Abstract
The enantioselective syntheses of several protected 4-substituted syn-3,5-dihydroxy carboxylic esters have been achieved from the corresponding achiral (E,E) or (E,Z)-1,3-dienoates. The route relies upon an enantio- and regioselective Sharpless dihydroxylation and a palladium-catalyzed reduction to form γ-substituted δ-hydroxy-1-enoates. The resulting δ-hydroxy-1-enoates are subsequently converted into benzylidene protected 4-substituted syn-3,5-dihydroxy carboxylic esters in one step. The benzylidene protected 3,5-dihydroxy carboxylic esters are produced in good overall yields (20% to 54%) and high enantiomeric excess (73%ee to 97%ee).
As part of our continuing program focused on the de novo asymmetric synthesis of polyketide based natural products,1 we developed a sequential hydration approach (enantioselective hydration 1 to 2 and a diastereoselective hydration 2 to 3) that converts achiral conjugated dienoates into enantiomerically enriched benzylidine protected syn-3,5-dihydroxyesters.2 The transformation relies upon a Sharpless asymmetric dihydroxylation followed by a Pd-π-allyl catalyzed allylic reduction to control both the regio-and enantioselectivity of the first hydration, and an Evans hemiacetal addition to achieve diastereoselectivity in the second hydration.3
With the successful application of this approach to various 1,3-polyol natural products, we targeted the structurally more complex polyene-polyol macrolides (e.g., mycoticin A4, Figure 1). Thus we required a strategy that would address two structural motifs of mycoticin A. That is to say, we required access to both 2-methyl-1,3-diol (C-11 to C-17),3,4 and δ-hydroxy-γ-methyl enoate (C-27 to C-31) subunits. Other approaches to δ-hydroxy-γ-methyl enoate synthons usually involve crotylation/metathesis, aldol/Wittig, or vinylogous aldol sequences; a few other more diverse strategies have been employed in recent years, as well.5 Unfortunately, our initial studies on a new catalytic asymmetric approach using various carbon nucleophiles to install an alkyl group at C-4 was met with little success (i.e., replacing the palladium hydride with a palladium alkyl in the Pd-π-allyl intermediate 5).
Scheme 1.
Asymmetric iterative hydration of C4-methyl dienoates
Alternatively, we envisioned that these two structural features could be prepared from C-4 substituted achiral dienoates by an iterative hydration approach (Scheme 1). This, of course, required that the initial asymmetric hydration reaction be stereospecific, which was demonstrated by substituting DCO2H for HCO2H (Scheme 1, R3 = H; see supporting information). Then, we embarked on an effort to expand the asymmetric hydration methodology to include substituted dienoates (1) for the preparation of the 4-methyl-5-hydroxyenoates (2) and the benzylidine protected 4-methyl-3,5-dihydroxy esters (3) via the substitution of cyclic carbonates 4 and Pd-π-allyl intermediates 5.6 Herein, we describe the successful development of a de novo asymmetric synthesis of these two structural motifs (2 and 3) from simple achiral dienoates (1).
While we were initially concerned about the problems associated with enantio- and regioselectivity in both the osmium and palladium steps, the initial dienoates (6a/b) we chose to study proved to be very promising (Scheme 2).7 Thus, exposure of dienoates 6a and 6b to Sharpless dihydroxylation conditions proceeded uneventfully (Table 1), providing diols 7a and 7b in good yields and excellent enantioselectivity. Similarly, the resulting diols were diastereoselectively converted to homo-allylic alcohols 8a and 8b by conversion to a cyclic carbonate and reduction with Et3N•HCO2H (Table 2).8 Finally, both homo allylic alcohols 8a and 8b were readily converted into the benzylidine protected syn-3,5-dihydroxyester 9a and 9b by exposure to the Evans conditions (PhCHO, cat. KOt-Bu, Table 3).
Scheme 2.
Asymmetric double hydration of (E,E)-dienoate
Table 1.
Asymmetric dihydroxylation of (E,E)-dienoates
 | |||||
|---|---|---|---|---|---|
| Entry | R | Ligand | Yield(%) | e.ea(11) | Ratiob(11:12) |
| a | CH2iPr | (DHQ)2PHAL | 82 | 86 | (1:1) |
| DHQ-4-Me-2-Quin | 75 | 73 | (>99:1) | ||
| b | iPr | (DHQ)2PHAL | 88 | 60 | (1.6:1) |
| DHQ-4-Me-2-Quin | 60c | 80 | (16:1) | ||
| c | Ph | (DHQ)2PHAL | 77 | —d | (1:2.5) |
| (DHQD)2PHAL | 78 | —d | (1:2.5) | ||
| DHQ-4-Me-2-Quine | 60 | 90 | (>99:1) | ||
| d | Me | (DHQ)2PHAL | 65 | 96 | (>99:1) |
| (DHQD)2PHAL | 68 | 99 | (>99:1) | ||
| 6a | (CH2)2OTBS | (DHQ)2PHAL | 68 (7a) | 94 | (>99:1) |
| (DHQD)2PHAL | 70 | 98 | (>99:1) | ||
| 6b | (CH2)2OBn | (DHQ)2PHAL | 71 (7b) | 97 | (>99:1) |
| (DHQD)2PHAL | 73 | 99 | (>99:1) | ||
determined by chiral HPLC
determined by 1H NMR
three eq NaHCO3 used as buffer
e.e. of minor isomer not determined
2% Os, 10% ligand
Table 2.
