A,3ˆ9.3 Hz, C)2)HA), 2.69)1H, dd, J2B,2Aˆ14.9Hz,
J2B,3ˆ5.7 Hz, C)2)HB), 3.33 )6H, s, CH)OMe)2), 3.48
)3H, s, CO2Me), 3.66 )1H, AB, Jˆ14.6 Hz, NCHA), 3.74
)1H, AB, Jˆ14.6 Hz, NCHB), 4.00 )1H, q, Jˆ6.8 Hz,
C)a)H), 4.46 )1H, dd, J3,2Aˆ9.3 Hz, J3,2Bˆ5.7 Hz,
C)3)H), 7.18±7.45 )14H, m, Ph); selected peaks for
minor diastereoisomer 2.95 )1H, dd, J2B,2Aˆ14.5 Hz,
J2B,3ˆ6.0 Hz, C)2)HB), 3.90 )1H, q, Jˆ6.9Hz, C) a)H);
dC )50 MHz, CDCl3) 15.9, 37.2, 50.7, 51.5, 52.7, 56.7,
58.9, 103.0, 126.9, 127.1, 127.5, 127.6, 128.8, 128.4,
137.2, 141.5, 142.3, 144.1, 172.4; m/z )APCI1) 448.6
)MH1, 100%), 470.0 )MNa1, 10%), 344.1 )MH12C4H8,
20%); HRMS )CI1) C28H34NO4 requires 448.2488; found
448.2492; nmax )®lm) 2948, 2830 )C±H), 1738 )CvO).
n-BuLi )1.55 equiv.) was added dropwise to a stirred solu-
tion of amine )1.6 equiv.) in anhydrous THF at 2788C and
stirred for 30 min under nitrogen before being added drop-
wise via cannula to a solution of the a,b-unsaturated ester
)1.0 equiv.) in anhydrous THF and stirred for 12 h before
the addition of saturated aqueous ammonium chloride. The
resultant solution was partitioned between brine and 1:1
DCM/Et2O, and the combined organic extracts dried
)MgSO4), ®ltered and concentrated in vacuo before being
partitioned between 10% aqueous citric acid and DCM,
dried and concentrated in vacuo before puri®cation by
column chromatography.
4.4. Representative procedure 3 for Horner±
Wadsworth±Emmons ole®nation
n-BuLi )1.1 equiv.) was added dropwise to a stirred solution
of phosphonate )1.15 equiv.) in anhydrous THF at 2788C
and stirred for 30 min under nitrogen before the drop-
wise addition of aldehyde )1.0 equiv.) in THF via cannula.
After 30 min, the solution was warmed to rt and stirred
for a further 12 h before cooling to 2788C and addition
of saturated aqueous ammonium chloride. The resultant
solution was partitioned between brine and DCM, and
the combined organic extracts dried )MgSO4), ®ltered
and concentrated in vacuo before puri®cation by column
chromatography.
4.4.4. /3R,aS)-Methyl 3-/N-benzyl-N-a-methylbenzyl-
amino)-3-/4-formylphenyl)-propanoate 18. Amberlyst-
15 )wet) )200 mg) was added to a stirred solution of acetal
17 )100 mg, 0.22 mmol) at rt in acetone/H2O )10:1,
5.5 mL). After 30 min, TLC analysis indicated that the reac-
tion had gone to completion and the resin was removed by
®ltration and the ®ltrate evaporated. Puri®cation by column
chromatography on silica gel )petrol )30/40)/Et2O 6:1) gave
18 as a pale yellow oil )78 mg, 87%) in 82% de; dH
)400 MHz, CDCl3) 1.28 )3H, d, Jˆ6.7 Hz, C)a)Me),
2.59±2.72 )2H, m, C)2)H2), 3.51 )3H, s, CO2Me), 3.69
)1H, AB, Jˆ14.6 Hz, NCHA), 3.74 )1H, AB, Jˆ14.6 Hz,
NCHB), 3.99 )1H, q, Jˆ6.8 Hz, C)a)H), 4.55 )1H, dd,
J3,2Aˆ8.9Hz, J3,2Bˆ5.5 Hz, C)3)H), 7.21±7.44 )10H, m,
Ph), 7.59±7.61 )2H, m, Ph), 7.83±7.86 )2H, m, Ph), 10.0
)1H, s, CHO); selected peaks for minor diastereoisomer 2.85
)1H, dd, J2A,2Bˆ14.5 Hz, J2A,3ˆ9.0 Hz, C)2)HA), 2.95 )1H,
dd, J2A,2Bˆ14.5 Hz, J2A,3ˆ6.0 Hz, C)2)HB); dC )100 MHz,
CDCl3) 16.6, 36.4, 50.9, 51.6, 57.2, 58.9, 126.9, 127.2,
127.8, 128.1, 128.3, 128.6, 129.8, 135.5, 140.8, 143.5,
149.2, 171.8, 191.9; m/z )APCI1) 402.2 )MH1, 70%),
298.1 )MH12C8H9, 100%); HRMS )CI1) C26H27NO3
requires 402.2074; found 402.2069; nmax )®lm) 3027,
2974 )C±H), 1737 )CvO), 1700 )CvO).
4.4.1. /E)-tert-Butyl 3-/4-formyl-phenyl)prop-2-enoate28
15.
A
mixture of 4-bromobenzaldehyde )10.0 g,
54.0 mmol), tert-butyl acrylate )11 g, 86.4 mmol), tri-o-
tolyl phosphine )0.64 g, 2.10 mmol) and Pd)OAc)2
)120 mg, 0.54 mmol) in NEt3 )25 mL) was re¯uxed over-
night. The resultant mixture was ®ltered through celite
)eluent Et2O), washed with water )50 mL), extracted with
DCM )3£100 mL), dried and concentrated in vacuo.
