Stereoselective hydrogenation of methylcyclohex-2-ene-1,4-diols used in the synthesis of ampelomins and deoxy-carbasugars

Article abstract of DOI:10.1016/j.tetlet.2013.12.036

Stereoselective hydrogenation of methylcyclohex-2-ene-1,4-diols used as important intermediates for the preparation of ampelomins and deoxy-carbasugars was studied. These olefins were obtained in few steps from a chiral cis-diol resulting from microbial oxidation of toluene. Although the stereoselective hydrogenation of this type of substrates is difficult, high yields were obtained for heterogeneous hydrogenation using Adam's catalyst, where steric hindrance controlled the stereochemical outcome of the process. On the other hand, for homogeneous hydrogenation of similar olefins using Crabtree's catalyst, coordination with the allylic alcohols allowed for a controlled hydrogen addition from the more hindered face. In this manner two protocols for the hydrogenation of these types of substrates resulting in complementary stereoselectivities are described.

Full text of DOI:10.1016/j.tetlet.2013.12.036

Tetrahedron Letters 55 (2014) 853–856
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective hydrogenation of methylcyclohex-2-ene-1,4-diols
used in the synthesis of ampelomins and deoxy-carbasugars
⇑
María Eugenia Lagreca, Ignacio Carrera, Gustavo A. Seoane, Margarita Brovetto
Laboratorio de Síntesis Orgánica, Departamento de Química Orgánica, Facultad de Química, Universidad de la República, C.C. 11400 Montevideo, Uruguay
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective hydrogenation of methylcyclohex-2-ene-1,4-diols used as important intermediates for
the preparation of ampelomins and deoxy-carbasugars was studied. These olefins were obtained in
few steps from a chiral cis-diol resulting from microbial oxidation of toluene. Although the stereoselec-
tive hydrogenation of this type of substrates is difficult, high yields were obtained for heterogeneous
hydrogenation using Adam’s catalyst, where steric hindrance controlled the stereochemical outcome of
the process. On the other hand, for homogeneous hydrogenation of similar olefins using Crabtree’s cata-
lyst, coordination with the allylic alcohols allowed for a controlled hydrogen addition from the more hin-
dered face. In this manner two protocols for the hydrogenation of these types of substrates resulting in
complementary stereoselectivities are described.
Received 7 October 2013
Revised 7 December 2013
Accepted 9 December 2013
Available online 14 December 2013
Keywords:
Stereoselective hydrogenation
Trisubstituted cycloalkenes
Bis-allylic diols
Ó 2013 Elsevier Ltd. All rights reserved.
Natural products
Introduction
undergo catalytic hydrogenation at very different rates and selec-
tivities, depending on the structure of the substrate.10
Stereoselective hydrogenation is, to date, one of the most
widely used and most reliable catalytic methods for the prepara-
tion of optically active compounds.1 An impressive number of cat-
alysts and ligands are known, which induce very high selectivity in
homogeneous metal-catalyzed hydrogenations,2–6 creating the
impression that the stereoselective hydrogenation of alkenes is a
solved problem. However, the range of olefins that can be hydroge-
nated with high enantiomeric excess is still limited. In fact, metal
diphosphine complexes do not hydrogenate tri- or tetra substi-
tuted alkenes at useful rates unless the substrate has one or more
coordinating functional groups to anchor to the metal, so facilitat-
ing catalysis.7 Thus, asymmetric hydrogenations mediated by Rh-,
Ir-, or Ru-diphosphine complexes are largely restricted to sub-
strates with coordinating groups, such as amides, alcohols, and car-
bonyl derivatives, disposed in the correct orientation. For metal
complexes such as Wilkinson’s and Crabtree’s catalysts, their suc-
cess in stereoselective hydrogenations is due to their ability to bind
hydrogen and the C@C double bond, as well as the coordinating
group, and the ligating ability of the coordinating groups may help
in predicting the outcome in cases where several groups are
present.8,9
In connection to our ongoing efforts to prepare polyoxygenated
natural products, our group has been working on the stereoselec-
tive hydrogenation of trisubstituted cycloalkenes bearing allylic
or bis-allylic alcohols. Specifically, during our studies directed to-
ward the chemoenzymatic synthesis of ampelomins11a,b and
deoxy-carbasugars,11c–e starting from microbially generated cyclo-
hexadienediols of type 1,12 we required a stereoselective route for
compounds 3 and 5 (Scheme 1). Both compounds can be obtained
through stereoselective hydrogenation of the corresponding
methyl-substituted bisallylic cycloalkenols 2 and 4. Herein we dis-
close the preparation of these cycloalkenes from a common precur-
sor, and their stereoselective hydrogenation on either face to give 3
and 5.