Diastereoselective carbonate reduction
 | ||||
|---|---|---|---|---|
| Entry | R | Yield% (13) | Yield% (14) | dra |
| a | CH2iPr | 90 | 96 | >95:5 |
| b | iPr | 84 | 98 | >95:5 |
| c | Ph | 91 | 98 | >95:5 |
| d | Me | 90 | 98 | >95:5 |
| e | Me(ent-1)b | 90 | 98 | >95:5 |
| 7a | (CH2)2OTBS | 71 (13f) | 95 (8a) | >95:5 |
| 7b | (CH2)2OBn | 88 (13g) | 96 (8b) | >95:5 |
determined by 1H NMR
dienoate subjected to (DHQD)2PHAL
Table 3.
Diastereoselective hydration of δ-hydroxyenoates
 | |||
|---|---|---|---|
| Entry | R | Yield% (15) | dr |
| a | CH2iPr | 75 | 90:10 |
| b | iPr | 57 | 89:11 |
| c | Ph | 33 | 90:10 |
| d | Me | 63 | 90:10 |
| 8a | (CH2)2OTBS | 58 (9a) | 88:12 |
| 8b | (CH2)2OBn | 69 (9b) | 89:11 |
Unfortunately, when we investigated the scope of this reaction sequence we uncovered complications with the dihydroxylation step (Table 1). The simplest dienoate substrate (Table 1, entry d, R = Me)9 underwent dihydroxylation using (DHQ)2PHAL and (DHQD)2PHAL with excellent enantio- and regioselectivity; however, the regioselectivities were diminished for branched-alkyl and aryl substituents (Table 1, entries a-c).10 For instance, when dienoate 10c (R = Ph) was dihydroxylated with the PHAL-linked dimeric ligands the α,β-olefin 12c was preferentially formed (2.5:1). To our delight, switching to a “first-generation” dihydroxylation ligand, DHQ-4-Me-2-Quinolyl ether (DHQ-MEQ), eliminated this problem and gave the desired diol with excellent selectivity in all three cases (entries a-c, Table 1) with greatly improved regio- (> 16:1) and enantioselectivity (73−90 %ee) for the diols 11a-c.
The palladium catalyzed reduction proved to be very tolerant to a variety of functionalities, giving excellent yields and selectivities in all cases. As with the diols 7a/b, the diastereomerically pure diols 11a-e were converted into the corresponding cyclic carbonates 13a-e (Table 2) in excellent yields using triphosgene and pyridine in CH2Cl2. We next examined the Pd-catalyzed reduction of the (E,E)-allylic carbonates 13a-e. After some experimentation it was found that the optimal conditions were 1% Pd2(dba)3•CHCl3/PPh3 in THF with 5 equiv. of Et3N•HCO2H.11 In all case the carbonates were cleanly converted into homoallylic alcohols in excellent yields (> 95%). It is worth noting that we have been able to use this procedure for the preparation of multigram quantities of 14b (i.e., several 10 g batches).
To demonstrate both the synthetic utility of this oxidation/reduction sequence as well as to assign the stereochemistry of the asymmetric hydration reaction the homoallylic alcohols 14a-d were converted into the 1,3-syn diols 15a-d. Thus exposure of alcohols 14a-d to the Evans 1,3-syn diol protocol provided the benzylidine protected syn-3,5-dihydroxyesters 15a-d. With the exception of the phenyl substituted substrate 14c the benzylidine acetals were formed in good yields (57 to 75%, Table 3).12
We next set out to test the stereospecificity of the overall transformation (6/10 to 9/15). To do so we chose the (Z,E)-methyl substituted dienoate 16 (c.f., Table 4 and Scheme 3). Once again the initial dihydroxylation proved to be problematic. While no regioisomers were detected, the enantioselectivities were unsatisfactory using the PHAL-linked dimeric ligands (Table 4 entries 1−2).
Table 4.
Asymmetric dihydroxylation of (E,Z)-dienoates
 | |||
|---|---|---|---|
| Entry | Ligand | Yield% (17) | ee%b |
| 1 | (DHQ)2PHAL | 63 | 56 |
| 2 | (DHQD)2PHAL | 35 | 70 |
| 3 | DHQ-4-Me-2-Quin | 50 | 49 |
| 4 | (DHQD)2PYR | 64 | 73 |
| 5 | DHQD-9-phen | 47 | 64 |
| 6 | (DHQD)2AQN | 35 | 61 |
| 7 | DHQD-4-CLB | 38 | 30 |
a) 17 is major from DHQD ligands whereas (ent)-17 is major from DHQ ligands.
ee% were determined by chiral HPLC
Scheme 3.
Shi epoxidation of (E,Z)-dienoates
We again turned to the DHQ-MEQ ligand but this time we were met with lower ee (entry 3, Table 4). A screening of commercially-available AD ligands was conducted in which the optimum ligand was determined to be (DHQD)2PYR (entry 4, Table 4).13 In an effort to further increase the enantioselectivity, a Shi epoxidation14 was attempted on 16 (Scheme 3). Indeed, epoxide 19 was formed in greater enantioexcess and was subjected to identical Pd-reduction conditions as the carbonate 18. Both 18 and 19 behaved similarly in the reaction giving excellent dr with the epoxide opening having higher yield (98% vs 86%). Finally, the conversion of 20 to the anti-methyl diastereomer 21 occurred in 80% yield and diastereoselectivity (> 95:5) via the Evans protocol.15
In summary we have demonstrated the utility of our asymmetric bis-hydration methodology for the stereospecific conversion of both (E,E)- and (E,Z)-dienoates into either C-4 diastereomer of benzylidine protected syn-3,5-dihydroxy esters (9, 15 and 21).9 Key to this development was the control of regioselectivity in both the osmium-catalyzed asymmetric dihydroxylation and palladium-catalyzed reduction reactions. Further development to improve the enantioselectivity of the oxidation of the (E,Z)-dienoates and its application toward natural product synthesis is ongoing.
