<chunk>Diastereoselective and enantioselective reduction of tetralin-1,4-dione</chunk>

Department of Organic Chemistry, University of Geneva, 1211 Geneva 4, Switzerland

<chunk>Diastereoselective and enantioselective reduction of tetralin-1,4-dione</chunk> asymmetric catalysis ketone reduction tautomer

<chunk>Background</chunk> The chemistry of tetralin-1,4-dione, the stable tautomer of 1,4-dihydroxynaphthalene, has not been explored previously. It is readily accessible and offers interesting opportunities for synthesis.

<chunk>Results</chunk> The title reactions were explored. L-Selectride reduced the diketone to give preferentially the cis -diol (d.r. 84 : 16). Red-Al gave preferentially the trans -diol (d.r. 13 : 87). NaBH 4 , LiAlH 4 , and BH 3 gave lower diastereoselectivities (yields: 76–98%). Fractional crystallization allowed isolation of the cis -diol and the trans -diol (55% and 66% yield, respectively). Borane was used to cleanly give the mono-reduction product. Highly enantioselective CBS reductions afforded the trans -diol (72% yield, 99% ee) and the mono-reduction product (81%, 95% ee).

<chunk>Conclusion</chunk> Diastereoselective and enantioselective reductions of the unexplored tetralin-1,4-dione provides a very convenient entry into a number of synthetically highly attractive 1,4-tetralindiols and 4-hydroxy-1-tetralone.

<chunk>Introduction</chunk> In this article, we briefly review synthetic approaches to 2,3-dihydro-1,4-naphthoquinone, more simply named tetralin-1,4-dione ( 2 ). This symmetric diketone is the stable tautomer of 1,4-dihydroxynaphthalene ( 1 ). Although known for many years, it has never been used in synthesis. The reactions of 2 that are reported in this article are those given in the title. Tetralin-1,4-dione ( 2 ) is accessible by tautomerization, reduction, oxidation, and photolytic cycloreversion ( and ). Tautomerization takes place upon melting 1 under an inert atmosphere or in a vacuum (>200 °C) . The equilibrium mixture at this temperature consists of 1 and 2 in a ratio of 2 : 1 . After cooling to ambient temperature, equilibration ceases and extracts with non-polar solvents are enriched with the more soluble 2 . Tautomerization of 1 was also reported in trifluoroacetic acid, with 2 being the largely dominant species in solution . Tetralin-1,4-dione ( 2 ) has also been obtained by catalytic hydrogenation of 1,4-naphthoquinone ( 3 ) using Wilkinson’s catalyst (70% yield) , by oxidation of 1-tetralone ( 4 ) with t -BuOOH and a dirhodium caprolactamate catalyst (27% yield at 29% conversion) , and by photolysis of the Dewar benzene 5 at low temperature in a solid matrix ( ). While dione 2 is readily synthesized, it remains a chemically unexplored curiosity. This simple molecule, and its π-metal complexes, drew our attention and interest for their potential in synthesis. Using the tautomerization of 1 in trifluoroacetic acid to generate 2 , we found that upon solvent evaporation the tautomer obtained was dihydroxynaphthalene 1 , rather than diketone 2 . During evaporation, the lower solubility of 1 led to its precipitation and this shifted the equilibrium back. This problem was solved by adding toluene to the mixture before evaporation under vacuum. This, and recrystallization (iPr 2 O) afforded 2 in 72% yield . The straightforward route allowed the synthesis of gram quantities of 2 and the opportunity to study its uncharted chemistry. This paper details the results of our studies of reductions of the carbonyl functions in diketone 2 .

<chunk>Results and Discussion</chunk>

<chunk>Diastereoselective bis-reduction of 2</chunk> Reduction of tetralin-1,4-dione ( 2 ) with a number of reducing agents afforded mixtures of diastereoisomeric cis -diol 6 and trans -diol 7 in the ratios shown in . It is important to mention here that these reactions do not occur when tautomer 1 is used. The reductions with NaBH 4 ( , entry 1) and BH 3 ·THF (entry 4) gave the diols in high yields but with low diastereoselectivity, slightly favoring the cis -diastereoisomer 6 . In contrast, reduction with LiAlH 4 (entry 2) and, more pronounced, with [Al(H 2 )(OCH 2 CH 2 OMe) 2 ][Na] (Red-Al) favored the trans -diastereoisomer 7 . Fractional crystallization of the 13 : 87 mixture (entry 3) afforded pure 7 in 55% yield. The reason for the diastereoselectivity in this reaction may have its origin in the delivery of the second hydride from the same aluminium moiety ( ). Conversely, lithium tri- sec -butylborohydride (L-selectride) afforded a product enriched with cis -tetralin-1,4-diol ( 6 ) (entry 5). The high diastereoselectivity presumably is a consequence of the bulky reducing agent. Following the first reduction and formation of the 4-(boranyloxy)-1-tetralone, addition of a second equivalent of L-selectride would be expected to occur from the less hindered face. Hydrolysis then yields preferentially the cis -diastereoisomer 6 . The ca. 5 : 1 mixture of 6 and 7 could not be efficiently separated by flash chromatography but recrystallization from iPr 2 O gave cis -1,4-dihydroxytetralin ( 6 ) in 66% yield. Diols 6 and 7 have been reported previously. They were obtained by treatment of tetralin with NBS to give a 1 : 1 mixture of the corresponding cis and trans -dibromides, which were converted into diacetates with AgOAc (81% yield). Saponification and fractional recrystallization from MeOH / Et 2 O then afforded pure 6 and 7 though isolated yields were not reported . The meso -diol 6 has been used as substrate in enantioselective oxidation and in asymmetric acylation . We conclude that while conditions for an efficient highly diastereoselective one-step reduction of both carbonyl functions in 2 have not been realized, enrichment of one or the other diastereoisomer by choice of reducing agent is feasible and acceptable yields of pure diastereoisomers can be obtained.

