Diels-Alder approaches to ring-functionalized cyclic β-amino acids

Article abstract of DOI:10.1016/S0040-4039(00)01576-8

Catalytic asymmetric Diels-Alder reactions with aminodiene 1 and desymmetrized fumarate 8 were used for efficient access to dihydroxylated cis- and trans-aminocyclohexane β-amino acids. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01576-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8747–8751
Diels–Alder approaches to ring-functionalized cyclic
b-amino acids
Peter Wipf* and Xiaodong Wang
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Received 13 September 2000; accepted 14 September 2000
Abstract
Catalytic asymmetric Diels–Alder reactions with aminodiene 1 and desymmetrized fumarate 8 were
used for efficient access to dihydroxylated cis- and trans-aminocyclohexane b-amino acids. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: enantioselective Diels–Alder reaction; b-amino acids; aminocyclohexanecarboxylate; scandium triflate;
Curtius rearrangement.
The use of oligomers of b-amino acids as novel foldamers that could mimic physical
characteristics and biological functions of peptides has led to a considerable need for efficient
synthetic routes toward the enantiopure building blocks.1 In particular, water-soluble hydroxy-
lated or aminated derivatives of cyclohexyl b-amino acids have attractive properties and a high
intrinsic propensity for helical folding.2,3 We now report an efficient approach toward dihydroxy-
lated cis- and trans-aminocyclohexanecarboxylic acids that takes advantage of modern catalytic
asymmetric Diels–Alder reactions (Fig. 1).
Starting with readily available N-Cbz-protected aminodiene 1,4,5 we explored the use of
Kobayashi’s chiral scandium catalyst for the Lewis acid-mediated Diels–Alder reaction with
acyl-1,3-oxazolidin-2-one 2 (Scheme 1).6,7 After a reaction time of 24 h, endo product 3 was
isolated in 92% yield and in 90% ee.8 The corresponding exo-product was also identified in 6%
yield in the reaction mixture. After saponification of 3 and benzyl ester formation, dihydroxyla-
tion proceeded smoothly to give the desired diol 4 in 74% overall yield from 1.
We also explored an alternative route to the b-amino acid building block 4 that took
advantage of a recently reported nucleophilic catalyst by MacMillan.9 Addition of 20 mol% of
the phenylalanine-derived imidazolidinone 7 to a mixture of aminodiene 1 and acrolein in
nitromethane/water provided cyclohexene 6 as a 14:1 mixture of endo:exo diastereomers
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01576-8

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Figure 1. Catalytic asymmetric Diels–Alder approaches toward cis-aminocyclohexanecarboxylate 4
Scheme 1. Chiral Lewis acid Diels–Alder approach
(Scheme 2). The use of 15 mol% of NaHCO3 was essential in this reaction due to the instability
of the aminodiene component towards protic acid and the pH-dependence of the reaction rate.
Pure 6 was isolated in 68% yield and in 89% ee after column chromatography and readily
converted to 4 by oxidation, esterification and dihydroxylation with catalytic OsO4 under the
Upjohn conditions. Both the Lewis acid- and the nucleophile-catalyzed asymmetric Diels–Alder
routes, thus provided the desired dihydroxylated b-amino acid 4 in high enantiomeric excess that
could be further increased to >98% by crystallization of 3.10
Scheme 2. Nucleophile-catalyzed Diels–Alder approach
While epimerization at the carbonyl a-carbon of cis-aminocyclohexanecarboxylates has been
used for the preparation of the corresponding trans-isomers,3 we found that this approach was
unreliable in providing preparative scale access to the desired trans-analogs of 4. In contrast, a
stereoselective strategy using Narasaka’s chiral titanium catalyst was much more efficient
(Scheme 3).11 Treatment of fumarate hemi-ester 812 with butadiene and 10 mol% of titanium
complex in the presence of 12 mol% of chiral diol 9 led to a slow, but highly enantioselective,
Diels–Alder process. If the reaction was allowed to proceed for 68 h at 0°C in the presence of
13
,
4 A molecular sieves, a quantitative yield of 10 in 85% ee was isolated. Increasing the reaction
temperature considerably accelerated the process, but was accompanied by significant reductions
in enantioselectivity. A single recrystallization of 10 led to material of >98% ee.

