Stereoselective preparation of syn α-hydroxy-β-amino ester units via regioselective opening of α,β-epoxy esters: Enantioselective synthesis of taxol C-13 side chain and cyclohexylnorstatine

Full text of DOI:10.1021/jo951441h

J . Org. Chem. 1996, 61, 3557-3560
3557
Ster eoselective P r ep a r a tion of Syn
r-Hyd r oxy-â-a m in o Ester Un its via
Regioselective Op en in g of r,â-Ep oxy
Ester s: En a n tioselective Syn th esis of Ta xol
C-13 Sid e Ch a in a n d Cycloh exyln or sta tin e
Giuliana Righi* and Giovanna Rumboldt
Centro CNR per lo Studio della Chimica delle Sostanze
Organiche Naturali, c/ o Dipartimento di Chimica,
Universita` “La Sapienza” P.le A. Moro 5, 00185 Roma, Italy
Carlo Bonini*
Dipartimento di Chimica, Universita` della Basilicata,
Via N. Sauro, 85, 85100 Potenza, Italy
Received August 3, 1995
A number of important compounds that show interest-
ing pharmacological properties possess R-hydroxy-â-
amino ester units within their structures. Such moieties
are present in several peptide enzyme inhibitors such as
bestatin and pepstatin.1 Taxol, a complex natural prod-
uct currently considered to be a promising anticancer
agent,2 bears the (2R,3S)-N-benzoyl-3-phenylisoserine
unit (see Figure 1) in its C-13 side chain and this is
essential to its antitumor activity.3
F igu r e 1.
Sch em e 1
A further example is seen in the structure of KRI-1314
(see Figure 1), one of the renin inhibitors developed for
its promising antihypertensive activity and oral efficacy.4
Its active site contains the (2R,3S)-isopropyl-2-hydroxy-
3-amino-4-cyclohexyl butyrate subunit (cyclohexylnorsta-
tine), essential for the activity of the drug.
Suitable precursors of syn R-hydroxy-â-amino esters
are the cis R-â-epoxy esters of type A (see Scheme 1)
which can be directly opened by nitrogen nucleophiles5
to the corresponding amino or azido alcohols of type B.
This direct approach is viable only if the cis epoxy esters
can be prepared in enantiopure form. However the
Sharpless AE usually fails to give more than 80% ee with
the corresponding Z allylic alcohols.6 The J acobsen
asymmetric epoxidation7 of cis-unsaturated esters8 might
be more promising, although the enantioselectivity of the
reaction varies depending upon the sterics of the sub-
strates.
On the contrary, trans R,â-epoxy esters of type C are
easily obtained in optically enriched form (ee >90%), by
Sharpless AE of the E allylic alcohols and subsequent
oxidation and esterification.9 Then the oxirane ring could
be regio- and stereoselectively opened to an intermediate
of type D with a first inversion of configuration. If the
nucleophile were a good leaving group, then the subse-
quent reaction with an aminating agent would produce
syn R-hydroxy-â-azido (or amino) esters of type B. In
order to achieve this, we looked to recent developments
in the regioselective opening of R,â-epoxy alcohols and
derivatives with metal halides.10 In particular, those
(1) See numerous references in a recent review on â-amino acids:
Cole, D. C. Tetrahedron 1994, 50, 9517.
(2) Kingston, D. G. I. Pharmacol. Ther. 1991, 52, 1. Swindell, C. S.
Org. Prep. Proc. Int. 1991, 23, 465. Bormann, S. Chem. Eng. News
1991, 69 (35), 11; 1992, 70 (41), 30. Potier, P.; Gue`nard, D.; Gue`ritte-
Voegelein, F. Acc. Chem. Res. 1993, 26, 160. Lavelle, F.; Gue`ritte-
Voegelein, F.; Gue`nard, D. Bull. Cancer 1993, 80, 326. Kingston, D.
