From cycloolefins to chiral, polyfunctionalized linear C6/C12 building blocks - Biocatalysis, (-)-conduramine E

Article abstract of DOI:10.1016/S0040-4039(00)01395-2

1,4-Cyclohexadiene is the starting material for the expeditious synthesis of the 1S2S3S4R- and 1R2R3R4S-epoxy-cyclohexene-1,4-diol monoacetates through enzyme-catalyzed hydrolysis and transesterification, respectively. The absolute configurations are established by correlation of (-)-10 and known (+)-conduramine E. Ozonation and functional group manipulation open access to fully protected, polyfunctionalized C₆-aldehydes whose reductive coupling to C₂-symmetrical C₁₂ building blocks is being explored. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01395-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7863–7867
From cycloolefins to chiral, polyfunctionalized linear C6/C12
building blocks—biocatalysis, (−)-conduramine E
Dirk Spielvogel, Ju¨rgen Kammerer, Manfred Keller and Horst Prinzbach*
Institut fu¨r Organische Chemie und Biochemie, Universita¨t Freiburg, Albertstraße 21,
D-79104 Freiburg i. Br., Germany
Received 3 August 2000; accepted 12 August 2000
Abstract
1,4-Cyclohexadiene is the starting material for the expeditious synthesis of the 1S2S3S4R- and
1R2R3R4S-epoxy-cyclohexene-1,4-diol monoacetates through enzyme-catalyzed hydrolysis and trans-
esterification, respectively. The absolute configurations are established by correlation of (−)-10 and known
(+)-conduramine E. Ozonation and functional group manipulation open access to fully protected,
polyfunctionalized C6-aldehydes whose reductive coupling to C2-symmetrical C12 building blocks is being
explored. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: biocatalysis; conduramines; reductive dimerization.
As part of our long standing program—utilisation of bulk chemicals for the synthesis of
chiral, polyfunctionalized, cyclic and linear, C6/C8/C12 building blocks (trisanhydro-inositols,1
inosadiamines,2 diaminopolyols,3,4 linear triepoxides,5 linear 1,4-diamino-2,3-diols,6 oxepanes,
azepanes4)—the construction of optically pure, polyfunctionalized C6/C12 structures of type A
and B from 1,4-cyclohexadiene has been explored.7
In earlier studies expeditious protocols for the large-scale preparation of the meso-configu-
rated diacetoxy-epoxy-cyclohexenes 1 and 4, and the respective diols 2 and 5 starting from
1,4-cyclohexadiene have been worked out.1 In a screening process8 with 1, the commercial
enzymes PLE (3 h, ee>95, 92%), PPL (ee=93, 89%)9 and SP 523 (ee=94, 80–90%)10 provided
the same monoacetate (+)-3 (1S2S3S4R) with preparatively useful selectivity, yields and
* Corresponding author. Fax: +0049-(0)761-203 6051; e-mail: horst.prinzbach@orgmail.chemie.uni-freiburg.de
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01395-2

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reaction rates (5 h, 0.1 molar scale).11 For the esterification of diol 2 with vinylacetate PPL and
Lipozyme IM delivered (−)-3 (1R2R3R4S) with comparably good results (ee]99, 60%, ee 96,
92%, 0.5 mmolar scale). With the anti-diacetate 4, as well as the diol 5 under the same set of
conditions the results were, however, not satisfactory: with AL AY30 and 4 monoacetate (+)-6
was generated in high yield but only low enantioselectivity (ee=60, 90%); a complication with
4 was its hydrolysis in the reaction medium to give with anchimeric assistance conduritol F –
diacetate (90%) fully characterized as tetraacetate rac-7.12 Exemplary for the generally unaccept-
ably slow transesterifications of 5 is the outcome with AL AY30 (13 days, ee=63, 35%). The
absolute configuration of the monoesters (+)-3 and (−)-3 was ultimately established through
correlation with (+)-conduramine E (see Scheme 1).
Scheme 1. (i) n-Hexane, 0.2N pH 7 phosphate buffer, SP 523 (4% w/w), room temp. (ii) TBME – vinylacetate,
Lipozym IM (5% w/w), room temp. (iii) n-Hexane, pH 7 phosphate buffer, AL AY30 (10% w/w), 5 h, room temp.
(iv) TBME – vinylacetate, AL AY30 (10% w/w), room temp. (v) pH 7 phosphate buffer, 3 days, room temp., then
Ac2O, Et3N, DMAP, 70%
The installation of the amino-function as defined in A was pursued through substitution of the
OH-group in hydroxy-acetate 3. To avoid the complications encountered in the mesylation
(tosylation), Mitsunobu conditions were applied.13 With the four O- and N-nucleophiles shown,
the products 8a–d were isolated in good to high yields; the loss of material is in part ascribed
to the competitive substitution by hydrogenated DEAD.13 Specifically allylic azide 8b equili-
brated with its Cope isomer (1.2:1) after heating in CDCl3 for 9 h at 60°C. For the preparation
of 9b as starting material for the sequence shown in Scheme 3, 8d was quantitatively transformed
into 8e. Standard conditions neatly effected the endo-cyclisation to give urethane 9a.14 Mild
hydrolytic conditions transformed 9a into the so far unreported (−)-conduramine (−)-10
([h]D25=−225.8°, c=1.5, MeOH; (+)-conduramine E [h]2D5=+239.7°, c=1.7, MeOH15) (Scheme 2).
Scheme 2. (i) Nucleophile (HO2CPh, (PhO)2PON3, HNZTos, HNZ2), PPh3, DEAD, THF, room temp., 80–92%. (ii)
NH3ꢀMeOH, room temp., quant. (iii) AcOH, H2O, 110°C, 92%. (iv) TBS–Cl, imidazole, DMF, room temp. 80%. (v)
Ba(OH)2, 50°C, 86%

