A synthetic approach to diaryl ethers using the Robinson annulation

Article abstract of DOI:10.1016/S0957-4166(98)00466-2

An alternative synthetic approach to diaryl ethers has been developed. In the key transformation, Robinson annulation of nonracemic aldehydes 16a,b, derived from L-glutamic acid 5-methyl ester and phenoxymethylvinyl ketone, provided α-phenoxyenones 17a,b.

Full text of DOI:10.1016/S0957-4166(98)00466-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 99–105
A synthetic approach to diaryl ethers using the Robinson
annulation
Xianqi Feng and Eric D. Edstrom ∗
Department of Chemistry, University of Montana, Missoula, MT 59812, USA
Received 20 October 1998; accepted 9 November 1998
Abstract
An alternative synthetic approach to diaryl ethers has been developed. In the key transformation, Robinson
annulation of nonracemic aldehydes 16a,b, derived from L-glutamic acid 5-methyl ester and phenoxymethylvinyl
ketone, provided α-phenoxyenones17a,b. The Cbz-protected oxazolidine 17b was further converted into the diaryl
ether 18b utilizing an oxidative selenation protocol. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The diaryl ether functionality is a key structural subunit in numerous bioactive natural products.1
The simplest member, isodityrosine,2 is formed in the cyclic tripeptide K-133 as the result of oxidative
phenolic coupling of two tyrosine residues. More elaborate examples include cycloisodityrosines 1–34
(Scheme 1), the bicyclic hexapeptide bouvardin 4–6,4 and highly complex glycopeptide antibiotics such
as the vancomycin family.5 In all cases the diaryl ether linkages are presented within macrocyclophane
frameworks having a ring size of either 14,4 16,5 or 173 members. Many important achievements have
resulted in the total syntheses of all but the most complicated diaryl ether containing natural products.1
From a synthetic standpoint one of the greater challenges remaining in this area is concerned with the
14-membered ring systems4 that are present in 4–6 and the G-O-F subunit of teicoplanin.6 At present,
the only viable approach to cycloisodityrosines incorporates an intramolecular SNAr based cyclo-
etherification reaction, first developed by Zhu and co-workers.1c Initial studies encountered difficulties
with facile epimerization at the C-9 stereocenter of the 14-membered network which is believed to be
related to the location of the aromatic nitro substituent derived from a 3-fluoro-4-nitrophenylalanine
coupling partner.4i,k However, further study revealed that by reversing the direction of coupling, i.e.,
incorporating 4-fluoro-3-nitrophenylalanine as the electrophilic partner with the appropriate dopa deri-
∗
Corresponding author. E-mail: edstrom@selway.umt.edu
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00466-2

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X. Feng, E. D. Edstrom / Tetrahedron: Asymmetry 10 (1999) 99–105
vative, this difficulty can be avoided.4l Efficient chemical routes to the hydroxylated cycloisodityrosines
2 and 3 still remain a desirable objective.
Scheme 1.
Much effort has been devoted towards the development of strategies to construct the key diaryl
ether linkage7 and can be grouped into five distinct approaches.1b However, one of the challenges that
remains includes an efficient method for the construction of the strained 14-membered ring hydroxylated
isodityrosine subunit present in bouvardin4 and RA-IV.1 Our interest in this area is to develop an
alternative approach to the strained 14-membered ring diaryl ethers 7 based on a Robinson annulation8
that can be conducted under mild, weakly basic reaction conditions (Scheme 2). In this way sensitive
β-elimination and epimerization problems can hopefully be avoided. Application of a dehydrogenation
transform to 7 would lead to enone 8, which can be seen to arise via an aldol condensation8,9 process from
the 16-membered ring precursor 9 by a macrocyclic two-atom ring contraction.9 Macrocycle 9 should be
easily obtained from acyclic precursors 10–12 through Michael addition and peptide coupling reactions.
Scheme 2.