G. I.; Molinero, A. A.; Rimoldi, J . M. Prog. Chem. Org. Nat. Prod. 1993,
61, Suffness, L. M. In Annual Reports in Medicinal Chemistry; Bristol,
J . A., Ed.; Academic Press: San Diego, 1993; Vol. 28, pp 305-314.
Nicolaou, K. C.; Dai, W-M.; Guy, R. K. Angew. Chem., Int. Ed. Engl.
1994, 33, 15.
(3) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A.
T. J . Am. Chem. Soc. 1971, 93, 2325. Rowinsky, E. K.; Cazenave, L.
A.; Nonehower, R. C. J . Natl. Cancer Inst. 1990, 82, 1247. Mathew, A.
E.; Mejillano, M. R.; Nath, J . P.; Himes, R. H.; Stella, V. J . J . Med.
Chem. 1992, 35, 145.
(4) Iizuka, K.; Kamijo, T.; Harada, H.; Ahakane, K.; Umeyama, H.;
Ishida, T.; Kiso, Y. J . Med. Chem. 1990, 33, 2707.
(5) For amine opening, see: (a) Chong, J . M.; Sharpless, K. B. J .
Org. Chem. 1985, 50, 1560. For azide opening, see: (b) Behrens, C.
H.; Sharpless, K. B. J . Org. Chem. 1985, 50, 5696.
(6) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(7) For a complete overview of the reaction, see: J acobsen, E. N. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers, Inc.:
New York, 1993; p 159.
(8) One of the most successful application of the J acobsen epoxida-
tion on unsaturated cis esters has led to a simple and direct synthesis
of the taxol C-13 side chain: Deng, L.; J acobsen, E. N. J . Org. Chem.
1992, 57, 4320.
11
methods utilizing Lewis acid promoters (i.e., MgI2 or
LiI12) appeared to be the most suitable to effect C-3
opening of 2,3-epoxy alcohols and esters.
11a
MgI2 was first applied to the regio- and stereoselec-
tive opening of 2,3-epoxy esters. Unfortunately, in our
hands this reagent did not give good results with known13
(9) Chong, J . M.; Sharpless, K. B. Tetrahedron Lett. 1985, 26, 4683
and references therein.
(10) See review: Bonini, C.; Righi, G. Synthesis 1994, 225.
(11) (a) Otsubo, K.; Inanaga, J .; Yamaguchi, M. Tetrahedron Lett.
1987, 38, 4435. (b) Bonini, C.; Righi, G.; Sotgiu, G. J . Org. Chem. 1991,
56, 6206. Bonini, C.; Righi, G. Tetrahedron 1992, 48, 1531.
(12) (a) Bonini, C.; Giuliano, C.; Righi, G.; Rossi, L. Synth. Commun.
1992, 22, 1863. (b) Federici, C.; Righi, G.; Rossi, L.; Bonini, C.;
Chiummientu, L.; Funicello, M. Tetrahedron Lett. 1994, 35, 797. These
papers reported the use of LiI with Amberlyst 15 in the regioselective
C-3 oxirane opening of 2,3-epoxy alcohols and derivatives. The ap-
plication of the reported conditions on 2,3-epoxy esters did not give
consistent results. More interestingly, the use of NaI and NaBr in
acetone afforded 2-halo-3-hydroxy esters: Righi, G.; Rumboldt, G.;
Bonini, C. Tetrahedron 1995, 51, 13401.
S0022-3263(95)01441-1 CCC: $12.00 © 1996 American Chemical Society

3558 J . Org. Chem., Vol. 61, No. 10, 1996
Notes
Sch em e 2. En a n tioselective Syn th esis of Ta xol
Ta ble 1. Regioselective C-3 Op en in g of r,â-Ep oxy Ester s
w ith MgBr 2 Eth er a te
Sid e Ch a in
Sch em e 3. En a n tioselective Syn th esis of
Cycloh exyln or sta tin e 19
reagent is commercially available and the reaction pro-
ceeds with clean inversion of configuration by a presumed
SN2 pathway.16
With optically active 3 on hand, we completed13 the
synthesis of the taxol C-13 side chain17 (see Scheme 2)
following previously described procedures17g (see data in
Experimental Section related to the compounds 3, 10, and
11).