<chunk>Enantioselective bis-reduction of 2</chunk> Asymmetric reduction of dione 2 was probed next. This was carried out successfully as shown in and gave, after two recrystallizations from diisopropylether, (−)-(1 R ,4 R )-tetralin-1,4-diol ( R , R - 7 ) in 72% yield and 99% ee . Only small amounts (ca. 7%) of the cis stereoisomer 6 were detected by 1 H NMR in the crude product. The synthesis of diol 7 in highly enantiomerically enriched form is thus easier than that of the racemate. The absolute configuration of (−)-(1 R ,4 R )- 7 agrees with the reliable stereochemical model for the CBS reduction. To our knowledge there is no viable published alternative synthetic access to this C 2 symmetric chiral diol. Compound (−)-(1 R ,4 R )- 7 was previously obtained by HPLC separation of a 1 : 1 mixture of the cis - and trans -diols obtained in 55% yield from a four step sequence from ( R )-1-tetralol .

<chunk>Mono-reduction of 2</chunk> Mono-reduction was achieved with a reduced amount of borane compared to the reduction detailed above. For the bis reduction, a molar ratio of 2 / BH 3 of 0.83 was used. Adjusting the ratio to 2.2 (see experimental part) afforded rac - 9 in good yield ( ). The high yield in mono-reduction is in accord with the expected higher reactivity of the dione 2 compared to the mono-ketone 9 .

<chunk>Enantioselective mono-reduction of 2</chunk> With an efficient protocol for the synthesis of rac - 9 and of R , R - 7 in hand, research then focused on the more challenging task of enantioselective mono-reduction. First, CBS reduction was performed by slow (1 h) addition of dione 2 to a solution of BH 3 ·THF (0.45 equiv) and catalyst 8 . However, background reduction by BH 3 ·THF was competitive under these conditions and while (−)-(4 R )-4-hydroxy-1-tetralone ( R - 9 ) could be isolated in 93% yield, its enantiomeric excess was a modest 53% ee. A way to achieve a high ee in mono-reduction was via 1-trimethylsiloxy-4-oxotetralin-1-carbonitrile ( 10 ) as protected equivalent of dione 2 . Slow addition over 2 h of a THF solution of ketone 10 to a solution of BH 3 ·THF (0.6 equiv) and catalyst 8 in THF at −30 °C gave, after MeOH quenching and TBAF deprotection, (−)- 9 in 85% yield and 95% ee ( ). Cyanohydrin silylether 10 partially hydrolyzes on silica and, as it turned out, isolation of this intermediate is not required and this provided a reliable and efficient sequence to highly enantiomerically enriched 9 ( ). In the course of this optimization, we also isolated cyanohydrin 11 . We note literature precedent for procedures for the asymmetric synthesis of 9 . The first involves as the key step kinetic resolution by enzymatic hydrolysis of the corresponding acetate with porcine pancreatic lipase giving (−)- 9 in 47% yield and 95% ee . A second approach uses a Pd-catalyzed asymmetric oxidation of meso -tetralin-1,4-diol ( 6 ) with (−)-sparteine (20 mol %) to give (+)- 9 in 72% yield and 95% ee . We note that chiral 1,4-disubstituted tetralins are of interest in medicinal chemistry. An example is the commercial antidepressant drug sertraline (Zoloft ®) . A number of natural products such as preussomerin A , catalponol , junglanoside A , and isoshinanolone contain the 4-hydroxy-1-tetralone unit. 4-Hydroxy-1-tetralone ( 9 ) itself is a naturally occurring compound isolated from Ampelocera edentula with activity against cutaneous leishmaniasis . The straightforward access to highly enantiomerically enriched 9 reported here will be useful.

Tautomerization of 1,4-dihydroxynaphthalene. Alternative routes of access to tetralin-1,4-dione. Proposed origin of diastereomeric preference in the reduction of 2 . Enantioselective reduction of 2 . Mono-reduction of 2 . Enantioselective mono-reduction of 2 .

Entry

Reducing agent a

Ratio b 6 : 7

Yield c

NaBH 4

58 : 42

98%

LiAlH 4

32 : 68

94%

Red-Al

13 : 87

76%

BH 3 ·THF

61 : 39

93%

L-Selectride

84 : 16

98%

a See for details. b 1 H NMR ratios in DMSO- d 6 . c Isolated mixture of 6 and 7 .

