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DOI: 10.1055/s-2005-922778
Desymmetrizing Asymmetric Epoxidations of Bis(cis-configured) Divinylcarbinols: Unusual syn-Selectivity Combined with ee-Enhancement through Kinetic Resolution
Publikationsverlauf
Publikationsdatum:
16. Dezember 2005 (online)
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Abstract
Bis(cis-1-alkenyl)methanols 2a and b were monoepoxidized by a 1:1:1 mixture of R tert OOH, an optically active tartaric acid derivative, and a Zr(IV) alkoxide. This provided epoxy alcohols syn-1a,b with perfect diastereoselectivity. These compounds are the minor products of analogous Ti(IV)-mediated epoxidations. The ee of epoxy alcohol syn-1a was increased up to 99% when less enantioenriched material was overoxidized under the reaction conditions (→ up to 66% bisepoxy alcohol syn,syn-5).
Key words
diastereoselectivity - enantioselectivity - epoxy alcohols - kinetic resolution - 1,4-pentadien-3-ols
-
1a Using stoichiometric or near-stoichiometric amounts of titanium tartrate:
Katsuki T.Sharpless KB. J. Am. Chem. Soc. 1980, 102: 5976 - Using molecular sieves and <10 mol% of titanium tartrate:
-
1b
Hanson RM.Sharpless KB. J. Org. Chem. 1986, 51: 1922 -
1c
Gao Y.Hanson RM.Klunder JM.Ko SY.Masamune H.Sharpless KB. J. Am. Chem. Soc. 1987, 109: 5765 - Sharpless oxidations:
-
2a
Pfenniger A. Synthesis 1986, 89 -
2b
Johnson RA.Sharpless KB. In Catalytic Asymmetric SynthesisOjima I. VCH; New York: 1993. p.103 -
2c
Katsuki T.Martín VS. Org. React. 1996, 48: 1 -
2d
Johnson RA.Sharpless KB. In Catalytic Asymmetric Synthesis 2nd ed.:Ojima I. Wiley-VCH; New York: 2000. p.231-286 - Tansformations of Sharpless epoxides:
-
2e
Hanson RM. Chem. Rev. 1991, 91: 47 -
2f
Pena PCA.Roberts SM. Curr. Org. Chem. 2003, 7: 555 -
3a
Hatakeyama S.Sakurai K.Takano S. J. Chem. Soc., Chem. Commun. 1985, 1759 -
3b
Häfele B.Schröter D.Jäger V. Angew. Chem., Int. Ed. Engl. 1986, 25: 87 ; Angew. Chem. 1986, 98, 89 -
3c
Schreiber SL.Schreiber TS.Smith DB. J. Am. Chem. Soc. 1987, 109: 1525 -
3d
Smith DB.Wang Z.Schreiber SL. Tetrahedron 1990, 46: 4793 -
3e
Nakatsuka M.Ragan JA.Sammakia T.Smith DB.Uehling DE.Schreiber SL. J. Am. Chem. Soc. 1990, 112: 5583 -
3f
Jäger V.Hümmer W.Stahl U.Gracza T. Synthesis 1991, 769 - 4 According to ref. 3c, overoxidation of the monoepoxide increases its ee because the minor epoxide enantiomer is more reactive than the major enantiomer. A more general analysis of the stereochemistry of consecutive asymmetric functionalizations of compounds with two identical prochiral sites led to a complementary conclusion: unless a fast and a slow reacting enantiomer emerge from the first functionalization, the ee does not change during the second functionalization:
Rautenstrauch R. Bull. Soc. Chim. Fr. 1994, 131: 515 -
5a
Hatakeyama S.Sakurai K.Numata H.Ochi N.Takano S. J. Am. Chem. Soc. 1988, 110: 5201 -
5b
Schreiber SL.Schreiber TS.Smith DB. J. Am. Chem. Soc. 1987, 109: 1525 -