The same strategy has also been applied to the
synthesis of cyclohexylnorstatine (see Scheme 3), which
has been the target of other synthetic approaches.18
The synthetic sequence is outlined in Scheme 3,
starting with commercially available alcohol 12. Quan-
titative oxidation to known aldehyde 1318c is followed by
optically active trans methyl cinnamoyl ester 1 (see Table
1). We were utilizing this compound for the synthesis of
the taxol C-13 side chain, as recently described in a
preliminary communication.14 The observed regioselec-
tivity (4:1 in favor of C-3 iodohydrin 2) prompted us to
investigate the alternative use of MgBr2 etherate, a
commercially available reagent. The results with com-
pound 1 were particularly satisfactory. The reaction
could be effected at -60 °C in ether with the quantitative
production of bromohydrin ester 3. This optically en-
riched bromohydrin was therefore used to complete the
synthesis of the taxol side chain.
In order to investigate the scope of this reaction, we
have submitted other trans R,â-epoxy esters (see Table
1, compounds 4, 6, and optically active 8 prepared as
described below) to the reaction conditions (MgBr2 ether-
ate, 1.5 equiv in ether). In all cases the regioselectivity15
and the chemical yields were excellent. Furthermore,
with these compounds the reaction can be carried out at
room temperature without significant loss of regioselec-
tivity and with very short reaction time.
(16) In some instances we observed an enhanced reactivity of the
iodo derivatives toward nucleophilic substitution with azide ion.
However reduced optical yields were also obtained with these com-
pounds. This may arise from an interfering SN1-like pathway or from
“self-displacement” by adventitious iodide ion. The lower reactivity of
the bromo alcohol results in longer reaction times but in a complete,
stereoselective displacement of the bromine by azide ion: Bonini, C.;
Righi, G., unpublished results.
(17) For some of the most recent taxol C-13 side chain syntheses,
see: (a) Denis, J . N.; Greene, A. E.; Serra, A. A.; Luche, M. J . J . Org.
Chem. 1986, 51, 46. (b) Honig, H.; Seufer-Wasserthal, P.; Weber, H.
Tetrahedron 1990, 46, 3841. (c) Denis, J . N.; Carrea, A.; Greene, A. E.
J . Org. Chem. 1990, 55, 1957. (d) Ojima, I.; Habus, I.; Zhao, M.; Georg,
G. I.; J ayasinge, L. R. J . Org. Chem. 1991, 56, 1681. (e) Denis, J . N.;
Carrea; A.; Greene, A. E. J . Org. Chem. 1991, 56, 6939. (f) Bunnage,
M. E.; Davies, S. G.; Goodwin, C. J . J . Chem. Soc., Perkin Trans. 1
1993, 1375. (g) Gou, D.-M.; Liu, Y.-C.; Chen, C.-S. J . Org. Chem. 1993,
58, 1287. (h) Koskinen, Ari, M. P.; Karvinen, E. K.; Siirila, J . P. J .
Chem. Soc., Chem. Commun. 1994, 21. (i) Kearnes, J .; Kayser, M. M.
Tetrahedron Lett. 1994, 35, 2845. (j) Wang, Z.; Kolb, H. C.; Sharpless,
K. B. J . Org. Chem. 1994, 59, 5104. (k) Dondoni, A.; Parroni, D.;
Semola, T. Synthesis 1995, 187.
The use of MgBr2 to obtain bromohydrins by oxirane
opening offers two principal advantages over MgI2: the
(13) Hiang, D.-F. Huang, L. Tetrahedron 1990, 46, 3135.
(14) Bonini, C.; Righi, G. J . Chem. Soc., Chem. Commun. 1994, 2767.
