The addition of ethylene to 1,3-dienes and 1-vinylcycloalkenes, catalyzed by two ruthenium complexes, proceeds in a regioselective fashion to afford 3-methyl-1,4-dienes as products. For a steroidal-based 1-vinylcycloalkene, the addition is stereospecific, giving a product with a 20(S) configuration

Donaldson, William A.

He, Zhengjie

Yi, Chae S.

English

epublications@Marquette

Marquette Universitye-Publications@MarquetteChemistry Faculty Research and Publications Chemistry, Department of4-1-2003Regio- and Stereoselective Ruthenium CatalyzedHydrovinylation of 1,3-Dienes: Application to theGeneration of a 20S-Steroidal SidechainZhengjie HeMarquette UniversityChae S. YiMarquette UniversityWilliam A. DonaldsonMarquette University, william.donaldson@marquette.eduAccepted version. Organic Letters, Volume 5, No. 9 (2003): 1567-1569. DOI. © 2003 AmericanChemical Society. Used with permission.NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 1    Regio- and Stereoselective Ruthenium-Catalyzed Hydrovinylation of 1,3-Dienes:  Application to the Generation of a 20(S) Steroidal Side Chain    Zhengjie He Department of Chemistry, Marquette University, Milwaukee, WI Chae S. Yi Department of Chemistry, Marquette University, Milwaukee, WI William A. Donaldson Department of Chemistry, Marquette University, Milwaukee, WI        NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 2  Abstract  The addition of ethylene to 1,3-dienes and 1-vinylcycloalkenes, catalyzed by two ruthenium complexes, proceeds in a regioselective fashion to afford 3-methyl-1,4-dienes as products. For a steroidal-based 1-vinylcycloalkene, the addition is stereospecific, giving a product with a 20(S) configuration.  Transition metal-catalyzed hydrovinylation1 holds tremendous potential as a generally useful C−C bond-forming reaction, since it uses a cheap feedstock (ethylene) and proceeds in an “atom economical” fashion.2 This reaction has largely focused on 1-arylethylenes as substrates since the products, 3-aryl-1-butenes, may be transformed into useful analgesics (e.g., ibuprofen, naproxen). While a number of recent reports describe highly enantioselective hydrovinylation of styrenes,3 further development of this reaction as a general synthetic tool will require broadening the scope of applicable substrates. Only limited examples of the hydrovinylation of cyclic dienes have been reported.4 In the course of examining the ruthenium-catalyzed coupling of ethylene with alkynes, one of our labs recently reported the use of two ruthenium catalytic systems 1 and 2 for the coupling of ethylene with alkynes and alkenes.5 We herein report the ruthenium-catalyzed hydrovinylation of unsymmetrically substituted 1,3-dienes. Reaction of 1,3-dienes 3a−h with excess ethylene, in the presence of either catalyst 1 or 2 gave predominantly the corresponding 3-methyl-1,4-dienes 4a−h, the products resulting from 1,2-hydrovinylation (Table 1).6 The structural assignment for 4 was based on its 1H NMR spectral data. In particular, signals at ca. δ 5.9 (ddd, 1H), 5.05 (m, 2H), and 1.2 ppm (d, 3H) are characteristic of the vinyl and methyl groups of a 3-substituted-1-butenyl functionality. In certain cases, the reaction was terminated prior to complete consumption of starting material 3, as prolonged contact with the NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 3  catalyst led to isomerization of the initially formed 4 to the more stable conjugated 3-methyl-1,3-diene.7 Any unreacted starting material or the isomerized 1,3-diene product could be chemically separated from the desired 1,4-diene 4 by treatment of the reaction mixture with phenyl triazodione (PTAD); the PTAD undergoes cycloaddition with the conjugated dienes, and the desired product 4 can be cleanly separated from these cycloaddition products.     Figure 1 Ruthenium catalyst structures.   NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 4   Table 1.  