2. Results and discussion
Based on the above retrosynthetic analysis, a Robinson annulation8,10 approach to diaryl ethers has
been demonstrated in our laboratory as revealed below (Scheme 3). Starting from the commercially
available L-glutamic 5-ethyl ester, the Boc protected amino alcohol 14a is processed from 13a in
more than 84% overall yield utilizing reported methodology.11 In a straightforward manner, the Cbz-
protected amino alcohol 14b was also made in high overall yield from L-glutamic acid 5-methyl ester
13b. Refluxing 14a–b with DMP and TsOH in benzene provides oxazolidines 15a–b in 78–86% yields.
Controlled DIBAL-H reduction delivers aldehydes 16a–b in 87–90% yield. Robinson annulation8,10 with
phenoxymethyl vinyl ketone12 provides α,β-unsaturated ketones 17a–b in 47–58% yields. It should be
pointed out that this Robinson annulation is a one-pot reaction involving three steps: (i) reflux of the

X. Feng, E. D. Edstrom / Tetrahedron: Asymmetry 10 (1999) 99–105
101
aldehydes with 1.0–1.5 equiv. of morpholine in benzene using molecular sieves for removal of water;
(ii) Michael addition of phenoxymethyl vinyl ketone to the newly generated enamine at 0°C; (iii) aldol
condensation of the resulting Michael product in the boiling benzene solution. Further transformation of
the Robinson annulation product into the diaryl ether was explored using several approaches from the
literature.13 For example, reaction of 17a with TipsOTf followed by DDQ oxidation of the intermediate
silylenol ether afforded the final diaryl ether 18a in a very poor yield (less than 10%). The CuBr2/LiBr13a
and Mn(OAc)313c oxidation reactions of the Robinson adducts have also been proven impractical. Finally,
treatment of 17b with PhSeCl2c,13d or PhSeCl/LHMDS followed by H2O2 oxidation, without isolation
of the intermediate selenium product, gave the desired diaryl ether 18b in 41–60% yield.
Scheme 3.
In summary, this simple model study has established an alternative methodology for construction
of diaryl ether bonds based on a Robinson aromatization protocol. Continued efforts will evaluate the
viability of this approach as an alternative to the classical Ullmann reaction and the SNAr approaches for
synthesis of 14-membered cycloisodityrosines.
3. Experimental section
All reagents were of commercial quality (Aldrich, Fluka, Sigma) and were used as received. Solvents
were dried and purified using standard techniques. Infrared spectra of samples were obtained on a
Perkin–Elmer 1600 Series FTIR. 1H NMR spectra were recorded at 400 MHz (Varian 400 NMR). 13
C
NMR were measured at 100.59 MHz using CDCl3 as solvent. HRMS was provided by the Mass Spec-
trometry Laboratory, Department of Chemistry and Biochemistry, Montana State University, Bozeman,
MT 59717.

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3.1. N-Boc-L-Glutamic acid γ-ethyl ester 13a
To a stirred solution of L-glutamic acid γ-ethyl ester (8.75 g, 50 mmol) in 150 ml of water was added
NaHCO3 (9.2 g, 110 mmol) at 0°C, followed by (Boc)2O (11.5 g, 53 mmol) in 150 ml dioxane for 2–3
h. The reaction mixture was stirred at rt overnight. The solution was extracted with ethyl ether (3×100
ml). The aqueous layer was acidified to pH 2 with 10% HCl. The product was extracted by ethyl acetate
(2×100 ml). The organic layer was washed with brine and dried over MgSO4. The solution was passed
through a short pad of silica gel (EtOAc) and concentrated to provide 13a (14.0 g, 100%) as semi-solid.