(15) The regioisomeric ratio can be easily determined on the mixture
of the peracetylated products. In the 1H-NMR spectra the acetyl group
in C-3 position (â to the carboxyl group) always resonates at 2.01-
2.03 ppm; on the contrary the acetyl group in C-2 position resonates
downfield at 2.16-2.18 ppm.

Notes
J . Org. Chem., Vol. 61, No. 10, 1996 3559
mixture extracted with EtOAc. The organic layers were evapo-
rated in vacuo, affording a crude mixture of regioisomers (100
mg, 98%). 1H-NMR: δ 7.60-7.20 (5H, m), 5.55 (0.2H, d, J )
2.8 Hz), 5.4 (0.8H, d, J ) 3.9 Hz), 4.65 (bs, OH) 4,.62 (0.8H, d,
J ) 3.88 Hz), 4.03 (0.2H, d, J ) 2.78 Hz), 3.82 (0.6H, s), 3.70
(2.4H, s), 3.10 (0.2H, bs, OH).
standard two-carbon homologation to unsaturated ester
14. Chemoselective reduction with DIBAL to allylic
alcohol 15, followed by AE, leads to epoxy alcohol 16 in
9
>92% ee. The oxidation of compound 16 with RuCl3 to
acid 17 and subsequent esterification produces trans
epoxy ester 8. Both MgBr2-mediated opening to bromo-
hydrin 9 and then azide substitution to produce com-
pound 18 proceed smoothly and with complete inversion
of stereochemistry in each step. The final hydrogenation
of 18 leads to the target compound 19 which shows
spectroscopic data identical to those of the same com-
pound prepared by another route.18c All steps in the
reaction sequence proceed in good to high yield, making
our synthetic approach competitive with the one already
published.
(2S,3R)-Meth yl 2-Hyd r oxy-3-br om o-3-p h en ylp r op ion a te
(3). According to the general procedure with MgBr2 (with the
reaction temperature kept at -60°C), chiral compound 113 (855
mg, 4.8 mmol) afforded pure compound 3 (1.278 g, 98%). [R]D
1
) -134 ° (c 1.1, CHCl3), lit.17g [R]D ) -138 ° (c 1.5, CHCl3). H-
NMR: δ 7.50-7.20 (5H, m), 5.24 (1H, d, J ) 4.0 Hz), 4.68 (1H,
d, J ) 4.3 Hz), 3.70 (3H, s), 3.10 (1H, bs, OH).
(2R,3S)-Meth yl 2-Hyd r oxy-3-a zid o-3-p h en ylp r op ion a te
(10). A mixture of compound 3 (1.278 g, 4.7 mmol) and NaN3
(1.222 g, 18.8 mmol) in DMF (4.7 mL) was stirred at 65 °C for
48 h. The reaction was diluted with EtOAc, washed with water,
dried over Na2SO4, and concentrated. Flash chromatography
(hexanes/EtOAc, 8:2) afforded pure compound 1017g (930 mg,
99%). 1H-NMR: δ 7.70-7.55 (5H, m), 4.86 (1H, d, J ) 2.9 Hz),
4.38 (1H, dd, J ) 2.9 and 6.6 Hz), 3.84 (3H, s), 3.05 (1H, bs,
OH). 13C-NMR: δ 172.5, 135.6, 129.0, 128.9, 127.9, 73.7, 66.9,
52.9.
In conclusion a highly regio- and stereoselective se-
quence from trans R,â-epoxy esters is now available for
the preparation of syn R-hydroxy-â-amino esters.
Exp er im en ta l Section
(2R,3S)-N-Ben zoyl-3-p h en ylisoser in e Meth yl Ester (11).
