Synthesis of optically active arylene bis-alanine derivatives carrying orthogonal protecting groups

Article abstract of DOI:10.1016/S0957-4166(98)00014-7

Derivatives of para- and meta-phenylene bis-alanine and related biphenyl systems, carrying four orthogonal protecting groups, were synthesised via combinations of Heck couplings and asymmetric hydrogenations. The intermediate unsaturated arylalanine derivatives were hydrogenated using [Rh(COD)((R,R)-DIPAMP)]⁺BF₄^- or [Rh(COD)(Me-DuPHOS)]⁺X^- as catalysts to produce the optically active, protected amino acid derivatives in ≤98% e.e. as analysed by chiral phase HPLC.

Full text of DOI:10.1016/S0957-4166(98)00014-7

Pergamon
Tetrahedron: Asymmetry 9 (1998) 503–512
Synthesis of optically active arylene bis-alanine derivatives
carrying orthogonal protecting groups
Andreas Ritzén, Basudeb Basu, Shital K. Chattopadhyay, Fahreen Dossa and Torbjörn Frejd ∗
Organic Chemistry 1, Department of Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden
Received 9 December 1997; accepted 12 January 1998
Abstract
Derivatives of para- and meta-phenylene bis-alanine and related biphenyl systems, carrying four orthogonal
protecting groups, were synthesised via combinations of Heck couplings and asymmetric hydrogenations.−The
intermediate unsaturated arylalanine derivatives were hydrogenated using [Rh(COD)((R,R)-DIPAMP)]+BF4 or
[Rh(COD)(Me-DuPHOS)]+X− as catalysts to produce the optically active, protected amino acid derivatives in
≥98% e.e. as analysed by chiral phase HPLC. © 1998 Elsevier Science Ltd. All rights reserved.
Bis-armed, aromatic amino acid substructures occur in several cyclic peptide antibiotics, such as the
biphenomycins, ristocetins, teichoplanins and vancomycin.1 This made us interested in the synthesis of
optically active aromatic amino acids, carrying two or more amino acid arms located in various positions
on the aromatic ring systems. Such compounds would be useful structural variants in the synthesis of
these types of antibiotics. They could also serve as structural units mimicking some of the possible
geometries of aromatic–aromatic interactions in peptides.2 We,3,4 and Jackson et al.,5 recently reported
the syntheses of some bis-armed amino acids based on ferrocene, and in the present work, the scope has
been broadened to include benzene- and biphenyl-based amino acids as well. Similar optically active
bis-amino acid derivatives have been reported.6–9
It is important to have access to pure stereoisomers of the target bis-armed amino acids. In the present
work we demonstrate how this can be accomplished by using asymmetric hydrogenations with cationic
Rh(I)–bisphosphine catalysts. The development of new ligands for this important reaction has made it
a preferred method for the synthesis of various aromatic amino acids.10 One of the most general and
stereoselective ligand classes so far developed is the DuPHOS family of bisphosphines.10 Since these
ligands were not available when this project was initiated, we started using the DIPAMP ligand.11 When
both enantiomers of Me-DuPHOS became available, we decided to switch to these (the DIPAMP was
only available to us as the (R,R)-enantiomer).
∗
Corresponding author. E-mail: Torbjorn.Frejd@orgk1.lu.se
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00014-7

504
A. Ritzén et al. / Tetrahedron: Asymmetry 9 (1998) 503–512
1. Results and discussion
The synthesis of the (S,S)- and (R,R)-isomers12 of the target amino acids start from dihaloaromatics 3,
4 and 5 (Scheme 1). Since the obtained amino acid derivatives should be useful for peptide synthesis, they
must carry suitable orthogonal protecting groups. To this end, the readily available 2-carbamatoacrylates
1 and 2,13 which carry the requisite protecting groups, were coupled to the aromatic core in two
successive Heck–Jeffery reactions.14,15 Each of the so-obtained dehydro derivatives 9, 10 and 11 was
then hydrogenated using a [Rh(COD)(bisphosphine)]+X− catalyst, where bisphosphine=DIPAMP or Me-
DuPHOS, and X=BF4 or OTf. This produced the target amino acid derivatives 12, 13 and 14 in ≥95%
yield and with very good stereoselectivity; e.e.≥98% and d.r.≥90:10. It is worth noting that the presence
of two dehydro amino acid functionalities in close proximity in the same molecule does not diminish
either the rate or the selectivity of the hydrogenation reaction. This is in contrast to our experience with
the related ferrocene systems.3,4
Scheme 1. (a) Pd(OAc)2, NaHCO3, Bu4NCl, DMF, 85–90°C, 18 h; (b) Pd(OAc)2, NaHCO3, Bu4NCl,
DMF, 85–90°C, 18 h; (c) H2, [Rh(COD)(bisphosphine)]+X−, MeOH. List of abbreviations: Bn=benzyl,
Boc=tert-butyloxycarbonyl, Cbz=benzyloxycarbonyl, COD=1,5-cyclooctadiene, dppe=1,2-bis(diphenylphosphino)ethane,
Teoc=2-(trimethylsilyl)etyloxycarbonyl
The double bond configuration of most of the Heck products was assigned by NOE in the same way as
for the ferrocene amino acids published earlier.4 In all cases examined, the configuration was (Z), which
also appears to be more thermodynamically stable than (E) for these compounds.16 This is fortunate,
since the (Z)-isomers are hydrogenated faster and with higher selectivity than the (E)-isomers.10,11
Having secured the (S,S) and (R,R) forms of the requisite bis-armed amino acids, we next turned to
the other diastereomer, represented by the (S,R)-isomer. For the para case, we started with commer-
cially available para-iodophenylalanine (Scheme 2). Protection of the amino and carboxylate functions,
followed by Heck reaction with 2, gave the mono-olefin 16. Hydrogenation of (R,Z)-16 with [Rh(-
COD)((R,R)-DIPAMP)]+BF4− afforded (R,S)-12 with high stereoselectivity; d.r.≥90:10, e.e.≥90%.