Recrystallization )DCM/pentane) gave 15 )11.4 g, 91%) as
a pale yellow solid; dH )200 MHz, CDCl3) 1.54 )9H, s,
CO2C-Me)3), 6.48 )1H, d, Jˆ16.1 Hz, CvCHCO2C)Me)3),
7.60 )1H, d, Jˆ16.1 Hz, HCvCHCO2C)Me)3), 7.62±7.91
)4H, m, Ph), 10.0 )1H, s, CHO); data consistent with that of
the literature.28
4.4.2. /E)-Methyl-3-/4-dimethoxymethyl-phenyl)prop-2-
enoate 16. Trimethylorthoformate )0.80 g, 7.5 mmol) was
added to a stirred solution of MeOH )20 mL) saturated with
HCl prior to the portionwise addition of 15 )1.65 g,
7.1 mmol) and re¯uxed for 1 h. After concentration in
vacuo, the pH was adjusted to pH7 with saturated sodium
bicarbonate solution and partitioned between DCM
)3£100 mL) and brine. The residue was puri®ed by column
chromatography on silica gel )hexane/Et2O 5:1) to give 16
)1.6 g, 96%) as a colourless oil; C13H16O4 requires C 66.1,
H, 6.8%; found C 65.7, H 6.9%; dH )200 MHz, CDCl3) 3.33
4.4.5. /3R,aS)-tert-Butyl 3-/N-benzyl-N-a-methylbenzyl-
amino)-3-/4-formyl-phenyl)-propanoate 21. Following
representative procedure 2, n-BuLi )1.6 M, 8.0 mL,
12.7 mmol), )S)-N-benzyl-N-a-methylbenzylamine )2.7 g,
12.9mmol) in THF )20 mL) and 15 )1.0 g, 4.3 mmol) in

S. D. Bull et al. / Tetrahedron 58 -2002) 4629±4642
4637
THF )20 mL) gave, after puri®cation by column chromato-
graphy on silica gel )hexane/Et2O 6:1), 21 )1.5 g, 81%) as a
pale yellow oil in 97% de; dH )400 MHz, CDCl3) 1.24 )9H,
s, CO2C-Me)3), 1.29)3H, d, Jˆ6.9Hz, C) a)Me), 2.54 )2H,
m, C)2)H2), 3.68 )2H, app s, NCH2), 3.96 )1H, q, Jˆ6.9Hz,
C)a)H), 4.49)1H, app t, Jˆ7.5 Hz, C)3)H), 7.18±7.42
)10H, m, Ph), 7.59±7.61 )2H, m, Ph), 7.86±7.88 )2H, m,
Ph), 10.00 )1H, s, CHO); dC )50 MHz, CDCl3) 17.2, 27.8,
37.4, 51.0, 57.6, 59.1, 80.6, 126.8, 127.1, 127.7, 127.9, 128.3,
128.8, 129.6, 130.1, 135.3, 141.1, 143.5, 149.5, 170.8, 192.0;
m/z )APCI1) 444.5 )MH1, 100%), 388.1 )MH12C4H8,
20%); HRMS )CI1) C29H34NO3 requires 444.2539; found
444.2547; nmax )®lm) 2973 )C±H), 1724 )CvO), 1704
of bromide 23 )1.0 g, 2.0 mmol), tri-o-tolylphosphine
)123 mg, 0.4 mmol) and tert-butyl acrylate )0.6 mL,
4.05 mmol) in NEt3 )10 mL) and heated at re¯ux for 12 h.
After cooling, the residue was ®ltered though celite, parti-
tioned between H2O )20 mL) and DCM )3£100 mL), and
concentrated in vacuo. Puri®cation by column chromato-
graphy )pentane/Et2O 20:1) gave 22 )1.02 g, 93%) as a
white foam with consistent spectroscopic properties to
those previously described.
4.5.1. /3R,aS,30R,a0S)-Di-tert-butyl benzene-1,4-bis[3-/N-
benzyl-N-a-methylbenzylamino)propanoate]24 8. Follow-
ing representative procedure 1b, n-BuLi )2.5 M, 2.2 mL,
5.45 mmol), )S)-N-benzyl-N-a-methylbenzylamine )1.2 g,
5.5 mmol) in THF )15 mL) and 22 )1.0 g, 1.85 mmol) in
THF )15 mL) gave, after puri®cation by column chromato-
graphy on silica gel )pentane/Et2O 12:1), 8 )1.14 g, 82%) as a
23
)CvO), 1153 )C±O); [a]D ˆ118.0 )c 1.0, CHCl3).
4.4.6. Horner±Wadsworth±Emmons preparation of
/3R,aS,E)-tert-butyl 3-/N-benzyl-N-a-methylbenzylamino)-
3-[4-tert-butoxy-3-oxoprop-1-enyl)phenyl]propanoate 22.
Following representative procedure 3, tert-butyl diethylphos-
phonoacetate )1.0 g, 3.9mmol), n-BuLi )2.5 M, 1.5 mL,
3.7 mmol) in THF )15 mL) and aldehyde 21 )1.5 g,
3.4 mmol) gave, after puri®cation by column chromatography
on silica gel )pentane/Et2O 20:1), 22 )1.63 g, 89%) as a white
foam in 97% de; dH )400 MHz, CDCl3) 1.23 )9 H, s,
CO2C-Me)3), 1.28 )3H, d, Jˆ6.9Hz, C) a)Me), 1.54 )9H, s,
CO2C-Me)3), 2.46±2.54 )2H, m, C)2)H2), 3.68 )2H, app s,
NCH2), 3.98 )1H, q, Jˆ6.9Hz, C) a)H), 4.41 )1H, dd,
J3,2Aˆ9.3 Hz, J3,2Bˆ5.8 Hz, C)3)H), 6.35 )1H, d, J ˆ
16.0 Hz, ArCHvCH), 7.17±7.50 )14H, m, Ph), 7.58 )1H,
d, Jˆ16.0 Hz, ArCHvCH); dC )100 MHz, CDCl3) 16.7,
27.8, 28.2, 37.8, 50.9, 57.3, 59.2, 80.3, 80.4, 119.7, 126.6,
126.9, 127.8, 127.9, 128.1, 128.2, 128.6, 133.4, 141.4,
143.3, 143.8, 144.2, 166.4, 170.9; m/z )APCI1) 542.9
)MH1, 100%), 486.3 )MH12C4H8, 20%); HRMS )EI1)
C35H44NO4 requires 542.3270; found 542.3272; nmax )KBr)
2976, 2931 )C±H), 1726, 1707 )CvO), 1635 )CvC), 1150
24
hygroscopic white foam in 96% de; [a]D ˆ111.8 )c 1.0,
CHCl3); dH )400 MHz, CDCl3) 1.17 )18H, s, CO2C-Me)3),
1.21 )6H, d, Jˆ6.8 Hz, C)a)Me), 2.49±2.57 )4H, m,
C)2)H2), 3.66 )4H, app s, NCH2), 3.97 )2H, q, Jˆ6.8 Hz,
C)a)H), 4.39)2H, dd, J3,2Aˆ9.0 Hz, J3,2Bˆ6.1 Hz, C)3)H),
7.14±7.42 )24H, m, Ph); data consistent with that contained
in the literature.24
4.5.2. /3R,aS,30S,a0R)-Di-tert-butyl benzene-1,4-bis[3-/N-
benzyl-N-a-methylbenzylamino)propanoate] 24. Follow-
ing representative procedure 1b, n-BuLi )2.5 M, 2.2 mL,
5.45 mmol), )R)-N-benzyl-N-a-methylbenzylamine )1.2 g,
5.5 mmol) in THF )15 mL) and 22 )1.0 g, 1.85 mmol) in
THF )15 mL) gave, after washing with pentane, 24 )1.24 g,
89%) as a white solid in 97% de; mp 158±1608C; dH
)400 MHz, CDCl3) 1.20 )18H, s, CO2C-Me)3), 1.22 )6H, d,
Jˆ7.1 Hz, C)a)Me), 2.50±2.58 )4H, m, C)2)H2), 3.67 )4H,
app s, NCH2), 3.97 )2H, q, Jˆ7.1 Hz, C)a)H), 4.41 )2H, dd,
J3,2Aˆ9.2 Hz, J3,2Bˆ6.0 Hz, C)3)H), 7.16±7.42 )24H, m, Ph);
dC )100 MHz, CDCl3) 17.1, 28.2, 38.6, 51.2, 57.5, 59.5, 80.5,
126.9, 127.2, 128.2, 128.4, 128.4, 128.5, 141.0, 142.0, 144.6,
171.5; nmax )KBr) 2971, 2930 )C±H), 1716 )CvO), 1151 )C±
O); m/z )APCI1) 753.5 )MH1, 100%); HRMS )EI1)
C50H61N2O4 requires 753.4631; found 753.4656.