Compound 10 (930 mg, 4.6 mmol) treated in CH2Cl2 (7 mL) with
DMAP (562 mg, 4.6 mmol) and BzCl (0.57 mL, 4.6 mmol) was
stirred at rt for 1 h. After standard workup, the crude product
was hydrogenated with 10% Pd/C (465 mg) in MeOH (15 mL)
under H2 (50 psi) for 4 h. The solution was then filtered and
allowed to stand at 25 °C for 48 h. Concentration under vacuo
of the solution and crystallization (2% CHCl3/MeOH) afforded
pure compound 11 (1.210 g, 85% from 10). [R]D ) -47.7° (c 1.2,
MeOH), lit.17g [R]D ) -49° (c 1, MeOH). 1H-NMR: δ 7.87-7.70
(5H, m), 7.6-7.13 (8H, m), 7.02 (1H, bd, J ) 5 Hz), 5.72 (1H,
dd, J ) 5 and 1.9 Hz), 4.62 (1H, d, J ) 2.0 Hz), 3.81 (3H, s),
2.75 (1H, bs, OH). 13C-NMR: δ 173.6, 167.1, 138.8, 131.9, 128.8,
128.7, 128.0, 127.5, 127.1, 127.0, 73.1, 54.7, 53.1.
2-Cycloh exyleth a n a l (13). To a solution of commercially
available compound 12 (2 g, 15.6 mmol) in CH2Cl2 (500 mL) was
added PCC (5.16 g, 23.8 mmol). After 3 h, Et2O (150 mL) was
added and the solution was allowed to stir for 1 h. After usual
workup, the combined organic layers were removed by evapora-
tion in vacuo, affording known 1318c (1.941 g, 98%).1H-NMR: δ
9.63 (1H, s), 2.15 (2H, d, J ) 6.5 Hz), 1.97-1.38 (6H, m), 1.32-
0.65 (5H, m). 13C-NMR: δ 202.6, 50.9, 32.7, 32.5, 32.1, 25.5.
(2E)-Eth yl 4-Cycloh exyl-2-bu ten oa te (14). To a solution
of compound 13 (1.941 g, 15.3 mmol) and LiOH (403 mg, 16.8
mmol) in THF (153 mL) was added TEPA (triethyl phospho-
noacetate, 3.796 g, 16.8 mmol). The reaction mixture was
refluxed for 2 h and then quenched with water (20 mL). The
mixture was then extracted with EtOAc (70 mL), and the organic
phase was concentrated in vacuo. Flash chromatography (hex-
anes/EtOAc, 9:1) afforded pure 14 (2.411 g, 80%).1H-NMR: δ
7.00-6.78 (1H, m), 5.73 (1H, dt, J ) 15.5 and 1.4 Hz), 4.11 (2H,
q, J ) 7.1 Hz), 2.15-1.96 (2H, m), 1.84-0.70 (11H, m), 1.12 (3H,
t, J ) 7.1 Hz). 13C-NMR: δ 166.7, 148.1, 122.2, 59.8, 39.9, 37.0,
32.8, 26.0, 25.9, 13.9. Anal. Calcd for C12H20O2: C, 73.43; H,
10.27. Found: C, 73.49; H, 10.22.
Gen er a l. 1H- and 13C-NMR spectra were recorded at 200 and
50.3 MHz, respectively. The enantiomeric excesses of the chiral
compounds were measured by 1H-NMR analysis with Eu(hfc)3
or via Mosher derivatives prepared by standard procedures.
Reactions were monitored by TLC using Merck silica gel 60
F-254 plates with UV indicator or/and visualized with phospho-
molybdic acid (10% solution in EtOH). All the organic layers
were dried over Na2SO4 before concentration in vacuo. Flash
column chromatography on silica gel was normally used for
purification of the reaction mixtures. All solvents were purified
before use with standard drying procedures, unless otherwise
specified. Elemental analyses for C, H, and N are in agreement
with the theoretical data, except for compounds containing
halogens, where combustion analysis could not be performed.
P r ep a r a tion of th e Sta r tin g Ep oxy Ester s. Epoxy esters
113 and 419 are known compounds. Epoxy ester 6 was prepared
according to ref 19; for epoxy ester 8 see below.