PCILLCXFKWDRMK-UHFFFAOYSA-N

InChI=1S/C10H8O2/c11-9-5-6-10(12)8-4-2-1-3-7(8)9/h1-6,11-12H C1=CC2=C(C=CC(=C2C=C1)O)O

C1=2C(C(=CC=C1O)O)=CC=CC2 |(43.33,-92.95,;43.25,-104.53,;53.23,-110.38,;63.22,-104.66,;63.3,-93.09,;53.31,-87.23,;53.23,-75.62,;53.15,-121.85,;33.39,-110.35,;23.4,-104.49,;23.5,-93.03,;33.44,-87.3,)|

AuxInfo=1/0/N:7,8,10,9,5,4,1,2,6,3,11,12/E:(1,2)(3,4)(5,6)(7,8)(9,10)(11,12)/rA:12nCCCCCCCCCCOO/rB:s1;s2;d3;s4;s1d5;;d7;d2s8;d1s7;s6;s3;/rC:43,3277,-92,9487,0;43,2478,-104,5253,0;53,2300,-110,3787,0;63,2191,-104,6633,0;63,2990,-93,0867,0;53,3098,-87,2254,0;23,4995,-93,0276,0;23,3978,-104,4901,0;33,3932,-110,3545,0;33,4381,-87,3026,0;53,2277,-75,6236,0;53,1479,-121,8504,0;

C10H8O2

CDK 04282612362D 0 0 0 0 0 999 V3000 M V30 BEGIN CTAB M V30 COUNTS 12 13 0 0 0 M V30 BEGIN ATOM M V30 1 C 43.32768 -92.9487 0 0 M V30 2 C 43.24783 -104.52534 0 0 M V30 3 C 53.22997 -110.37866 0 0 M V30 4 C 63.21915 -104.6633 0 0 M V30 5 C 63.29898 -93.08665 0 0 M V30 6 C 53.3098 -87.22539 0 0 M V30 7 C 23.49953 -93.02765 0 0 M V30 8 C 23.39784 -104.49007 0 0 M V30 9 C 33.39323 -110.35451 0 0 M V30 10 C 33.43814 -87.30258 0 0 M V30 11 O 53.22769 -75.62364 0 0 M V30 12 O 53.14787 -121.85039 0 0 M V30 END ATOM M V30 BEGIN BOND M V30 1 1 1 2 M V30 2 1 1 6 M V30 3 1 2 3 M V30 4 2 3 4 M V30 5 1 4 5 M V30 6 2 5 6 M V30 7 2 7 8 M V30 8 1 8 9 M V30 9 2 9 2 M V30 10 2 1 10 M V30 11 1 10 7 M V30 12 1 6 11 M V30 13 1 3 12 M V30 END BOND M V30 END CTAB M END

ZWGGJMFMHQHTFR-UHFFFAOYSA-N

InChI=1S/C10H8O2/c11-9-5-6-10(12)8-4-2-1-3-7(8)9/h1-4H,5-6H2 C1=CC2=C(C=C1)C(=O)CCC2=O

C1=2C(C(CCC1=O)=O)=CC=CC2 |(145.39,-93.29,;145.31,-104.87,;155.3,-110.72,;165.29,-105.01,;165.37,-93.43,;155.38,-87.57,;155.29,-75.97,;155.21,-122.19,;135.46,-110.7,;125.46,-104.83,;125.57,-93.37,;135.5,-87.64,)|

AuxInfo=1/0/N:7,8,10,9,5,4,1,2,6,3,11,12/E:(1,2)(3,4)(5,6)(7,8)(9,10)(11,12)/rA:12nCCCCCCCCCCOO/rB:s1;s2;s3;s4;s1s5;;d7;d2s8;d1s7;d6;d3;/rC:145,3940,-93,2910,0;145,3141,-104,8677,0;155,2962,-110,7210,0;165,2854,-105,0056,0;165,3653,-93,4290,0;155,3761,-87,5677,0;125,5658,-93,3700,0;125,4641,-104,8324,0;135,4595,-110,6969,0;135,5044,-87,6449,0;155,2940,-75,9660,0;155,2142,-122,1927,0;

C10H8O2

CDK 04282612362D 0 0 0 0 0 999 V3000 M V30 BEGIN CTAB M V30 COUNTS 12 13 0 0 0 M V30 BEGIN ATOM M V30 1 C 145.39397 -93.29103 0 0 M V30 2 C 145.31412 -104.86766 0 0 M V30 3 C 155.29625 -110.72099 0 0 M V30 4 C 165.28543 -105.00563 0 0 M V30 5 C 165.36526 -93.42899 0 0 M V30 6 C 155.37608 -87.5677 0 0 M V30 7 C 125.56581 -93.37 0 0 M V30 8 C 125.46413 -104.83238 0 0 M V30 9 C 135.45952 -110.69685 0 0 M V30 10 C 135.50443 -87.64493 0 0 M V30 11 O 155.29399 -75.96599 0 0 M V30 12 O 155.21416 -122.19272 0 0 M V30 END ATOM M V30 BEGIN BOND M V30 1 1 1 2 M V30 2 1 1 6 M V30 3 1 2 3 M V30 4 1 3 4 M V30 5 1 5 6 M V30 6 2 7 8 M V30 7 1 8 9 M V30 8 2 9 2 M V30 9 2 1 10 M V30 10 1 10 7 M V30 11 2 6 11 M V30 12 2 3 12 M V30 13 1 5 4 M V30 END BOND M V30 END CTAB M END

FRASJONUBLZVQX-UHFFFAOYSA-N

InChI=1S/C10H6O2/c11-9-5-6-10(12)8-4-2-1-3-7(8)9/h1-6H C1=CC2=C(C=C1)C(=O)C=CC2=O

C1=2C(C(C=CC1=O)=O)=CC=CC2 |(22.19,-54.62,;22.11,-66.19,;32.09,-72.05,;42.08,-66.33,;42.16,-54.75,;32.17,-48.89,;32.09,-37.29,;32.01,-83.52,;12.25,-72.02,;2.26,-66.16,;2.36,-54.69,;12.3,-48.97,)|