Results and discussion
The synthetic sequence for both trisubstituted cycloalkenes
started with the preparation of enantiopure cis-diol 1 using the tol-
uene dioxygenase-mediated oxidation of toluene. The enzymatic
dioxygenation of aromatic substrates is a well-established syn-
thetic methodology.12 In this case, E. coli JM109 (pDTG601) was
used as the whole-cell biocatalyst to prepare diol 1 in 23 g/L of
the culture broth (Scheme 2).13 Protection of the diol functionality
with the isopropylidene group followed by acetoxyiodination
using acetyl hypoiodite as source of halogen (Prévost reaction)
gave the acetylated halohydrin 6a. The regio- and stereoselectivity
of the halohydrin formation were thoroughly optimized, varying
the halonium donor, polarity of the medium, and temperature,
In this context, the hydrogenation of tri- or tetrasubstitued
cycloalkenes is highly substrate dependent. In particular cyclohex-
ene derivatives bearing one or two hydroxyls at the allylic posi-
tions (allylic or bis-allylic alcohols) have been reported to
⇑
Corresponding author. Tel.: +598 292 7881; fax: +598 294 1906.
E-mail address: mbrovetto@fq.edu.uy (M. Brovetto).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.036

854
M. E. Lagreca et al. / Tetrahedron Letters 55 (2014) 853–856
Scheme 1. Stereoselective hydrogenation of methylcycloalkenols in route to ampelomins and deoxy-carbasugars.
Scheme 2. Synthesis of cycloalkenes 2 and 4.
allowing for an excellent stereoselectivity (97:3 anti:syn) and a
very good regioselectivity toward the less hindered olefin
(85:15).14 Radical-mediated dehalogenation of compound 6a fol-
lowed by deprotection of the cis-diol in acetic acid afforded com-
pound 2a, which could be deacetylated in basic conditions to
give triol 2b.
conformational rigidity could be affecting the hydrogen addition.
When Adams’s catalyst was used with compound 2b, hydrogena-
tion effectively took place, together with hydrogenolysis of the
allylic CAO bond (entry 9). This result can be expected since the Le-
wis-acidic nature of this catalyst has been previously mentioned as
a potential source of unwanted side reactions.15 Thus, when the
reaction was tried in basic medium by addition of K2CO3 the hydro-
genation was clean, affording the saturated triol in 91% yield as a
4:1 mixture of diastereomers (entry 10). As expected, hydrogena-
tion was directed by steric factors, resulting in the anti addition of
the hydrogen atoms to the hydroxyl groups. Again in agreement
with the literature,10g this kind of trisubstituted cyclic alkenes, con-
stituting a bis-allylic alcohol system, was difficult to hydrogenate,
but we found that PtO2 with K2CO3 is a good choice for the hydro-
genation of the fully deprotected isomer 2b.