Experimental Section16
General Procedure for dihydroxylations
Into a round bottom flask containing K3Fe(CN)6 (3 equiv.), K2CO3 (3 equiv.), MeSO2NH2 (3 equiv.) and (DHQ)2-PHAL (5 mol%) was added t-BuOH and water (1:1, 0.2 M). The mixture was stirred at 0°C for 5 minutes and then to this solution was added OsO4 (1 mol%) immediately followed by addition of dienoate. The reaction was stirred vigorously at 0°C for 2−18 h. Ethyl acetate was added to the reaction mixture followed by quenching with solid sodium sulfite. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and then dried over Na2SO4. After concentration the crude mixture was purified by silica gel column chromatography.
(+)-(E,4S,5S)-Ethyl 7-(tert-butyldimethylsilyloxy)-4,5-dihydroxy-4-methylhept-2-enoate (7a)
After flash column chromatography (30% EtOAc/hexanes) the reaction yielded 380 mg (68%) of diol as a clear, colorless oil. Rf = 0.10 (4:1 hexanes:EtOAc), [α]D24 +5.2 (c 0.61, CH2Cl2); IR (neat, cm−1) 3459(br), 2932, 2859, 1713, 1658, 1469, 1369, 1257, 1183, 1089, 987, 941, 836, 778, 728; 1H NMR (CDCl3, 600 MHz) δ 6.99 (d, J = 15.6 Hz, 1H), 6.11 (d, J = 15.6 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.90 (m, 2H), 3.74 (dd, J = 6, 6 Hz, 1H), 1.99 (brs, 2H), 1.71 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.25 (s, 3H), 0.88 (s, 9H), 0.07 (s, 6H); 13C NMR (CDCl3, 150 MHz) δ 166.6, 152.3, 120.2, 77.2, 74.6, 62.5, 60.3, 32.2, 25.7 (3C), 22.8, 18.0, 14.1, −5.6 (2C); HRMS (ESI) calcd for [C16H32O5Si + Na]+: 355.1911, Found: 355.1909.
(+)-(E,4S,5S)-Ethyl 7-(benzyloxy)-4,5-dihydroxy-4-methylhept-2-enoate (7b)
After purification by flash column chromatography (50% EtOAc/hexanes) the diol was obtained in 71% yield as a clear, colorless oil. Rf = 0.11 (4:1 hexanes:EtOAc), [α]D24 +5.2 (c 2.0, CH2Cl2); IR (neat, cm−1) 3461(br), 2931, 2860, 1715, 1453, 1367, 1282, 1186, 1095, 1031, 987, 698; 1H NMR (CDCl3, 600 MHz) δ 7.35 (m, 3H), 7.30 (m, 2H), 6.99 (d, J = 15.6 Hz, 1H), 6.11 (d, J = 15.6 Hz, 1H), 4.52 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.75 (m, 2H), 3.68 (m, 1H), 3.51 (s, 1H), 2.71 (s, 1H), 1.81 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H), 1.27 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 166.5, 152.0, 138.1, 128.5 (2C), 127.9, 127.7 (2C), 120.3, 76.7, 74.6, 73.5, 69.2, 60.4, 30.2, 22.8, 14.2; HRMS (ESI) calcd for [C17H24O5 + Na]+: 331.1515, Found: 331.1516.
(−)-(E,4S,5S)-Ethyl 4,5-dihydroxy-4,7-dimethyloct-2-enoate (11a)
After purification by flash column chromatography (50% EtOAc/hexanes) the reaction yielded 44 mg (75%) of diol as a clear oil with no detectable regioisomer. Rf = 0.15 (4:1 hexanes:EtOAc), [α]D24 −21.7 (c 1.0, CH2Cl2); IR (neat, cm−1) 3460, 2957, 2870, 1701, 1656, 1466, 1368, 1307, 1282, 1189, 1034, 988, 869, 766, 743, 652; 1H NMR (CDCl3, 600 MHz) δ 6.95 (d, J = 15.6 Hz, 1H), 6.10 (d, J = 15.6 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.56 (ddd, J = 10.8, 4.2, 2.4 Hz, 1H), 2.53 (brs, 1H), 2.31 (brs, 1H), 1.80 (m, 1H), 1.38 (ddd, J = 13.8, 10.8, 3.6 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H),1.26 (s, 3H), 1.20 (ddd, J = 13.8, 10.2, 4.2 Hz, 1H), 0.94 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 166.6, 151.9, 120.6, 75.4, 74.7, 60.5, 39.7, 24.6, 23.8, 21.8, 21.2, 14.1; HRMS (ESI) calcd for [C12H22O4 + Na]+: 253.1410, Found: 253.1402.
(−)-(E,4S,5S)-Ethyl 4,5-dihydroxy-4,6-dimethylhept-2-enoate (11b)
After purification by silica gel column chromatography (30% EtOAc/hexanes) the reaction yielded 72 mg (60%) of diols as a 16:1 mixture of regioisomers. Rf = 0.11 (4:1 hexanes:EtOAc), [α]D24 −3.0 (c 0.5, CH2Cl2); IR (neat, cm−1) 3448, 2962, 2874, 1698, 1655, 1467, 1368, 1303, 1279, 1179, 1096, 1031, 984, 869, 725, 679; 1H NMR (CDCl3, 600 MHz) δ 6.89 (d, J = 15.6 Hz, 1H), 5.99 (d, J = 15.6 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.27 (dd, J = 4.8, 3.6 Hz, 1H), 2.32 (s, 1H), 1.95 (d, J = 4.8 Hz, 1H), 1.86 (m, 1H), 1.22 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 166.8, 153.4, 120.2, 80.1, 75.6, 60.7, 29.0, 23.1, 22.0, 16.6, 14.4; HRMS (ESI) calcd for [C11H20O4 + Na]+: 239.1253, Found: 239.1249.