AuxInfo=1/0/N:7,8,10,9,5,4,1,2,6,3,11,12/E:(1,2)(3,4)(5,6)(7,8)(9,10)(11,12)/rA:12nCCCCCCCCCCOO/rB:s1;s2;s3;d4;s1s5;;d7;d2s8;d1s7;d6;d3;/rC:22,1862,-54,6159,0;22,1064,-66,1926,0;32,0885,-72,0459,0;42,0777,-66,3305,0;42,1575,-54,7539,0;32,1684,-48,8926,0;2,3581,-54,6949,0;2,2564,-66,1573,0;12,2518,-72,0217,0;12,2967,-48,9698,0;32,0863,-37,2909,0;32,0064,-83,5176,0;

C10H6O2

CDK 04282612362D 0 0 0 0 0 999 V3000 M V30 BEGIN CTAB M V30 COUNTS 12 13 0 0 0 M V30 BEGIN ATOM M V30 1 C 22.18625 -54.61592 0 0 M V30 2 C 22.1064 -66.19255 0 0 M V30 3 C 32.08853 -72.04588 0 0 M V30 4 C 42.07771 -66.33052 0 0 M V30 5 C 42.15755 -54.75388 0 0 M V30 6 C 32.16837 -48.89259 0 0 M V30 7 C 2.35809 -54.69489 0 0 M V30 8 C 2.25641 -66.15727 0 0 M V30 9 C 12.2518 -72.02174 0 0 M V30 10 C 12.29671 -48.96982 0 0 M V30 11 O 32.08627 -37.29088 0 0 M V30 12 O 32.00644 -83.51761 0 0 M V30 END ATOM M V30 BEGIN BOND M V30 1 1 1 2 M V30 2 1 1 6 M V30 3 1 2 3 M V30 4 1 3 4 M V30 5 1 5 6 M V30 6 2 7 8 M V30 7 1 8 9 M V30 8 2 9 2 M V30 9 2 1 10 M V30 10 1 10 7 M V30 11 2 6 11 M V30 12 2 3 12 M V30 13 2 5 4 M V30 END BOND M V30 END CTAB M END

XHLHPRDBBAGVEG-UHFFFAOYSA-N

InChI=1S/C10H10O/c11-10-7-3-5-8-4-1-2-6-9(8)10/h1-2,4,6H,3,5,7H2 C1=CC2=C(C=C1)C(=O)CCC2

C1=2C(CCCC1=O)=CC=CC2 |(109.94,-22.03,;109.86,-33.6,;119.84,-39.46,;129.83,-33.74,;129.91,-22.16,;119.92,-16.3,;119.84,-4.7,;100,-39.43,;90.01,-33.57,;90.11,-22.1,;100.05,-16.38,)|

AuxInfo=1/0/N:8,7,4,9,3,10,5,2,1,6,11/rA:11nCCCCCCCCCCO/rB:s1;s2;s3;s4;s1s5;;d7;d2s8;d1s7;d6;/rC:109,9362,-22,0250,0;109,8564,-33,6017,0;119,8385,-39,4550,0;129,8277,-33,7396,0;129,9075,-22,1630,0;119,9184,-16,3017,0;90,1081,-22,1040,0;90,0064,-33,5664,0;100,0018,-39,4309,0;100,0467,-16,3789,0;119,8363,-4,7000,0;

C10H10O

CDK 04282612362D 0 0 0 0 0 999 V3000 M V30 BEGIN CTAB M V30 COUNTS 11 12 0 0 0 M V30 BEGIN ATOM M V30 1 C 109.93625 -22.02504 0 0 M V30 2 C 109.8564 -33.60167 0 0 M V30 3 C 119.83853 -39.455 0 0 M V30 4 C 129.82771 -33.73964 0 0 M V30 5 C 129.90755 -22.16299 0 0 M V30 6 C 119.91837 -16.30171 0 0 M V30 7 C 90.10809 -22.104 0 0 M V30 8 C 90.00641 -33.56639 0 0 M V30 9 C 100.0018 -39.43086 0 0 M V30 10 C 100.04671 -16.37894 0 0 M V30 11 O 119.83627 -4.7 0 0 M V30 END ATOM M V30 BEGIN BOND M V30 1 1 1 2 M V30 2 1 1 6 M V30 3 1 2 3 M V30 4 1 3 4 M V30 5 1 5 6 M V30 6 2 7 8 M V30 7 1 8 9 M V30 8 2 9 2 M V30 9 2 1 10 M V30 10 1 10 7 M V30 11 2 6 11 M V30 12 1 5 4 M V30 END BOND M V30 END CTAB M END

FTCMTZXWNUAYHT-AOOOYVTPSA-N

InChI=1S/C10H12O2/c11-9-5-6-10(12)8-4-2-1-3-7(8)9/h1-4,9-12H,5-6H2/t9-,10+ C1=CC2=C(C=C1)[C@@H](CC[C@@H]2O)O

C1C[C@@H](C2=C(C=CC=C2)[C@@H]1O)O |(350.95,-369.37,;351.03,-357.84,;341.11,-352.01,;331.18,-357.84,;331.1,-369.28,;321.09,-374.9,;311.3,-369.15,;311.38,-357.7,;321.25,-352.02,;340.95,-375.03,;340.95,-386.39,;341.03,-340.46,)|