We were also interested to find out whether the stereoselectivities in the hydrogenations were different
for substrates such as 16 (carrying one unsaturated and one saturated arm; Scheme 2) as compared
to substrates such as 9 (carrying −two unsaturated arms). To this end, we hydrogenated (S,Z)-16 with
[Rh(COD)((R,R)-DIPAMP)]+BF4 to afford (S,S)-12. The selectivity was equally high for this reaction
as for the hydrogenation of 9 above.

A. Ritzén et al. / Tetrahedron: Asymmetry 9 (1998) 503–512
505
Scheme 2. (a) 1. (Boc)2O, K2CO3, dioxane:H2O 1:1; 2. BnBr, DMF; (b) 2, Pd(OAc)2, NaHCO3, Bu4NCl, DMF, 85–90°C, 18
h; (c) H2, [Rh(COD)((R,R)-DIPAMP)]+BF4−, MeOH
2. Stereochemical analysis12
It should be emphasised that the analysis of the stereoisomeric composition of the products is not
trivial. HPLC analysis on chiral stationary phases seems to be the method of choice, but although three
different phases (Chiralcel OJ, covalent DNBPG and Whelk-O1) were tried, most of our compounds
were at the limit of resolution at best, and were not resolved at all at worst. Overall, the best column
generally seemed to be the Whelk-O1, but even with this column, it was necessary to change the Teoc
protecting group of 13 to Cbz to give 17 (see Experimental), in order to get acceptable separation of the
four different stereoisomers.
Compound 12 may be taken as a representative example of the stereochemical analysis. HPLC analysis
of (ꢀ)-1217 on the (R,R)-Whelk-O1 column yielded a chromatogram with four poorly resolved peaks; Rt
(min)=17.2 (S,S), 17.7 (R,S), 18.2 (probably (S,R)) and 19.3 (probably (R,R) assuming the same elution
order as for (ꢀ)-1717). Co-injection with (S,S)-12 resulted in an increase in the height of the first eluted
peak (Rt=17.2 min), thus identifying this peak as corresponding to the (S,S)-isomer. Co-injection with
(R,S)-12 increased the height of the second eluted peak (Rt=17.7 min), thus identifying this peak as
corresponding to the (R,S) isomer.
Now, HPLC analysis of (S,S)-12 on the (R,R)-Whelk-O1 column gave a single peak, but given the
poor resolution of the different stereoisomers, a small amount (≤10%) of the (S,R) and/or (R,S) isomers
may be present. We therefore concluded that the d.r. was ≥90:10. Since the (S,S) and (R,R) isomers were
fairly well-resolved (assuming that (R,R)-12 corresponded to the last eluted peak), and no trace of the
(R,R) was seen. The e.e. was estimated at ≥98%, assuming a 1% detection limit in this case.
1
It should also be stressed that for compounds 12 and 14, the different diastereomers have identical H
and 13C NMR spectra. Thus, NMR analysis could not be used to determine the d.r. for these compounds.
3. Conclusion
We have demonstrated that various aromatic, bis-armed amino acids can be synthesised in a few steps
and with very good stereoselectivity. By the appropriate route, both the (S,S)/(R,R) and the (S,R)/(R,S)
diastereomer of the para-substituted compound 12 could be obtained in ≥98% e.e. Since orthogonal
protecting groups are present in the amino acids synthesised, they would be versatile building blocks for
a wide range of applications, one of which may be the synthesis of peptide analogues.

506
A. Ritzén et al. / Tetrahedron: Asymmetry 9 (1998) 503–512
4. Experimental
NMR spectra were recorded on a Bruker DRX 400 NMR spectrometer in CDCl3. For 1H experiments,
residual CHCl3 at δ 7.27 was used as an internal standard, while the central peak of the CDCl3 triplet
at δ 77.23 was used for 13C experiments. Optical rotations were measured on a Perkin–Elmer 241
polarimeter. TLC retention values (TLC Rf) are given in the same solvent as used in the respective
column chromatographies unless otherwise stated. Stereochemical analyses were performed using HPLC
on a covalent DNBPG column (J. T. Baker Inc., 250×4.6 mm; DNBPG=dinitrobenzoylphenylglycine)
or an (R,R)-Whelk-O1 column (Merck, 250×4.6 mm). Two detectors in tandem were routinely used; one
refractive index detector and one ultraviolet detector at 254 nm.
−
[Rh(COD)((R,R)-DIPAMP)]+BF4
was
a
gift from Searle Chemical Corporation, and
[Rh(COD)((S,S)-Me-DuPHOS)]+BF4 and [Rh(COD)((R,R)-Me-DuPHOS)]+OTf− were synthesised
according to the published procedure.10 The DuPHOS ligands are commercially available from Strem.