(+)-(S,E)-Ethyl 4-hydroxy-4-((S)-hydroxy(phenyl)methyl)pent-2-enoate (11c)
After purification by flash column chromatography (50% EtOAc/hexanes) the reaction yielded 490 mg (60%) of diol as a clear, yellow oil. Rf = 0.10 (4:1 hexanes:EtOAc), [α]D24 +15.7 (c 1.2, CH2Cl2); IR (neat, cm−1) 3436, 2981, 1699, 1656, 1453, 1368, 1304, 1278, 1182, 1094, 1026, 985, 910, 868, 721, 700; 1H NMR (CDCl3, 600 MHz) δ 7.33 (m, 5H), 7.01 (d, J = 15.6 Hz, 1H), 6.11 (d, J = 15.6 Hz, 1H), 4.60 (d, J = 3.0 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.70 (s, 1H), 2.47 (s, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.17 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 166.5 151.8, 138.9, 128.2, 128.1 (2C), 127.5 (2C), 120.5, 79.2, 75.5, 60.4, 22.9, 14.1; HRMS (ESI) calcd for [C14H18O4 + Na]+: 273.1097, Found: 273.1091
(+)-( E,4R,5S)-Ethyl 4,5-dihydroxy-4-methylhex-2-enoate (17)
After purification by flash column chromatography (30% EtOAc/hexanes) the reaction yielded 153 mg (64%) of diol as a clear, colorless oil. Rf = 0.10 (4:1 hexanes:EtOAc), [α]D24 +2.5 (c 1.00, CH2Cl2); IR (neat, cm−1) 3434(br), 2980, 2936, 1699, 1655, 1449, 1368, 1303, 1276, 1181, 1090, 1033, 985, 920, 887, 729; 1H NMR (CDCl3, 600 MHz) δ 6.97 (d, J = 15.6 Hz, 1H), 6.11 (d, J = 15.6 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.71 (q, J = 6.6 Hz, 1H), 2.64 (brs, 1H), 2.28 (brs, 1H), 1.31 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.17 (dd, J = 6.6, 1.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 166.7, 150.0, 121.2, 75.6, 74.0, 60.7, 24.6, 18.2, 14.4.
General procedure for carbonate formation
To diol in CH2Cl2 (0.4 M) in an ice bath was added pyridine (5 equiv.). Triphosgene (1.1 equiv.) in CH2Cl2 (0.4 M, total reaction concentration equals 0.2 M) was added via syringe and the reaction was allowed to stir for 5 min until determined complete by TLC (UV, PMA stain). The reaction was diluted with diethyl ether and was placed in a separatory funnel. The crude mixture, including salts, was washed vigorously with a saturated aqueous CuSO4 solution until all salts dissolved. The layers were then separated and the organic layer was washed with brine. After separation the organic layer was dried over Na2SO4 and concentrated. The crude mixture was then purified by flash column chromatography.
(+)-(E)-Ethyl 3-((4S,5S)-5-isobutyl-4-methyl-2-oxo-1,3-dioxolan-4-yl)acrylate (13a)
The crude mixture was purified by flash column chromatography (20% EtOAc/hexanes) to yield carbonate in 90% yield as a clear, colorless oil. Rf = 0.26 (4:1 hexanes:EtOAc), [α]D24 +35.6 (c 1.0, CH2Cl2); IR (neat, cm−1) 2961, 1799, 1719, 1663, 1468, 1385, 1367, 1309,1280, 1232, 1177, 1088, 1063, 1013, 982, 870, 774; 1H NMR (CDCl3, 600 MHz) δ 6.85 (d, J = 15.6 Hz, 1H), 6.16 (d, J = 15.6 Hz, 1H), 4.41 (dd, J = 10.8, 2.4 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 1.84 (m, 1H), 1.71 (m, 1H), 1.46 (s, 3H), 1.32 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H), 0.99 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 165.3, 153.2, 144.0, 122.3, 84.15, 82.0, 61.0, 37.4, 25.1, 23.1, 21.5, 19.2, 14.1; HRMS (ESI) calcd for [C13H20O5 + Na]+: 279.1202, Found: 279.1204.
(+)-(E)-Ethyl 3-((4S,5S)-5-isopropyl-4-methyl-2-oxo-1,3-dioxolan-4-yl)acrylate (13b)
The crude mixture was purified by flash column chromatography (20% EtOAc/hexanes) to yield carbonate in 84% yield as a clear, colorless oil. Rf = 0.22 (4:1 hexanes:EtOAc), [α]D24 +18.3 (c 1.0, CH2Cl2); IR (neat, cm−1) 2973, 1801, 1720, 1663, 1472, 1368, 1281, 1245, 1175, 1109, 1062, 1027, 982, 839, 774; 1H NMR (CDCl3, 600 MHz) δ 6.84 (d, J = 15.6 Hz, 1H), 6.20 (d, J = 15.6 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.98 (d, J = 9.6 Hz, 1H), 2.04 (m, 1H), 1.54 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.11 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 165.6, 153.1, 144.5, 123.0, 89.1, 84.5, 61.2, 28.2, 19.8, 19.1, 18.7, 14.3; HRMS (ESI) calcd for [C12H18O5 + Na]+: 265.1046, Found: 265.1050.