Ru-Catalyzed Hydrovinylation of 1,3-Dienes  a From ref 5b.b Mixture of diastereomers (1:1).c Single diastereomer. Hydrovinylation of dienes bearing aryl substituents (3a,b) as well as 1-vinylcycloalkenes (3c−h) proceeded with excellent 1,2-addition regioselectivity. For certain substrates bearing a resident stereocenter (e.g., 3d,f,g), hydrovinylation was not stereoselective, giving a 1:1 mixture of diastereomeric products. In contrast, hydrovinylation of the steroidal diene 3h proceeded with excellent regio- and stereoselectivity, giving a single diastereomer 4h in good isolated yield. Since assignment of the C20 configuration of the product 4h was not possible on the basis of NMR spectral data, a crystalline derivative was sought. To this end, hydroboration/oxidation of 4h proceeded only at the vinyl group to afford the primary alcohol 5 (Scheme 1). Oxidation of 5 with Jones reagent, followed by treatment NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 5  of the crude product with diazomethane, gave a separable mixture of ester 68 and spirocyclic lactone 7.9 Crystals of 7 suitable for X-ray diffraction analysis revealed the relative configurations within the molecule;10 since the precursor 3h was prepared from optically pure estrone,11 the absolute configurations at the C17 and C20 stereocenters of 7 were assigned as (R) and (S), respectively. Thus, the hydrovinylation product 4h has the 20(S) configuration, which is opposite to the configuration of most naturally occurring steroids [i.e., 20(R)]. Recently, a nonnatural 20(S) vitamin D3 analogue has been reported that selectively induces bone formation.12 While there are many strategies for the preparation of the 20(R) side chain,13 there is a general lack of stereoselective routes to side chains with the 20(S) configuration.14    Scheme 1  To demonstrate the synthetic potential of this diastereoselective hydrovinylation reaction, alcohol 5 was transformed into unsaturated alcohol 9a via a three-step protocol (Scheme 2). Structure 9a is a hybrid between estrone and the Roche vitamin D3 analogue, Ro 26-9228 (9b), which is reported to increase bone mineral density in rats.12a Additionally, functionalized estrone analogues structurally similar to 9a are described as agents for the modulation of cell growth and differentiation.12d   NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 6   Scheme 2  The hydrovinylation of 1,3-dienes with either 1 or 2 is proposed to involve a ruthenium hydride species 10 in which the less substituted olefin of the diene is coordinated to Ru (Scheme 3).15 Insertion of the conjugated diene into the Ru−H bond generates the 1-methyl-π-allyl intermediate 11 in a reversible fashion. Ethylene insertion into the σ-allyl species 12, with retention of configuration, followed by β-hydride and subsequent ligand exchange with a 1,3-diene, regenerates species 10, and affords the product 1,4-diene. The stereoselective formation of 4h may be rationalized on the preferential formation of π-allyl intermediate 13 (Scheme 3) in which Ru is trans to the sterically bulky angular methyl group and the allylic methyl group occupies the anti position in order to avoid steric interaction with the C12 methylene (steroid numbering).   NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 7   Scheme 3  In summary, regio- and stereoselective hydrovinylation of 1,3-dienes 3 has been achieved by using Ru catalysts 1 or 2. Further developments in the scope of this reaction as well as synthetic applications will be reported in due course.  Acknowledgment Financial support for this work was provided by the National Institutes of Health (GM-42641 to W.A.D. and GM-55987 to C.S.Y.). High-resolution mass-spectral determinations were made at the Washington University Mass Spectrometry Resource, an NIH Research Resource (Grant P41RR0954). W.A.D. acknowledges stimulating discussions with Prof. T. V. RajanBabu.    NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 8  References 1(a) Jolly, P. W.; Wilke, G. In Applied Homogeneous Catalysis with Organometallic Compounds; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH:  New York, 2000; pp 1024−1072. (b) Goossen, L. J. Angew. Chem., Int. Ed. 2002, 41, 3775−3778. 