AuxInfo=1/0/N:3,4,8,5,2,1,7,6,9,11,12,10/E:(1,2)(3,4)(5,6)(7,8)(9,10)(11,12)/rA:12nCCCCCCCCC.oOC.eO/rB:s1;;s3;d4;s5;d6;d3s7;s2s7;;s1s6p10;P9;/rC:350,9494,-369,3654,0;351,0300,-357,8433,0;311,3760,-357,7040,0;311,2954,-369,1455,0;321,0869,-374,9036,0;331,1031,-369,2848,0;331,1837,-357,8433,0;321,2480,-352,0206,0;341,1100,-352,0086,0;340,9466,-386,3883,0;340,9466,-375,0274,0;341,0272,-340,4612,0;

C10H12O2

CDK 04282612362D 0 0 0 0 0 999 V3000 M V30 BEGIN CTAB M V30 COUNTS 12 13 0 0 1 M V30 BEGIN ATOM M V30 1 C 350.9494 -369.36536 0 0 M V30 2 C 351.03 -357.84326 0 0 M V30 3 C 311.37598 -357.70404 0 0 M V30 4 C 311.29541 -369.14554 0 0 M V30 5 C 321.08685 -374.90363 0 0 M V30 6 C 331.10312 -369.28479 0 0 M V30 7 C 331.18372 -357.84326 0 0 M V30 8 C 321.24799 -352.02063 0 0 M V30 9 C 341.11002 -352.00864 0 0 CFG=2 M V30 10 O 340.94659 -386.38834 0 0 M V30 11 C 340.94659 -375.0274 0 0 CFG=1 M V30 12 O 341.02716 -340.46124 0 0 M V30 END ATOM M V30 BEGIN BOND M V30 1 1 2 1 M V30 2 1 3 4 M V30 3 2 3 8 M V30 4 2 4 5 M V30 5 1 5 6 M V30 6 2 6 7 M V30 7 1 7 8 M V30 8 1 7 9 M V30 9 1 6 11 M V30 10 1 11 10 CFG=1 M V30 11 1 2 9 M V30 12 1 1 11 M V30 13 1 9 12 CFG=1 M V30 END BOND M V30 END CTAB M END

FTCMTZXWNUAYHT-NXEZZACHSA-N

InChI=1S/C10H12O2/c11-9-5-6-10(12)8-4-2-1-3-7(8)9/h1-4,9-12H,5-6H2/t9-,10-/m1/s1 C1=CC2=C(C=C1)[C@@H](CC[C@H]2O)O

C1C[C@H](C2=C(C=CC=C2)[C@@H]1O)O |(347.56,-258.38,;347.64,-246.86,;337.72,-241.03,;327.8,-246.86,;327.72,-258.3,;317.7,-263.92,;307.91,-258.16,;307.99,-246.72,;317.86,-241.04,;337.56,-264.05,;337.56,-275.41,;337.64,-229.48,)|

AuxInfo=1/0/N:3,4,8,5,2,1,7,6,9,11,12,10/E:(1,2)(3,4)(5,6)(7,8)(9,10)(11,12)/it:im/rA:12nCCCCCCCCC.eOC.eO/rB:s1;;s3;d4;s5;d6;d3s7;s2s7;;s1s6p10;N9;/rC:347,5635,-258,3835,0;347,6441,-246,8615,0;307,9901,-246,7222,0;307,9095,-258,1637,0;317,7010,-263,9218,0;327,7172,-258,3029,0;327,7978,-246,8615,0;317,8621,-241,0388,0;337,7241,-241,0268,0;337,5607,-275,4066,0;337,5607,-264,0456,0;337,6413,-229,4794,0;

C10H12O2

CDK 04282612362D 0 0 0 0 0 999 V3000 M V30 BEGIN CTAB M V30 COUNTS 12 13 0 0 1 M V30 BEGIN ATOM M V30 1 C 347.56354 -258.38354 0 0 M V30 2 C 347.6441 -246.86147 0 0 M V30 3 C 307.99008 -246.72223 0 0 M V30 4 C 307.90952 -258.1637 0 0 M V30 5 C 317.70099 -263.92181 0 0 M V30 6 C 327.71722 -258.30295 0 0 M V30 7 C 327.79782 -246.86147 0 0 M V30 8 C 317.86212 -241.03882 0 0 M V30 9 C 337.72412 -241.02681 0 0 CFG=1 M V30 10 O 337.56073 -275.40656 0 0 M V30 11 C 337.56073 -264.04559 0 0 CFG=1 M V30 12 O 337.6413 -229.47942 0 0 M V30 END ATOM M V30 BEGIN BOND M V30 1 1 2 1 M V30 2 1 3 4 M V30 3 2 3 8 M V30 4 2 4 5 M V30 5 1 5 6 M V30 6 2 6 7 M V30 7 1 7 8 M V30 8 1 7 9 M V30 9 1 6 11 M V30 10 1 11 10 CFG=1 M V30 11 1 2 9 M V30 12 1 1 11 M V30 13 1 9 12 CFG=3 M V30 END BOND M V30 END CTAB M END

VMKAFJQFKBASMU-KRWDZBQOSA-N

InChI=1S/C18H20BNO/c1-19-20-14-8-13-17(20)18(21-19,15-9-4-2-5-10-15)16-11-6-3-7-12-16/h2-7,9-12,17H,8,13-14H2,1H3/t17-/m0/s1 CB1N2CCC[C@@]2([H])[C@@](C3=CC=CC=C3)(C4=CC=CC=C4)O1

C1CCN2[C@@]1([C@@](OB2C)(C3=CC=CC=C3)C4=CC=CC=C4)[H] |(80.08,-33.19,;76.39,-44.09,;85.62,-50.96,;95.01,-44.31,;91.58,-33.33,;100.97,-26.67,;110.2,-33.55,;106.52,-44.45,;112.19,-55.93,;96.57,-17.77,;111.56,4.72,;99.75,30.48,;71.59,33.15,;55.15,10.05,;66.95,-15.64,;104.89,-15.1,;132.86,-9.5,;141.27,17.56,;122.08,38.35,;94.42,32.12,;86.05,5.12,;87.55,-25.17,)|