(−)-(E)-Ethyl 3-((4S,5S)-4-methyl-2-oxo-5-phenyl-1,3-dioxolan-4-yl)acrylate (13c)
The crude mixture was purified by flash column chromatography (20% EtOAc/hexanes) to yield carbonate in 91% yield as a clear, colorless oil. Rf = 0.21 (4:1 hexanes:EtOAc), [α]D24 −24.9 (c 1.3, CH2Cl2); IR (neat, cm−1) 2984, 1802, 1718, 1663, 1456, 1367, 1308, 1288, 1245, 1180, 1088, 1069, 1044, 1028, 979, 771, 700; 1H NMR (CDCl3, 600 MHz) δ 7.43 (m, 3H), 7.28 (m, 2H), 7.01 (d, J = 15.6 Hz, 1H), 6.20 (d, J = 15.6 Hz, 1H), 5.47 (s, 1H), 4.26 (qd, J = 7.2, 1.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H), 1.12 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 165.3, 153.0, 144.5, 132.2, 129.5, 128.9 (2C), 125.5 (2C), 122.6, 85.2, 84.4, 61.1, 20.9, 14.1; HRMS (ESI) calcd for [C15H16O5 + Na]+: 299.0889, Found: 299.0897.
(+)-(E)-Ethyl 3-((4S,5S)-4,5-dimethyl-2-oxo-1,3-dioxolan-4-yl)acrylate (13d)
The crude mixture was purified by flash column chromatography (20% EtOAc/hexanes) to yield carbonate in 90% yield as a clear, colorless oil. Rf = 0.25 (4:1 hexanes:EtOAc), [α]D24 +12.7 (c 1.00, CH2Cl2); IR (neat, cm−1) 2987, 2941, 2301, 1821, 1726, 1664, 1446, 1390, 1348, 1312, 1235, 1183, 1086, 1034, 868, 774, 630; 1H NMR (CDCl3, 600 MHz) δ 6.86 (d, J = 16.2 Hz, 1H), 6.15 (d, J = 16.2 Hz, 1H), 4.54 (q, J = 6.6 Hz, 1H), 4.22 (q, J = 6.6 Hz, 2H), 1.48 (s, 3H), 1.41 (d, J = 6.6 Hz, 3H), 1.30 (t, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 165.3, 153.1, 144.0, 122.3, 84.1, 79.6, 61.0, 19.1, 14.3, 14.1; HRMS (ESI) calcd for [C10H14O5 + Na]+: 237.0733, Found: 237.0726.
(−)-(E)-Ethyl 3-((4S,5S)-5-(2-(tert-butyldimethylsilyloxy)ethyl)-4-methyl-2-oxo-1,3-dioxolan-4-yl)acrylate (13f)
The crude mixture was purified by flash column chromatography (20% EtOAc/hexanes) to yield carbonate in 71% yield as a clear, colorless oil. Rf = 0.50 (4:1 hexanes:EtOAc), [α]D24 −52.2 (c 1.00, CH2Cl2); IR (neat) 2956, 2858, 1813, 1723, 1665, 1469, 1388, 1309, 1258, 1179, 1088, 1033, 982, 835, 777, 721; 1H NMR (CDCl3, 600 MHz) δ 6.89 (d, J = 15.6 Hz, 1H), 6.15 (d, J = 15.6 Hz, 1H), 4.59 (dd, J = 9.6, 3.6 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.77 (m, 2H), 1.87 (m, 2H), 1.49 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.06 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 165.3, 153.1, 144.1, 122.2, 83.9, 80.3, 61.0, 58.5, 32.1, 25.8 (3C), 19.6, 18.2, 14.1, −5.5 (2C); HRMS (ESI) calcd for [C17H30O6Si + Na]+: 381.1703, Found: 381.1718.
(−)-(E)-Ethyl 3-((4S,5S)-5-(2-(benzyloxy)ethyl)-4-methyl-2-oxo-1,3-dioxolan-4-yl)acrylate (13g)
The crude mixture was purified by flash column chromatography (20% EtOAc/hexanes) to yield carbonate in 88% yield as a clear, colorless oil. Rf = 0.23 (4:1 hexanes:EtOAc), [α]D24 −23. 8 (c 2.3, CH2Cl2); IR (neat, cm−1) 2985, 2863, 1810, 1720, 1662, 1556, 1495, 1454, 1382, 1188, 1090, 985, 773, 741;; 1H NMR (CDCl3, 600 MHz) δ 7.35 (m, 3H), 7.31 (m, 2H), 6.88 (d, J = 15.6 Hz, 1H), 6.15 (d, J = 15.6 Hz, 1H), 4.62 (t, J = 7.2 Hz, 1H), 4.51 (dd, J = 27.0, 6.0 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.63 (m, 2H), 1.95 (dd, J = 12.6, 6.0 Hz, 2H), 1.48 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 165.3, 153.0, 144.1, 137.5, 128.4 (2C), 127.8, 127.7 (2C), 122.2, 84.0, 80.5, 73.4, 65.4, 61.0, 29.6, 19.5, 14.1; HRMS (ESI) calcd for [C18H22O6 + Na]+: 357.1308, Found: 357.1290.