[α]D25 +2.4 (c 1.0, EtOAc); IR (film) 3340–3000, 2980, 1730–1650, 1450, 1390, 1250, 1160, 1050 cm−1;
1H NMR (400 MHz, CDCl3) δ 5.40 (d, 1H), 4.61 (m, 1H), 4.12 (q, J=8.0 Hz, 2H), 2.45 (m, 2H), 2.20
(m, 1H), 2.00 (m, 1H), 1.43 (s, 9H), 1.24 (t, J=8.0 Hz, 3H); 13C NMR (100.59 MHz, CDCl3) δ 176.11
(d), 173.08, 155.66, 80.34, 67.02, 60.80, 52.84 (d), 30.42 (d), 28.26, 14.12.
3.2. N-Cbz-L-Glutamic acid γ-methyl ester 13b
To a stirred solution of L-glutamic acid γ-methyl ester (16.1 g, 100 mmol) in 220 ml of water and 100
ml of dioxane was added Na2CO3 (10.6 g, 100 mmol) at 0°C, followed by benzyl chloroformate (17.2
g, 101 mmol) in 120 ml dioxane for 2–3 h. The reaction mixture was stirred at rt overnight. The solution
was extracted with ethyl acetate (3×100 ml). The aqueous layer was acidified to pH 2 with 6 N HCl.
The product was extracted with ethyl acetate (2×100 ml). The organic layer was washed with brine and
dried over MgSO4. The solution was passed through a short pad of silica gel (EtOAc) and concentrated
25
to provide 26.9 g (91%) of 13b as semi-solid. [α]D +0.5 (c 0.93, EtOAc); IR (film) 3330–3000, 2950,
1730–1690, 1540, 1450, 1340, 1220, 1050 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.33 (m, 5H), 5.49 (d,
J=7.2 Hz), 5.11 (s, 2H), 4.43 (m, 1H), 3.66 (s, 3H), 2.47 (m, 2H), 2.24 (m, 1H), 2.04 (m, 1H); 13C NMR
(100.59 MHz, CDCl3) δ 176.02, 173.50, 156.17, 135.94, 128.53, 128.22, 128.10, 67.22 (d), 53.18 (d),
51.90, 29.99 (d), 27.23.
3.3. Ethyl (4S)-N-(t-butoxycarbonyl)amino-5-hydroxypentanoate 14a
To a stirred solution of N-Boc-L-glutamic acid γ-ethyl ester (14.0 g, 50 mmol) in 250 ml of ethyl
acetate was added N-HOSu (6.9 g, 60 mmol) and DCC (12.4 g, 60 mmol) at 0°C. The mixture was
allowed to warm to rt overnight. The mixture was filtered and the solution was washed with satd NaHCO3
and brine, dried over MgSO4, and concentrated to provide 19 g of crude product. To a stirred solution of
the crude product in 150 ml THF was added 2.0 g of NaBH4 at 0°C, followed by 50 ml of EtOH over 30
min. The reaction mixture was stirred for an additional 15 min and then quenched with satd NH4Cl. The
product mixture was extracted with ethyl acetate and the separated organic phase was washed with brine,
dried over MgSO4 and concentrated in vacuo. The oily product was purified by flash chromatography
25
on silica gel with 65 to 70% EtOAc:hexanes to provide 14a (11.2 g, 85%) as a colorless oil. [α]D −16
1
(c 1.3, EtOAc); IR (film) 3620–3390, 2980, 1730–1680, 1385, 1170, 1050 cm−1; H NMR (400 MHz,
CDCl3) δ 4.90 (br d, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.58 (br s, 2H), 3.53 (br s, 1H), 2.92 (br s, 1H), 2.37 (m,
2 H), 1.86 (m, 1H), 1.74 (m, 1H), 1.40 (s, 9H), 1.22 (t, J=7.2 Hz, 3H); 13C NMR (100.59 MHz, CDCl3)
δ 173.78, 156.18, 79.52, 65.01, 60.58, 52.24, 30.87, 28.29, 26.23, 14.12.