AuxInfo=1/0/N:9,14,20,13,15,19,21,2,12,16,18,22,1,3,11,17,5,8,6,4,7/E:(2,3)(4,5,6,7)(9,10,11,12)(15,16)/it:im/rA:22nCCCNC.oBOC.eCHCCCCCCCCCCCC/rB:s1;s2;s3;s1s4;s4;s6;s5s7;s6;N5;N8;d11;s12;d13;s14;s11d15;P8;d17;s18;d19;s20;s17d21;/rC:80,0760,-33,1874,0;76,3890,-44,0895,0;85,6181,-50,9650,0;95,0090,-44,3122,0;91,5838,-33,3251,0;106,5169,-44,4498,0;110,2039,-33,5478,0;100,9748,-26,6723,0;112,1941,-55,9295,0;87,5516,-25,1716,0;96,5703,-17,7663,0;111,5566,4,7173,0;99,7535,30,4779,0;71,5872,33,1487,0;55,1544,10,0471,0;66,9457,-15,6438,0;104,8885,-15,1000,0;132,8583,-9,5036,0;141,2666,17,5561,0;122,0778,38,3470,0;94,4210,32,1161,0;86,0505,5,1162,0;

C18H20BNO

C1=CC=C(C=C1)* Ph CDK 04282612362D 0 0 0 0 0 999 V3000 M V30 BEGIN CTAB M V30 COUNTS 22 25 0 0 1 M V30 BEGIN ATOM M V30 1 C 80.07602 -33.18741 0 0 M V30 2 C 76.38899 -44.08948 0 0 M V30 3 C 85.61812 -50.96497 0 0 M V30 4 N 95.00905 -44.31219 0 0 M V30 5 C 91.58385 -33.32506 0 0 CFG=1 M V30 6 B 106.51688 -44.44984 0 0 M V30 7 O 110.2039 -33.54778 0 0 M V30 8 C 100.97478 -26.67229 0 0 CFG=2 M V30 9 C 112.19414 -55.92947 0 0 M V30 10 C 96.5703 -17.76625 0 0 M V30 11 C 111.55664 4.71729 0 0 M V30 12 C 99.75348 30.47794 0 0 M V30 13 C 71.5872 33.14874 0 0 M V30 14 C 55.15436 10.04713 0 0 M V30 15 C 66.94574 -15.64375 0 0 M V30 16 C 104.88847 -15.09999 0 0 M V30 17 C 132.85828 -9.50362 0 0 M V30 18 C 141.26656 17.55606 0 0 M V30 19 C 122.0778 38.34703 0 0 M V30 20 C 94.42101 32.1161 0 0 M V30 21 C 86.05052 5.1162 0 0 M V30 22 H 87.55156 -25.17162 0 0 M V30 END ATOM M V30 BEGIN BOND M V30 1 1 1 2 M V30 2 1 2 3 M V30 3 1 3 4 M V30 4 1 4 5 M V30 5 1 5 1 M V30 6 1 4 6 M V30 7 1 6 7 M V30 8 1 7 8 M V30 9 1 8 5 M V30 10 1 6 9 M V30 11 1 5 22 CFG=3 M V30 12 2 10 11 M V30 13 1 11 12 M V30 14 2 12 13 M V30 15 1 13 14 M V30 16 2 14 15 M V30 17 1 10 15 M V30 18 1 8 10 CFG=3 M V30 19 2 16 17 M V30 20 1 17 18 M V30 21 2 18 19 M V30 22 1 19 20 M V30 23 2 20 21 M V30 24 1 16 21 M V30 25 1 8 16 CFG=1 M V30 END BOND M V30 END CTAB M END

BGPJTIXJFAGUIF-UHFFFAOYSA-N

InChI=1S/C10H10O2/c11-9-5-6-10(12)8-4-2-1-3-7(8)9/h1-4,9,11H,5-6H2 C1=CC2=C(C=C1)C(=O)CCC2O

C1=2C(C(CCC1O)=O)=CC=CC2 |(322.78,-237.7,;322.7,-249.27,;332.68,-255.13,;342.67,-249.41,;342.75,-237.83,;332.76,-231.97,;332.68,-220.37,;332.6,-266.6,;312.84,-255.1,;302.85,-249.24,;302.95,-237.78,;312.89,-232.05,)|

AuxInfo=1/0/N:7,8,10,9,5,4,1,2,6,3,11,12/rA:12nCCCCCCCCCCOO/rB:s1;s2;s3;s4;s1s5;;d7;d2s8;d1s7;s6;d3;/rC:322,7763,-237,6960,0;322,6965,-249,2727,0;332,6786,-255,1260,0;342,6678,-249,4106,0;342,7476,-237,8340,0;332,7585,-231,9727,0;302,9482,-237,7750,0;302,8465,-249,2374,0;312,8419,-255,1019,0;312,8868,-232,0499,0;332,6764,-220,3710,0;332,5965,-266,5977,0;

