An efficient protocol for the preparation of primary alcohols bearing a β-chiral center via an oxazolidinone auxiliary mediated resolution, and application to the synthesis of 4,4-disubstituted piperidine substance P antagonists

Full text of DOI:10.1021/jo9918246

J . Org. Chem. 2000, 65, 2615-2618
2615
An Efficien t P r otocol for th e P r ep a r a tion
of P r im a r y Alcoh ols Bea r in g a â-Ch ir a l
Cen ter via a n Oxa zolid in on e Au xilia r y
Med ia ted Resolu tion , a n d Ap p lica tion to
th e Syn th esis of 4,4-Disu bstitu ted
P ip er id in e Su bsta n ce P An ta gon ists
F igu r e 1.
Richard T. Lewis,* Tamara Ladduwahetty,*
Kevin J . Merchant, Linda E. Keown, Laure Hitzel,
Hugh Verrier, Graeme I. Stevenson, and
Angus M. MacLeod
Sch em e 1a
Neuroscience Research Centre, Merck Sharp and Dohme
Research Laboratories, Terlings Park, Eastwick Road,
Harlow, Essex, CM20 2QR, UK
Received November 29, 1999
The role of the neuropeptide substance P in the
physiological responses associated with the transmission
of pain, and the induction of inflammation as a result of
noxious stimuli, has received considerable attention in
recent years.1,2 It has been suggested that suitable
substance P receptor antagonists may be of significant
clinical utility in the treatment of a range of clinical
conditions, including arthritis,3 migraine,4 and in control-
ling the emesis induced by a variety of cytotoxic agents.5
Furthermore, recent clinical findings suggest significant
potential as a novel treatment for depression.6 As a result
of extensive interest in this field, a number of structurally
diverse classes of substance P receptor antagonists are
now known, including a class of 4,4-disubstituted pip-
eridines developed in these laboratories.7
a
Reagents: (i) p-NO2PhSO2N3, DBU, CH3CN, -5 °C; (ii) 2,
Rh2(OAc)4, PhH, 80 °C; (iii) LiBH4, MeOH; (iv) Ac2O, Py.
advanced intermediate (1). This necessitated develop-
ment of an expedient route to the preparation, in homo-
chiral form, of a bis(trifluoromethyl)benzyl ether bearing
a pendant hydroxymethyl substituent at the benzylic
position, from alcohol 2 (Figure 1). At the onset of this
work we were not aware of which enantiomer was
required and so chose to pursue a resolution strategy
which could provide access to either enantiomer at will.
In this paper we describe an expedient route for prepara-
tion of homochiral 1 on a multigram scale.
As a consequence of our interest in this structural
class, we required access to significant quantities of an
(1) Salter, M. W.; Henry, J . L. Neuroscience 1991, 43, 601.
(2) Laird, J . M. A.; Hargreaves, R. J .; Hill, R. G. Br. J . Pharmacol.
1993, 109, 713.
(3) Walsh, D. A.; Mapp, P. I.; Terenghi, G.; Chen, S. T.; Cruwys, S.
C.; Garrett, N.; Kidd, B. L.; Polak, J . M.; Blake, D. R. Neuroscience
1993, 57, 1091.
(4) Shepheard, S. L.; Williamson, D. J .; Williams, J .; Hill, R. G.;
Hargreaves, R. J . Neuropharmacology 1995, 34, 255.
(5) Tattersall, F. D.; Rycroft, W.; Francis, B.; Pearce, D.; Merchant,
K.; MacLeod, A. M.; Ladduwahetty, T.; Keown, L.; Swain, C.; Baker,
R.; Cascieri, M.; Ber, E.; Metzger, J .; MacIntyre, D. E.; Hill, R. G.;
Hargreaves, R. J . Neuropharmacology 1996, 35 , 1121.
(6) Kramer, M. S.; Cutler, N.; Feighner, J .; Shrivastava, R.; Carman,
J .; Sramek, J .; Reines, S.; Liu, G.; Snavely, D.; Wyatt-Knowles, E.;
Hale, J .; Mills, S.; Maccoss, M.; Swain, C.; Harrison, T.; Hill, R.; Hefti,
F.; Scolnick, E. M.; Cascieri, M.; Chicchi, G.; Sadowski, S.; Williams,
A.; Hewson, L.; Smith, D.; Carlson, E.; Hargreaves, R. J .; Rupniak, N.
Science 1998, 281 (5383), 1640.
(7) (a) Stevenson, G. I.; MacLeod, A. M.; Huscroft, I.; Cascieri, M.
A.; Sadowski, S.; Baker, R. J . Med. Chem. 1995, 38, 1264. For
additional examples, see Patent Appl. WO 95/19344. (b) Taber, D.;
Gleave, D. M.; Herr, R. J .; Moody, K.; Hennessy, M., J . Org. Chem.