6a
Herunsalee A.Isobe M.Pikul S.Goto T. Synlett 1991, 199 -
6b
Hatakeyama S.Satoh K.Takano S. Tetrahedron Lett. 1993, 34: 7425 -
6c
Esumi T.Fukuyama H.Oribe R.Kawazoe K.Iwabuchi Y.Irie H.Hatakeyama S. Tetrahedron Lett. 1997, 38: 4823 -
6d
Nishioka T.Iwabuchi Y.Irie H.Hatakeyama S. Tetrahedron Lett. 1998, 39: 5597 -
6e
Masaki H.Maeyama J.Kamada K.Esumi T.Iwabuchi Y.Hatakeyama S. J. Am. Chem. Soc. 2000, 122: 5216 -
6f
Bayer A.Svendsen JS. Eur. J. Org. Chem. 2001, 1769 - 7
Berkenbusch T.Brückner R. Synlett 2003, 1813 - 8
Spivey AC.Woodhead SJ.Weston M.Andrews BI. Angew. Chem. Int. Ed. 2001, 40: 769 - Method:
-
19a
Hatakeyama S.Satoh K.Takano S. Tetrahedron Lett. 1993, 34: 7425 -
19b
Esumi T.Fukuyama H.Oribe R.Kawazoe K.Iwabuchi Y.Irie H.Hatakeyama S. Tetrahedron Lett. 1997, 38: 4823 -
19c
Nishioka T.Iwabuchi Y.Irie H.Hatakeyama S. Tetrahedron Lett. 1998, 39: 5597 - 20
Still WC.Kahn M.Mitra A. J. Org. Chem. 1978, 43: 2923 - Epoxy alcohol openings at C3:
-
25a Using DIBAL-H:
Finan JM.Kishi Y. Tetrahedron Lett. 1982, 23: 2719 -
25b Using LiBH4/Ti(Oi-Pr)4:
Dai L.-X.Lou B.Zhang Y.Guo G. Tetrahedron Lett. 1986, 27: 4343
References and Notes
The diastereomeric compositions of monoepoxidation product 1a were determined by comparing the integrals over the following 1H NMR signals (300 MHz, CDCl3): δ = 2.99 [dd, J 3,4 = 7.5 Hz, J 3,2 = 4.3 Hz, 3-H (anti-1a [7] )] vs. δ = 3.07 [dd, J 3,4 = 7.4 Hz, J 3,2 = 4.5 Hz, 3-H (syn-1a)]. ‘ds >98:2’ means that the mentioned 1H NMR signal of the minor diastereomer could not be detected.
10All new compounds gave satisfactory 1H NMR and 13C NMR spectra and provided correct combustion analyses (C and H ± 0.4%).
11The ee of monoepoxidation product syn-1a was determined by HPLC. Column: Chiralpak AD; eluent: n-heptane-
i-PrOH 90:10; flow rate: 1.0 mL/min; UV detector: 238 nm; t
R = 48.2 min for syn-1a; t
R = 53.4 min for ent-syn-1a.
Synthesis of cis
-(2
R
,3
S
,4
R
)-2,3-Epoxy-1,7-bis[(4-methoxybenzyl)oxy]-5-hepten-4-ol (
syn
-1a).
At -20 °C, l-(+)-DiPT (51 µL, 57 mg, 0.24 mmol, 1.1 equiv) and t-BuOOH (4.43 M in CH2Cl2, 100 µL, 0.44 mmol, 2.0 equiv) were added to a suspension of Zr(Oi-Pr)4·i-PrOH (84 mg, 0.22 mmol, 1.0 equiv) and 4 Å MS (140 mg, powdered) in CH2Cl2 (4.5 mL). The mixture was stirred for 1 h at
-20 °C before a solution of divinylcarbinol 2a (85 mg, 0.22 mmol) in CH2Cl2 (2.0 ml) was added slowly. After stirring at -20 °C for 4 h, the reaction was quenched at -20 °C with a solution (1.0 mL) prepared from NaOH (30 g), NaCl (5 g), and H2O (90 mL). The cooling bath was removed and the mixture stirred for 2 h at r.t. t-BuOMe (10 mL) was followed by Na2SO4 for drying. After filtration through a pad of Celite® excess t-BuOOH was removed by azeotropic distillation with toluene (2 × 5 mL). The residue was purified by flash chromatography
[20]