(2R*,3S*)-Eth yl 2,3-Ep oxyp en ta n oa te (6). 1H-NMR:
δ
4.03 (2H, q, J ) 7.9 Hz), 3.15-2.85 (2H, m), 1.70-1.30 (2H, m),
1.15 (3H, t, J ) 7.4 Hz), 0.90 (3H, t, J ) 7.8 Hz). 13C-NMR: δ
169.3, 61.1, 59.0, 52.4, 24.1, 13.6, 9.0. Anal. Calcd for
C7H12O3: C, 58.32; H, 8.39. Found: C, 58.39; H, 8.36.
Gen er al P r epar ation of 2-Hydr oxy-3-br om o Ester s: Rep-
r esen ta tive P r oced u r e for th e P r ep a r a tion of (2R*,3S*)-
Meth yl 2-Hyd r oxy-3-br om oh exa n oa te (5). To a solution of
compound 4 (144 mg, 1 mmol) in Et2O (6 mL) was added MgBr2‚
Et2O (193 mg, 1.5 mequiv) was added. The solution was stirred
at rt for 2 h and then washed with brine, and the organic layers
were evaporated in vacuo. The crude mixture was purified by
flash chromatography (hexanes/EtOAc, 9:1), affording pure 5
(220 mg, 98%). 1H-NMR: δ 4.38 (1H, d, J ) 3.1 Hz), 4.25-4.12
(1H, m), 3.80 (3H, s), 3.18 (1H, bd, OH, J ) 7.3 Hz), 2.05-1.10
(4H, m), 0.90 (3H, t, J ) 7.3 Hz). 13C-NMR: δ 171.9, 74.4, 56.6,
52.7, 35.6, 20.7, 13.0.
(2E)-4-Cycloh exyl-2-bu ten -1-ol (15). To a cooled solution
(-78 °C) of compound 14 (2.411 g, 12.24 mmol) in toluene (160
mL) under argon was added DIBAL (16.3 mL of a 1.5 M solution
in toluene, 24.28 mmol) slowly. After 1 h the reaction was
quenched with saturated NH4Cl and the mixture was extracted
with Et2O; the organic layer was then dried over Na2SO4 and
concentrated in vacuo. Flash chromatography (hexanes/EtOAc,
7:3) afforded 15 (1.79 g, 95%). 1H-NMR: δ 5.75-5.42 (2H, m),
4.20 (2H, d, J ) 4.1 Hz), 2.22 (1H, bs, OH), 1.88 (2H, t, J ) 6.3
Hz), 1.80-1.40 (5H, m), 1.38-1.00 (4H, m), 0.99-0.67 (2H, m).
13C-NMR: δ 131.7, 130.1, 63.4, 40.0, 37.6, 32.9, 26.3, 26.1, 13.9.
Anal. Calcd for C10H18O: C, 77.87; H, 11.76. Found: C, 77.94;
H, 11.71.
(2S,3S)-2,3-Ep oxy-4-cycloh exylbu ta n -1-ol (16). To a 250
mL round bottom flask under argon were added Ti(OiPr)4 (3.297
g, 11.6 mmol) and L-(+)-DET (2.628 g, 12.76 mmol) in CH2Cl2
(116 mL) at -23 °C. The solution was allowed to stir for 5 min;
then compound 15 (1.79 g, 11.6 mmol) and successively TBHP
(7.75 mL of a 3 M solution in isooctane, 23.2 mmol) were added.
After 24 h tartaric acid (29 mL of a 10% aqueous solution) was
(2R*,3S*)-Eth yl 2-Hyd r oxy-3-br om op en ta n oa te (7). Ac-
cording to the general procedure with MgBr2, compound 6 (290
mg) afforded pure compound 7 (437 mg, 98%). 1H-NMR:
δ
4.45-4.03 (4H, m), 3.20 (1H, bs, OH), 2.07-1.70 (2H, m), 1.23
(3H, t, J ) 7.3 Hz), 1.04 (3H, t, J ) 7.3 Hz). 13C-NMR: δ 171.5,
74.0, 62.2, 59.0, 27.2, 13.9, 12.3.