1995, 60, 2283. While we have experienced no difficulties with the
preparation or subsequent reaction of diazo compound 4 on the scale
reported, and 4 appears to be stable to prolonged storage at -18 °C (5
years), the usual precautions against explosion when handling organic
azides and organic diazo compounds should be observed. For prepara-
tion of diazo-transfer reagents, including an excellent discussion of the
hazards and safety considerations in their handling and usage, see
Bollinger, F. W.; Tuma, L. D. Synlett 1996, 407. Diazo compound 4
has been subjected to differential scan calorimetry which indicates that
the compound melts in the region of 48-50 °C, with a heat of fusion
of 66.53 J /g, which is not especially large. TGA analysis indicates a
moderate rate of decomposition above the melting point, presumably
by loss of nitrogen, with a 7.6% weight loss. Diazo compounds flanked
by two electron-withdrawing π-systems are generally observed to be
relatively stable entities.
An attractive option appeared to be construction of the
ether linkage via transition metal catalyzed carbene
insertion into the readily available7 alcohol 2, followed
by reduction of the resulting ester 3 and subsequent
resolution by derivatization of the primary alcohol. The
required R-diazo ester 4, a stable crystalline solid, was
prepared in 92% yield, on multigram scale, by diazo-
transfer from p-nitrophenylsulfonyl azide, mediated by
DBU (Scheme 1).7b p-Nitrophenylsulfonyl azide was
found to be superior to other reagents such as trisyl azide,
in that it is readily purified by crystallization, and the
sulfonamide byproduct of diazo-transfer is easily removed
due to the greater polarity and hence enhanced aqueous
solubility of its sodium salt. Upon slow addition of the
R-diazo ester 4 to 1.75 equiv of alcohol 2 in benzene at
reflux in the presence of catalytic rhodium acetate, a
smooth insertion reaction occurred to afford desired ether
3 in 70-85% yield, isolated from the recoverable excess
of alcohol by a simple chromatographic separation. Boro-
hydride reduction of the ester of 3 proceeded cleanly to
afford the desired racemic alcohol (()-1. This route
10.1021/jo9918246 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/25/2000

2616 J . Org. Chem., Vol. 65, No. 8, 2000
Notes
Sch em e 2a
a
Reagents: (i) KOH, MeOH:H2O (60:1), 0 °C; (ii) (COCl)2, DCM, cat. DMF; (iii) EDC, HOBT, (+)-R-methylbenzylamine; (iv) Me3CCOCl,
Et3N, DCM; (v) (a) THF, nBuLi, (S)-(-)-4-benzyl-2-oxazolidinone, -78 °C, (b) 8, PhMe; (vi) LiBH4, THF, H2O.
proved to be amenable to the rapid preparation of 100 g
batches of 3.
alcohols without loss of stereochemical integrity.11 The
acid 7 was converted to (S)-(-)-4-benzyl-2-oxazolidinone
derivative 11 via the action of the lithio salt of the
oxazolidinone on acid chloride 8 in 54% overall yield from
methyl ester 3. Preparation of the imides using the
pivalic anhydride12 intermediate 10 resulted in far lower
yields. The Rf difference between the two resulting
diastereoisomers 11A and 11B was sufficient to make
them readily separable on ca. 20 g scale. Reduction with
lithium borohydride to yield alcohol 1 was significantly
improved upon the addition of 1 equiv of water.14 Reduc-
tion of the more polar imide (diastereoisomer 11B)
derived from (S)-(-)- 4-benzyl oxazolidinone gave (-)1
in 97% ee and 88% yield, whereas reduction of the less
polar imide (diastereoisomer 11A) gave (+)-1 in only 88%
ee. Hence the (R)-(+)-benzyl oxazolidinone was chosen
as the preferred auxiliary for the synthesis of the desired
(+)-enantiomer, since in this case it would be derived
from the more polar imide and therefore retain a higher
degree of stereochemical integrity during the reduction,
to afford (+)-1 in 97% ee15 as assessed by HPLC.16
Removal of the Boc protecting group with methanolic HCl
allows crystallization of the amine hydrochloride salt.
To improve the efficiency of the route, racemization of
the undesired diastereoisomer 11A to provide more of the
desired diastereoisomer 11B was examined. The two
flanking electron-withdrawing groups should render the
chiral center prone to epimerization. A range of bases
were screened for their ability to induce racemization of
diastereomer 11A. Strong bases such as LDA apparently
caused decomposition of the starting material. Conditions
used by Evans et al. for the generation of the boron
enolates13 from similar imides, however, resulted in a
clean racemization to a 1:1 mixture of diastereoisomers
With a reliable route to alcohol (()-1 in hand, attention
was focused upon the resolution strategy. A number of
potential approaches to the resolution of a primary
alcohol bearing a â-chiral center were considered worthy
of exploration. A variety of derivatizing agents for the
chromatographic resolution of alcohols have been re-
ported in the literature; however, many are most effective
for secondary alcohols.8 Attempts to resolve the primary
alcohol (()-1 by coupling it with a variety of chiral
auxiliaries failed to provide a practical means of separa-
1
tion of the resulting diastereoisomers. Furthermore, H
NMR (360 MHz) also failed to show resolved spectra of
the mixture of diastereoisomers. The derived acetate 6,
after cleavage of the N-Boc protecting group, was resolved
enzymatically by iterative treatment with porcine pan-
creatic lipase,9 and subsequent reprotection afforded
(+)-1 in high enantiomeric excess (98% ee), but only 10
mg of the homochiral alcohol was obtained from 850 mg
of the racemic mixture. Although this route was not
viable for the large-scale synthesis of (+)-1, it did allow
us to establish that the biological activity resided prin-
cipally with compounds which were derived from the
(+)-enantiomer of 1.