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Scheme 3. Chiral Lewis acid Diels–Alder/Curtius rearrangement approach
Cyclohexene diester 10 was selectively saponified at 0°C, and the resulting acid was subjected
to a Curtius rearrangement with DPPA in t-butanol (Scheme 3).1e,14 While this strategy provided
a convenient access to the desired trans-aminocyclohexenecarboxylate 11, introduction of the
backbone hydroxyl groups that would provide for suitable water-solubility of this b-amino acid
building block was problematic. Hydroxylation under a range of reaction conditions only led to
mixtures of diastereomers due to lack of facial- and regioselectivity in the attack onto the alkene
moiety of 11. In contrast, exposure of the acid derived from 11 to metachloroperbenzoic acid
and in situ cyclization of the intermediate epoxy carboxylate provided the hydroxy lactone 12 as
a single diastereomer.15 Subsequent mild methanolysis led to the all-trans tetrasubstituted
cyclohexane derivative 13.16
In conclusion, we have been able to identify three stereocontrolled and efficient Diels–Alder
approaches toward dihydroxylated cis- and trans-aminocyclohexanecarboxylates. Both Lewis
acid and nucleophilic catalysis are suitable for the preparation of the cis-derivative 4 from
aminodiene 1, and a combination of a titanium-catalyzed asymmetric Diels–Alder reaction with
fumarate 8 followed by Curtius rearrangement and neighboring group-assisted alkene function-
alization provides the trans-analog 13. We expect that building blocks 4 and 13 will be of
considerable use for the design of helical, water-soluble b-peptidic foldamers as well as for the
synthesis of new chiral ligands for asymmetric catalysis, and further studies toward these goals
will be reported in due course.
Acknowledgements
This work was supported by the National Science Foundation (CHE-0078944). The authors
thank Professor Sam Gellman for stimulating discussions.

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References
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(c) Sibi, M. P.; Deshpande, P. K. J. Chem. Soc., Perkin Trans. 1 2000, 1461. (d) Abele, S.; Seebach, D. Eur. J.
Org. Chem. 2000, 1. (e) Evans, D. A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J. S.; Ripin, D. H. B.; Tedrow, J.
S. J. Org. Chem. 1999, 64, 6411. (f) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959. (g)
Gademann, K.; Ernst, M.; Hoyer, D.; Seebach, D. Angew. Chem., Int. Ed. 1999, 38, 1223. (h) Enantioselective
synthesis of i-amino acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997.
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6206.
3. Appella, D. H.; LePlae, P. R.; Raguse, T. L.; Gellman, S. H. J. Org. Chem. 2000, 65, 4766.
4. This compound was obtained from the Curtius rearrangement of pentadienoate in benzyl alcohol according to
the protocol of: Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E. Org. Syn. 1980, 59, 1.
5. For other Diels–Alder reactions with amino dienes, see: (a) Oppolzer, W.; Fro¨stl, W. Helv. Chim. Acta 1975, 58,
590. (b) Overman, L. E.; Taylor, G. F.; Jessup, P. J. Tetrahedron Lett. 1976, 36, 3089. (c) Kozmin, S. A.; Rawal,
V. H. J. Org. Chem. 1997, 62, 5252 and references cited therein.
6. Kobayashi, S.; Araki, M.; Hachiya, I. J. Org. Chem. 1994, 59, 3758.
7. Santelli, M.; Pons, J.-M. Lewis Acids and Selectivity in Organic Synthesis; CRC: Boca Raton, 1996.
8. Enantiomeric excess was determined by chiral HPLC on a Chiralcel OD column. All new compounds were
characterized by 1H NMR, 13C NMR, IR, MS, and HR-MS. The structure of 3 was also secured by X-ray.
9. Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243.