3.4. Methyl (4S)-N-(Benzyloxycarbonyl)amino-5-hydroxypentanoate 14b
To a stirred solution of N-Cbz-L-glutamic acid γ-methyl ester (7.0 g, 24 mmol) in 100 ml of ethyl
acetate was added N-HOSu (2.9 g, 25 mmol) and DCC (5.2 g, 25 mmol) at 0°C. The mixture was

X. Feng, E. D. Edstrom / Tetrahedron: Asymmetry 10 (1999) 99–105
103
allowed to warm to rt overnight. The mixture was filtered and the resulting solution was washed with
satd NaHCO3 and brine, dried over MgSO4, and concentrated to provide 9.5 g of crude product. To a
stirred solution of the crude product in 75 ml of THF was added 1.0 g of NaBH4 at 0°C followed by 25
ml of MeOH over 30 min. The reaction mixture was stirred for an additional 15 min and quenched with
satd NH4Cl. The product was extracted with ethyl acetate. The organic phase was washed with brine,
dried over MgSO4 and concentrated in vacuo. The oily product was purified by flash chromatography on
25
silica gel with 65 to 70% EtOAc:hexanes to provide 14b (5.8 g, 87%) as a colorless oil. [α]D −21 (c
0.91, EtOAc); IR (film) 3350–3060, 3030, 2950, 1730–1680, 1540, 1450, 1370, 1250, 1170, 1060 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.08 (s, 2H), 5.05 (br s, 1H), 3.72 (m, 2H), 3.65 (s, 3H),
3.60 (br d, 1H), 2.42 (m, 2H), 2.27 (br s, 1H), 1.87 (m, 1H), 1.83 (m, 1H); 13C NMR (100.59 MHz,
CDCl3) δ 174.23, 156.57, 136.30, 128.53 (d), 128.16, 128.07, 66.83, 64.77, 52.72, 51.84, 30.54, 26.08.
3.5. (4S)-3-(t-Butoxycarbonyl)-2,2-dimethyl-4-(ethoxycarbonylethyl)oxazolidine 15a
To a solution of 14a (6.0 g, 23 mmol) in 240 ml of benzene was added 18 ml of DMP and 180 mg of
TsOH. The reaction mixture was refluxed for 0.5 h and slowly distilled over 3 h until 120 ml of benzene
was removed. The mixture was quenched with 0.3 ml of pyridine and concentrated in vacuo. The residue
was subjected to flash column chromatography using 15% EtOAc:hexanes to provide 15a (6.0 g, 86%)
as a colorless oil. [α]D25 +22 (c 0.95, EtOAc); IR (film) 2980, 1730, 1690, 1460, 1385, 1260, 1180, 1070
1
cm−1; H NMR (400 MHz, CDCl3) δ 4.12 (q, J=8.8 Hz, 2H), 3.94–3.71 (m, 2H+1H), 2.32 (m, 2H),
2.03–1.89 (m, 2H), 1.59–1.43 (m, 6H), 1.46 (s, 9H), 1.25 (t, 3H); 13C NMR (100.59 MHz, CDCl3) δ
173.02, 159.29 (d), 93.87 (d), 80.06 (d), 66.92 (d), 60.40, 56.72 (d), 31.02 (d), 28.87, 28.38, 27.50 (d),
24.38 (d), 14.15.
3.6. (4S)-3-(Benzyloxycarbonyl)-2,2-dimethyl-4-(methoxycarbonylethyl)oxazolidine 15b
To a solution of 14b (5.0 g, 18 mmol) in 100 ml of dried acetone was added 24 ml of DMP and 500 mg
of TSOH. The reaction mixture was stirred at rt overnight, quenched with 0.5 ml of pyridine, and then
concentrated in vacuo. The residue was dissolved in 100 ml of EtOAc and 20 ml of satd NaHCO3. The
organic phase was washed with satd NaHCO3 and brine, and dried over MgSO4. After concentration, the
residue was subjected to flash column chromatography using 15% EtOAc:hexanes to provide 15b (4.8 g,
25
84%) as an oil. [α]D +6.4 (c 1.2, EtOAc); IR (film) 2950, 1760, 1670, 1580, 1490, 1350, 1250, 1070
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.34 (m, 5H), 5.16 (q, J=12 Hz), 4.05–3.95 (m, 2H), 3.78–3.76
(d, 1H), 3.68–3.60 (d, 3H), 2.40–2.31 (m, 2H), 2.10–1.80 (m, 2H), 1.64–1.45 (q, 6H); 13C NMR (100.59
MHz, CDCl3) δ 173.05, 152.17 (d), 136.16, 128.38, 127.86, 127.77, 94.15 (d), 67.01 (d), 66.44, 56.09
(d), 51.45, 30.39 (d), 28.69 (d), 26.41 (d), 22.83 (d).