2(a) Trost, B. M. Science 1991, 254, 1471−1477. (b) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259−281. 3(a) Bayersdorfer, R.; Ganter, B.; Englert, U.; Keim, W.; Vogt, D. J. Organomet. Chem. 1998, 552, 187−194. (b) Albert, J.; Cadena, M.; Granell, J.; Muller, G.; Ordinas, J. I.; Panyella, D.; Puerta, C.; Sanudo, C.; Valerga, P. Organometallics 1999, 18, 3511−3518. (c) Englert, U.; Haerter, R.; Vasen, D.; Salzer, A.; Eggerling, E. B.; Vogt, D. Organometallics 1999, 18, 4390−4398. (d) Wegner, A.; Leitner, W. J. Chem. Soc., Chem. Commun. 1999, 1583−1584. (e) Bosmann, A.; Francio, G.; Jenssen, E.; Solinas, M.; Leitner, W.; Wasserscheid, P. Angew. Chem., Int. Ed. 2001, 40, 2697−2699. (f) Francio, G.; Faraone, F.; Leitner, W. J. Am. Chem. Soc. 2002, 124, 736−737. (g) Nomura, N.; Jin, J.; Park, H.; RajanBabu, T. V. J. Am. Chem. Soc. 1998, 120, 459−460. (h) Nandi, M.; Jin, J.; RajanBabu, T. V. J. Am. Chem. Soc. 1999, 121, 9899−9900. (i) Park, H.; RajanBabu, T. V. J. Am. Chem. Soc. 2002, 124, 734−735. 4(a) Beger, J.; Duschek, C.; Gericke, C. J. Prakt. Chem. 1974, 316, 952−962. (b) Buono, G.; Siv, C.; Peiffer, G.; Triantaphylides, C.; Denis, P.; Mortreux, A.; Petit, F. J. Org. Chem. 1985, 50, 1781−1782. (c) Hilt, G.; du Mesnil, F.-X.; Luers, S. Angew. Chem., Int. Ed. 2001, 40, 387−389. 5(a) Yi, C. S.; Lee, D. W.; Chen, Y. Organometallics 1999, 18, 2043−2045. (b) Yi, C. S.; He, Z.; Lee, D. W. Organometallics 2001, 20, 802−804. 6Neither 1,4-diphenyl-1,3-butadiene or 2,5-dimethyl-2,4-hexadiene reacted with ethylene in the presence of either 1 or 2. 7Isomerization (over longer reaction periods) is observed with both catalysts 1 and 2. Thus, at least for catalyst 1, this isomerization cannot be attributed to the presence of acid. 8Both the 20(S)- and 20(R)-isomers of the methyl ether corresponding to benzyl ether 6 have been previously prepared. The close similarity of their literature NMR spectral data does not allow for an unambiguous assignment. Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1978, 100, 3435−3443. 9Formation of γ-lactones from 4-penten-1-ols or δ-lactones from 5-hexen-1-ols via oxidation with chromium reagents has been previously reported. (a) Chakraborty, T. K.; Chandrasekaran, S. Tetrahedron Lett. 1984, 25, 2895−2896. (b) Schlecht, M. F.; Kim, H. Tetrahedron NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 9  Lett. 1985, 26, 127−130. (c) Rathore, R.; Vankar, P. S.; Chandrasekaran, S. Tetrahedron Lett. 1986, 27, 4079−4082. 10Bennett, D. W.; Siddiquee, T. A.; Murphy, K. L.; Haworth, D. T.; He, Z.; Donaldson, W. A. J. Chem. Cryst. Submitted for publication. CCDC number 201892. 11De Riccardis, F.; Meo, D.; Izzo, I.; Di Filippo, M.; Casapullo, A. Eur. J. Org. Chem. 1998, 1965−1970. 12(a) Kabat, M. M.; Garofalo, L. M.; Daniewski, A. R.; Hutchings, S. D.; Liu, W.; Okabe, M.; Radinov, R.; Zhou, Y. J. Org. Chem. 2001, 66, 6141−6150. (b) Sicinski, R. R.; Rotkewicz, P.; Kolinski, A.; Sicinska, W.; Prahl, J. M.; Smith, C. M.; DeLuca, H. F. J. Med. Chem. 2002, 45, 3366−3380. (c) Shevde, N. K.; Plum, L. A.; Clagett-Dame, M.; Yamamoto, H.; Pike, J. W.; DeLuca, H. F. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 13487−13491. (d) Hesse, R. H.; Setty, S. K. S.; Ramgopal, M.; Kugabalusooriar, S. Patent WO 2000068246, 2000; CAN 133 350395, 2000. 13For a review, see:  Gui-Dong, Z.; Okamura, W. H. Chem. Rev. 1995, 95, 1877−1952. For a more recent synthesis, see:  Yan, J.; Herndon, J. W. J. Org. Chem. 1998, 63, 2325−2331 and references therein. 1420(S) vitamin D3 precursors have been prepared by ozonolytic degradation of ergocalciferol, followed by a base-catalyzed epimerization and separation of the 20(R)- and 20(S)-diastereomers:  Hijikuro, D. T.; Takahashi, T. J. Am. Chem. Soc. 2001, 123, 3716−3722. For a route to the 20(S) side chain that uses stoichiometric palladium, see ref 8. 15Notably, the Ru−H species 10 has been proposed as an intermediate in the coupling of alkynes with ethylene using catalyst 1 (see ref 5a).  Supporting Information Available  