(2R*,3S*)-Meth yl 2-Hyd r oxy-3-iod o-3-p h en ylp r op ion a te
(2). A solution of MgI2 in Et2O (0.5 mequiv) was added to
racemic compound 1 (60 mg, 0.33 mmol) under argon at -60
°C. After 2 h, the reaction was quenched with water and the
(18) For recent syntheses of norstatine analogs, see: (a) Iizuka, K.;
Kamijo, T.; Harada, H.; Akahane, K.; Kobata, T.; Umeyama, H.; Ishida,
T.; Kiso, Y. J . Med. Chem. 1990, 33, 2707. (b) Ojima, I.; Park, Y. H.;
Sun, C. M.; Brigaud, T.; Zhao, M. Tetrahedron Lett. 1992, 33, 5737.
(c) Kobayashi, Y.; Takemoto, Y.; Kamjio, T.; Harada, H.; Ito, Y.;
Terashima, S. Tetrahedron 1992, 48, 1853. (d) Hattori, K.; Yamamoto,
H. Tetrahedron 1994, 50, 2785.
(19) Legster, J .; Thijs, L.; Zwanenburg, B. Recl. Trav. Chim. Pays-
Bas 1992, 111, 1.

3560 J . Org. Chem., Vol. 61, No. 10, 1996
Notes
added and the solution was stirred at -23 °C. After 30 min,
the cooling bath was removed and stirring was continued at room
temperature for 1 h until the aqueous layer became clear. After
separation of the aqueous layer, the organic layer was washed
once with water, dried over Na2SO4, and concentrated. This oil
was diluted with Et2O (87 mL) and cooled in a ice bath, and
then NaOH (34 mL of 1 N solution in brine) was added; the two-
phase mixture was stirred at 0 °C for 0.5 h, and then the ether
phase was washed with brine, dried over Na2SO4, and concen-
trated. Flash chromatography (hexanes/EtOAc, 7:3) afforded
pure 16 (1.577 g, 80%). [R]D ) -7.43° (c 0.88, CHCl3). 1H-
NMR: δ 3.83 (1H, dd, J ) 12.6 and 2.5 Hz), 3.50 (1H, dd, J )
12.6 and 4.6 Hz), 2.99-2.67 (2H, m), 2.6 (1H, bs, OH), 1.95-
0.70 (13H, m). 13C-NMR: δ 61.6, 58.7, 54.6, 39.2, 35.5, 33.4,
32.9, 26.1, 26.0, 25.9. Anal. Calcd for C10H18O2: C, 70.55; H,
10.66. Found: C, 70.48; H, 10.69.
(2R,3S)-2,3-Ep oxy-4-cycloh exylbu ta n oic Acid (17). To a
vigorously stirred mixture of compound 16 (1.577 g, 9.28 mmol)
were added NaIO4 (5.96 g, 27.84 mmol) in CCl4 (18.5 mL), CH3-
CN (18.5 mL), H2O (27.8 mL), and RuCl3‚H2O (46 mg, 0.2 mmol).
The mixture was stirred at 20 °C for 2 h; then the acidic material
was carefully extracted at 0 °C into ether, which was dried
briefly over Na2SO4. The residue obtained after evaporation of
the solvents was purified by flash chromatography (hexane/
ether, 9:1) to afford 17 (1.22 g, 71.5%). 1H-NMR: δ 10.83 (1H,
bs, OH), 3.18 (2H, m), 2.06-0.70 (13 H, m). 13C-NMR: δ 175.0,
57.7, 39.0, 35.4, 33.2, 32.7, 26.0, 25.9, 25.8.