23
)C±O); [a]D ˆ 113.2 )c 1.1, CHCl3).
4.4.7. /3R,aS)-tert-Butyl 3-/N-benzyl-N-a-methylbenzyl-
amino)-3-/4-bromophenyl)propanoate 23. Following
representative procedure 1a, n-BuLi )2.5 M, 6.6 mL,
16.4 mmol), )S)-N-benzyl-N-a-methylbenzylamine )3.6 g,
17.0 mmol) in THF )35 mL) and )E)-tert-butyl 3-)4-bromo-
phenyl)propanoate )3.0 g, 10.6 mmol) in THF )35 mL)
gave, after puri®cation by column chromatography on silica
gel )pentane/Et2O 20:1), 23 )4.8 g, 91%) as a colourless oil
in 97% de; dH )400 MHz, CDCl3) 1.25 )9H, s, CO2C-Me)3),
1.28 )3H, d, Jˆ6.8 Hz, C)a)Me), 2.42±2.54 )2H, m,
C)2)H2), 3.66 )2H, app s, NCH2), 3.95 )1H, q, Jˆ6.8 Hz,
C)a)H), 4.37 )1H, dd, J3,2Aˆ10.1 Hz, J3,2Bˆ5.1 Hz, C)3)H),
7.17±7.48 )14H, m, Ph); dC )100 MHz, CDCl3) 16.9, 27.8,
37.8, 50.8, 57.3, 58.8, 80.4, 120.9, 126.6, 127.0, 127.7,
127.9, 128.1, 128.2, 129.9, 131.2, 141.1, 141.3, 143.7,
170.9; m/z )APCI1) 496.2 )MH1, 100%), 438.2
)MH12C4H8, 20%); HRMS )EI1) C28H33NO2Br requires
494.1695; found 494.1684; nmax )®lm) 2975, 2932 )C±H),
4.5.3. /3R,30S)-Di-tert-butyl benzene-1,4-bis[3-amino-
propanoate] 25. Pd)OH)2 on C )150 mg) was added to a
solution of 24 )200 mg, 0.27 mmol) in a mixture of degassed
MeOH/acetic acid )5:1, 6 mL) and the resultant black
suspension stirred under a hydrogen atmosphere )5 atm)
for 16 h. The reaction mixture was ®ltered through a plug
of celite )eluent MeOH) and concentrated in vacuo before
puri®cation by column chromatography on silica gel
)CHCl3/MeOH 20:1) to give 25 )78 mg, 81%) as a colour-
less oil in .95% de which solidi®ed upon standing; nmax
)®lm) 3491 )N±H), 2973, 2931 )C±H), 1721 )CvO); dH
)500 MHz, CDCl3) 1.41 )18H, s, CO2C-Me)3), 1.79)4H,
br s, NH), 2.55±2.57 )4H, m, C)2)H2), 4.34±4.37 )2H,
br m, C)3)H), 7.32 )4H, s, Ph); dC )125 MHz, CDCl3)
28.0, 45.1, 52.3, 80.6, 126.4, 143.7, 171.2; m/z )APCI1)
365 )MH1, 20%); HRMS )EI1) C20H33N2O4 requires
365.2440; found 365.2434.
23
1726 )CvO), 1153 )C±O); [a]D ˆ13.6 )c 1.8, CHCl3).
4.5. Heck preparation of /3R,aS,E)-tert-butyl 3-/N-
benzyl-N-a-methylbenzylamino)-3-[4-tert-butoxy-3-
oxoprop-1-enyl)phenyl]propanoate 22
4.5.4. /3R,aS)-tert-Butyl 3-/N-allyl-N-a-methylbenzyl-
amino)-3-/4-formyl-phenyl)propanoate 26. Following
representative procedure 2, n-BuLi )1.6 M, 8.0 mL,
Pd)OAc)2 )23 mg, 0.1 mmol) was added to a stirred solution

4638
S. D. Bull et al. / Tetrahedron 58 -2002) 4629±4642
12.7 mmol), )S)-N-allyl-N-a-methylbenzylamine )2.7 g,
12.9mmol) in THF )20 mL) and 15 )1.0 g, 4.3 mmol) in
THF )20 mL) gave, after puri®cation by column chromato-
graphy on silica gel )hexane/Et2O 6:1), 26 )1.07 g, 63%) as a
pale yellow oil in 92% de; dH )400 MHz, CDCl3) 1.21 )3H,
d, Jˆ6.8 Hz, C)a)Me), 1.30 )9H, s, CO2C-Me)3), 2.61 )1H,
dd, J2A,2Bˆ15.0 Hz, J2A,3ˆ9.4 Hz, C)2)HA), 2.73 )1H, dd,
J2B,2Aˆ15.0 Hz, J2B,3ˆ5.5 Hz, C)2)HB), 3.15 )2H, m,
NCH2CHvCH2), 4.00 )1H, q, Jˆ6.8 Hz, C)a)H), 4.51
)1H, dd, J3,2Aˆ9.4 Hz, J3,2Bˆ5.5 Hz, C)3)H), 5.05±5.08
)2H, m, NCH2CHvCH2), 5.74±5.84 )1H, m, NCH2CH v
CH2), 7.22±7.41 )5H, m, Ph), 7.56±7.58 )2H, m, Ph), 7.85±
7.88 )2H, m, Ph), 10.01 )1H, s, CHO); dC )100 MHz,
CDCl3) 17.2, 27.9, 38.1, 49.9, 56.8, 58.8, 80.6, 116.1,
126.8, 127.4, 128.2, 128.7, 129.6, 135.3, 138.4, 144.2,
149.4, 170.8, 192.0; m/z )APCI1) 394.1 )MH1, 100%),
338.1 )MH12C4H8, 20%); HRMS )CI1) C25H32NO3
requires 394.2382; found 394.2381; nmax )®lm) 2972 )C±
H), 1724 )CvO), 1704 )CvO), 1605 )CvC), 1153 )C±O);
67.7, 121.0, 126.7, 127.0, 127.8, 127.9, 128.2, 129.8, 131.1,
131.3, 141.0, 141.3, 143.7, 171.1; m/z )APCI1) 480.1
)MH1, 30%); HRMS )EI1) C27H31NO2Br requires
480.1538; found 480.1527; nmax )®lm) 2978, 2933 )C±H),
1728 )CvO); [a]D ˆ15.1 )c 1.0, CHCl3).