Regio- and Stereoselective Ruthenium Catalyzed Hydrovinylation of 1,3-Dienes:  Application to the Generation of a 20S-Steroidal Sidechain

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Regio- and Stereoselective Ruthenium-Catalyzed Hydrovinylation of 1,3-Dienes: Application to the Generation of a 20(S) Steroidal Side Chain.

Zhengjie He

Chae S. Yi

William A. Donaldson

Marquette University
e-Publications@Marquette
Chemistry Faculty Research and Publications Chemistry, Department of
4-1-2003
Regio- and Stereoselective Ruthenium Catalyzed
Hydrovinylation of 1,3-Dienes: Application to the
Generation of a 20S-Steroidal Sidechain
Zhengjie He
Marquette University
Chae S. Yi
Marquette University
William A. Donaldson
Marquette University, william.donaldson@marquette.edu
Accepted version. Organic Letters, Volume 5, No. 9 (2003): 1567-1569. DOI. © 2003 American
Chemical Society. Used with permission.
NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be 
accessed by following the link in the citation at the bottom of the page. 
Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and 
permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does 
not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission 
from American Chemical Society. 
1 
 
 
 
Regio- and Stereoselective 
Ruthenium-Catalyzed 
Hydrovinylation of 1,3-Dienes:  
Application to the Generation of a 
20(S) Steroidal Side Chain 
 
 
 
Zhengjie He 
Department of Chemistry, Marquette University, 
Milwaukee, WI 
Chae S. Yi 
Department of Chemistry, Marquette University, 
Milwaukee, WI 
William A. Donaldson 
Department of Chemistry, Marquette University, 
Milwaukee, WI 
 
 
 
 
 
  
NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be 
accessed by following the link in the citation at the bottom of the page. 
Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and 
permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does 
not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission 
from American Chemical Society. 
2 
 