10. Experimental protocols for preparation of 4: (1R,6S)-[6-(2-oxo-oxazolidine-3-carbonyl)-cyclohex-2-enyl]-carbamic
acid benzyl ester (3). To a mixture of Sc(OTf)3 (443 mg, 0.900 mmol), (R)-BINOL (309 mg, 1.08 mmol), and 4
i
,
A MS (1.17 g) was added Pr2 NEt (279 mg, 376 mL, 2.16 mmol) in dichloromethane (18 mL) at −78°C. The
reaction mixture was stirred for 30 min at −78°C, and then solutions of 2 (1.27 g, 9.00 mmol) and 1 (1.83 g, 9.00
mmol) in dichloromethane (9 mL) were added successively via cannula. The resulting solution was slowly warmed
to 0°C, stirred at 0°C for 24 h, quenched with water, and extracted with EtOAc. The combined organic layers
were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on SiO2
(EtOAc/hexanes, 30:70) to give 3 as a white crystalline solid (2.85 g, 92%, 90% ee) and exo-product as a colorless
1
oil (174 mg, 6%). 3: mp 131.0–133.0°C; [h]D +151 (c 1.16, CH2Cl2); H NMR l 7.36–7.25 (m, 5H), 5.90–5.86 (m,
1H), 5.70–5.65 (m, 1H), 5.07–4.93 (m, 3H), 4.75–4.74 (m, 1H), 4.24 (dd, 2H, J=7.9, 8.3 Hz), 3.91–3.88 (m, 1H),
3.82–3.79 (m, 1H), 3.52–3.48 (m, 1H), 2.16–2.00 (m, 2H), 1.80–1.72 (m, 2H); 13C NMR l 173.4, 155.7, 153.8,
136.8, 131.3, 128.5, 128.1, 127.8, 125.6, 66.6, 62.3, 45.6, 43.5, 42.8, 24.4, 19.3. (1S,2R)-2-Benzyloxycarbonylamino-
cyclohex-3-ene carboxylic acid. To a solution of 3 (2.83 g, 8.22 mmol) in THF (125 mL) and H2O (34.5 mL) was
added 30% H2O2 (2.24 g, 6.72 mL, 65.8 mmol) followed by addition of LiOH·H2O (690 mg, 16.4 mmol) at 0°C.
The resulting mixture was stirred at room temperature for 38 h, cooled to 0°C, and treated with a 1.35N solution
of Na2SO3 in H2O (54 mL) followed by 0.5N NaHCO3 (82 mL). The THF was evaporated in vacuo. The aqueous
residue was diluted with H2O and extracted with CH2Cl2 to remove oxazolidinone. The aqueous phase was
acidified to pH 1–2 with 5N HCl and extracted with EtOAc. The combined organic layers were dried (MgSO4)
and concentrated. The residue was purified by chromatography on SiO2 (MeOH/CH2Cl2, 5:95) to give
(1S,2R)-2-benzyloxycarbonylamino-cyclohex-3-ene carboxylic acid as an off-white solid (2.13 g, 94%). (1S,2R)-2-
Benzyloxycarbonylamino-cyclohex-3-ene carboxylic acid benzyl ester. To a solution of this acid (118 mg, 0.428
mmol) in acetonitrile (4.0 mL) was added DBU (130 mg, 0.855 mmol) and benzyl bromide (165 mg, 0.964 mmol).
The mixture was stirred at room temperature for 7 h. The solvent was removed in vacuo. The residue was purified
by chromatography on SiO2 (EtOAc/hexanes, 15:85) to give (1S,2R)-2-benzyloxycarbonylamino-cyclohex-3-ene
carboxylic acid benzyl ester as a colorless oil (158 mg, quant.). (1S,2S,3R,4S)-2-Benzyloxycarbonylamino-3,4-dihy-
droxy-cyclohexane carboxylic acid benzyl ester (4). To a solution of this ester (147 mg, 0.401 mmol) in tert-butyl
t
alcohol (4.0 mL) was added OsO4 (2.5 wt.% in BuOH; 250 mL) and NMO (141 mg, 1.20 mmol) at room
temperature. The reaction mixture was stirred at room temperature for 12.5 h. The solvent was removed in
vacuo. The residue was purified by chromatography on SiO2 (EtOAc/hexanes, 60:40) to give 4 as a white solid
(137 mg, 86%): mp 123.0–124.0°C; [h]D −46.7 (c 1.24, CH2Cl2); 1H NMR l 7.34 (s, 10H), 5.83 (d, 1H, J=8.7 Hz),
5.18–5.03 (m, 4H), 4.20–4.13 (m, 1H), 4.00–3.94 (m, 2H), 3.57 (d, 1H, J=5.1 Hz), 3.34 (s, 1H), 3.10–3.00 (m, 1H),
2.12–2.03 (m, 1H), 1.88–1.75 (m, 2H), 1.47–1.39 (m, 1H); 13C NMR l 173.7, 157.2, 136.3, 135.6, 128.7, 128.6,
128.4, 128.2, 128.1, 71.4, 68.8, 67.1, 66.6, 51.5, 44.1, 27.2, 21.7; HRMS (EI) m/e calculated for C22H25O6N:
399.1682, found: 399.1679.