23
4.5.7. /3S,aR,E)-iso-Propyl 3-/N-benzyl-N-a-methyl-
benzylamino)-3-[4-tert-butoxy-3-oxoprop-1-enyl)phenyl]
propanoate 30. Pd)OAc)2 )70 mg, 0.31 mmol) was added
to a stirred solution of bromide 29 )3.0 g, 6.26 mmol), tri-o-
tolylphosphine )380 mg, 1.25 mmol) and tert-butyl acrylate
)1.9mL, 12.5 mmol) in NEt 3 )30 mL) and heated at re¯ux
for 12 h. After cooling, the residue was ®ltered though
celite, partitioned between H2O )20 mL) and DCM
)3£100 mL), and concentrated in vacuo. Puri®cation by
column chromatography )pentane/Et2O 20:1) gave 30
)2.95 g, 89%) as a yellow oil in 95% de; dH )400 MHz,
CDCl3) 0.99, 1.05 )2£3H, d, Jˆ6.4 Hz, CH-Me)2), 1.28
)3H, d, Jˆ6.8 Hz, C)a)Me), 1.54 )9H, s, CO2C-Me)3),
2.51±2.59)2H, m, C)2) H2), 3.69)2H, app s, NC H2), 3.98
)1H, q, Jˆ6.8 Hz, C)a)H), 4.45 )1H, dd, J3,2Aˆ9.0 Hz,
J3,2Bˆ5.9Hz, C)3) H), 4.80 )1H, sept, Jˆ6.4 Hz,
CH)Me)2), 6.36 )1H, d, Jˆ15.9Hz, ArCH vCH), 7.17±
7.49)14H, m, Ph), 7.57 )1H, d, Jˆ15.9Hz, ArC HvCH);
dC )100 MHz, CDCl3) 16.5, 21.5, 28.2, 37.2, 50.8, 57.2,
59.2, 67.6, 80.4, 119.8, 126.6, 126.9, 127.8, 127.9, 128.2,
128.6, 133.5, 141.3, 143.2, 143.8, 144.2, 166.4, 171.2; m/z
)APCI1) 528.4 )MH1, 100%); HRMS )EI1) C34H42NO4
requires 528.3114; found 528.3116; nmax )KBr) 2976,
2933 )C±H), 1726, 1708 )CvO), 1636 )CvC), 1148 )C±
23
[a]D ˆ118.7 )c 1.0, CHCl3).
4.5.5. /3R,aS,E)-tert-Butyl 3-/N-allyl-N-a-methylbenzyl-
amino)-3-[4-iso-propoxy-3-oxoprop-1-enyl)phenyl]pro-
panoate 27. Following representative procedure 3, iso-
propyl diethylphosphonoacetate )1.13 g, 4.75 mmol,
1.5 equiv.), n-BuLi )2.5 M, 4.58 mmol, 1.8 mL) in THF
)10 mL) and 26 )1.2 g, 3.16 mmol) gave, after puri®cation
by column chromatography on silica gel )hexane/Et2O
20:1), 27 )1.3 g, 87%) as a white foam in 91% de; dH
)400 MHz, CDCl3) 1.20 )3H, d, Jˆ6.8 Hz, C)a)Me), 1.30
23
)9H, s, CO2C-Me)3), 1.32 )6H, d, Jˆ6.3 Hz, OCH-Me)2),
O); [a]D ˆ25.9) c 1.55, CHCl3).
0
0
0
0
0
2.59)1H, dd, J2 A,2 Bˆ14.8 Hz, J2 A,3 ˆ9.3 Hz, C)2 )HA),
0
2.73 )1H, dd, J2 B,2 Aˆ14.8 Hz, J2 B,3 ˆ5.7 Hz, C)2 )HB),
4.5.8. /3R,aS,10S,a0R)-tert-Butyl 3-/N-allyl-N-a-methyl-
benzylamino)-3-[4-iso-propoxy-30-oxo-10-/N-benzyl-N-
a-methylbenzylamino)propanoate)phenyl]propanoate
28. Following representative procedure 1b, n-BuLi )2.5 M,
2.55 mL, 4.1 mmol), )S)-)N-benzyl-N-a-methylbenzylamine
)880 mg, 4.15 mmol) in THF )10 mL) and 30 )660 mg,
1.38 mmol, 1 equiv.) in THF )10 mL) gave, after puri®cation
by column chromatography on silica gel )hexane/Et2O
10:1), 28 )780 mg, 82%) as a colourless oil in 95% de; dH
)400 MHz, CDCl3) 0.98, 1.03 )2£3H, d, Jˆ6.2 Hz,
OCH-Me)2), 1.10, 1.25 )2£3H, d, Jˆ6.8 Hz, C)a)Me and
C)a0)Me), 1.28 )9H, s, CO2C-Me)3), 2.53±2.63 )3H, m,
0
0
0
0
3.15 )2H, app d, NCH2CHvCH2), 4.01 )1H, q, J ˆ
6.8 Hz, C)a0)H), 4.45 )1H, dd, J3 ,2 Aˆ9.3 Hz, J3 ,2 B
ˆ
0
0
0
0
5.7 Hz, C)30)H), 5.04±5.17 )3H, m, OCH)CH3)2 and
NCH2CHvCH2), 5.75±5.84 )1H, m, NCH2CHvCH2),
6.41 )1H, d, Jˆ16.0 Hz, PhCHvCH), 7.21±7.50 )9H, m,
Ph), 7.67 )1H, d, Jˆ16.0 Hz, PhCHvCH); dC )125 MHz,
CDCl3) 16.8, 22.0, 27.8, 38.6, 49.7, 56.5, 58.7, 67.7, 80.3,
115.8, 118.3, 126.6, 127.4, 127.8, 128.0, 128.5, 133.3,
144.3, 144.5, 138.6, 144.0, 166.6, 171.0; nmax )®lm)
2968 )C±H), 1726 )CvO), 1637 )CvC), 1171 )C±O);
m/z )APCI1) 478.0 )MH1, 100%), 500.1 )MNa1, 5%),
422.2 )MH12C4H8, 20%); HRMS )CI1) C30H40NO4
C)2)H2 and C)20)HA), 2.65 )1H, dd, J2 B,2 Aˆ14.6 Hz,
0
0
23
0
0
0
requires 478.2957; found 478.2975; [a]D ˆ19.1 )c 1.0,
J2 B,3 ˆ6.3 Hz, C)2 )HB), 3.13 )2H, app d, NCH2CHvCH2),
3.69)2H, app s, NC H2Ph), 3.96±4.03 )2H, m, C)a)H
and C)a0)H), 4.43±4.47 )2H, m, C)3)H and C)10)H), 4.78
)1H, sept, Jˆ6.2 Hz, OCH)CH3)2), 5.02±5.17 )2H, m,
NCH2CHvCH2), 5.78 )1H, m, NCH2CHvCH2), 7.16±
7.44 )19H, m, Ph); dC )100 MHz, CDCl3) 16.4, 16.7, 21.5,
21.6, 27.9, 37.5, 38.9, 49.7, 50.7, 56.0, 57.0, 58.5, 59.2,
67.5, 80.2, 115.8, 126.5, 126.8, 127.5, 127.8, 127.9, 128.0,
128.1, 138.9, 140.4, 140.5, 141.6, 144.1, 145.0, 171.2,
171.3; nmax )®lm) 2968 )C±H), 1728 )CvO), 1170 )C±
O); m/z )APCI1) 690 )MH1, 100%), 712 )MNa1, 20%);
HRMS )CI1); C45H57N2O4 requires 689.4318; found
CHCl3).