(−)-(E)-Ethyl 3-((4R,5S)-4,5-dimethyl-2-oxo-1,3-dioxolan-4-yl)acrylate (18)
The crude mixture was purified by flash column chromatography (20% EtOAc/hexanes) to yield carbonate in 89% yield as a clear, colorless oil. Rf = 0.20 (4:1 hexanes:EtOAc), [α]D24 −30.2 (c 0.65, CH2Cl2); IR (neat, cm−1) 2985, 2940, 1793, 1717, 1662, 1594, 1448, 1387, 1367, 1310, 1287, 1225, 1180, 1097, 1074, 1000, 905, 870, 773, 732, 685; 1H NMR (CDCl3, 600 MHz) δ 6.76 (d, J = 15.6 Hz, 1H), 6.19 (d, J = 15.6 Hz, 1H), 4.55 (dd, J = 6.6, 6.6 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 1.60 (s, 3H), 1.32 (d, J = 6.6 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 165.4, 153.3, 142.1, 123.2, 84.4, 81.9, 61.2, 24.4, 16.1, 14.3; HRMS (ESI) calcd for [C10H14O5 + Na]+: 237.0733, Found: 237.0736.
General procedure for the Pd-catalyzed carbonate reduction
To a flask containing carbonate in THF (0.2 M) was added Pd2(dba)3·CHCl3 (1 mol%), PPh3 (1 mol%), Et3N (5 equiv.) and finally formic acid (5 equiv.). The reaction was then refluxed for 20−40 min at which time it was determined complete by TLC (UV, anisaldehyde). The reaction was then allowed to cool to RT then diluted with ether and filtered through a plug of silica gel to remove Pd(0) before concentration. The crude mixture was then concentrated and subjected to flash column chromatography.
(−)-(E,4S,5S)-Ethyl 7-(tert-butyldimethylsilyloxy)-5-hydroxy-4-methylhept-2-enoate (8a)
The crude mixture was concentrated and subjected to flash column chromatography (20% EtOAc/hexanes) to yield δ-hydroxy enoate in 95% yield as a clear, colorless oil. Rf = 0.45 (4:1 hexanes:EtOAc), [α]D24 −16.5 (c 0.63, CH2Cl2; IR (neat, cm) 3499(br), 2955, 2859, 1720, 1651, 1463, 1368, 1256, 1181, 1144, 1093, 1038, 986, 835, 777, 726; 1H NMR (CDCl3, 600 MHz) δ 6.93 (dd, J = 16.2, 7.8 Hz, 1H), 5.84 (dd, J = 16.2, 1.2 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.89 (m, 1H), 3.78 (m, 2H), 2.41 (m, 1H), 1.61 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.10 (d, J = 7.2 Hz, 3H), 0.88 (s, 9H), 0.07 (d, J = 1.2 Hz, 6H); 13C NMR (CDCl3, 150 MHz) δ 166.6, 150.9, 121.4, 75.1, 63.0, 60.2, 42.7, 35.4, 25.8 (3C), 18.0, 14.7, 14.2, −5.6 (2C); HRMS (ESI) calcd for [C16H32O4Si + Na]+: 339.1962, Found: 339.1954.
(−)-(E,4S,5S)-Ethyl 7-(benzyloxy)-5-hydroxy-4-methylhept-2-enoate (8b)
The crude mixture was concentrated and subjected to flash column chromatography (20% EtOAc/hexanes) to yield δ-hydroxy enoate in 96% yield as a clear, colorless oil. Rf = 0.23 (4:1 hexanes:EtOAc), [α]D24 −18.9 (c 1.20, CH2Cl2); IR (neat, cm−1) 3486(br), 2932, 2854, 1725, 1646, 1467, 1273, 1193, 1107, 1090, 741, 705; 1H NMR (CDCl3, 600 MHz) δ 7.31 (m, 5H), 6.95 (dd, J = 15.6, 7.8 Hz, 1H), 5.84 (dd, J = 15.6, 1.8 Hz, 1H), 4.51 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.74 (m, 2H), 3.64 (ddd, J = 12.6, 6.6, 2.4 Hz, 1H), 3.01 (d, J = 3.0 Hz, 1H), 2.43 (sextet, J = 6.6 Hz, 1H), 1.73 (q, J = 6.0 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H), 1.11 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 166.5, 150.7, 137.7, 128.4 (2C), 127.8, 127.7 (2C), 121.5, 74.4, 73.4, 69.4, 60.2, 42.6, 33.6, 14.6, 14.2; HRMS (ESI) calcd for [C17H24O4Si + Na]+: 315.1566, Found: 315.1568.
(−)-(E,4S,5S)-ethyl 5-hydroxy-4,7-dimethyloct-2-enoate (14a)
The crude mixture was concentrated and subjected to flash column chromatography (20% EtOAc/hexanes) to yield δ-hydroxy enoate in 96% yield as a clear, colorless oil. Rf = 0.27 (4:1 hexanes:EtOAc), [α]D24 −43.7 (c 1.0, CH2Cl2); IR (neat, cm−1) 3436(br), 2957, 2871, 1702, 1651, 1467, 1368, 1272, 1182, 1150, 1095, 1034, 989, 865, 729; 1H NMR (CDCl3, 600 MHz) δ 6.95 (dd, J = 15.6, 7.8 Hz, 1H), 5.86 (dd, J = 15.6, 1.8 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.67 (ddd, J = 9.0, 8.4, 5.4 Hz, 1H), 2.40 (sextet, J = 7.2 Hz, 1H), 1.77 (m, 2H), 1.57 (brs, 1H), 1.35 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.08 (d, J = 7.2 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 166.5, 150.9, 121.6, 72.4, 60.2, 43.4, 42.8, 24.6, 23.6, 21.6, 14.2, 13.8; HRMS (ESI) calcd for [C12H22O3 + Na]+: 237.1461, Found: 237.1460.