(2S,3R)-Isop r op yl 2-Hyd r oxy-3-br om o-4-cycloh exylbu -
ta n oa te (9). According to the general procedure with MgBr2,
compound 8 (1.053 g, 4.64 mmol) gave pure compound 9 (1.40
g, 98%). 1H-NMR: δ 5.23-5.02 (1H, m), 4.45-4.22 (2H, m), 3.20
(1H, bs, OH), 2.02-0.60 (13H, m), 1.22 (6H, d, J ) 6.6 Hz). 13C-
NMR: δ 170.8, 74.4, 70.4, 54.5, 40.7, 35.0, 33.6, 31.5, 26.2, 25.9,
25.7, 21.6, 21.5.
(2R,3S)-Isop r op yl 2-H yd r oxy-3-a zid o-4-cycloh exylb u -
ta n oa te (18). A mixture of 9 (1.40 g, 4.54 mmol) and NaN3
(1.18 g, 18.16 mmol) in DMF (4.54 mL) was stirred at 65 °C for
6 h. The mixture was then diluted with EtOAc, washed with
water, and concentrated in vacuo. Flash chromatography (hex-
anes/ether, 7:3) afforded pure 18 (856 mg, 70%). 1H-NMR: δ
5.26-5.04 (1H, m), 4.09 (1H, dd, J ) 5.5 and 2.4 Hz), 3.62-3.48
(1H, m), 3.07 (1H, d, OH, J ) 5.4 Hz), 1.90-0.72 (13H, m), 1.23
(6H, d, J ) 6.5 Hz). 13C-NMR: δ 172.5; 73.2; 70.5; 60.5; 37.1;
34.2; 33.3; 32.7; 26.2; 26.0; 25.9; 21.5.
(2R,3S)-Isop r op yl 2-Hyd r oxy-3-a m in o-4-cycloh exylbu -
ta n oa te (19). A mixture of 18 (856 mg, 3.17 mmol) was
hydrogenated with 10% Pd/C (85.6 mg) in EtOAc (8.6 mL) under
H2 for 4 h; then the solution was filtered and concentrated in
vacuo. Flash chromatography (hexanes/EtOAc, 1:1) afforded
pure compound 19 (618 mg, 80%). [R]D ) -21.8° (c 0.32, CHCl3),
lit.18c [R]D ) -22° (c 1.18, CHCl3). 1H-NMR: δ 5.2-5.02 (1H,
m), 3.95 (1H, d, J ) 2.6 Hz), 3.18-3.09 (1H, m), 1.85-0.72 (16H,
m), 1.25 (6H, d, J ) 6.5 Hz). Anal. Calcd for C13H25NO3: C,
64.16; H, 10.36; N, 5.76. Found: C, 64.09; H, 10.39; N, 5.78.
(2R,3S)-Isop r op yl 2,3-Ep oxy-4-cycloh exylbu ta n oa te (8).
To an ice bath cooled solution of 17 (1.220 g, 6.63 mmol) in CH2-
Cl2 (9.28 mL) and iPrOH (2.13 mL, 27.8 mmol) was added DCC
(2.167 g, 10.2 mmol) under stirring. After 5 min the solution
was allowed at rt for 3 h; then it was filtered, washed with HCl
(2 mL of 0.5 N solution) and then with saturated NaHCO3, and
filtered again. The organic phase was concentrated in vacuo
and purified by flash chromatography (hexanes/EtOAc, 9:1),
affording pure 8 (1.053 g, 70%). 1H-NMR: δ 5.15-4.95 (1H, m),
3.20-3.02 (2H, m), 1.85-0.75 (13H, m), 1.22 (6H, d, J ) 6.2 Hz).
13C-NMR: δ 169.1, 69.0, 57.0, 53.2, 39.0, 35.5, 33.2, 32.7, 26.0,
25.9, 25.8, 21.5, 21.4. Anal. Calcd for C13H22O3: C, 68.99; H,
9.8. Found: C, 68.90; H, 10.1.
Ack n ow led gm en t. This work was partially sup-
ported by a 40% MURST grant and by CNR Progetto
Finalizzato “Chimica Fine e Secondaria”.
Su p p or tin g In for m a tion Ava ila ble: 1H- and 13C-NMR
spectra (21 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O951441H