4.5.6. /3S,aR)-iso-Propyl 3-/N-benzyl-N-a-methylbenzyl-
amino)-3-/4-bromophenyl)propanoate 29. Following
representative procedure 1a, n-BuLi )2.5 M, 6.9mL,
17.4 mmol), )S)-N-benzyl-N-a-methylbenzylamine )3.8 g,
17.9mmol) in THF )40 mL) and ) E)-iso-propyl 3-)4-
bromophenyl)propanoate )3.0 g, 11.2 mmol) in THF
)40 mL) gave, after puri®cation by column chromatography
on silica gel )pentane/Et2O 20:1), 29 )4.8 g, 89%) as a
colourless oil in 95% de; dH )400 MHz, CDCl3) 1.03, 1.08
)2£3H, d, Jˆ6.2 Hz, CH-Me)2), 1.30 )3H, d, Jˆ6.8 Hz,
C)a)Me), 2.48±2.60 )2H, m, C)2)H2), 3.69)2H, app s,
NCH2), 3.98 )1H, q, Jˆ6.8 Hz, C)a)H), 4.43 )1H, dd,
J3,2Aˆ9.8 Hz, J3,2Bˆ5.0 Hz, C)3)H), 4.83 )1H, sept,
23
689.4325; [a]D ˆ11.4 )c 0.85, CHCl3).
4.5.9. /3S,aR,10S,a0R)-tert-Butyl 3-/N-allyl-N-a-methyl-
benzylamino)-3-[4-iso-propoxy-30-oxo-10-/N-benzyl-N-
a-methylbenzylamino)propanoate)phenyl]propanoate
31. Following representative procedure 1b, n-BuLi )2.5 M,
Jˆ6.2 Hz, CH)Me)2), 7.20±7.49)14H, m,
Ph); dC
)100 MHz, CDCl3) 16.6, 16.7, 21.6, 37.2, 50.8, 57.2, 58.9,

S. D. Bull et al. / Tetrahedron 58 -2002) 4629±4642
4639
2.2 mL, 5.6 mmol), )R)-N-benzyl-N-a-methylbenzylamine
)920 mg, 5.7 mmol) in THF )15 mL) and 30 )1.0 g,
1.9mmol, 1 equiv.) in THF )15 mL) gave, after puri®cation
by column chromatography on silica gel )hexane/Et2O
10:1), 31 )1.13 g, 87%) as a colourless oil in 95% de; dH
)400 MHz, CDCl3) 1.01, 1.05 )2£3H, d, Jˆ6.2 Hz,
OCH-Me)2), 1.12, 1.27 )2£3H, d, Jˆ6.7 Hz, C)a)Me and
C)a0)Me), 1.29)9H, s, CO 2C-Me)3), 2.56±2.66 )3H, m,
d, Jˆ6.5 Hz, C)a)Me), 1.35 )9H, s, CO2C-Me)3), 1.76
)1H, br s, NH), 2.50±2.66 )4H, m, C)2)H2 and C)20)H2),
3.59)1H, q,
NCH2Ph), 3.97 )1H, q, Jˆ6.7 Hz, C)a0)H), 4.14 )1H, dd,
Jˆ6.5 Hz, C)a)H), 3.67 )2H, app s,
0
0
J3A,2ˆ7.7 Hz, J3B,2ˆ6.5 Hz, C)3)H), 4.42 )1H, dd, J1 ,2 A
ˆ
9.5 Hz, J1 ,2 Bˆ5.7 Hz, C)10)H), 4.81 )1H, sept, Jˆ6.2 Hz,
0
0
OCH)CH3)2), 7.16±7.49)1H9, m,
Ph); dC )100 MHz,
CDCl3) 16.5, 21.6, 21.6, 22.3, 28.0, 37.4, 43.8, 50.9, 54.6,
56.8, 57.1, 59.2, 67.4, 80.4, 126.5, 126.8, 126.8, 127.8,
127.9, 128.1, 128.1, 128.2, 128.3, 140.7, 141.6, 141.7,
144.0, 146.0, 171.0, 171.4; m/z )APCI1) 649.3 )MH1,
100%), 593.3 )MH12C4H8, 10%); HRMS )EI)
C42H53N2O4 requires 649.4005; found 649.4005; nmax
)®lm) 2976, 2930 )C±H), 1726 )CvO), 1150 )C±O);
C)2)H2 and C)20)HA), 2.80 )1H, dd, J2 B,2 Aˆ14.9Hz,
0
0
0
0
0
J2 B,3 ˆ6.5 Hz, C)2 )HB), 3.15 )2H, app d, NCH2CHvCH2),
3.70 )2H, app s, NCH2Ph), 3.98±4.07 )2H, m, C)a)H
and C)a0)H), 4.46±4.49)2H, m, C)3) H and C)10)H), 4.81
)1H, sept, Jˆ6.2 Hz, OCH)CH3)2), 5.04±5.19)2H, m,
NCH2CHvCH2), 5.76±5.86 )1H, m, NCH2CHvCH2),
7.17±7.46 )19H, m, Ph); dC )100 MHz, CDCl3) 17.2, 17.3,
22.1, 22.2, 28.4, 37.8, 39.6, 50.2, 51.3, 56.6, 57.7, 59.2, 59.7,
68.0, 80.7, 116.3, 127.1, 127.1, 127.3, 127.4, 128.1, 128.2,
128.4, 128.5, 128.6, 128.7, 128.2, 139.5, 140.9, 141.1, 142.2,
144.7, 145.6, 171.8, 171.9; nmax )®lm) 2976, 2932 )C±H),
1728 )CvO), 1158, 1145 )C±O); m/z )APCI1) 689.4 )MH1,
100%); HRMS )EI) C45H57N2O4 requires 689.4318; found
23
[a]D ˆ18.4 )c 1.6, CHCl3).
