Asymmetric synthesis of deoxypolypropionate units via stereoselective hydrogenation of optically active cycloheptatriene

Article abstract of DOI:10.1021/ol0483596

(Chemical equation presented) Optically active polypropionate units were synthesized in 9-11 steps from 3,5-dimethylphenol. The sequence consists of the Buechner reaction controlled by a chiral 2,4-pentanediol tether and diastereoselective hydrogenation o

Full text of DOI:10.1021/ol0483596

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4439-4442
Asymmetric Synthesis of
Deoxypolypropionate Units via
Stereoselective Hydrogenation of
Optically Active Cycloheptatriene
Takashi Sugimura,* Yasuhiro Sato, Chun Young Im, and Tadashi Okuyama
Graduate School of Material Science, Himeji Institute of Technology,
UniVersity of Hyogo, 3-2-1 Kohto, Kamigori, Ako-gun, Hyogo 678-1297, Japan
sugimura@sci.u-hyogo.ac.jp
Received August 18, 2004
ABSTRACT
Optically active polypropionate units were synthesized in 9
−11 steps from 3,5-dimethylphenol. The sequence consists of the Bu1chner reaction
controlled by a chiral 2,4-pentanediol tether and diastereoselective hydrogenation over Raney nickel.
Polyketides are ubiquitous natural products including many
important antibiotics such as macrolides. The structure of
the skipped methyl groups in a polyketide is biologically
synthesized by the propionyl-CoA or R-methylmalonyl-CoA
cycle, which constructs chiral centers in a variety of patterns
under strict control.1 For the synthesis of such compounds,
many elegant stereocontrolled reactions have been developed,
but the reactions controlling the formation of multichiral
centers are still limited.2
4, prepared from 3,5-dimethylphenol via the PD-tethered
Bu¨chner reaction of 5, to synthesize a chiral building block
1 (X ) H or OH) that corresponds to a deoxytripropionate
unit (Scheme 1). A key step of this procedure is the hy-
drogenation of 3 at the conjugated diene to generate two
Scheme 1. Retrosynthesis of Chiral Polypropionate Unit 1 via
Optically Active Cycloheptatriene 4
Optically active 2,4-pentanediol (PD) is a popular chiral
auxiliary and exhibits strict stereocontrollability when it is
used as a tether connecting two reactants.3 The Bu¨chner
reaction is one of the successful examples that produces many
chiral cycloheptatriene derivatives in optically active forms.4
In the present study, we planned to use such a compound,
(1) ComprehensiVe Natural Products Chemistry; Sankawa, U., Ed.;
Elsevier: Amsterdam, 1999; Vol. 1. Macrolide Antibiotics; Omura, S. Ed.;
Academic Press: Amsterdam, 2002.
(2) A typical exception is desymmetrization of meso-compounds. For a
review, see: Hoffmann, R. W. Angew. Chem., Int. Ed. 2003, 42, 1096-
1109.
(3) Sugimura, T. In Recent Research DeVelopments in Organic Chem-
istry; Pandalai, S. G., Ed.; Transworld Research Network: Trivandrum,
1998; Vol. 2, pp 47-53.
10.1021/ol0483596 CCC: $27.50
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chiral centers stereocontrolled by the substituents at the 7-
and/or 12-positions, and thus these chiral centers must also
be stereoselectively generated.
The optically active 4 was prepared by the reported
method5 and converted to 6 (>99% ee) by reduction in 95%
yield (Scheme 2). The oxidation of 6 by the addition of
For the hydrogenation of 3, the stereochemical purity of
the produced 10 (100 × 10a/(10a + 10b)) is over 80% in
all cases, and the Ni and Pt catalysts provided better
selectivity than does the Pd catalyst. When both hydroxy
groups were protected, 7 showed lower selectivities, sug-
gesting that the effects of the hydroxy group(s) decrease in
the order of Ni > Pt > Pd.8 For the Ni-catalyzed hydrogena-
tion, the results with 8 and 9 suggest that the 7-OH (R1 )