Abstract 
 
The addition of ethylene to 1,3-dienes and 1-vinylcycloalkenes, 
catalyzed by two ruthenium complexes, proceeds in a regioselective 
fashion to afford 3-methyl-1,4-dienes as products. For a steroidal-
based 1-vinylcycloalkene, the addition is stereospecific, giving a 
product with a 20(S) configuration.  
Transition metal-catalyzed hydrovinylation1 holds tremendous 
potential as a generally useful C−C bond-forming reaction, since it 
uses a cheap feedstock (ethylene) and proceeds in an “atom 
economical” fashion.2 This reaction has largely focused on 1-
arylethylenes as substrates since the products, 3-aryl-1-butenes, may 
be transformed into useful analgesics (e.g., ibuprofen, naproxen). 
While a number of recent reports describe highly enantioselective 
hydrovinylation of styrenes,3 further development of this reaction as a 
general synthetic tool will require broadening the scope of applicable 
substrates. Only limited examples of the hydrovinylation of cyclic 
dienes have been reported.4 In the course of examining the 
ruthenium-catalyzed coupling of ethylene with alkynes, one of our labs 
recently reported the use of two ruthenium catalytic systems 1 and 2 
for the coupling of ethylene with alkynes and alkenes.5 We herein 
report the ruthenium-catalyzed hydrovinylation of unsymmetrically 
substituted 1,3-dienes. Reaction of 1,3-dienes 3a−h with excess 
ethylene, in the presence of either catalyst 1 or 2 gave predominantly 
the corresponding 3-methyl-1,4-dienes 4a−h, the products resulting 
from 1,2-hydrovinylation (Table 1).6 The structural assignment for 4 
was based on its 1H NMR spectral data. In particular, signals at ca. δ 
5.9 (ddd, 1H), 5.05 (m, 2H), and 1.2 ppm (d, 3H) are characteristic of 
the vinyl and methyl groups of a 3-substituted-1-butenyl functionality. 
In certain cases, the reaction was terminated prior to complete 
consumption of starting material 3, as prolonged contact with the 
NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be 
accessed by following the link in the citation at the bottom of the page. 
Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and 
permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does 
not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission 
from American Chemical Society. 
3 
 
catalyst led to isomerization of the initially formed 4 to the more 
stable conjugated 3-methyl-1,3-diene.7 Any unreacted starting 
material or the isomerized 1,3-diene product could be chemically 
separated from the desired 1,4-diene 4 by treatment of the reaction 
mixture with phenyl triazodione (PTAD); the PTAD undergoes 
cycloaddition with the conjugated dienes, and the desired product 4 
can be cleanly separated from these cycloaddition products.  
 
 
 Figure 1 Ruthenium catalyst structures. 
  
NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be 
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Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and 
permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does 
not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission 
from American Chemical Society. 
4 
 
 Table 1.  Ru-Catalyzed Hydrovinylation of 1,3-Dienes 
 
a From ref 5b.b Mixture of diastereomers (1:1).c Single diastereomer. 
Hydrovinylation of dienes bearing aryl substituents (3a,b) as 
well as 1-vinylcycloalkenes (3c−h) proceeded with excellent 1,2-
addition regioselectivity. For certain substrates bearing a resident 
stereocenter (e.g., 3d,f,g), hydrovinylation was not stereoselective, 
giving a 1:1 mixture of diastereomeric products. In contrast, 
hydrovinylation of the steroidal diene 3h proceeded with excellent 
regio- and stereoselectivity, giving a single diastereomer 4h in good 
isolated yield. Since assignment of the C20 configuration of the 
product 4h was not possible on the basis of NMR spectral data, a 
crystalline derivative was sought. To this end, hydroboration/oxidation 
of 4h proceeded only at the vinyl group to afford the primary alcohol 5 
(Scheme 1). Oxidation of 5 with Jones reagent, followed by treatment 
NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be 
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permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does 
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from American Chemical Society. 
5 
 
of the crude product with diazomethane, gave a separable mixture of 
ester 68 and spirocyclic lactone 7.9 Crystals of 7 suitable for X-ray 
diffraction analysis revealed the relative configurations within the 
molecule;10 since the precursor 3h was prepared from optically pure 
estrone,11 the absolute configurations at the C17 and C20 
stereocenters of 7 were assigned as (R) and (S), respectively. Thus, 
the hydrovinylation product 4h has the 20(S) configuration, which is 
opposite to the configuration of most naturally occurring steroids [i.e., 
20(R)]. Recently, a nonnatural 20(S) vitamin D3 analogue has been 
reported that selectively induces bone formation.12 While there are 
many strategies for the preparation of the 20(R) side chain,13 there is 
a general lack of stereoselective routes to side chains with the 20(S) 
configuration.14  
 
 
Scheme 1  
To demonstrate the synthetic potential of this diastereoselective 
hydrovinylation reaction, alcohol 5 was transformed into unsaturated 
alcohol 9a via a three-step protocol (Scheme 2). Structure 9a is a 
hybrid between estrone and the Roche vitamin D3 analogue, Ro 26-
9228 (9b), which is reported to increase bone mineral density in 
rats.12a Additionally, functionalized estrone analogues structurally 
similar to 9a are described as agents for the modulation of cell growth 
and differentiation.12d  
 