4.5.12. /3R,aS,10S,a0R)-tert-Butyl 3-/N-allyl-N-a-methyl-
benzylamino)-3-[4-iso-propoxy-30-oxo-10-/N-a-methyl-
benzylamino)propanoate)phenyl]propanoate 33. CAN
)670 mg, 1.22 mmol) was added to a stirred solution of 28
)400 mg, 0.58 mmol) in MeCN/H2O )5:1, 20 mL) at room
temperature. After 12 h, saturated aqueous sodium bicarbon-
ate solution )20 mL) was added and the resultant mixture
partitioned between brine and Et2O )3£50 mL), dried and
concentrated in vacuo. Puri®cation by column chromato-
graphy )hexane/Et2O 6:1 to 4:1) gave 33 )275 mg, 79%)
as a pale yellow oil in 95% de; dH )400 MHz, CDCl3)
1.15±1.21 )9H, m, OCH-Me)2 and C)a)Me), 1.32 )9H, s,
CO2C-Me)3), 1.37 )3H, d, Jˆ6.5 Hz, C)a0)Me), 1.90 )1H, br
s, NH), 2.57±2.81 )4H, m, C)2)H2 and C)20)H2), 3.16 )2H,
app d, NCH2), 3.64 )1H, q, Jˆ6.5 Hz, C)a0)H), 4.02 )1H, q,
Jˆ6.7 Hz, C)a)H), 4.22 )1H, dd, Jˆ7.8, 6.4 Hz, C)10)H),
4.45 )1H, dd, Jˆ8.7, 6.3 Hz, C)3)H), 4.98 )1H, sept,
Jˆ6.2 Hz, OCH)CH3)2), 5.04±5.19)2H, m, NCH 2CHv
CH2), 5.77±5.85 )1H, m, NCH2CHvCH2), 7.18±7.45
)14H, m, Ph); dC )100 MHz, CDCl3) 16.4, 21.8, 21.8,
22.2, 28.0, 39.2, 43.1, 49.7, 54.6, 56.1, 56.7, 58.8, 67.7,
80.1, 115.7, 126.5, 126.7, 126.8, 127.5, 128.0, 128.2,
128.3, 138.9, 140.6, 141.5, 144.9, 146.0, 171.2; nmax )®lm)
2975, 2930 )C±H), 1727 )CvO), 1150 )C±O); m/z )APCI1)
599.3 )MH1, 100%); HRMS )EI) C38H50N2O4 requires
23
689.4332; [a]D ˆ 27.3 )c 1.0, CHCl3).
4.5.10. /3R,aS,10S,a0R)-tert-Butyl
3-/N-a-methyl-
benzylamino)-3-[4-iso-propoxy-30-oxo-10-/N-benzyl-N-
a-methylbenzylamino)propanoate)phenyl]propanoate
32. Rh)PPh3)3Cl )93 mg, 0.1 mmol) was added to a stirred
solution of 28 )700 mg, 1.0 mmol) in MeCN/H2O )8.5:1.5)
)15 mL) under nitrogen and heated at re¯ux for 8 h. The
volatiles were removed, and the residue passed through a
small plug of alumina )eluent Et2O), before puri®cation by
column chromatography on silica gel )pentane/Et2O 5:1) to
give 32 )545 mg, 82%) as a colourless oil in 95% de; dH
)400 MHz, CDCl3) 0.98, 1.05 )2£3H, d, Jˆ6.3 Hz,
OCH-Me)2), 1.25 )3H, d, Jˆ6.8 Hz, C)a0)Me), 1.34 )3H,
d, Jˆ6.5 Hz, C)a)Me), 1.35 )9H, s, CO2C-Me)3), 1.79
)1H, br s, NH), 2.49±2.66 )4H, m, C)2)H2 and C)20)H2),
3.60 )1H, q, Jˆ6.5 Hz, C)a)H), 3.67 )2H, ABq, Jˆ14.7,
NCH2Ph), 3.98 )1H, q, Jˆ6.8 Hz, C)a0)H), 4.14 )1H, dd,
0
0
J3,2Aˆ7.7 Hz, J3,2Bˆ6.6 Hz, C)3)H), 4.42 )1H, dd, J1 ,2 A
ˆ
9.7 Hz, J1 ,2 Bˆ5.3 Hz, C)10)H), 4.79)1H, sept, Jˆ6.3 Hz,
OCH)CH3)2), 7.14±7.42 )19H, m, Ph); dC )100 MHz,
CDCl3) 16.1, 21.5, 21.6, 22.2, 28.0, 37.7, 43.8, 50.8, 54.6,
56.8, 57.0, 59.3, 67.4, 80.4, 126.5, 126.8, 126.8, 127.8,
127.9, 128.1, 128.2, 128.3, 128.4, 140.7, 141.6, 141.7,
144.0, 146.0, 171.0, 171.3; m/z )APCI1) 649.9 )MH1,
100%), 672.0 )MNa1, 80%), 545.4 )MH12C4H8, 30%);
HRMS )CI1) C42H53N2O4 requires 649.4005; found
649.4008; nmax )®lm) 2976 )C±H), 1727 )CvO), 1149
0
0
23
599.3849; found 599.3848; [a]D ˆ17.2 )c 1.0, CHCl3).
4.5.13. /3S,aR,10S,a0R)-tert-Butyl 3-/N-allyl-N-a-methyl-
benzylamino)-3-[4-iso-propoxy-30-oxo-10-/N-a-methyl-
benzylamino)propanoate)phenyl]propanoate 35. CAN
)602 mg, 1.1 mmol) was added to a stirred solution of 31
)350 mg, 0.53 mmol) in MeCN/H2O )5:1, 20 mL) at room
temperature. After 12 h, saturated aqueous sodium bicarbon-
ate solution )20 mL) was added and the resultant mixture
partitioned between brine and Et2O )3£50 mL), dried and
concentrated in vacuo. Puri®cation by column chromato-
graphy )hexane/Et2O 7:1 to 4:1) gave 35 )265 mg, 87%)
as a colourless oil in 95% de; dH )400 MHz, CDCl3)
1.15±1.20 )9H, m, OCH-Me)2 and C)a)Me), 1.31 )9H, s,
CO2C-Me)3), 1.35 )3H, d, Jˆ6.6 Hz, C)a0)Me), 1.85 )1H, br
s, NH), 2.55±2.79)4H, m, C)2) H2 and C)20)H2), 3.14 )2H,
app d, NCH2), 3.64 )1H, q, Jˆ6.6 Hz, C)a0)H), 4.01 )1H, q,
Jˆ6.6 Hz, C)a)H), 4.20 )1H, dd, Jˆ7.8, 6.5 Hz, C)10)H),
4.44 )1H, dd, Jˆ8.8, 6.3 Hz, C)3)H), 4.98 )1H, sept,
Jˆ6.3 Hz, OCH)CH3)2), 5.03±5.17 )2H, m, NCH2CHv
CH2), 5.76±5.86 )1H, m, NCH2CHvCH2), 7.17±7.34
)12H, m, Ph), 7.41±7.43 )2H, m, Ph); dC )100 MHz,
23
)C±O); [a]D ˆ27.6 )c 1.0, CHCl3).