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With aldehyde 17 as target, a monomer unit of type A with all other positions being protected
for the reductive dimerization into B, bis-TBS-protected 9b was exposed to ozone until total
1
conversion (bluish colour). TLC and H NMR control confirmed the nearly quantitative
generation of a circa 3:1 mixture of 1,2-dioxocane 11 and linear hydroperoxy-aldehyde 12 (both
circa 1:1 mixture of epimers)—besides traces of unknown structure. After standard work-up
(NaBH4, 2.5 molar equiv.) a 1:1 mixture of non-crystalline solids was isolated and separated for
chromatographic characterization: the structures as 13 (36%, epimers) and oxepane 14 (44%)
made it clear that the latter had originated from 13 after reduction and loss of methanol-13
upon treatment with triethylamine quantitatively transformed into 14. In practice, oxepane 14 is
economically prepared from 9b without isolation of any intermediate in a reproducible total
yield of 90–95%. Of several reagents tested, TEMPO proved to be the one of choice for the
oxidation lactol 14“lactone 15, readily converted to 16 with MeOH/K2CO3. The critical
oxidation of 16 to a-amino-aldehyde (+)-17 was, after extensive experimentation, achieved with
full retention of stereochemistry along the Dess–Martin procedure,16 if only in moderate yield.
The alternative to proceed from 13 to 16 via 18 proved disadvantageous in view of the limited
yield of 13 (Scheme 3).
Scheme 3. (i) O3, CH2Cl2/MeOH (5/1), NaHCO3, −78°C, >95%. (ii) NaBH4, −78 to −20°C. (iii) Et3N, 4°C, 90–95%
from 9b. (iv) TEMPO, nBu4NBr, mCPBA, CH2Cl2, 0°C, quant. (v) K2CO3, MeOH, room temp., quant. (vi)
Periodinane, CH2Cl2, room temp., 68%. (vii) Ac2O, Et3N, room temp., quant.
Intensive efforts directed at the VII-mediated pinacol-homocoupling17 of (+)-17 to give 20 have
not been successful; the protection pattern proved not compatible with these reaction conditions.
Cyclohexanone (+)-19 was isolated (50%) from a complex mixture of products. In a parallel
study7 this roadblock was circumvented by constructing C6-aldehydes with better adapted
protection measures. Thus from 21, prepared from conduramine 9c via a multistep sequence