(−)-(E,4S,5S)-Ethyl 5-hydroxy-4-methylhex-2-enoate (14d)
The crude mixture was concentrated and subjected to flash column chromatography (20% EtOAc/hexanes) to yield δ-hydroxy enoate in 98% yield as a clear, colorless oil. Rf = 0.40 (4:1 hexanes:EtOAc), [α]D24 −29.8 (c 0.77, CH2Cl2); IR (neat, cm−1) 3410(br), 2971, 2850, 1716, 1650, 1273, 1183, 1155, 1093, 1034; 1H NMR (CDCl3, 600 MHz) δ 6.93 (dd, J = 15.6, 7.8 Hz, 1H), 5.86 (dd, J = 15.6, 1.2 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.77 (m, 1H), 2.39 (m, 1H), 1.58 (brs, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 166.5, 150.4, 121.8, 70.5, 60.2, 43.7, 20.4, 14.4, 14.2; HRMS (ESI) calcd for [C9H16O3 + Na]+: 195.0991, Found: 195.1000.
General procedure for the Evans' hemiacetal addition
Enoate was dissolved in THF (0.2 M) and cooled to 0 °C. To the solution was added benzaldehyde (1.1 equiv.) and potassium tert-butoxide (0.15 equiv.). The addition of base and aldehyde was repeated 3 times at 20 minute intervals. The reaction was allowed to stir at 0 °C, and was quenched after 1 hour by adding pH 7 buffered phosphate solution. The layers were separated and the aqueous layer was extracted with Et2O. The organic layers were combined and washed with brine, then dried over Na2SO4, and the solvent removed under reduced pressure. The product was purified by silica gel chromatography.
(−)-Ethyl 2-((2S,4R,5R,6S)-6-(2-(tertbutyldimethylsilyloxy)ethyl)-5-methyl-2-phenyl-1,3-dioxan-4-yl)acetate (9a)
The product was purified by silica gel chromatography eluting with 5 % EtOAc/hexanes to yield benzylidine acetal in 58% yield as a clear, colorless oil. Rf = 0.62 (4:1 hexanes:EtOAc), [α]D24 −27.5 (c 0.50, CH2Cl2); IR (neat, cm−1) 2955, 2930, 2858, 1738, 1461, 1390, 1349, 1314, 1254, 1182, 1098, 1064, 1027, 941, 835, 776, 697; 1H NMR (CDCl3, 600 MHz) δ 7.49 (m, 2H), 7.34 (m, 3H), 5.58 (s, 1H), 4.43 (ddd, J = 7.8, 6.0, 2.4 Hz, 1H), 4.16 (dq, J = 7.2, 1.2 Hz, 2H), 4.13 (ddd, J = 8.4, 3.0, 3.0 Hz, 1H), 3.78 (m, 1H), 3.73 (m, 1H), 2.71 (dd, J = 15.6, 8.4Hz, 1H), 2.48 (dd, J = 15.6, 6.0 Hz, 1H), 1.87 (m, 1H), 1.66 (m, 1H), 1.58 (qdd, J = 7.2, 2.4, 2.4 Hz, 1H), 1.26 (t, J = 7.2 Hz, 3H), 1.01 (d, J = 7.2, Hz, 3H), 0.91 (d, J = 1.2 Hz, 9H), 0.06 (d, J = 6.4 Hz, 6H); 13C NMR (CDCl3, 150 MHz) δ 171.0, 138.6, 128.6, 128.1 (2C), 126.1 (2C), 101.5, 77.3, 77.1, 60.5, 59.2, 38.1, 35.8, 34.6, 25.9 (3C), 18.3, 14.1, 6.2, −5.3(2C); HRMS (ESI) calcd for [C23H38O5 + Na]+: 445.2380, Found: 445.2398.
(−)-Ethyl 2-((2S,4R,5R,6S)-6-(2-(benzyloxy)ethyl)-5-methyl-2-phenyl-1,3-dioxan-4-yl)acetate (9b)
The product was purified by silica gel chromatography eluting with 5 % EtOAc/hexanes to yield benzylidine acetal in 69% yield as a clear, colorless oil. Rf = 0.39 (4:1 hexanes:EtOAc), [α]D24 −20.5 (c 1.0, CH2Cl2); IR (neat, cm−1) 2978, 2869, 1735, 1496, 1454, 1369, 1350, 1264, 1182, 1151, 1100, 1066, 1027, 754, 697; 1H NMR (CDCl3, 600 MHz) δ 7.33 (m, 10H), 5.5 (s, 1H), 4.54 (d, J = 12.0 Hz, 1H), 4.50 (d, J = 12.0, Hz, 1H), 4.42 (ddd, J = 8.4, 5.4, 2.4 Hz, 1H), 4.18 (qd, J = 7.2, 1.8 Hz, 1H), 4.17 (ddd, J = 8.4, 3.6, 2.4 Hz, 1H), 4.15 (qd, J = 7.2, 1.8 Hz, 1H), 3.65 (ddd, J = 13.2, 9.0, 4.8 Hz, 1H), 3.59 (ddd, J = 12.0, 9.0, 6.0 Hz, 1H), 2.71 (dd, J = 15.6, 7.8 Hz, 1H), 2.47 (dd, J = 15.6, 5.4 Hz, 1H), 1.97 (m, 1H), 1.76 (m, 1H), 1.58 (qdd, J = 6.6, 2.4, 2.4 Hz, 1H), 1.27 (t, J = 7.2 Hz, 3H), 1.01 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 170.9, 138.6, 138.4, 128.6, 128.3 (2C), 128.1 (2C), 127.6 (2C), 127.5, 126.1 (2C), 101.4, 77.5, 77.2, 73.0. 66.4, 60.5, 38.1, 34.5, 33.1, 14.1, 6.1; HRMS (ESI) calcd for [C24H30O5 + Na]+: 421.1985, Found: 421.2014.