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Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and 
permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does 
not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission 
from American Chemical Society. 
6 
 
 
Scheme 2  
The hydrovinylation of 1,3-dienes with either 1 or 2 is proposed 
to involve a ruthenium hydride species 10 in which the less substituted 
olefin of the diene is coordinated to Ru (Scheme 3).15 Insertion of the 
conjugated diene into the Ru−H bond generates the 1-methyl-π-allyl 
intermediate 11 in a reversible fashion. Ethylene insertion into the σ-
allyl species 12, with retention of configuration, followed by β-hydride 
and subsequent ligand exchange with a 1,3-diene, regenerates species 
10, and affords the product 1,4-diene. The stereoselective formation 
of 4h may be rationalized on the preferential formation of π-allyl 
intermediate 13 (Scheme 3) in which Ru is trans to the sterically bulky 
angular methyl group and the allylic methyl group occupies the anti 
position in order to avoid steric interaction with the C12 methylene 
(steroid numbering).  
 
NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be 
accessed by following the link in the citation at the bottom of the page. 
Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and 
permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does 
not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission 
from American Chemical Society. 
7 
 
 
Scheme 3  
In summary, regio- and stereoselective hydrovinylation of 1,3-
dienes 3 has been achieved by using Ru catalysts 1 or 2. Further 
developments in the scope of this reaction as well as synthetic 
applications will be reported in due course.  
Acknowledgment 
Financial support for this work was provided by the National Institutes of 
Health (GM-42641 to W.A.D. and GM-55987 to C.S.Y.). High-resolution mass-
spectral determinations were made at the Washington University Mass 
Spectrometry Resource, an NIH Research Resource (Grant P41RR0954). 
W.A.D. acknowledges stimulating discussions with Prof. T. V. RajanBabu.  
  
NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be 
accessed by following the link in the citation at the bottom of the page. 
Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and 
permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does 
not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission 
from American Chemical Society. 
8 
 
References 
1(a) Jolly, P. W.; Wilke, G. In Applied Homogeneous Catalysis with 
Organometallic Compounds; Cornils, B., Herrmann, W. A., Eds.; Wiley-
VCH:  New York, 2000; pp 1024−1072. (b) Goossen, L. J. Angew. 
Chem., Int. Ed. 2002, 41, 3775−3778. 
2(a) Trost, B. M. Science 1991, 254, 1471−1477. (b) Trost, B. M. Angew. 
Chem., Int. Ed. Engl. 1995, 34, 259−281. 
3(a) Bayersdorfer, R.; Ganter, B.; Englert, U.; Keim, W.; Vogt, D. J. 
Organomet. Chem. 1998, 552, 187−194. (b) Albert, J.; Cadena, M.; 
Granell, J.; Muller, G.; Ordinas, J. I.; Panyella, D.; Puerta, C.; Sanudo, 
C.; Valerga, P. Organometallics 1999, 18, 3511−3518. (c) Englert, U.; 
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NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be 
accessed by following the link in the citation at the bottom of the page. 
Organic Letters, Vol 5, No. 9 (May 1, 2003): pg. 1567-1569. DOI. This article is © American Chemical Society and 
permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does 
not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission 
from American Chemical Society. 
9 
 
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1420(S) vitamin D3 precursors have been prepared by ozonolytic degradation 
of ergocalciferol, followed by a base-catalyzed epimerization and 
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Regio- and Stereoselective Ruthenium-Catalyzed Hydrovinylation of 1,3-Dienes:  Application to the Generation of a 20(S) Steroidal Side Chain

https://epublications.marquette.edu/cgi/viewcontent.cgi?article=1079&amp;context=chem_fac

Regio- and Stereoselective Ruthenium Catalyzed Hydrovinylation of 1,3-Dienes: Application to the Generation of a 20S-Steroidal Sidechain

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