Analytical grade methanol was used in all hydrogenations. The hydrogen gas was of zero grade quality
(<2 ppm oxygen). The following compounds were prepared according to literature procedures: 118, 219,
619, 719 and 9.19
−
4.1. General procedure for the Heck–Jeffery coupling reactions
The aryl halide (1 equiv.), olefin (1.4 equiv.), Pd(OAc)2 (0.03 equiv.), Bu4NCl (1 equiv.), NaHCO3 (2.5
equiv.) and a few mg of hydroquinone (to avoid polymerisation of the olefin) in DMF (10 mL per mmol
of olefin) were heated at 85–90°C for 18 h in a closed screw-capped vial under nitrogen. The reaction
mixture was then cooled to room temperature and diluted with EtOAc to 10 times its original volume.
The mixture was washed four times with half-saturated brine to remove most of the DMF. After drying
with Na2SO4 and evaporation of the solvent on a rotary evaporator, the residue was purified using flash
chromatography on Matrex (Amicon) silica gel, particle size 35–70 µm.
4.2. General procedure for hydrogenations
The catalyst and the substrate were placed in the hydrogenation vessel, which was then flushed with
nitrogen. Methanol, deoxygenated by sonication and purging with nitrogen for 30 min, was then added
and the nitrogen was replaced by hydrogen by four successive vacuum–pressurisation cycles. With the
DuPHOS-derived catalyst, the pressure was set to 2.7 atm and the reactions were, in general, complete
after 1 to 4 hours at r.t. depending on the substrate-to-catalyst ratio. After this time the methanol was
removed by evaporation and the residue was dissolved in EtOAc and filtered through a short plug of
silica to remove the catalyst. After evaporation of the solvent the pure product was obtained.
4.3. (Z)-4-[200-(Benzyloxycarbonyl)-200 -[(tert-butyloxycarbonyl)amino]ethenyl]-40 -iodo-biphenyl 8
The coupling reaction was done following the general procedure using 4,40-diiodobiphenyl (154 mg,
0.380 mmol) and 1. Chromatography (hexane:EtOAc=2:1) of the crude product gave 8 (49 mg, 23%, TLC
Rf=0.31, mp 173–175°C), and the bis-coupled product19 (57 mg, 22%). 1H NMR (400 MHz, CDCl3) δ
1.27 (s, 9H), 5.31 (s, 2H), 6.33 (br s, 1H), 7.33–7.48 (m, 8H), 7.54–7.63 (m, 4H), 7.76–7.80 (m, 2H);
13C NMR δ 28.33, 67.73, 81.30, 93.78, 124.71 (br), 127.01, 128.65, 128.83, 129.04, 129.86, 130.58,
133.81, 135.73, 138.15, 139.99, 140.79, 152.82 (br), 165.67; HRMS (FAB+) m/z calcd for C27H26INO4:
556.0985 [M+H]. Found: 556.0987.

A. Ritzén et al. / Tetrahedron: Asymmetry 9 (1998) 503–512
507
4.4. (Z0,Z00)-1-[20-(Benzyloxycarbonyl)-20 -[(tert-butyloxycarbonyl)amino]ethenyl]-3-[200 -
(methoxycarbonyl)-200 -[[2000-(trimethylsilyl)ethyloxycarbonyl]amino]ethenyl]benzene 10
Following the general procedure of coupling using the bromide 719 (0.86 g, 1.99 mmol) and olefin
219 (0.77 g, 3.14 mmol) the product was isolated as a viscous, pale yellow oil, 0.92 g (77%), after flash
chromatography using heptane:ethyl acetate (2:1) as eluent (TLC Rf=0.24). NOE experiments confirmed
the assigned (Z) stereochemistry.4 1H NMR (CDCl3, 400 MHz) δ 0.02 (s, 9H), 0.87–1.02 (m, 2H), 1.38
(s, 9H), 3.86 (s, 3H), 4.13–4.19 (m, 2H), 5.29 (s, 2H), 6.32 (br s, 2H), 7.26 (s, 2H), 7.34–7.44 (m,
6H) 7.51 (d, 2H, J=7.9 Hz), 7.64 (s, 1H); 13C NMR δ −1.33, 17.77, 28.24, 52.93, 64.47, 67.73, 81.35,
125.22, 128.58, 128.64, 128.81, 128.92, 129.48, 130.04, 130.43, 131.41, 134.26, 134.78, 135.62, 152.73
(br), 154.25 (br), 165.51, 165.90; HRMS (FAB+) m/z calcd for C31H40N2O8Si: 597.2632 [M+H]. Found:
597.2638.