In addition the other alkene substrate, 4, important for ampelo-
min preparation, could also be obtained from compound 6a in a
two-step sequence (Scheme 2). In this case the deprotection of
the isopropylidene derivative in acetic medium had to be carefully
monitored, since the competitive deacetylation was evident at pro-
longed reaction times. Thus, the reaction was quenched before
completion, giving the diol in 79% yield based on recovered start-
ing material (brsm). The closure to the b-epoxide 4 proceeded
uneventfully using basic conditions at room temperature. Thus,
the alkene 4 was obtained in four steps from diol 1 in 40% overall
yield. The preparation of 5 requires hydrogen addition to the olefin
With cycloalkenes 6a, 6b, and 2b prepared through the afore-
mentioned sequence, we were ready to study the stereoselective
hydrogenation of the trisubstituted double bond to produce com-
pound 3 (Table 1). In this particular case, hydrogenation must take
place from the less hindered face of the ring, opposite to the oxy-
genated functionalities. We first tried heterogeneous hydrogena-
tion of 6a and 6b, expecting a high hindering effect of the
adjacent isopropylidene group, as reported in the literature for
the hydrogenation of similar systems.10a–d As shown (entries 1–9,
Table 1), the fully protected system was reluctant to hydrogenation,
and in most cases (entries 3–8) the starting material was recovered
unchanged after using Pd, Ni, or Adams’s catalysts and a H2 pressure
up to 4 atm during 4 days. In the case of the hydrogenation of the
iodine-containing alkene 6a (entries 1 and 2) using Ni-Ra, only
dehalogenation took place, without further reduction of the alkene.
The heterogeneous hydrogenation was also studied over alkene 8
(entry 8), using Pd/C as catalyst during 4 days in a mixture of ethyl
acetate–toluene (1:1) but no reaction took place, recovering the
starting material. So we decided to remove the isopropylidene
group and try hydrogenation on substrate 2b, suspecting that some

M. E. Lagreca et al. / Tetrahedron Letters 55 (2014) 853–856
855
Table 1
Stereoselective heterogeneous hydrogenation
Entry
Substrate
Reaction conditions
Compound and yield
Catalyst
Weight (%)
Solvent and d base
H2 pressure (atm)
Time (days)
1
2
3
4
5
6
7
8
9
6a
6b
Ni Raney
Ni Raney
Pd/C
Ni Raney
Pd/C
Pd/C
PtO2
Pd/C
PtO2
10
10
5
10
5
10
10
10
5
MeOH
MeOH
AcOH
MeOH
AcOEt:Ph (1:1)
AcOH:Hexane (1:2)
MeOH
AcOEt:Ph (1:1)
MeOH
1
4
4
1
4
4
4
4
4
4
1
1
4
4
4
4
4
4
6b, 10%
6b, 10%
6a, no reaction
6b, no reaction
6b, no reaction
6b, no reaction
6b, no reaction
8, no reaction
8
2b
0.2
0.2
9, 9%; 3b, 36%; 10, 38%
9, 18%; 3b, 73%
10
PtO2
5
MeOH, K2CO3 (cat)
through the same face of the oxygen functionalities of 4, so we
decided to use coordinating metal species like Wilkinson’s or Crab-
tree’s catalysts.16
molar) in CH2Cl2 and up to 4 atm of H2 pressure during 11 days,
compound 5 was obtained in 40% yield based on recovered starting
material, (entry 7). Finally, best results for hydrogenation were
achieved using a catalytic load of 25% molar under 4.5 atm of H2
in CH2Cl2, over 10 days, (entry 8). Attempts to improve the yield
by increasing further the H2 pressure were not made in order to
avoid using non-standard hydrogenation equipment. In these con-
ditions compound 5 was prepared in 90% yield brsm.
Spectroscopic data for compounds 3b/9 and 5/11 showed that
they were epimers at the carbon bearing the methyl group. Stereo-
chemical assignments were made using information from coupling
constants, and comparing these values to those from similar com-
pounds reported recently by Boyd et al.10a,17 Thus, vicinal coupling
constants for Ha and Hf (see Scheme 3) were 8.5 and 7.5 Hz for
compounds 9 and 5, respectively, indicative of a diaxial relation-
ship. Also, the corresponding coupling constants for compounds
3b and 11 were 4.2 and 4.6 Hz, respectively, indicative of an equa-
torial-axial relationship.10a,17 In addition, for compounds 5 and 11
the assignment was confirmed by NOE experiments and NMR shift
reagents (Eu(fod)3), see Supporting information.
