A new diastereoselective synthesis of a 1β-methylcarbapenem intermediate

Article abstract of DOI:10.1039/a907922j

A 1β-methylcarbapenem key intermediate is synthesized from methyl (R)- 3-hydroxybutyrate via the diastereoselective alkylation and regioselective cuprate ring opening of a chiral epoxide which is readily prepared from Sharpless asymmetric epoxidation of the corresponding allylic alcohol.

Full text of DOI:10.1039/a907922j

A new diastereoselective synthesis of a 1b-methylcarbapenem
intermediate
Chang-Young Oh and Won-Hun Ham*
College of Pharmacy, SungKyunKwan University, Suwon 440-746, Korea. E-mail: whham@speed.skku.ac.kr
Received (in Cambridge, UK) 1st October 1999, Accepted 13th October 1999
A 1b-methylcarbapenem key intermediate is synthesized
from methyl (R)-3-hydroxybutyrate via the diastereose-
lective alkylation and regioselective cuprate ring opening of
a chiral epoxide which is readily prepared from Sharpless
asymmetric epoxidation of the corresponding allylic alco-
hol.
methyl (R)-3-hydroxybutyrate 4 followed by a short trans-
formation.
Thus, methyl ester 4, available in high enantiomeric purity,
was converted into the allylic alcohol 7 as shown in Scheme 2.
To this end, b-hydroxy ester 4 was alkylated with benzyloxy-
methyl chloride (BOMCl). Generally, alkylation of the dianions
of such b-hydroxy esters has been shown to yield products of
high diastereomeric excess with predictable stereoselectivity,
but in this case alkylation with BOMCl afforded the benzyl
ether with moderate stereoselectivity (ca. 10:+1) and low
conversion yield (ca. 50%).4–6 Fortunately, there was a
dramatic improvement both in conversion yield and diastereo-
meric ratio (70% and 35+1) when we added HMPA as an
additive.7 The secondary alcohol of the resulting benzyl ether 6
was protected as an TBDMS ether in high yield and the ester
was subsequently reduced to the corresponding alcohol 6 with
DIBAL-H at 278 °C. Swern oxidation of 6 afforded the
aldehyde, which without purification was subjected to a Horner
olefination with triethyl phosphonoacetate under the conditions
developed by Masamune and Roush.8 to give the a,b-
unsaturated ester with complete E-selectivity. Reduction of the
E-unsaturated ester using DIBAL-H at 278 °C produced the
allylic alcohol 7. The epoxidation of this allylic alcohol under
Sharpless conditions employing d-(2)-diisopropyl tartrate as
stereodirecting ligand gave rise to the epoxide 3 with excellent
diastereoselectivity (15+1). The stage was now set to introduce
the fourth chiral center in 3 and for this we made use of the
ubiquitous high order cuprate protocol; the highly regio-
selective opening of the epoxide with Me2Cu(CN)Li2 gave the
1,3-diol. The primary hydroxy group of the resulting diol was
selectively protected as a TBDMS ether to give 8.
The discovery that 1b-methylcarbapenem has potent and broad-
spectrum antibacterial activitiy as well as enhanced metabolic
and chemical stability1 has prompted many synthetic organic
chemists to develop efficient methods for the stereoselective
synthesis of the key 1b-methyl intermediate 1, and recent
reviews describe impressive progress in this area.2, 3
Our approach to the enantioselective synthesis of 1 relies on
regioselective ring opening of chiral epoxy alcohol 3, which is
readily available from Sharpless asymmetric epoxidation of the
allylic alcohol (Scheme 1). This allylic alcohol 7, containing
two stereocenters which are requisite for key intermediate 1,
could be easily obtained from diastereoselective alkylation of
The conversion of 8 to 9 was accomplished by a four step
sequence. Mesylation of the secondary alcohol followed by
Scheme 1
Scheme 2 Reagents and conditions: i, LDA (2 equiv.), BOMCl, HMPA, 278 °C, 70%; ii, TBDMSCl, imidazole, DMF, 90%; iii, DIBAL-H, Et2O, 278 °C,
86%; iv, (COCl)2, DMSO, Et3N, CH2Cl2, 265 to 255 °C; v, (MeO)2POCH2CO2Me, LiCl, Pri2NEt, MeCN, 84% for 2 steps; vi, DIBAL-H, Et2O, 278 °C,
95%; vii, Ti(OPri)4, d-(2)-diisopropyl tartrate, ButOOH, 76.5%; viii, Me2Cu(CN)Li2, Et2O, 220 to 0 °C, 72.4%; ix, TBDMSCl, Et3N, DMAP, CH2Cl2,
84.4%; x, MsCl, pyridine, 97.7%; xi, NaN3, DMF, 76.4%; xii, Pd(OH)2, H2 (1 atm,), MeOH, EtOAc; xiii, ClCO2Bn, NaHCO3, Et2O, 0 °C, 51% for 2 steps;
xiv, (COCl)2, DMSO, Et3N, CH2Cl2, 265 to 55 °C; xv, NaClO2, 2-methylbut-2-ene, NaH2PO4, H2O, ButOH, 71% for 2 steps; xvi, Pd-black, MeOH, H2
(1 atm); xvii, (PyS)2, PPh3, MeCN, reflux, 79% for 2 steps.
Chem. Commun., 1999, 2365–2366
This journal is © The Royal Society of Chemistry 1999
2365

sequential azide substitution, reduction of the corresponding
azide under Pd/C and the protection of the amino group with
ClCO2Bn afforded 9 in 41% overall yield in four steps.
Unfortunately attempts, including Mitsunobu conditions, to
directly convert the alcohol to amine stereospecifically were not
successful. This result may be due to the steric hindrance
present in 8. Swern oxidation of 9 led to the b-amino aldehyde,
which was further oxidized to the corresponding acid 10 with
NaClO2. Finally removal of the Z group by catalytic hydro-
genation followed by cyclization using Ohno’s conditions9
furnished the known key intermediate 11.10–12 The phys-
icochemical properties of 11 obtained by the present synthesis
were in complete agreement with those reported in the literature
{[a]D27 27.8755 (c 0.53, CHCl3) [lit,12 [a]2D227.8777 (c 1.03,
CHCl3)]}.
In summary, we report a new synthetic method for the 1b-
methylcarbapenem key intermediate from commercially availa-
ble methyl (R)-3-hydroxybutyrate 4. The key features in this
strategy are the diastereoselective alkylation of the dianion of
the b-hydroxy ester, Sharpless asymmetric epoxidation and
subsequent regioselective cuprate ring opening of the chiral
epoxide.
Notes and references
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3 For a review, see: A. H. Berks, Tetrahedron, 1996, 52, 331 and
references cited therein.
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7 Details will be published in full elsewhere.
8 M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masamune,
W. R. Roush and T. Sakai, Tetrahedron Lett., 1984, 25, 2183.
9 S. Kobayashi, T. Iimori, T. Izawa and M. Ohno, J. Am. Chem. Soc.,
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12 N. Tsukada, T. Shimada, Y. S. Gyoung, N. Asao and Y. Yamamoto,
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The financial support provided by the GITP is gratefully
acknowledged.
Communication 9/07922J
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Chem. Commun., 1999, 2365–2366