C10H10O2

CDK 04282612362D 0 0 0 0 0 999 V3000 M V30 BEGIN CTAB M V30 COUNTS 12 13 0 0 0 M V30 BEGIN ATOM M V30 1 C 322.77634 -237.69604 0 0 M V30 2 C 322.69647 -249.27267 0 0 M V30 3 C 332.67862 -255.12601 0 0 M V30 4 C 342.66779 -249.41064 0 0 M V30 5 C 342.74762 -237.834 0 0 M V30 6 C 332.75845 -231.97272 0 0 M V30 7 C 302.94818 -237.77501 0 0 M V30 8 C 302.8465 -249.2374 0 0 M V30 9 C 312.84189 -255.10187 0 0 M V30 10 C 312.88678 -232.04994 0 0 M V30 11 O 332.67636 -220.371 0 0 M V30 12 O 332.59653 -266.59772 0 0 M V30 END ATOM M V30 BEGIN BOND M V30 1 1 1 2 M V30 2 1 1 6 M V30 3 1 2 3 M V30 4 1 3 4 M V30 5 1 5 6 M V30 6 2 7 8 M V30 7 1 8 9 M V30 8 2 9 2 M V30 9 2 1 10 M V30 10 1 10 7 M V30 11 1 6 11 M V30 12 2 3 12 M V30 13 1 5 4 M V30 END BOND M V30 END CTAB M END

BEIIGAWJWLEZJP-UHFFFAOYSA-N

InChI=1S/C14H17NO2Si/c1-18(2,3)17-14(10-15)9-8-13(16)11-6-4-5-7-12(11)14/h4-7H,8-9H2,1-3H3 C[Si](C)(C)OC1(CCC(=O)C2=C1C=CC=C2)C#N

C1=2C(C(CCC1(O[Si](C)(C)C)C#N)=O)=CC=CC2 |(176.97,-95.59,;176.89,-107.16,;186.87,-113.02,;196.86,-107.3,;196.94,-95.73,;186.95,-89.86,;180.86,-79.31,;186.61,-69.35,;198.11,-69.35,;180.86,-59.39,;192.36,-59.39,;193.34,-78.79,;199.09,-68.83,;186.79,-124.49,;167.03,-112.99,;157.04,-107.13,;157.14,-95.67,;167.08,-89.94,)|

AuxInfo=1/0/N:12,13,14,8,7,9,10,4,5,17,2,1,3,6,18,16,15,11/E:(1,2,3)/rA:18nCCCCCCCCCCSiCCCOOCN/rB:s1;s2;s3;s4;s1s5;;d7;d2s8;d1s7;;s11;s11;s11;s6s11;d3;s6;t17;/rC:176,9668,-95,5882,0;176,8870,-107,1649,0;186,8691,-113,0182,0;196,8583,-107,3028,0;196,9381,-95,7262,0;186,9489,-89,8649,0;157,1387,-95,6672,0;157,0370,-107,1296,0;167,0324,-112,9940,0;167,0773,-89,9421,0;186,6056,-69,3517,0;198,1056,-69,3517,0;180,8556,-59,3924,0;192,3556,-59,3924,0;180,8556,-79,3110,0;186,7870,-124,4899,0;193,3406,-78,7942,0;199,0906,-68,8349,0;

C14H17NO2Si

C[Si](C)(C)O* TMSO,C(#N)* CN CDK 04282612362D 0 0 0 0 0 999 V3000 M V30 BEGIN CTAB M V30 COUNTS 18 19 0 0 0 M V30 BEGIN ATOM M V30 1 C 176.96681 -95.58823 0 0 M V30 2 C 176.88696 -107.16486 0 0 M V30 3 C 186.86909 -113.01819 0 0 M V30 4 C 196.85828 -107.30283 0 0 M V30 5 C 196.93811 -95.72618 0 0 M V30 6 C 186.94893 -89.8649 0 0 M V30 7 C 157.13866 -95.66719 0 0 M V30 8 C 157.03697 -107.12958 0 0 M V30 9 C 167.03236 -112.99405 0 0 M V30 10 C 167.07727 -89.94212 0 0 M V30 11 Si 186.60564 -69.3517 0 0 M V30 12 C 198.10564 -69.3517 0 0 M V30 13 C 180.85564 -59.3924 0 0 M V30 14 C 192.35564 -59.39241 0 0 M V30 15 O 180.85564 -79.31099 0 0 M V30 16 O 186.787 -124.48991 0 0 M V30 17 C 193.34058 -78.79424 0 0 M V30 18 N 199.09058 -68.83495 0 0 M V30 END ATOM M V30 BEGIN BOND M V30 1 1 1 2 M V30 2 1 1 6 M V30 3 1 2 3 M V30 4 1 3 4 M V30 5 1 5 6 M V30 6 2 7 8 M V30 7 1 8 9 M V30 8 2 9 2 M V30 9 2 1 10 M V30 10 1 10 7 M V30 11 1 11 12 M V30 12 1 11 13 M V30 13 1 11 14 M V30 14 1 11 15 M V30 15 1 6 15 M V30 16 2 3 16 M V30 17 1 5 4 M V30 18 3 17 18 M V30 19 1 6 17 M V30 END BOND M V30 END CTAB M END

BGPJTIXJFAGUIF-SECBINFHSA-N

InChI=1S/C10H10O2/c11-9-5-6-10(12)8-4-2-1-3-7(8)9/h1-4,9,11H,5-6H2/t9-/m1/s1 C1=CC2=C(C=C1)C(=O)CC[C@H]2O

C1=2C(C(CC[C@H]1O)=O)=CC=CC2 |(375.66,-95.95,;375.58,-107.52,;385.57,-113.38,;395.55,-107.66,;395.63,-96.08,;385.65,-90.22,;385.56,-78.62,;385.48,-124.85,;365.73,-113.35,;355.73,-107.49,;355.83,-96.03,;365.77,-90.3,)|