H) group has greater effects on the selectivity than does the
12-CH2OH group (R2 ) H). The selectivity with the 7-OH
substrates (3 and 9) over the Ni catalyst reaches 98% purity
(96% diastereomeric excess of 10a) in an optimum solvent.
Scheme 2. Hydrogenation of the Conjugate Diene
1
When the hydrogenation process was monitored by H
NMR under one of the best conditions (3/Ni/EtOAc), three
mono-ene intermediates were detected in a similar quantity
during the very early stage (<5% consumption of 3). One
of the intermediates was not accumulated during the hydro-
genation, whereas the other two intermediates and 10a
increased at a similar rate until the 50% consumption of 3.
In further reaction, the intermediates decreased with an
increase in 10a. The minor mono-ene isomer should be a
reactive intermediate, which was isolated and assigned as
12, where the stereochemistry at the 10-position was
determined by NOE between H-10 and H-12 (Scheme 3).
MCPBA in dichloromethane at -40 °C was sufficiently
stereocontrolled to give 3 as a single diastereomer (>99%
pure, up to 75% yield, 50-60% on a large scale).6 Since
the oxidation introducing 7-OH and the acetal formation
occur at the same stereoface (anti to the 12-hydroxymethyl
group), the hydroxy group in the PD part of 6 should
effectively direct the peracid to the reaction site.7
Scheme 3. Three Intermediates during the Hydrogenation of 3
to Give 10a
The hydrogenation of 3 can in principle produce four
diastereomers of 10, but when Raney nickel, Pt on alumina,
or Pd on carbon was employed as a catalyst, only two
isomers, 10a and 10b, were produced in a quantitative yield.
Table 1 shows the product selectivity of the hydrogenation
Table 1. Stereochemical Purity of the Product (100 ×
10a/(10a + 10b))a for the Hydrogenation of 3 and Its
Analogues 7-9 in Different Solvents
substrate (R1, R2)
catalyst
MeOH
EtOAc
hexane
Because the hydrogenation of all of the intermediates gave
10a, the structure of the other two intermediates should be
13 and 14, where the stereochemistries at the 8-position are
determined by the chemical conversion of 10a, as will be
shown later. It should be worth noting that all three sets of
the two-step reaction pathways (six independent reactions)
3 (H, H)
RNi
93
97
83
69
68
75
77
90
98
88
83
76
86
78
84
94
96
91
86
76
88
80
87
98
Pt/Al2O3
Pd/C
RNi
Pt/Al2O3
Pd/C
RNi
7 (Ac, Ac)
8 (Ac, H)
9 (H, Ac)
(5) Sugimura, T.; Nishida, F.; Tei, T.; Morisawa, A.; Tai, A.; Okuyama,
T. Chem. Commun. 2001, 2180-2181.
(6) Stereochemistry and purity at the 7-position of 3 was determined by
NMR in comparison with a 7,12-syn-isomer of 3. Details of the diastereomer
preparation will be published elsewhere.
RNi
a Determined by a GLC analysis after conversion to 11.
(7) Sugimura, T.; Nishiyama, N.; Tai, A. Tetrahedron: Asymmetry 1993,
4, 43-44. Sugimura, T.; Iguchi, H.; Tsuchida, R.; Tai, A.; Nishiyama, N.;
Hakushi, T. Tetrahedron: Asymmetry 1998, 9, 1007-1013.
(8) Brown, J. M. In StereoselectiVe Synthesis; Helmchen, G., Hoffmann,
R. W., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol. 7.
pp 4317-4333. Bartok, M. Stereochemistry of Heterogeneous Metal
Catalyst; Wiley: Chichester, 1985; pp 53-290. Nishimura, S. Handbook
of Heterogeneous Catalytic Hydrogenation for Organic Synthesis; Wiley:
New York, 2001; pp 64-147. Rylander, P. N. Hydrogenation Methods;
Academic Press: London, 1985; pp 29-52.
of 3 and its hydroxy-protected substrates, 7-9, in methanol,
ethyl acetate, or hexane.
(4) Sugimura, T.; Nagano, S.; Tai, A. Chem. Lett. 1998, 45-46.
Sugimura, T.; Hagiya, K.; Sato, Y.; Tei, T.; Tai, A.; Okuyama, T. Org.
Lett. 2001, 3, 37-40. Sugimura, T.; Ohuchi, N.; Kagawa, M.; Hagiya, K.;
Okuyama, T. Chem. Lett. 2004, 33, 404-405.
4440
Org. Lett., Vol. 6, No. 24, 2004