8751
11. Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima, M.; Sugimori, J. J. Am. Chem. Soc. 1989, 111,
5340.
12. Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238.
13. The enantiomeric excess of 10 was based on [h]D comparison to reference 11.
14. (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203. (b) Back, T. G.; Nakajima, K. J.
Org. Chem. 1998, 63, 6566.
15. Corey, E. J.; Huang, H.-C. Tetrahedron Lett. 1989, 30, 5235.
16. Experimental protocols for the preparation of 13: (1R,6R)-6-(2-oxo-oxazolidine-3-carbonyl)-cyclohex-3-ene car-
boxylic acid methyl ester (10). To a mixture of Ti(OiPr)2 Cl2 (54.7 mg, 0.231 mmol) and 9 (147 mg, 0.277 mmol)
was added toluene (9.5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1
,
h, and then transferred to a suspension of 4 A MS (500 mg) in toluene (9.5 mL). The mixture was cooled to 0°C.
A solution of 8 (460 mg, 2.31 mmol) in toluene (13 mL) was added, followed by hexanes (16 mL) and butadiene
(7 mL). The reaction mixture was stirred at 0°C for 28 h, treated with 10 mL of butadiene, stirred at 0°C for
another 40 h, quenched with H2O, and extracted with EtOAc. The combined organic layers were dried (MgSO4)
and concentrated. The residue was purified by chromatography on SiO2 (EtOAc/hexanes, 50:50) to give 10 as a
1
white solid (568 mg, 97, 85% ee): mp 100.0–102.0°C; [h]D −149 (c 1.50, CH2Cl2); H NMR l 5.68–5.67 (m, 2H),
4.44–4.38 (m, 2H), 4.08–3.92 (m, 2H), 3.64 (s, 3H), 3.06–2.96 (m, 1H), 2.55–2.40, 2.20–1.95 (2m, 5H); 13C NMR
l 176.1, 175.5, 153.2, 125.0, 124.9, 62.0, 51.9, 42.7, 41.2, 39.8, 28.2, 28.1. (1R,2R)-Cyclohex-4-ene-1,2-dicarboxylic
acid monomethyl ester. To a solution of 10 (440 mg, 1.74 mmol) in THF (27.0 mL) and H2O (7.6 mL) was added
at 0°C 30% H2O2 (473 mg, 1.42 mL, 13.9 mmol)) followed by LiOH·H2O (91.0 mg, 2.17 mmol). The resulting
mixture was stirred at room temperature for 18 h, cooled to 0°C, and treated with a 1.35N solution of Na2SO3
in H2O (12.5 mL) followed by 0.5N NaHCO3 (21.8 mL). The THF was evaporated in vacuo. The aqueous
residue was diluted with H2O and extracted with CH2Cl2 to remove oxazolidinone. The aqueous phase was
acidified to pH 1–2 with 5N HCl and extracted with EtOAc. The combined organic layers were dried (MgSO4)
and concentrated. The residue was purified by chromatography on SiO2 (MeOH/CH2Cl2, 5:95) to give
(1R,2R)-cyclohex-4-ene-1,2-dicarboxylic acid monomethyl ester as a colorless oil (272 mg, 85%). (1R,6R)-6-tert-
Butoxycarbonylamino-cyclohex-3-ene carboxylic acid methyl ester (11). To a solution of the ester (262 mg, 1.42
mmol) in dry tBuOH (7.5 mL) was added Et3N (173 mg, 1.71 mmol) and diphenylphosphonyl azide (471 mg, 1.71
mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h, and then heated at
reflux for 24 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was purified
by chromatography on SiO2 (EtOAc/hexanes, 8:92) to give 11 as a white crystalline solid (270 mg, 74%): mp
83.6–84.2°C; [h]D −25.1 (c 1.12, CH2Cl2); IR (neat) 3385, 3032, 2984, 2952, 2926, 1723, 1683, 1525, 1435, 1369,
1
1312, 1256, 1192, 1168, 1016, 660 cm−1; H NMR l 5.60–5.67 (m, 2H), 4.64 (br-s, 1H), 4.01 (br-s, 1H), 3.68 (s,
3H), 2.69–2.64 (m, 1H), 2.54–2.46 (m, 2H), 2.44–2.42 (m, 1H), 1.99–1.91 (m, 1H), 1.42 (s, 9H); 13C NMR l 174.1,
155.1, 125.1, 124.3, 79.4, 51.9, 47.4, 44.8, 31.2, 28.4, 26.6. (1R,6R)-6-tert-Butoxycarbonylamino-cyclohex-3-ene
carboxylic acid. A solution of 11 (89.7 mg, 0.351 mmol) in THF/water (10:1, 4.4 mL) was treated with LiOH·H2O
(73.7 mg, 1.76 mmol). The resulting mixture was stirred at room temperature for 78 h before THF was removed
in vacuo. The residue was diluted with water, acidified to pH 1–2 with 5N HCl, and extracted with EtOAc. The
combined organic layers were dried (MgSO4) and concentrated. The residue was purified by chromatography on
SiO2 (MeOH/CH2Cl2, 6:94) to give (1R,6R)-6-tert-butoxycarbonylamino-cyclohex-3-ene carboxylic acid as a
colorless oil (82.7 mg, 98%). (1R,2R,4S,5S)-(4-Hydroxy-7-oxo-6-oxa-bicyclo[ 3.2.1]oct-2-yl)-carbamic acid tert-
butyl ester (12). A solution of this acid (86.2 mg, 0.357 mmol) in CCl4 (3.6 mL) was treated with m-chloroperoxy-
benzoic acid (67.8 mg, 0.393 mmol) at 0°C for 4 h. Then, triethylamine (79.5 mg, 0.786 mmol) was added. The
reaction mixture was heated at 55°C for 3.5 h. The solvent was removed in vacuo. The residue was purified by
chromatography on SiO2 (ethyl acetate/hexanes, 50:50) to give slightly impure 12 as a white solid (38.6 mg, 42%)
that was carried on without further purification. (1R,2R,4S,5S)-2-tert-Butoxycarbonylamino-4,5-dihydroxy-cyclo-
hexane carboxylic acid methyl ester (13). A solution of crude 12 (34.9 mg, 0.136 mmol) in MeOH (1.4 mL) was
treated with sodium bicarbonate (11.4 mg, 0.135 mmol). The reaction mixture was stirred at room temperature
for 27 h. The solvent was removed in vacuo and the residue was purified by chromatography on SiO2 (ethyl
acetate/hexanes, 80:20) to give 13 as a white solid (29.7 mg, 76%): mp 155.0–155.5°C; [h]D −13.8 (c 1.0, MeOH);
1H NMR (CD3OD) l 6.72 (d, 1H, J=8.7 Hz), 4.86 (s, 1H), 3.63 (s, 3H), 3.37–3.24 (m, 2H), 2.45–2.37 (m, 1H),
2.09–1.96 (m, 2H), 1.59–1.28 (m, 11H); 13C NMR (CD3OD) l 173.8, 156.1, 78.7, 72.9, 72.4, 51.1, 49.5, 38.5, 33.6,
27.3; HRMS (EI) m/e calculated for C H O N (M−C H ): 233.0899, found: 233.0897.
.
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