4.5.11. /3S,aR,10S,a0R)-tert-Butyl
3-/N-a-methyl-
benzylamino)-3-[4-iso-propoxy-30-oxo-10-/N-benzyl-N-
a-methylbenzylamino)propanoate)phenyl]propanoate
34. Rh)PPh3)3Cl )120 mg, 0.13 mmol) was added to a stirred
solution of 31 )900 mg, 1.3 mmol) in MeCN/H2O )8.5:1.5)
)15 mL) under nitrogen and heated at re¯ux for 8 h. The
volatiles were removed, and the residue passed through a
small plug of alumina )eluent Et2O), before puri®cation by
column chromatography on silica gel )pentane/Et2O 4:1) to
give 34 )782 mg, 92%) as a colourless oil in 95% de; dH
)400 MHz, CDCl3) dH 0.99, 1.05 )2£3H, d, Jˆ6.2 Hz,
OCH-Me)2), 1.26 )3H, d, Jˆ6.7 Hz, C)a0)Me), 1.34 )3H,

4640
S. D. Bull et al. / Tetrahedron 58 -2002) 4629±4642
CDCl3) 16.5, 21.7, 21.8, 22.2, 27.8, 39.0, 43.0, 49.7, 54.6,
56.2, 56.7, 58.8, 67.7, 80.1, 115.6, 126.5, 126.7, 126.8,
127.5, 128.0, 128.2, 128.3, 138.9, 140.7, 141.5, 144.9,
146.0, 171.2; nmax )®lm) 2977, 2931 )C±H), 1729 )CvO),
4.5.16. /3S,aR,10R)-iso-Propyl 3-/N-benzyl-N-a-methyl-
benzylamino)-3-{4-[1-/N-benzyloxycarbonyl)propionic
acid]phenyl}propanoate 38. Formic acid )5 mL) was
added to 36 )80 mg, 0.10 mmol) and heated at re¯ux for
3 h under nitrogen before cooling and concentration in
vacuo. The resultant oil was puri®ed by column chromato-
graphy on silica gel )CHCl3/MeOH 50:1) to give 38 as a
colourless oil )48 mg, 75%); dH )400 MHz, CD3OD) 0.95,
1.01 )2£3H, d, Jˆ6.2 Hz, OCH-Me)2), 1.21 )3H, d,
Jˆ6.8 Hz, C)a)Me), 2.53±2.67 )2H, m, C)2)H2), 2.71±
2.82 )2H, m, C)20)H2), 3.70 )2H, app s, NCH2Ph), 4.00
1149)C±O); m/z )APCI1) 599.3 )MH1, 100%); HRMS )EI)
23
C38H51N2O4 requires 599.3849; found 599.3860; [a]D
19.7 )c 1.0, CHCl3).
ˆ
4.5.14. /3R,aS,10S,a0R)-tert-Butyl 3-/N-benzyloxy-
carbonyl-N-a-methylbenzylamino)-3-[4-iso-propoxy-30-
oxo-10-/N-benzyl-N-a-methylbenzylamino)propanoate)-
phenyl]propanoate 36. Dibenzyl dicarbonate )400 mg,
1.39mmol) was added neat to 32 )300 mg, 0.46 mmol)
and the mixture stirred under high vacuum at rt for three
days. The resultant oil was puri®ed by column chromato-
graphy on silica gel )hexane/Et2O 4:1) to give 36 )255 mg,
70%); dH )500 MHz, toluene-d8, 363 K) 0.94, 0.95 )2£3H,
d, Jˆ6.3 Hz, OCH-Me)2), 1.20 )3H, d, Jˆ6.9Hz, C) a)Me),
1.24 )9H, s, CO2C-Me)3), 1.37 )3H, d, Jˆ6.9Hz, C) a)Me),
0
0
)1H, q, Jˆ6.8 Hz, C)a)H), 4.39)1H, dd, J3 ,2 Bˆ9.8 Hz,
0
0
J3 ,2 Aˆ5.1 Hz, C)3)H), 4.72 )1H, sept, Jˆ6.2 Hz,
OCH)CH3)2), 5.05 )2H, s, OCH2Ph), 5.13 )1H, app t,
Jˆ7.3 Hz, C)10)H), 7.14±7.92 )20H, m, Ph and NH); dC
)400 MHz, CD3OD) 17.6, 22.3, 38.4, 42.5, 52.1, 53.5,
59.0, 61.1, 67.8, 69.4, 127.7, 128.0, 128.4, 129.1, 129.3,
129.4, 129.5, 129.7, 129.8, 130.0, 138.7, 142.5, 143.0,
143.4, 146.0, 158.4, 173.6; nmax )®lm) 3027, 2979, 2929
)C±H), 1716, 1698 )CvO); m/z )APCI1) 623.6 )MH1,
25%), 645.4 )MNa1, 20%); HRMS )ESI) C38H41N2O6
2.63±2.70 )3H, m, C)2)H2 and C)20)HA), 3.10 )1H, dd,
0
0
0
0
0
J2 B,2 Aˆ16.0 Hz, J2 B,3 ˆ8.8 Hz, C)2 )HB), 3.68 )2H, ABq,
23
Jˆ15.0 Hz, NCH2Ph), 4.01 )1H, q, Jˆ6.9Hz, C) a0)H), 4.62
requires 621.2965; found 621.2957; [a]D ˆ110.5 )c 1.0,
)1H, dd, J3 ,2 Bˆ8.5 Hz, J3 ,2 Aˆ6.5 Hz, C)10)H), 4.80 )1H,
sept, Jˆ6.3 Hz, OCH)CH3)2), 4.97±5.06 )3H, m, OCH2Ph
and C)a)H), 5.51 )1H, dd, J3,2Bˆ8.8 Hz, J3,2Aˆ5.3 Hz,
C)3)H), 7.03±7.40 )24H, m, Ph); dC )125 MHz, toluene-
d8, 363 K) )some aromatic C obscured by toluene) 17.8,
18.5, 21.6, 28.0, 37.4, 40.5, 51.4, 55.5, 56.1, 58.3, 59.5,
67.2, 80.0, 125.3, 126.8, 127.0, 127.4, 127.5, 127.6, 128.2,
128.3, 128.4, 128.4, 129.0, 140.5, 141.5, 141.9, 142.8,
144.8, 156.0, 169.9, 170.5; m/z )APCI1) 784.0 )MH1,
50%), 805.9)MNa 1, 100%); HRMS )CI1) C50H58N2O6
CHCl3).
0
0
0
0
4.5.17. /3S,aR,10S)-iso-Propyl 3-/N-benzyl-N-a-methyl-
benzylamino)-3-{4-[10-/N-benzyloxycarbonyl)propionic
acid]phenyl}propanoate 39. Formic acid )5 mL) was
added to 37 )200 mg, 0.25 mmol) and heated at re¯ux for
3 h under nitrogen before cooling and concentration in
vacuo. The resultant oil was puri®ed by column chromato-
graphy on silica gel )CHCl3/MeOH 50:1) to give 39 as a
colourless oil )112 mg, 71%); dH )400 MHz, CD3OD) 0.96,
1.01 )2£3H, d, Jˆ6.2 Hz, OCH-Me)2), 1.22 )3H, d, J ˆ
requires 783.4373; found 783.4374; nmax )®lm) 2977,
ˆ
23
6.8 Hz, C)a)Me), 2.56 )1H, dd, J2A,2Bˆ14.6 Hz, J2A,3
ˆ
ˆ
2933 )C±H), 1727, 1695 )CvO), 1148 )C±O); [a]D
14.5 )c 1.0, CHCl3).