Consequently, homogenous hydrogenation studies were per-
formed with both catalysts, and the results are shown in Table 2.
The starting material was recovered unchanged when using 5%
and 15% molar of Wilkinson’s catalyst, under 1 and 4 atm of H2
in CH2Cl2 or MeOH (entries 1, 3, and 4). Increasing the catalytic
load to 20% molar led to some hydrogenation under 4 atm of H2
in CH2Cl2, to afford the desired compound 5 in very low yield
(10% brsm over 5 days, entry 2). In turn, when using MeOH as sol-
vent (entries 5 and 6) the corresponding epimer 11 was obtained
exclusively, also in low yield (up to 10% brsm over 3 days and up
to 18% brsm over 7 days). This outcome can be explained consider-
ing the coordinating effect of the solvent that prevents catalyst
interaction with the substrate’s oxygens allowing hydrogen addi-
tion to take place from the less hindered face. Due to the observed
difficulties for getting good conversions we decided to use a more
electrophilic catalytic species. This strategy was successful since
when the reaction was performed using Crabtree’s catalyst (20%
Table 2
Stereoselective homogeneous hydrogenation
Reaction
CH3
CH3
CH3
S
R
Conditions
OH
OH
OH
AcO
AcO
O
AcO
O
O
4
11
5
Entry
Reaction conditions
Compound and yield
Catalyst
Molar(%)
Solvent
H2 pressure (atm)
Time (days)
1
2
3
4
5
6
7
8
Wilkinson’s
Wilkinson’s
Wilkinson’s
Wilkinson’s
Wilkinson’s
Wilkinson’s
Crabtree’sa
Crabtree’s
5
CH2Cl2
CH2Cl2
MeOH
MeOH
MeOH
MeOH
CH2Cl2
CH2Cl2
1
4
1
4
4
4
4
4.5
1
5
5
5
3
7
11
10
4, no reaction
5, 10% (brsm)b
4, no reaction
4, no reaction
11, 10% (brsm)b
11, 18% (brsm)b
5, 40% (brsm)b
5, 90% (brsm)b
20
15
15
20
20
20
25
Wilkinson’s catalyst = (PPh3)3RhCl; Crabtree’s catalyst = Ir(cod)py(PCy3)PF6.
a
Added in two portions.
brsm = based on recovered starting material.
b

856
M. E. Lagreca et al. / Tetrahedron Letters 55 (2014) 853–856
Scheme 3. Experimental values for coupling constants of epimeric pairs 3b/9 and 5/11.
3. Zhang, W.; Chi, Y.; Zhang, X. Acc. Chem. Res. 2007, 40, 1278–1290.
4. Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357–1366.
Conclusions
5. Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de Vries, J. G. Acc. Chem. Res. 2007, 40,
1267–1277.
6. Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029–3070.
7. Landis, C. R.; Halpern, J. J. Am. Chem. Soc. 1987, 109, 1746–1754.
8. (a) Crabtree, R. H. Acc. Chem. Res. 1979, 12, 331–338; (b) Stork, G.; Kahne, D. E. J.
Am. Chem. Soc. 1983, 105, 1072–1073; (c) Crabtree, R. H.; Davis, M. W. J. Org.
Chem. 1986, 51, 2655–2661.
9. (a) Evans, D. A.; Morrissey, M. M. J. Am. Chem. Soc. 1984, 106, 3866–3868; (b)
Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515–1517; (c) Wüstenberg, B.; Pfaltz,