4.5. (Z00,Z000)-4-[200-(Benzyloxycarbonyl)-200 -[(tert-butyloxycarbonyl)amino]ethenyl]-40 -[2000-
(methoxycarbonyl)-20 00-[[20000-(trimethylsilyl)ethyloxycarbonyl]amino]ethenyl]biphenyl 11
The coupling reaction was performed following the general procedure using 8 (0.50 g, 0.90 mmol) and
2 (0.29 g, 1.17 mmol). Purification of the crude product by chromatography (hexane:EtOAc=2:1, TLC
Rf=0.25) gave 11 in 74% yield. Recrystallisation from ethyl acetate:hexane afforded the analytically
pure compound (0.40 g, 66%, mp 161–162°C). 1H NMR (CDCl3, 400 MHz) δ 0.03 (s, 9H), 0.92–1.01
(m, 2H), 1.41 (s, 9H), 3.88 (s, 3H), 4.16–4.22 (m, 2H), 5.30 (s, 2H), 6.31 (br s, 2H), 7.34–7.46 (m,
7H), 7.61–7.63 (m, 8H); 13C NMR δ −1.28, 17.79, 28.33, 52.96, 64.53, 67.72, 81.32, 124.55, 127.18,
127.30, 128.64, 128.65, 128.84, 129.94, 130.53, 130.56, 130.82, 133.47, 133.85, 135.74, 140.97, 141.26,
152.84 (br), 154.27 (br), 165.69, 166.07; HRMS (FAB+) m/z calcd for C37H44N2O8Si: 672.2867. Found:
672.2861.
4.6. (20S,200S)-1-[20-(Benzyloxycarbonyl)-20 -[(tert-butyloxycarbonyl)amino]ethyl]-4-[200 -
(methoxycarbonyl)-200 -[[2000-(trimethylsilyl)ethyloxycarbonyl]amino]ethyl]benzene (S,S)-12
(a) Hydrogenation of bis-olefin 9: Bis-olefin 919 (400 mg, 0.670 mmol) was dissolved in methanol (20
mL) and hydrogenated at 2.8 atm at 40°C in the presence of [Rh(COD)((R,R)-DIPAMP)]+BF4− (10 mg)
as catalyst for 4 days. The solvent was then removed in vacuo and the crude mass was passed through a
short pad of silica to give the title compound (370 mg, 92%) as a highly viscous liquid using heptane:ethyl
acetate (2:1) as an eluent (TLC Rf=0.3); [α]D22 +30 (c 3.7, CHCl3). HPLC analysis (see Stereochemical
analysis) on an (R,R)-Whelk-O1 column (hexane:2-propanol=90:10+0.5% HOAc; 1.0 mL/min) gave a
single peak (Rt=16.8 min); d.r.≥90:10; e.e.≥98%. 1H NMR (CDCl3, 400 MHz) δ 0.03 (s, 9H), 0.95–0.99
(m, 2H), 1.42 (s, 9H), 3.00–3.11 (m, 4H), 3.70 (s, 3H), 4.12–4.17 (m, 2H), 4.58–4.63 (m, 2H), 4.98 (br
d, 1H, J=8.4 Hz), 5.06 (br d, 1H, J=8.4 Hz), 5.10 (d, 1H, J=12 Hz), 5.17 (d, 1H, J=12 Hz), 6.95–7.00
(m, 4H), 7.30–7.40 (m, 5H); 13C NMR δ −1.30, 17.86, 28.49, 38.02, 38.10, 52.46, 54.56, 54.80, 63.67,
67.30, 80.15, 128.69, 128.79, 129.58, 129.78, 134.70, 134.90, 135.37, 155.25, 156.19, 171.87, 172.35;
HRMS (CI-CH4) m/z calcd for C31H44N2O8Si: 601.2945 [M+H]. Found: 601.2929.
(b) Hydrogenation of mono-olefin (S,Z)-16: Olefin (S,Z)-16 (198 mg, 0.331 mmol) dissolved in
methanol (10 mL) was hydrogenated at 3 atm and at room temperature for 3 days using [Rh(COD)((R,R)-
DIPAMP)]+BF4− (6 mg) as a catalyst. The solvent was removed in vacuo and the crude viscous mass was
passed through a short pad of silica using hexane:ethyl acetate (2:1) as eluent to give the title compound

508
A. Ritzén et al. / Tetrahedron: Asymmetry 9 (1998) 503–512
22
(190 mg, 96%) as a viscous liquid (TLC Rf=0.3); [α]D +29 (c 2.7, CHCl3). The NMR and HPLC data
were identical with those reported for procedure (a) above.
4.7. (20R,200S)-1-[20-(Benzyloxycarbonyl)-20 -[(tert-butyloxycarbonyl)amino]ethyl]-4-[200 -
(methoxycarbonyl)-200 -[[2000-(trimethylsilyl)ethyloxycarbonyl]amino]ethyl]benzene (R,S)-12
Compound (R,Z)-16 (200 mg, 133 mmol) dissolved in methanol (10 mL)−was hydrogenated at 3.1
atm at room temperature for 3 days using [Rh(COD)((R,R)-DIPAMP)]+BF4 (6 mg) as catalyst. The
solvent was removed in vacuo and the crude mass was passed through a short pad of silica using
22
hexane:ethyl acetate (2:1) as eluent to give 190 mg (95%) of white solid (TLC Rf=0.3); [α]D +25 (c
2.7, CHCl3); mp 66–67°C. HPLC analysis (see Stereochemical analysis) on a (R,R)-Whelk-O1 column
(hexane:2-propanol=90:10+0.5% HOAc; 1.0 mL/min) gave a single peak (Rt=18.3 min); d.r.≥90:10;
e.e.≥90%. The NMR data were identical with those of the (S,S) isomer, although there is a diastereomeric
relationship between these compounds. HRMS (FAB+) m/z calcd for C31H44N2O8Si: 601.2945 [M+H].