(cyclohexane-EtOAc, 5:2) to afford syn-1a (56 mg, 63%) in the early fractions and a 68:32-mixture of syn,syn-5/syn-1a [33 mg, composed of 10 mg syn-1a (11%) and 23 mg syn,syn-5 (25%)] thereafter, both samples being colorless liquids. The total yield of syn-1a was 74% and its ee value 82.0% (by HPLC
[11]
). Sample of 98.3% ee from the time resolved experiment (Figure
[1]
; 16 h, 44% yield): [α]D
20 -8.7 (c 0.8, CHCl3), [α]365
20 -33.1 (c 0.8, CHCl3). 1H NMR (499.9 MHz, CDCl3/TMS): δ = 2.67 (br s, OH), 3.07 (dd, J
3,4 = 7.4 Hz, J
3,2 = 4.5 Hz, 3-H), 3.25 (ddd, J
2,1-H
(
A) = 6.5 Hz, J
2,3 = J
2,1-H
(
B) = 4.2 Hz, 2-H), AB signal (δA = 3.50, δB = 3.65, J
AB = 11.4 Hz, in addition split by J
A,2 = 6.6 Hz, J
B,2 = 3.7 Hz, 1-H2), 3.79 (s, 2 × OCH3), AB signal (δA = 4.02, δB = 4.06, J
AB = 12.8 Hz, in addition split by J
A,6 = 5.9 Hz, 4
J
A,5 = 1.2 Hz, J
B,6 = 6.2 Hz, 4
J
B,5 = 1.5 Hz, 7-H2), 4.27 (br dd, J
4,5 = J
4,3 = 7.8 Hz, 4-H), 4.39-4.51 (m, 2 × Ar-CH
2), AB signal (δA = 5.66, δB = 5.78, J
AB = 11.3 Hz, in addition split by J
A,4 = 8.2 Hz, J
B,7-H
(
A) = J
B,7-H
(
B) = 5.9 Hz, A: 5-H, B: 6-H), AA′BB′ signal centered at δ = 6.87 and δ = 7.24 (2 × C6H4). 13C NMR (125.7 MHz, CDCl3/CDCl3): δ = 55.33 (2 × OCH3), 56.00 (C-2), 58.93 (C-3), 65.83 (C-7), 66.79 (C-4), 67.79 (C-1), 72.41 and 73.02 (2 × benzylic CH2), 113.92 and 113.96 (2 × C
meta
), 129.52 and 129.56 (2 × C
ortho
), 129.78 (2 × C
ipso
), 130.24 (C-5), 130.38 (C-6), 159.43 and 159.44 (2 × C
para
). Anal. Calcd (%) for C23H28O6 (400.5): C, 68.98; H, 7.05. Found: C, 69.16; H, 7.16.
The diastereomeric composition of monoepoxidation product 1b was determined by comparing the integrals over the following 1H NMR signals (300 MHz, CDCl3): δ = 3.02 [dd, J 3,4 = 7.5 Hz, J 3,2 = 4.1 Hz, 3-H (anti-1b [7] )] vs. δ = 3.07 [dd, J 3,4 = 7.4 Hz, J 3,2 = 4.5 Hz, 3-H (syn-1b)]. ‘ds >98:2’ means that the mentioned 1H NMR signal of the minor diastereomer could not be detected.
14The ee of monoepoxidation product syn-1b was determined by HPLC. Column: Chiralpak OD-H; eluent: n-heptane-
i-PrOH 200:1; flow rate: 1.0 mL/min; UV detector: 210 nm; t
R = 24.5 min for syn-1b; t
R = 27.8 min for ent-syn-1b.
Analytical Data for cis , cis -2,3-5,6-Bisepoxy-1,7-bis[4-methoxybenzyl)oxy]-4-heptanol ( syn , syn -5). Colorless solid (mp 90-91 °C). 1H NMR (499.9 MHz, CDCl3/TMS): δ = 2.53 (br d, J OH,4 = 5.4 Hz, OH), 3.13 (dd, J 3,4 or J 5,4 = 6.0 Hz, respectively, J 3,2 or J 5,6 = 4.5 Hz, respectively, 3-H, 5-H), 3.27 (ddd, J 2,1-H ( A) or J 6,7-H ( A) = 5.5 Hz, respectively, J 2,3 = J 2,1-H ( B) or J 6,5 = J 6,7-H ( B) = 4.6 Hz, respectively, 2-H, 6-H), 3.63-3.72 (m, 1-H2, 4-H, 7-H2), 3.79 (s, 2 × OCH3), AB signal (δA = 4.42, δB = 4.50, J AB = 11.4 Hz, 2 × Ar-CH 2), AA′BB′ signal centered at δ = 6.87 und 7.24 (2 × C6H4). 13C NMR (125.7 MHz, CDCl3/CDCl3): δ = 55.33 (C-2, C-6), 55.60 (2 × OCH3), 56.98 (C-3, C-5), 66.74 (C-4), 67.54 (C-1, C-7), 73.12 (2 × benzylic CH2), 113.96 (2 × C meta ), 129.57 (2 × C ortho ), 129.64 (2 × C ipso ), 159.48 (2 × C para ). Anal. Calcd (%) for C23H28O7 (416.5): C, 66.33; H, 6.78. Found: C, 66.14; H, 6.83.