A. Adv. Synth. Catal. 2008, 350, 174–178.
In summary we studied the stereoselective hydrogenation of
compounds 2b and 4 to afford useful intermediates for the prepa-
ration of ampelomins and deoxy-carbasugars. Two protocols for
the hydrogenation of these types of unreactive substrates resulting
in complementary stereoselectivities are described. Compounds 3b
and 5 are key intermediates for synthetic routes to deoxy-carbasu-
gars and ampelomins, respectively; moreover triol 3b is 2-deoxy-
10. (a) Boyd, D. R.; Sharma, N. D.; Berberian, V.; Dunne, K. S.; Hardacre, C.; Kaik, M.;
Kelly, B.; McGregor, S. T.; Malone, J. F.; Stevensona, P. J. Adv. Synth. Catal. 2010,
352, 855–868; (b) Boyd, D. R.; Sharma, N. D.; Llamas, N. M.; Malone, J. F.;
O’Dowda, C. R.; Allen, C. C. R. Org. Biomol. Chem. 2005, 3, 1953–1963; (c) Boyd,
D. R.; Sharma, N. D.; Bowers, N. I.; Coen, G. B.; Malone, J. F.; O’Dowda, C. R.;
Stevenson, P. J.; Allen, C. C. R. Org. Biomol. Chem. 2010, 8, 1415–1423; (d)
Hudlicky, T.; Luna, H.; Barbieri, G.; Kwart, L. D. J. Am. Chem. Soc. 1988, 110,
4735–4741; (e) Semak, V.; Metcalf, T. A.; Endoma-Arias, M. A. A.; Mach, P.;
Hudlicky, T. Org. Biomol. Chem. 2012, 10, 4407; (f) Fabris, F.; Collins, J.; Sullivan,
B.; Leischa, H.; Hudlicky, T. Org. Biomol. Chem. 2009, 7, 2619–2627; (g) Cui, X.;
Burgess, K. Chem. Rev. 2005, 105, 3272–3296.
carba-b-
L
-fucose and acetate
5
is acetyl 4-epi-ampelomin
B. Further work in this area will be published in the near future.
Acknowledgments
Support of this work from CSIC, (Universidad de la República,
Uruguay) is gratefully acknowledged.
Supplementary data
11. (a) Prasada Rao, J.; Venkateswara Rao, B. Tetrahedron: Asymmetry 2010, 21,
930–935; (b) Zhang, H.; Xue, J.; Wu, P.; Xu, L.; Xie, H.; Wei, X. J. Nat. Prod. 2009,
´
72, 265–269; (c) Shan, M.; ODoherty, G. A. Org. Lett. 2008, 10, 3381–3384; (d)
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.12.
036.
´
Shan, M.; ODoherty, G. A. Synthesis 2008, 19, 3171–3179; (e) Breit, B.; Bigot, A.
Chem. Commun. 2008, 6498–6500.
12. (a) Hudlicky, T.; González, D.; Gibson, D. Aldrichimica Acta 1999, 32, 35–62; (b)
Hudlicky, T.; Reed, J. W. Synlett 2009, 685–703.
13. Vila, M. A.; Brovetto, M.; Gamenara, D.; Bracco, P.; Zinola, G.; Seoane, G.;
Rodríguez, S.; Carrera, I. J. Mol. Catal. B: Enzymatic 2013, 96, 14–20.
14. Carrera, I.; Brovetto, M. C.; Seoane, G. Tetrahedron 2007, 63, 4095–4107.
15. Peng, X.; Bondar, D.; Paquette, Leo A. Tetrahedron 2004, 60, 9589–9598.
16. (a) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029–3069; (b) Schultz, A. G.;
McCloskey, P. J. J. Org. Chem. 1985, 50, 5905–5907.
References and notes
1. (a) Brown, J. M. Hydrogenation of Functionalized Carbon–Carbon Double
Bonds. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, Y., Eds.; ; Springer: Berlin, 1999; Vol. I,. Chapter 5.1 (b) Noyori, R.
Angew. Chem., Int. Ed. 2002, 41, 2008–2022.
17. (a) Ardashov, O. V.; Genaev, A. M.; Il’ina, I. V.; Korchagina, D. V.; Volcho, K. P.;
Salakhutdinov, N. F. Russian J. Org. Chem. 2010, 46, 1786–1789.
2. Zhu, Y.; Burgess, K. Acc. Chem. Res. 2012, 45, 1623–1636.