AuxInfo=1/0/N:7,8,10,9,5,4,1,2,6,3,11,12/it:im/rA:12nCCCCCC.oCCCCOO/rB:s1;s2;s3;s4;s1s5;;d7;d2s8;d1s7;N6;d3;/rC:375,6631,-95,9460,0;375,5833,-107,5227,0;385,5654,-113,3760,0;395,5546,-107,6606,0;395,6344,-96,0840,0;385,6452,-90,2227,0;355,8350,-96,0250,0;355,7333,-107,4874,0;365,7287,-113,3519,0;365,7736,-90,2999,0;385,5631,-78,6210,0;385,4833,-124,8477,0;

C10H10O2

CDK 04282612362D 0 0 0 0 0 999 V3000 M V30 BEGIN CTAB M V30 COUNTS 12 13 0 0 1 M V30 BEGIN ATOM M V30 1 C 375.66312 -95.94604 0 0 M V30 2 C 375.58325 -107.52267 0 0 M V30 3 C 385.5654 -113.37601 0 0 M V30 4 C 395.55457 -107.66064 0 0 M V30 5 C 395.6344 -96.084 0 0 M V30 6 C 385.64523 -90.22272 0 0 CFG=2 M V30 7 C 355.83496 -96.02501 0 0 M V30 8 C 355.73328 -107.4874 0 0 M V30 9 C 365.72867 -113.35187 0 0 M V30 10 C 365.77356 -90.29994 0 0 M V30 11 O 385.56314 -78.621 0 0 M V30 12 O 385.48331 -124.84773 0 0 M V30 END ATOM M V30 BEGIN BOND M V30 1 1 1 2 M V30 2 1 1 6 M V30 3 1 2 3 M V30 4 1 3 4 M V30 5 1 5 6 M V30 6 2 7 8 M V30 7 1 8 9 M V30 8 2 9 2 M V30 9 2 1 10 M V30 10 1 10 7 M V30 11 1 6 11 CFG=3 M V30 12 2 3 12 M V30 13 1 5 4 M V30 END BOND M V30 END CTAB M END

NTHQTPMQTBDQGH-UHFFFAOYSA-N

InChI=1S/C11H9NO2/c12-7-11(14)6-5-10(13)8-3-1-2-4-9(8)11/h1-4,14H,5-6H2 C1=CC2=C(C=C1)C(CCC2=O)(C#N)O

C1=2C(C(CCC1(O)C#N)=O)=CC=CC2 |(192.41,-207.16,;192.33,-218.74,;202.31,-224.59,;212.3,-218.88,;212.38,-207.3,;202.39,-201.44,;196.3,-190.89,;208.79,-190.37,;214.54,-180.41,;202.23,-236.07,;182.48,-224.57,;172.48,-218.71,;172.58,-207.24,;182.52,-201.52,)|

AuxInfo=1/0/N:8,7,9,10,4,5,13,2,1,3,6,14,12,11/rA:14nCCCCCCCCCCOOCN/rB:s1;s2;s3;s4;s1s5;;d7;d2s8;d1s7;s6;d3;s6;t13;/rC:192,4115,-207,1644,0;192,3316,-218,7410,0;202,3138,-224,5943,0;212,3030,-218,8790,0;212,3828,-207,3023,0;202,3936,-201,4410,0;172,5833,-207,2433,0;172,4817,-218,7057,0;182,4771,-224,5702,0;182,5220,-201,5183,0;196,3003,-190,8871,0;202,2317,-236,0661,0;208,7853,-190,3704,0;214,5353,-180,4111,0;

C11H9NO2

C(#N)* CN CDK 04282612362D 0 0 0 0 0 999 V3000 M V30 BEGIN CTAB M V30 COUNTS 14 15 0 0 0 M V30 BEGIN ATOM M V30 1 C 192.4115 -207.16437 0 0 M V30 2 C 192.33165 -218.741 0 0 M V30 3 C 202.31378 -224.59433 0 0 M V30 4 C 212.30296 -218.87897 0 0 M V30 5 C 212.3828 -207.30232 0 0 M V30 6 C 202.39362 -201.44104 0 0 M V30 7 C 172.58334 -207.24333 0 0 M V30 8 C 172.48166 -218.70572 0 0 M V30 9 C 182.47705 -224.57019 0 0 M V30 10 C 182.52196 -201.51826 0 0 M V30 11 O 196.30032 -190.88713 0 0 M V30 12 O 202.23169 -236.06606 0 0 M V30 13 C 208.78526 -190.37038 0 0 M V30 14 N 214.53526 -180.41109 0 0 M V30 END ATOM M V30 BEGIN BOND M V30 1 1 1 2 M V30 2 1 1 6 M V30 3 1 2 3 M V30 4 1 3 4 M V30 5 1 5 6 M V30 6 2 7 8 M V30 7 1 8 9 M V30 8 2 9 2 M V30 9 2 1 10 M V30 10 1 10 7 M V30 11 1 6 11 M V30 12 2 3 12 M V30 13 1 5 4 M V30 14 3 13 14 M V30 15 1 6 13 M V30 END BOND M V30 END CTAB M END

Experimental procedures, full spectroscopic and analytical data of compounds 2 , 6 , 7 , 9 – 11 .

<chunk>Acknowledgements</chunk> Support of this work by the Swiss National Science Foundation (Project 200020_119947/1) is gratefully acknowledged.

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