3.7. (4S)-3-(t-Butoxycarbonyl)-2,2-dimethyl-4-(3-oxo-propyl)oxazolidine 16a
To a stirred solution of 15a (4.8 g, 16 mmol) in 40 ml of toluene was added 16 ml of DIBAL-H (1.5 M
in toluene), dropwise at −78°C. The reaction was kept at −78°C for 45 min, and then quenched with 1 ml
of methanol. The reaction mixture was diluted with 25 ml of 1 N HCl at 0°C, and then stirred for 15 min.
The solution was extracted with 2×50 ml of EtOAc. The combined organic layer was washed with brine
and dried over MgSO4. The residue was purified by flash column chromatography over silica gel using
20% EtOAc:hexanes to provide 16a (3.8 g, 90%) as a colorless oil. The aldehyde was then immediately

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X. Feng, E. D. Edstrom / Tetrahedron: Asymmetry 10 (1999) 99–105
1
subjected to the next reaction. H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 3.82–3.97 (m, 2H), 3.74 (d,
1H), 2.47 (m, 2H), 1.90–2.02 (m, 2H), 1.58–1.40 (m, 6H), 1.46 (s, 9H).
3.8. (4S)-3-(Benzyloxycarbonyl)-2,2-dimethyl-4-(3-oxo-propyl)oxazolidine 16b
To a stirred solution of 15b (6.9 g, 21 mmol) in 70 ml of toluene was added 20 ml of DIBAL-H (1.5
M in toluene), dropwise at −78°C. The reaction was kept at −78°C for 45 min, quenched with 1 ml
of methanol, and then diluted with 200 ml of ethyl acetate. The organic layer was washed in 2×15 ml
of 6 N HCl and 2×15 ml of brine, then dried over MgSO4. The residue was purified by flash column
chromatography over silica gel using 20% EtOAc:hexanes to provide 16b (5.2 g, 87%) as a colorless oil.
The aldehyde was then immediately subjected to the next reaction. 1H NMR (400 MHz, CDCl3, chemical
shifts sensitive to the ratio of rotamers) δ 9.78–9.68 (d, 1H), 7.35 (m, 5H), 5.10 (m, 2H), 4.02–3.96 (m,
2H), 3.71 (d, 1H), 2.50–2.38 (m, 2H), 1.96 (m, 2H), 1.62–1.42 (q, 4H).
3.9. The α,β-unsaturated Robinson adduct 17a
The adduct 17a was synthesized in the same manner as the adduct 17b. Yield: 48%. The α,β-
1
unsaturated Robinson adduct was then immediately subjected to the next reaction. H NMR (400 MHz,
CDCl3, chemical shifts sensitive to ratios of both rotamers and diastereomers) δ 7.28 (m, 5H), 6.92–7.05
(m, 5H), 6.21–6.00 (m, H), 4.03–3.81 (m, 2H), 3.66 (d, 1H), 2.65 (m, 1H), 2.52 (m, 2H), 2.17 (m, 1H),
1.88–1.61 (m, 3H), 1.58–1.37 (m, 6H), 1.42 (s, 9H).