Found: 601.2948.
4.8. (ꢀ)-1-[20-(Benzyloxycarbonyl)-20 -[(tert-butyloxycarbonyl)amino]ethyl]-4-[200 -(methoxycarbonyl)-
200-[[2000-(trimethylsilyl)ethyloxycarbonyl]amino]ethyl]benzene (ꢀ)-12
Bis-olefin 919 (30 mg) was dissolved in methanol and hydrogenated at 4 atm at r.t. in the presence of
−
[Rh(COD)(dppe)]+BF4 for 2 days. After work-up, 28 mg of a 1:1:1:1 mixture of stereoisomers of 12
was obtained. HPLC analysis on an (R,R)-Whelk-O1 column (hexane:2-propanol=90:10+0.5% HOAc)
yielded a chromatogram with four poorly resolved peaks; Rt (min)=17.2 (S,S), 17.7 (R,S), 18.2 (probably
(S,R)) and 19.3 (probably (R,R); compare with elution order for (ꢀ)-17 below). The NMR data were
identical with those of the pure (S,S)-isomer, although the product is a 1:1 mixture of diastereomers.
4.9. (20S,200S)-1-[20-(Benzyloxycarbonyl)-20 -[(tert-butyloxycarbonyl)amino]ethyl]-3-[200 -
(methoxycarbonyl)-200 -[[2000-(trimethylsilyl)ethyloxycarbonyl]amino]ethyl]benzene (S,S)-13
A solution of 10 (218 mg, 0.365 mmol) in methanol (3 mL) was hydrogenated in the presence of
−
[Rh(COD)((S,S)-Me-DuPHOS)]+BF4 (4 mg) as a catalyst at 2.7 atm and r.t. for 4.5 h. After work-
25
up, (S,S)-13 was obtained as a viscous oil (218 mg, 99%); [α]D +23 (c 4.3, CHCl3). However,
no separation of the stereoisomers could be obtained on any of the tested HPLC columns: Chiralcel
OJ, Covalent DNBPG and (R,R)-Whelk-O1, respectively. To be able to analyse the stereoisomeric
composition of the product, the Teoc protecting group was exchanged for a Cbz group, since we knew
from previous experience that the stereoisomers could then be separated on the (R,R)-Whelk-O1 column.
After the protecting group change, see (S,S)-17 below, HPLC analysis showed a single peak; d.r.≥90:10;
e.e.≥98%. 1H NMR (CDCl3, 400 MHz) δ 0.02 (s, 9H), 0.93–0.98 (m, 2H), 1.42 (s, 9H), 2.99–3.07 (m,
4H), 3.69 (s, 3H), 4.10–4.15 (m, 2H), 5.01–5.04 (m, 2H), 5.02 (br d, 1H, J=8.0 Hz), 5.09–5.19 (m, 3H),
6.83 (s 1H), 6.91 (d, 1H, J=7.4 Hz), 6.99 (d, 1H, J=7.6 Hz), 7.15 (t, 1H, J=7.6 Hz), 7.29–7.38 (m, 5H);
13C NMR δ −1.37, 17.80, 28.43, 38.20, 38.32, 52.42, 54.54, 54.78, 63.58, 67.21, 80.06, 128.01, 128.27,
128.62, 128.64, 128.74, 128.91, 130.58, 135.37, 136.25, 136.33, 155.20, 156.16, 171.75, 172.24; HRMS
(FAB+) m/z calcd for C31H44N2O8Si: 601.2945 [M+H]. Found: 601.2963.

A. Ritzén et al. / Tetrahedron: Asymmetry 9 (1998) 503–512
509
4.10. (20R,200R)-1-[20-(Benzyloxycarbonyl)-20 -[(tert-butyloxycarbonyl)amino]ethyl]-3-[200 -
(methoxycarbonyl)-200 -[[2000-(trimethylsilyl)ethyloxycarbonyl]amino]ethyl]benzene (R,R)-13
A solution of 10 (100 mg, 0.168 mmol) in methanol (2 mL) was hydrogenated in the presence of
[Rh(COD)((R,R)-Me-DuPHOS)]+OTf− (4 mg) as catalyst at 2.7 atm and r.t. for 1.5 h. After work-up,
23
(S,S)-13 was obtained as a viscous oil (100 mg, 99%); [α]D −26 (c 1.2, CHCl3). After the protecting
group change as for (S,S)-13 (see (R,R)-17 below) HPLC analysis showed a single peak; d.r.≥90% and
e.e.≥98%. The NMR data were identical with those of the (S,S)-isomer. HRMS (FAB+) m/z calcd for
C31H44N2O8Si: 601.2945 [M+H]. Found: 601.2955.