16This study was effected starting with 1.56 mmol 2a in 48 mL CH2Cl2. After the indicated times, 8 mL aliquots were removed from the reaction mixture and worked up extractively as described in ref. 12. After assessing the yields of the constituents of the crude product [17] the latter was flash-chromatographed [20] for obtaining pure samples of syn-1a for ee determination. [11]
17The overall weights of the crude products and their 1H NMR spectra allowed determining the yields of the constituents syn-1a, 2a, and 5 of these mixtures.
18This experiment was performed before we learnt to prepare epoxy alcohol syn-1a as enantioselectively as documented in Table [1] and Figure [1] .
21
Analytical Data for (2
S
,4
R
)-1-[4-Methoxybenzyl)oxy]-6-heptene-2,4-diol [(2
S
,4
R
)-7].
Colorless liquid. [α]D
20 = -7.7 (c 0.92, CHCl3) when prepared from anti-
6 the ee of which was 96.8% (by HPLC). 1H NMR (499.9 MHz, CDCl3/TMS): AB signal (δA = 1.55, δB = 1.63, J
AB = 14.4 Hz, in addition split by J
A,4 = 8.9 Hz*, J
A,2 = 3.5 Hz*, J
B,2 = 8.5 Hz**, J
B,4 = 2.8 Hz**, 3-H2), δ = 2.20-2.31 (m, 5-H2), 2.54 and 2.79 (2 × br s, 2 × OH), AB signal (δA = 3.38, δB = 3.47, J
AB = 9.5 Hz, in addition split by J
A,2 = 7.7 Hz, J
B,2 = 3.7 Hz, 1-H2), 3.80 (s, OCH3), 3.92-3.98 (m, 4-H), 4.12 (mC, 2-H), 4.49 (s, Ar-CH
2), 5.09-5.14 (m, 7-H2), 5.82 (dddd, J
6,7-H
(
Z
) = 16.3 Hz, J
6,7-H
(
E
) = 11.0 Hz, J
6,5-H
(
A) = J
6,5-H
(
B) = 7.2 Hz, 6-H), AA′BB′ signal centered at δ = 6.88 and 7.25 (C6H4); *,** assignments interchangeable. 13C NMR (125.7 MHz, CDCl3/CDCl3): δ = 38.78 (C-3), 42.20 (C-5), 55.35 (OCH3), 67.93 and 67.99 (C-2 and C-4), 73.09 (benzylic CH2), 74.19 (C-1), 113.95 (C
meta
), 118.05 (C-7), 129.48 (C
ortho
), 130.05 (C
ips
), 134.77 (C-6), 159.42 (C
para
). Anal. Calcd (%) for C15H22O4 (266.3): C, 67.64; H, 8.33. Found: C, 67.41; H, 8.52.
The ee of monoepoxidation products anti-6/ent-anti-6 was determined by HPLC. Column: Chiralpak AD; eluent: n-heptane-i-PrOH 85:15; flow rate: 1.0 mL/min; UV detector: 227 nm; t R = 58.1 min for anti-6; t R = 52.7 min for ent-anti-6.
23The diastereomeric composition of monoepoxidation products 6/ent-6 was determined by comparing the integrals over the following 1H NMR signals (300 MHz, CDCl3): δ = 2.99 [dd, J 3,4 = 4.6 Hz, J 3,2 = 2.3 Hz, 3-H (syn-6)] vs. 3.02 [dd, J 3,4 = J 3,2 = 2.7 Hz, 3-H (anti-6)] and δ = 3.19 [ddd, J 2,1-H ( A) = 5.4 Hz, J 2,1-H ( B) = J 2,3 = 2.7 Hz, 2-H (syn-6)] vs. 3.25 [ddd, J 2,1-H ( A) = 5.3 Hz, J 2,1-H ( B) = J 2,3 = 2.7 Hz, 2-H (anti-6)].
24The ee of monoepoxidation products syn-6/ent-syn-6 were determined by HPLC. Column: Chiralpak AD-H; eluent: n-heptane-i-PrOH 80:20; flow rate: 1.0 mL/min; UV detector: 227 nm; t R = 28.6 min for syn-6; t R = 26.4 min for ent-syn-6.
26This can be inferred from the coupling constants causing the hyperfine structure of the 4-H resonance in the 500 MHz 1H NMR spectrum in CDCl3: 4-H of the major product 9 is a ddd at δ = 4.68 with 3 vicinal H-C-C-H couplings
(J
4,3-H
(
A) = J
4,3-H
(
B) = J
4,5 = ca. 6.4 Hz); in contrast, 4-H of the minor product 10 is a ddd at δ = 4.19 with 2 vicinal
H-C-C-H couplings (J
4,5 = 8.5 Hz, J
4,3 = 6.5 Hz) and an additional long-range coupling 4
J
4,6 = 1.0 Hz.