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(total yield 24%), C2-symmetrical, solid C12 diamino-decaol (+)-22 was secured in good yield
(70–75%); no stereoisomer of (+)-22 could be detected (Scheme 4).
Scheme 4.
Acknowledgements
This project has been supported by the Deutsche Forschungsgemeinschaft. We thank F. Lay
for competent technical assistance, Dipl.-Chem. H. Glatz for explorative experimentation, Dr.
D. Hunkler and Dr. J. Wo¨rth for NMR and MS spectra and Dr. L. Knothe for help with the
manuscript.
References
1. (a) Schwesinger, R.; Prinzbach, H. Angew. Chem., Int. Ed. Engl. 1972, 11, 942; (b) Prinzbach, H.; Keller, R.;
Schwesinger, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 633; (c) Keller, R.; Schwesinger, R.; Fritsche, W.;
Schneider, H.-W.; Hunkler, D.; Prinzbach, H. Chem. Ber. 1979, 112, 3347.
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7. Spielvogel, D. Dissertation, University of Freiburg, 27867.
8. List of enzymes: (a) Novo Nordisk: SP 523 (Novozym 398), SP 524 (Novozym 388), SP 525 (Novozym 525), SP
526 (Novozym 868), Novozym 435, Lipozym IM; (b) Amano: A 6, AP 6, AY30, CE 5, D 20, F-AP 15, G 50,
GC 4, L 5, M 10, N conc., PS, R 10; (c) Fluka: PPL; (d) Boehringer Mannheim: PLE.
9. Kammerer, J. Dissertation, University of Freiburg, 1990.
10. Carrera, G.; Riva, S. Angew. Chem., Int. Ed. Engl. 2000, 39, 2226-2254, and references cited therein.
1
11. All new compounds have been fully characterized by elemental analysis (or HRMS) and spectra (IR, H, 13C,
1
NMR, MS).—e.g. 22: mp: 53°C (CH2Cl2), [a]2D1=+39.0° (c=2.8, CH2Cl2), H NMR (500 MHz, CDCl3): l=5.58
(d, NH), 4.20–4.11 (m, 2H, 11H, 4H, 9H), 4.01 (dd, 3H, 10H), 3.90 (s, 6H, 7H), 3.74 (dd, 1aH, 12aH), 3.58 (dd,

7867
1bH, 12bH), 3.57 (s, OH), 3.42 (dd, 5H, 8H), 1.41 (s, Me), 1.39 (s, SitBu), 1.28 (s, Me), 0.11 (s, SiMe), 0.10 (s,
SiMe), 0.09 (s, SiMe), 0.09 (s, SiMe); J1a,1b=J12a,12b=11.0, J1a,2=J11,12a=4.3, J1b,2=J11,12b=5.8, J2,3=J10,11
=
5.2, J3,4=J9,10=9.1, J4,5=J8,9=4.9, J5,NH=J8,NH=9.2 Hz; 13C NMR (125.8 MHz, CDCl3): l=155.4 (CꢁO),
107.3 (Cq-acetonide), 79.1 (Cq-Boc), 78.5 (C-3, C-10), 77.2 (C-2, C-11), 72.8 (C-4, C-9), 69.9 (C-6, C-7), 62.9 (C-1,
C-12), 53.0 (C-5, C-8), 28.6 (tBu), 27.9 (Me), 26.3 (SiCH(CH3)), 26.2 (SiCH(CH3)), 25.6 (Me), 18.8 (SiCH(CH3)),
18.6 (SiCH(CH3)), −3.9 (SiMe), −4.5 (SiMe), −5.3 (SiMe), −5.3 (SiMe); MS (CI–NH3): 1100.0 (10), 1099.0 (24),
1098.0 (45), 1097.0 (38) [M]+, [M+H]+, 141.0 (23), 999.0 (51), 998 (82), 997 (100); ESI-MS: m/z=1137.8 (4),
1136.8 (5), 1135.8 (7) [M+K]+, 1122.9 (14), 1121.8 (44), 1120.9 (77), 1119.8 (100) [M+Na]+, 1100.9 (17), 1099.9
(41), 1098.9 (70), 1097.8 (93) [M]+, [M+H]+; C52H108N2O14Si4 (1097.8): calc. C, 56.89; H, 9.91; N, 2.55; found: C,
56.89; H, 9.65; N, 2.32.
12. Le Drian, C.; Vionnet, J.-P.; Vogel, P. Helv. Chim. Acta 1990, 31, 161–168.
13. Mitsunobu, O. Synthesis 1981, 1–28.
14. Crystallographic data for 9a (Schakal plot) have been deposited with the Cambridge Crystallographic Data
Centre, Cambridge, UK. Copies of the data can be obtained free of charge (e-mail: deposit@chemcrys.cam.ac.uk)
on quoting the deposition number CCDC 147577. Efforts to prove the absolute configuration by anomalous
X-ray diffraction have remained futile.
15. Trost, B. M.; Pulley, S. R. Tetrahedron Lett. 1995, 36, 8737–8740.
16. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1983, 48, 4155–4156.
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