4.11. (200S,2000S)-4-[200-(Benzyloxycarbonyl)-200 -[(tert-butyloxycarbonyl)amino]ethyl]-40 -[2000
(methoxycarbonyl)-20 00-[[20000-(trimethylsilyl)ethyloxycarbonyl]amino]ethyl]biphenyl (S,S)-14
-
Bisolefin 11 (200 mg, 0.296 mmol) was dissolved in methanol (10 mL) and THF (5 mL) (the olefin
was not very soluble in pure metha−nol) and hydrogenated at 40°C, 3.5 atm for 89 h in the presence
of [Rh(COD)((R,R)-DIPAMP)]+BF4 (8 mg) as a catalyst. The solvent was removed in vacuo and the
residue was passed through a short pad of silica using hexane:EtOAc (2:1) as an eluent to give the title
22
compound (195 mg, 97%) as a viscous liquid, which solidified in the freezer; TLC Rf=0.3; [α]D +28
(c 1.6, CHCl3); mp 44–46°C. HPLC analysis on a DNBPG column (iPrOH:hexane=10:90, flow rate 1
mL/min) gave a single peak (Rt=14.9 min); d.r.≥90:10; e.e.≥98%. Also note that the NMR data were
identical to those of (ꢀ)-14, see below, implying that NMR cannot be used to measure the diastereomeric
1
ratio for this compound. H NMR (CDCl3, 400 MHz) δ 0.03 (s, 9H), 0.96–1.00 (m, 2H), 1.43 (s, 9H),
3.11–3.18 (m, 4H), 3.75 (s, 3H), 4.14–4.19 (m, 2H), 4.66–4.70 (m, 2H), 5.02 (br d, 1H, J=8.0 Hz),
5.10–5.21 (m, 3H), 7.11 (d, 2H, J=7.8 Hz), 7.20 (d, 2H, J=8.2 Hz), 7.28–7.36 (m, 5H), 7.44 (d, 2H,
J=8.0 Hz), 7.49 (d, 2H, J=8.2 Hz); 13C NMR δ −1.28, 17.91, 28.52, 38.18, 52.54, 54.67, 54.85, 63.71,
67.38, 80.19, 127.29, 127.36, 128.70, 128.79, 128.81, 129.92, 130.02, 135.10, 135.20, 135.39, 139.56,
139.76, 155.30, 156.24, 171.93, 172.38; HRMS (FAB+) m/z calcd for C37H48N2O8Si: 676.3180. Found:
676.3192.
4.12. (ꢀ)-4-[200-(Benzyloxycarbonyl)-200 -[(tert-butyloxycarbonyl)amino]ethyl]-40 -[2000-
(methoxycarbonyl)-20 00-[[20000-(trimethylsilyl)ethyloxycarbonyl]amino]ethyl]biphenyl (ꢀ)-14
Bisolefin 11 (100 mg, 0.148 mmol) in EtOH (20 mL) was hydrogenated at 50°C and 4.5 atm in the
presence of [Rh(PPh3)3]Cl (25 mg). The solvent was then removed and the crude mixture was passed
through a short pad of silica using hexane:ethyl acetate (2:1) as an eluent to give the title compound
(68 mg, 67%) as a 1:1:1:1 mixture of stereoisomers; TLC Rf=0.3. HPLC analysis on a DNBPG column
(iPrOH:hexane 10:90, flow rate 1 mL/min) yielded a chromatogram with four poorly resolved peaks; Rt
(min)=14.9 ((S,S); assigned by co-injection with (S,S)-14), 15.4 (probably (R,S) or (S,R)), 15.6 (probably
(S,R) or (R,S)) and 16.4 (probably (R,R); compare with the elution order for (ꢀ)-17). The NMR data were
identical with those of the pure (S,S)-isomer, although the product was a 1:1 mixture of diastereomers.
4.13. (S)-1-[20-(Benzyloxycarbonyl)-20 -[(tert-butyloxycarbonyl)amino]ethyl]-4-iodobenzene (S)-15
A mixture of (S)-para-iodophenylalanine (1.00 g, 3.43 mmol), Boc2O (825 mg, 3.78 mmol) and
KHCO3 (344 mg, 3.43 mmol) in 1:1 dioxane:water (28 mL) was stirred overnight at room temperature.
The solvent was then co-evaporated with toluene and the residual off-white viscous mass was dissolved

510
A. Ritzén et al. / Tetrahedron: Asymmetry 9 (1998) 503–512
in dry DMF (10 mL) and then BnBr (646 mg, 3.78 mmol) was added. The mixture was heated at 60°C
for 8 h and then cooled to 5°C. Water (100 mL) was added and the crude product was obtained after
extractive work-up and evaporation of the solvent. The crude product was dissolved in hexane–EtOAc
and kept in the freezer overnight. A solid separated which was collected by filtration (815 mg). Another
515 mg of product was obtained by chromatography of the filtrate using hexane:EtOAc (3:1) as eluent.
22
Total yield 1.33 g (82%, TLC Rf=0.40); [α]D −10.9 (c 0.92, EtOH 99%); mp 109–110°C. HPLC
analysis ((R,R)-Whelk-O1, hexane:2-propanol (98:2), flow rate 1 mL/min) showed one single peak at
1
Rt=11.3 min. Co-injection of both enantiomers gave two peaks at 11.3 and 11.6 min, respectively. H
NMR (CDCl3, 400 MHz) δ 1.43 (s, 9H), 2.96–3.06 (m, 2H), 4.58–4.63 (m, 1H), 4.99 (br d, 1H, J=7.4
Hz), 5.09 (d, 1H, J=12 Hz), 5.18 (d, 1H, J=12 Hz), 6.75–6.78 (m, 2H), 7.27–7.30 (m, 2H), 7.36–7.40 (m,
3H), 7.52–7.55 (m, 2H); 13C NMR (CDCl3, 20 MHz) δ 28.49, 38.09, 54.44, 67.45, 80.29, 92.68, 128.81,
128.87, 131.57, 135.23, 135.76, 137.75, 155.18, 171.61; HRMS (FAB+) m/z calcd for C21H24INO4:
482.0828 [M+H]. Found: 482.0832.