(−)-Ethyl 2-((2S,4R,5R,6S)-6-isobutyl-5-methyl-2-phenyl-1,3-dioxan-4-yl)acetate (15a)
The product was purified by silica gel chromatography eluting with 5−10 % EtOAc/hexanes to yield benzylidine acetal in 75% yield as a clear, colorless oil. Rf = 0.39 (4:1 hexanes:EtOAc), [α]D24 −7.3 (c 0.50, CH2Cl2); IR (neat, cm−1) 2955, 2870, 1734, 1456, 1391, 1368, 1349, 1259, 1180, 1102, 1056, 1021, 993, 922, 853, 755, 696; 1H NMR (CDCl3, 600 MHz) δ 7.48 (m, 2H), 7.33 (m, 3H), 5.58 (s, 1H), 4.42 (ddd, J = 7.8, 5.4, 2.4 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.99 (ddd, J = 8.4, 4.8, 2.4 Hz, 1H), 2.71 (dd, J = 15.6, 7.8 Hz, 1H), 2.48 (dd, J = 15.6, 6.0 Hz, 1H), 1.78 (m, 1H), 1.64 (m, 1H), 1.54 (qdd, J = 7.2, 2.4, 2.4 Hz, 1H), 1.27 (t, J = 7.2 Hz, 3H), 1.26 (m, 1H), 0.99 (d, J = 7.2 Hz, 3H), 0.95 (d, J = 6.6 Hz, 6H); 13C NMR (CDCl3, 150 MHz) δ 171.1, 138.7, 128.5, 128.1 (2C), 126.0 (2C), 101.4, 79.0, 77.4, 60.5, 41.5, 38.1, 34.6, 24.3, 23.0, 22.6, 14.2, 6.0; HRMS (ESI) calcd for [C19H28O4 + Na]+: 343.1879, Found: 343.1880.
(+)-Ethyl 2-((2R,4R,5S,6R)-5-methyl-2,6-diphenyl-1,3-dioxan-4-yl)acetate (15c)
The product was purified by silica gel chromatography eluting with 10 % EtOAc/hexanes to yield benzylidine acetal in 33% yield as a clear, colorless oil. Rf = 0.26 (4:1 hexanes:EtOAc), [α]D24 +11.1 (c 1.0, CH2Cl2); IR (neat, cm−1) 2982, 2165, 1734, 1497, 1452, 1348, 1260, 1183, 1135, 1100, 1052, 1027, 993, 755, 698; 1H NMR (CDCl3, 600 MHz) δ 7.59 (d, J = 7.2 Hz, 1H), 7.37 (m, 9H), 5.79 (s, 1H), 5.15 (d, J = 2.4 Hz, 1H), 4.65 (ddd, J = 7.8, 6.0, 2.4 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.76 (dd, J = 15.6, 8.4 Hz, 1H), 2.53 (dd, J = 15.6, 6.0 Hz, 1H), 1.97 (qdd, J = 6.6, 2.4, 2.4 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 170.9, 140.1, 138.5, 128.8, 128.1 (2C), 128.1 (2C), 127.0, 126.2 (2C), 125.3 (2C), 101.5, 81.7, 77.1, 60.6, 38.2, 36.6, 14.2, 6.1; HRMS (ESI) calcd for [C21H24O4 + Na]+: 363.1566, Found: 363.1562.
(+)-Ethyl 2-((2S,4R,5R,6S)-5,6-dimethyl-2-phenyl-1,3-dioxan-4-yl)acetate (15d)
The product was purified by silica gel chromatography eluting with 10 % EtOAc/hexanes to yield benzylidine acetal in 63% yield as a clear, colorless oil. Rf = 0.42 (9:1 hexanes:EtOAc), [α]D24 +21.6 (c 1.00, CH2Cl2); IR (neat, cm−1) 3453, 3066, 3037, 2980, 2935, 2890, 2360, 1958, 1882, 1732, 1496, 1375, 1263, 1183, 1062, 918, 851, 757, 699, 650, 584; 1H NMR (CDCl3, 600 MHz) δ 7.49 (m, 2H), 7.33 (m, 3H), 5.58 (s, 1H), 4.40 (ddd, J = 7.8, 6.0, 2.4 Hz, 1H), 4.14 (dq, J = 7.2, 2.4 Hz, 2H), 4.10 (dq, , J = 6.6, 2.4 Hz, 1H), 2.69 (dd, , J = 15.6, 7.8 Hz, 1H), 2.48 (dd, , J = 15.6, 6.0 Hz, 1H), 1.54 (qdd, , J = 7.2, 2.4, 2.4 Hz, 1H), 1.27 (d, , J = 6.6 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.01 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 170.9, 138.5, 128.6, 128.1 (2C), 126.1 (2C), 101.6, 77.2, 76.4, 60.4, 37.9, 35.4, 18.5, 14.1, 5.5; HRMS (ESI) calcd for [C16H22O4 + Na]+: 301.1410, Found: 301.1422.
Supplementary Material
Figure 1.
Asymmetric hydration approach to mycoticin A
Acknowledgment
We are grateful to NIH (GM63150) and NSF (CHE-0415469) for the support of our research program and NSF-EPSCoR (0314742) for a 600 MHz NMR and an LTQ-FT Mass Spectrometer at WVU.
Footnotes
Supporting Information Available: Complete experimental procedures and spectral data for all new compounds can be found in the Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org.
References
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