3.10. The α,β-unsaturated Robinson adduct 17b
A solution of 16b (4.8 g, 16.5 mmol) in 70 ml of benzene was added to 1.43 ml (16 mmol) of
morpholine. The reaction mixture was refluxed for 3 h using 4 Å power molecular sieves in a Soxhlet
apparatus for the removal of water. The mixture was concentrated to about 30 ml, and then a solution of
phenoxymethyl vinyl ketone (3.3 g, 20 mmol) in 30 ml of benzene was added at 0°C. The reaction was
slowly warmed up to rt overnight and then heated at reflux for 3 h. After removal of benzene, the residue
was dissolved in 30 ml of H2O and 30 ml of MeOH. The resulting mixture was refluxed for 8 h. The
solution volume was reduced in vacuo to approximately one-half of the original and then extracted with
ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by flash column chromatography over silica gel using 20–30% EtOAc:hexanes
to provide 17b (4.1 g, 58%) as a colorless oil. The adduct was immediately subjected to the next reaction.
1H NMR (400 MHz, CDCl3, chemical shifts sensitive to ratios of both rotamers and diastereomers) δ
7.32 (m, 5H), 7.05–6.82 (m, 5H), 6.18–5.92 (m, 1H), 5.16–4.97 (m, 2H), 4.09–4.82 (m, 2H), 3.72 (d,
1H), 2.85–2.05 (m, 3H), 1.98–1.75 (m, 2H), 1.62–1.41 (m, 6H+2H).
3.11. N-Benzyloxycarbonyl-N,O-isopropylidenyl-3-phenoxy-(S)-tyrosinol 18b
To a solution of 17b (0.30 g, 0.69 mmol) in 6 ml of EtOAc was added PhSeCl (0.29 g, 1.5 mmol)
and K2CO3 (0.10 g, 0.75 mmol). The mixture was heated at reflux for 1–3 h (monitored by TLC). After
cooling to rt, the mixture was diluted with EtOAc and then washed with water and brine. The organic
layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in a solution of 0.5
ml of pyridine in CH2Cl2 (6 ml). After cooling to 0°C, 0.5 ml of H2O2 was added slowly. The mixture
was warmed up to rt for 1 h and extracted with ethyl acetate. The residue was chromatographed over

X. Feng, E. D. Edstrom / Tetrahedron: Asymmetry 10 (1999) 99–105
105
25
silica gel using 20% EtOAc:hexanes to provide 18b (0.15 g, 41%) as a white foam. [α]D −17 (c 0.98,
EtOAc); IR (film) 3060, 2980, 2850, 1690, 1595, 1500, 1460, 1385, 1250, 1170, 1060 cm−1; 1H NMR
(400 MHz, CDCl3, chemical shifts sensitive to the ratio of rotamers) δ 6.61–7.39 (series of m, 13H), 5.51
(br s, 1H), 5.02–5.19 (two A2B2 q, 2H, Cbz benzylic), 4.03 and 3.95 (two sets of m, 1H, αH), 3.70–3.80
(m, 2H), 2.90 and 3.10 (two sets of dd, 1H, dopa benzylic), 2.55 (t, 1H, dopa benzylic), 1.42, 1.48, 1.50
and 1.58 (series of s, 6H, oxazolidine Me); 13C NMR (100.59 MHz, CDCl3) δ major isomer 156.70,
152.20, 146.20, 143.15, 136.25, 130.68, 129.92, 128.53, 128.13, 127.98, 125.49, 123.61, 119.72, 117.76,
116.21, 94.80, 66.74, 66.23, 59.00, 38.85, 26.62, 23.14; minor isomer 152.60, 127.10, 125.85, 120.00,
116.10, 67.08, 65.77, 59.58, 37.55, 27.50, 24.56; HRMS m/e 433.1883 (C26H27NO5 requires 433.1889).
Acknowledgements
This research was supported by funds provided from the Montana NSF EPSCoR Program (MONTS)
and the Research Office, University of Montana.
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