4.14. (R)-1-[20-(Benzyloxycarbonyl)-20 -[(tert-butyloxycarbonyl)amino]ethyl]-4-iodobenzene (R)-15
This compound was prepared from (R)-para-iodophenylalanine following the procedure for the (S)-
isomer and was obtained in 81% yield; [α]D22 +10.7 (c 0.94, EtOH 95%). HPLC analysis ((R,R)-Whelk-
O1, hexane:2-propanol (98:2), flow rate 1 mL/min) showed one single peak at Rt=11.6 min. Co-injection
of both enantiomers gave two peaks at 11.3 and 11.6 min respectively. The NMR data and melting point
were identical with those of the (S)-isomer. HRMS (FAB+) m/z calcd for C21H24INO4: 482.0828 [M+H].
Found: 482.0842.
4.15. (20S,100Z)-1-[20-(Benzyloxycarbonyl)-20 -[(tert-butyloxycarbonyl)amino]ethyl]-4-[200 -
(methoxycarbonyl)-200 -[[2000-(trimethylsilyl)ethyloxycarbonyl]amino]ethenyl]benzene (S,Z)-16
The general procedure of coupling was followed using (S)-15 (721 mg, 1.50 mmol) and 2 (542 mg,
2.21 mmol). After standard work-up the crude material was chromatographed (hexane:ethyl acetate=2:1)
to give the product (645 mg, 72% yield) as a colourless viscous liquid which solidified in the freezer
22
(TLC Rf=0.24); [α]D −2.9 (c 2.6, CHCl3); mp 43°C. HPLC analysis on the chiral DNBPG column
gave only one peak (iPrOH:hexane (10:90), flow rate 1 mL/min, Rt=15.9 min). Co-injection of the (S)-
and (R)-forms gave two peaks at Rt=15.9 min and 16.6 min, respectively. NOE experiments confirmed
the assigned (Z) stereochemistry.4 1H NMR (CDCl3, 400 MHz) δ 0.03 (s, 9H), 0.90–1.04 (m, 2H), 1.42
(s, 9H), 3.03–3.14 (m, 2H), 3.86 (s, 3H), 4.17–4.21 (m, 2H), 4.62–4.66 (m, 1H), 5.02 (d, 1H, J=8.2 Hz),
5.10 (d, 1H, J=12.2 Hz), 5.18 (d, 1H, J=12.2 Hz), 6.19 (br s, 1H), 7.02–7.05 (m, 2H), 7.26–7.41 (m,
8H); 13C NMR δ −1.31, 17.76, 28.47, 38.33, 52.85, 54.44, 64.42, 67.38, 80.23, 124.55, 128.74, 128.80,
128.82, 129.84, 130.14, 131.23, 132.57, 135.27, 137.74, 154.45, 155.21, 166.05, 171.69; HRMS (FAB+)
m/z calcd for C31H42N2O8Si: 599.2789 [M+H]. Found: 599.2783.
4.16. (20R,100Z)-1-[20-(Benzyloxycarbonyl)-20 -[(tert-butyloxycarbonyl)amino]ethyl]-4-[200 -
(methoxycarbonyl)-200 -[[2000-(trimethylsilyl)ethyloxycarbonyl]amino]ethenyl]benzene (R,Z)-16
The general procedure of coupling was followed using (R)-15 (625 mg, 1.30 mmol) and 2 (447 mg,
1.82 mmol). Chromatography of the crude product using hexane:ethyl acetate (2:1) as eluent gave the
22
title compound (560 mg, 72% yield) as a viscous liquid (TLC Rf=0.24); [α]D +3.0 (c 2.9, CHCl3).
HPLC analysis on the chiral DNBPG column gave only one peak (iPrOH:hexane (10:90), flow rate 1

A. Ritzén et al. / Tetrahedron: Asymmetry 9 (1998) 503–512
511
mL/min, Rt=16.6 min). Co-injection of the (S)- and (R)-forms gave two peaks at Rt=15.9 min and 16.6
min, respectively. The NMR data were identical with those of the (S)-isomer. HRMS (FAB+) m/z calcd
for C31H42N2O8Si: 599.2789 [M+H]. Found: 599.2780.