are stereocontrolled in the same direction, and the present
high stereoselectivity could not have been achieved if any
one of the six reaction steps could not be controlled.9 Such
a strict stereocontrollability through the hydrogenation is
attributable to the effective cooperation of the steric and polar
interactions between the substrate and the catalyst surface;
the 7-OH is fixed at the axial position to contribute the polar
interaction, while the 12-CH2OH is equatorially placed to
force one of the reaction faces open. The difference between
the 7- and 12-substituents in their conformations must be
due to the difference in the steric hindrance caused by the
acetal ring.10
to be >99% after conversion to 20 via 19. That is, the
obtained 20 showed a single peak based on the chiral
GLC analysis, whereas the racemic 20 prepared from 18 gave
two separate peaks.12 Overall, the optically active 17 was
synthesized in 11 steps from 3,5-dimethylphenol in 22%
yield.13
To disclose the diversity of 10a, the ring-cleavage step
was performed prior to the removal of the hydroxy group at
the 12-methylene. When 21 obtained by the hydrolysis of
10a was treated with lead tetraacetate, the ring cleavage again
proceeded without isomerization to give the diastereomeri-
cally pure 23 in 80% yield (Scheme 5). During this
The stereochemically pure 10a obtained by recrystalliza-
tion was converted to 15 by mono-methanesulfonylation
(73%) and lithium aluminum hydride reduction (91%)
(Scheme 4). The hydrolysis of 15 by the TsOH catalysis in
Scheme 5. Ring Cleavage Prior to Removal of the Hydroxy
Groupa
Scheme 4. Asymmetric Synthesis of 2,4,6-Trimethylheptanoic
Acid Derivativesa
a Reagents and conditions: (a) TsOH/THF/H2O (88%); (b)
Pb(OAc)4/benzene/MeOH (80% for 23, 91% for 26); (c) TBSCl/
imidazole/DMAP (99%); (d) PhLi (58%) or BuLi (78%), and then
TBAF/THF (95% or 50%); (e) NaIO4/AcOH (92% for 26, 87%
for 27).
a Reagents and conditions: (a) MsCl/NEt3/CH2Cl2 (73%); (b)
LiAlH4/ether (65% for 18); (c) TsOH/THF/H2O (79%); (d)
Pb(OAc)4/benzene/MeOH (74%); (e) NaBH4/MeOH (94%); (f)
TBSCl/imidazole/DMF (quant).
conversion, the hydroxymethyl was found to survive without
protection. The product 23 can be a synthon not only for
compounds having a hydroxymethyl group but also for those
having methylene or substituted methyl groups. Switching
of the chirality at the 2-position of 23 by changing the
terminal position from the ester to the hydroxymethyl also
becomes possible.
An alternative use of 10a as a chiral synthon is that another
unit (R′) is introduced prior to the ring cleavage. The two
hydroxy groups of 21 were first protected by the TBS group
(22, 99%). When 22 was treated with phenyllithium in ether
at -78 °C, the adduct was produced as a single stereoisomer
(58%), which was converted to 24 by deprotection (95%).
The 1H NMR spectrum of this adduct is noteworthy because
1
THF/H2O resulted in 16 (79%), the H NMR of which
showed no epimerization unless the reaction time was
prolonged. Oxidative cleavage of the purified 16 with lead
tetraacetate in benzene/methanol11 gave (+)-17 as the sole
product (74%).
The stereochemistries of 17 are 2S,4S because those
positions correspond to 12 and 10 of 10a, respectively. Since
18 obtained by the reduction of 17 is a symmetric compound
showing only six carbons in the NMR, the 6-position of 17
is determined to be R, and thus two methyl groups of the
reactant 10a are both syn to the 12-hydroxymethyl as shown
in Scheme 4. The stereochemical purity of 17 was confirmed
(12) Note that the epimerization of 16 at the R-ketol part during the
formation and the reaction results in an exchange of the keto and alcohol
positions to reduce the stereochemical purities of its derivatives.
(13) Compound 17 can be used for the syntheses of, e.g., borrelidin,a
lardolure,b TCM-151,c and verucopeptin.d (a) Berger, J.; Jampolsky, L. M.;
Goldberg, M. W. Arch. Biochem, 1949, 22, 476-478. (b) Kuwahara, Y.;
Yen, L. T. M.; Tominaga, Y.; Matsumoto, K.; Wada, Y. Agric. Biol. Chem.
1982, 46, 2283-2291. (c) Kohno, J.; Nishio, M.; Sakurai, M.; Kawano,
K.; Hiramatsu, H.; Kameda, N.; Kishi, N.; Yamashita, T.; Okuda, T.;
Komatsubara, S. Tetrahedron 1999, 55, 7771-7786. (d) Sugawara, K.;
Toda, S.; Moriyama, T.; Konishi, M.; Oki, T. J. Antibiotics 1993, 46, 928-
935.
(9) The regioselectivity of the hydrogenation of the conjugated diene is
generally poor to moderate. For an example, see: Kazanskii, B. A.;
Gostunskaya, I. V.; Granat, A. M. IzV. Akad. Nauk SSSR, Otdel. Kim. Nauk
1953, 670-674. See also ref 8.
(10) The stable conformations of 3, 12, 13, and 14 were estimated by
MM3 calculations. Their structures are given in Supporting Information.
(11) Baer, E. J. Am. Chem. Soc. 1942, 64, 1416-1421.
Org. Lett., Vol. 6, No. 24, 2004
4441

tetraacetate (91%). The same procedure, except for the use
of butyllithium instead of phenyllithium, afforded the alkyl-
substituted 25 (78% for two steps), and the ring cleavage
with sodium periodate/acetic acid gave the stereochemically
pure 27 in 87% yield.
In the present study, we have demonstrated that the
optically active cycloheptatriene prepared from 3,5-dimeth-
ylphenol can be converted into several deoxy polypropionate
units under efficient stereocontrol. Judging from the avail-
ability of phenol analogues, the present procedure can be
extended to the synthesis of many other optically active
compounds.
Figure 1. Selected H-H NOE signals observed for the TBS-
protected 24.
all of the ring protons are observed as separate peaks. The
result of the NOESY spectra shown in Figure 1 not only
indicates the stereochemistry of the nucleophilic addition but
also confirms all of the other stereochemistries. In this case,
the ring cleavage to give 26 could be performed both by
sodium periodate with acetic acid (92%) and by lead
Supporting Information Available: Experimental details
and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0483596
4442
Org. Lett., Vol. 6, No. 24, 2004