10.1 Hz, C)2)HA), 2.63 )1H, dd, J2B,2Aˆ14.6 Hz, J2B,3
0
5.1 Hz, C)2)HB), 2.68±2.79)2H, m, C)2 )H2), 3.70 )2H,
app s, NCH2Ph), 3.99 )1H, q, Jˆ6.8 Hz, C)a)H), 4.40
4.5.15. /3S,aR,10S,a0R)-tert-Butyl 3-/N-benzyloxycar-
bonyl-N-a-methylbenzylamino)-3-[4-iso-propoxy-30-oxo-
10-/N-benzyl-N-a-methylbenzylamino)propanoate)phenyl]
propanoate 37. Dibenzyl dicarbonate )661 mg, 2.31 mmol)
was added neat to 34 )500 mg, 0.77 mmol) and the mixture
stirred under high vacuum at rt for three days. The resultant
oil was puri®ed by column chromatography on silica gel
)hexane/Et2O 4:1) to give 37 )432 mg, 72%); dH
)500 MHz, toluene-d8, 363 K) 0.94, 0.95 )2£3H, d,
Jˆ6.2 Hz, OCH-Me)2), 1.20 )3H, d, Jˆ7.1 Hz, C)a)Me),
1.23 )9H, s, CO2C-Me)3), 1.35 )3H, d, Jˆ7.0 Hz,
C)a)Me), 2.60±2.70 )3H, m, C)2)H2 and C)200)HA), 3.10
0
0
0
0
)1H, dd, J3 ,2 Bˆ9.7 Hz, J3 ,2 Aˆ6.0 Hz, C)3)H), 4.72 )1H,
sept, Jˆ6.2 Hz, OCH)CH3)2), 5.05 )2H, s, OCH2Ph),
5.12±5.15 )1H, br m, C)10)H), 7.14±7.50 )19H, m, Ph);
dC )400 MHz, CD3OD) 17.7, 22.2, 22.3, 38.5, 42.5, 52.1,
53.5, 59.0, 61.0, 67.9, 69.4, 127.7, 128.0, 128.4, 129.1,
129.3, 129.4, 129.5, 129.6, 129.8, 130.0, 130.2, 138.7,
142.5, 143.0, 143.4, 146.0, 158.4, 173.6; nmax )®lm) 3027,
2976 )C±H), 1736, )br, CvO); m/z )APCI1) 623.0 )MH1,
10%); HRMS )ESI) C38H43N2O6 requires 623.3121; found
23
621.3124; [a]D ˆ211.9) c 1.25, CHCl3).
0
0
0
0
)1H, dd, J2 B,2 Aˆ15.7 Hz, J2 B,3 ˆ8.8 Hz, C)2 )HB), 3.67
4.6. X-Ray crystal structure data for 23
)2H, ABq, Jˆ14.6 Hz, NCH2Ph), 4.00 )1H, q, Jˆ7.1 Hz,
C)a0)H), 4.62 )1H, dd, J3 ,2 Bˆ9.7 Hz, J3 ,2 Aˆ5.9Hz,
C)10)H), 4.80 )1H, sept, Jˆ6.2 Hz, OCH)CH3)2), 4.98±
5.05 )3H, m, OCH2Ph and C)a)H), 5.51 )1H, dd,
J3,2Bˆ8.8 Hz, J3,2Aˆ5.3 Hz, C)3)H), 6.99±7.40 )24H, m,
Ph); dC )125 MHz, toluene-d8, 363 K) )some aromatic C
obscured by toluene) 17.7, 18.5, 21.6, 21.6, 28.0, 37.5,
40.5, 51.4, 55.5, 56.1, 58.2, 59.5, 67.2, 67.2, 80.0, 125.3,
126.8, 127.0, 127.6, 127.8, 127.9, 128.3, 128.4, 129.0,
140.5, 141.5, 141.9, 142.8, 144.8, 156.0, 169.8, 170.5; m/z
)APCI1) 783.2 )MH1, 100%); HRMS )EI) C50H59N2O6
requires 783.4373; found 783.4373; nmax )®lm) 2976,
2934 )C±H), 1727, 1693 )CvO), 1147 )C±O);
0
0
0
0
Data were collected using an Enraf Nonius Kappa CCD
diffractometer with graphite monochromated Cu Ka radia-
tion using standard procedures at 190 K. The structure was
solved by direct methods )Sir92), all non-hydrogen atoms
were re®ned with anisotropic thermal parameters. Hydrogen
atoms were added at idealised positions. The structure was
re®ned using CRYSTALS.37
Crystal Data for 23: [C25H30NO2], colourless block, M ˆ
376.52, monoclinic, space group P121/a1, aˆ14.3547)4),
Ê
bˆ10.4856)1), cˆ15.6342)5) A, bˆ114.9141)11)8, U ˆ
Ê 3
2134.2 A , Zˆ4, mˆ0.073, crystal dimensions 0.2£
23
[a]D ˆ213.9) c 1.0, CHCl3).
0.2£0.2 mm, A total of 4840 unique re¯ections were

S. D. Bull et al. / Tetrahedron 58 -2002) 4629±4642
4641
2103. Uyehara, T.; Shida, N.; Yamamoto, Y. J. Org. Chem.
1992, 57, 3139. Asao, N.; Uyehara, T.; Yamamoto, Y. Tetra-
hedron 1990, 46, 4563.
measured for 5.23,u,27.50 and 3289re¯ections were
used in the re®nement. The ®nal parameters were wR2 ˆ
0.0251 and R1ˆ0.0422 [I.3s)I)].
10. Hawkins, J. M.; Fu, G. C. J. Org. Chem. 1986, 51, 2820.
Rudolf, K.; Hawkins, J. M.; Loncharich, R. J.; Houk, K. N.
J. Org. Chem. 1988, 53, 3879. Hawkins, J. M.; Lewis, T. A. J.
Org. Chem. 1992, 57, 2114.
Crystallographic data )excluding structure factors) has been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC175460.
Copies of the data can be obtained, free of charge, on appli-
cation to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
)fax: 144-1223-336033 or e-mail: deposit@ccdc.cam.
ac.uk).
11. Rico, J. G.; Lindmark, R. J.; Rogers, T. E.; Bovy, P. R. J. Org.
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Acknowledgements
The authors wish to acknowledge the support of the EPSRC
Ã
and Rhone-Poulenc-Rorer for a CASE Award )A. D. S.) and
to New College, Oxford for a Junior Research Fellowship
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