4.17. (20S,200S)-1-[20-(Benzyloxycarbonyl)-20 -[(tert-butyloxycarbonyl)amino]ethyl]-3-[200 -
(methoxycarbonyl)-200 -[(benzyloxycarbonyl)amino]ethyl]benzene (S,S)-17
A solution of (S,S)-13 (80 mg, 0.13 mmol) and Bu4NF (90 mg, 0.34 mmol) in THF (1 mL) was stirred
under N2 for 1 h at r.t. After this time, water (1 mL) was added, and the pH was adjusted to ∼6 with
HOAc (3 drops). After 5 min, Et3N was added to pH∼10 (ca 100 µL) and then benzyl chloroformate (4
drops, ca 50 µL) was added, after which the reaction mixture was stirred overnight. EtOAc (5 ml) was
then added and the organic phase was washed with half-saturated brine (3×5 mL), dried over Na2SO4
and filtered through a short silica plug to yield a crude product (74 mg). An analytically pure product
could be obtained by preparative HPLC on a normal-phase silica column using heptane:EtOAc (4:1) as
25
an eluent. In this way, 22 mg (29%) of pure (S,S)-17 was obtained, [α]D +24 (c 1.1, CHCl3). HPLC
analysis of (ꢀ)-1720 on a (R,R)-Whelk-O1 column (hexane:2-propanol=80:20+0.25% HOAc) resulted in
a chromatogram with four poorly resolved peaks; Rt (min)=14.4 (S,S), 15.1 ((R,S) or (S,R)), 15.6 ((S,R)
or (R,S)) and 16.4 (R,R); assignment by co-injection of known stereoisomers. Under the same conditions,
1
analysis of (S,S)-17 yielded a single peak (Rt=13.9 min); d.r.≥90% and e.e.≥98%. H NMR (CDCl3,
400 MHz) δ 1.42 (s, 9H), 2.97–3.09 (m, 4H), 3.71 (s, 3H), 4.59–4.66 (m, 2H), 4.99 (br d, 1H, J=8.6
Hz), 5.07–5.19 (m, 4H), 5.23 (br d, 1H, J=7.9 Hz), 6.80 (s, 1H), 6.90–6.98 (m, 2H), 7.14 (t, 1H, J=7.5),
7.28–7.38 (m, 10H); 13C NMR δ 28.48, 38.23, 38.32, 52.55, 54.58, 54.97, 67.17, 67.29, 80.17, 128.09,
128.34, 128.37, 128.68, 128.71, 128.80, 128.99, 130.63, 135.42, 136.13, 136.42, 155.27, 155.82, 171.80,
172.09; HRMS (FAB+) m/z calcd for C33H38N2O8: 591.2706 [M+H]. Found: 591.2711.
4.18. (20R,200R)-1-[20-(Benzyloxycarbonyl)-20 -[(tert-butyloxycarbonyl)amino]ethyl]-3-[200 -
(methoxycarbonyl)-200 -[(benzyloxycarbonyl)amino]ethyl]benzene (R,R)-17
The preparation of the title compound from (R,R)-13 was analogous to the procedure above for the
(S,S) isomer. HPLC analysis of this compound as for (S,S)-17 gave a single peak (Rt=16.4 min); d.r.≥90%
and e.e.≥98%.
Acknowledgements
Part of this work was performed at the Department of Organic Chemistry at Umeå University, Sweden.
We thank The Knut and Alice Wallenberg Foundation, The Crafoord Foundation and the Swedish Natural
Research Council for financial support and post doc scholarships to S. K. C. and B. B. We also th−ank Dr.
T. Dygos at Searle Chemical Corporation for generous gifts of [Rh(COD)((R,R)-DIPAMP)]+BF4
.
References
1. Rao, A. V. R.; Gurjar, M. K.; Reddy, K. L.; Rao, A. S., Chem. Rev. 1995, 95, 2135.
2. Burley, S. K.; Petsko, G. A., Science 1985, 229, 23.
3. Carlström, A. S.; Frejd, T., J. Org. Chem. 1990, 55, 4175.
4. Basu, B.; Chattopadhyay, S. K.; Ritzén, A.; Frejd, T., Tetrahedron: Asymmetry 1997, 8, 1841.

512
A. Ritzén et al. / Tetrahedron: Asymmetry 9 (1998) 503–512
5. Jackson, R. F. W.; Turner, D.; Block, M. H., Synlett 1996, 862.
6. Fitzi, R.; Seebach, D., Tetrahedron 1988, 44, 5277.
7. Undheim, K.; Solbakken, M., PCT Int. Appl. WO 93 24522; Chem. Abstr. 1994, 121, 281231e.
8. Möller, B. S.; Benneche, T.; Undheim, K., Tetrahedron 1996, 52, 8807.
9. Kremmingner, P.; Undheim, K., Tetrahedron 1997, 53, 6925.
10. Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L., J. Am. Chem. Soc. 1993, 115, 10125.
11. Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.; Weinkauff, D. J., J. Am. Chem. Soc. 1977, 99, 5946.
12. The absolute configuration is assigned from the known absolute configuration of the Rh catalyst ligand. (R,R)-DIPAMP and
(S,S)-Me-DuPHOS give (S) amino acids, whereas (R,R)-Me-DuPHOS gives (R) amino acids, see Refs. 6 and 7.
13. Compounds 1 and 2 were synthesised in three steps from DL-serine, see Refs. 14 and 15.
14. Jeffery, T., J. Chem. Soc., Chem. Commun. 1984, 1287.
15. Jeffery, T., Tetrahedron Lett. 1985, 26, 2667.
16. Schmidt, U.; Greisser, H.; Leitenberger, V.; Lieberknecht, A.; Mangold, R.; Meyer, R.; Riedl, B., Synthesis 1992, 487.
17. For convenience, the notation (ꢀ)-X is taken to mean a 1:1:1:1 mixture of the four stereoisomers of X.
18. Carlström, A. S.; Frejd, T., Synthesis 1989, 414.
19. Carlström, A. S.; Frejd, T., J. Org. Chem. 1991, 56, 1289.
20. (ꢀ)-17 was available to us from another project (unpublished results).