Derivatization of the acid 7 was then examined as an
alternative approach; it was found that the menthyl ester
1
offered resolved H NMR spectra of the diastereoisomers,
but separation by chromatography under a variety of
conditions was not feasible. In contrast, the R-methyl
benzamide diastereoisomers 9 were readily separable by
chromatography, but conversion to homochiral alcohol 1
under mild conditions was not achievable. Reasoning that
the notable Rf difference between the diastereoisomeric
amides may be due to the more conformationally con-
strained nature of the amide bond as compared with the
ester, other chiral auxiliaries that confer a similar degree
of torsional rigidity were examined. Diastereoisomeric
imides derived from chiral oxazolidinones have previously
been suggested as being easily separable by chromatog-
raphy.10 It is also well documented that oxazolidinone
imides can be reduced to the corresponding primary
(10) Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J . Am. Chem. Soc.
1985, 107, 4346.
(11) Baker, R.; Cummings, W. J .; Hayes, J . F.; Kumar, A. J . Chem.
Soc., Chem Commun. 1986, 1237.
(12) Evans, D. A.; Weber, A. E. J . Am. Chem. Soc. 1986, 108, 6757.
(13) Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E.
Tetrahedron Lett. 1987, 28, 39.
(14) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J .;
Miyashiro, J . M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20,
307.
(15) After installation of the desired N-substituent (see ref 7), a
single crystallization typically raised the ee of the product above 99.5%.
(16) Enantiomeric purity was determined on a Diacel Chiralpak AD
column, eluent 3% ethanol in hexane @ 1.5 mL min-1 @ 40 °C,
monitored at 210 nM.
(8) J acques, J .; Collet, A.; Wilen, S. H. Enantiomers, Racemates and
Resolutions; J ohn Wiley & Sons: New York, 1981, 332 and references
therein.
(9) Guanti, G.; Banfi, L.; Narisano, E. J . Org. Chem. 1992, 57, 1540.

Notes
J . Org. Chem., Vol. 65, No. 8, 2000 2617
eluent 80% CH3CN/0.1% aqueous trifluoroacetic acid @ 1 mL/
min monitored at 210 nM).
11. Furthermore, it was observed that the action of
triethylamine alone, in DCM at room temperature,
resulted in a 1.8:1 ratio of 11B to 11A, presumably
reflecting thermodynamic control. Hence, iterative treat-
ment of the undesired diastereomer with triethylamine
resulted in almost complete conversion of the material
to the desired diastereoisomer.17
N-{2-[(N-ter t-Bu t oxyca r b on yl-4-p h en ylp ip er id in -4-yl)-
m eth oxy]-2-(3,5-bis(tr iflu or om eth yl)p h en yl)a cetyl}-4(R)-
ben zyl-2-oxa zolid in on e (11). To a solution of methyl ester 3
(11 g, 0.019 mol) in methanol (100 mL) at 0 °C was added KOH
(3.2 g, 0.057 mol), followed by water (3 mL). The homogeneous
solution was stirred at 0 °C for 1 h. The methanol was removed
in vacuo and pH 4 buffer (100 mL) added to the residue. The
product was extracted into Et2O, dried (MgSO4), and evaporated
in vacuo. The resulting white foam (10.6 g) was dissolved in
anhydrous DCM (50 mL). DMF (0.5 mL) was added followed by
oxalyl chloride (2.23 mL, 25.7 mmol) dropwise. After stirring at
25 °C for 0.5 h, the solvent was removed in vacuo. The resulting
residue was azeotroped with toluene (50 mL) and then, as a
solution in anhydrous toluene (40 mL), added at -78 °C to the
lithium anion of (4R)-4-benzyl-2-oxazolidinone (generated by
adding n-BuLi (11.8 mL, 1.6 M, 18.8 mmol) to a solution of (4R)-
(+)-4-benzyl-2-oxazolidinone (3.34 g, 18.8 mmol) in THF (100
mL) at -78 °C and stirring for 0.5 h). The resulting colorless
solution was stirred at -78 °C for a further 0.75 h and quenched
by addition of Et2O (400 mL), and sat. NH4Cl aq (30 mL). The
organic layer was dried (MgSO4). The clear oil obtained after
removal of solvent in vacuo was chromatographed on silica gel
(eluent 20% ethyl acetate/hexane to obtain diastereomer 11A
(3.4 g, 25%), and then 30% ethyl acetate/hexane to obtain
diastereomer 11B (4.0 g, 29%), as colorless foams.
Dia ster eoisom er 11A. 1H NMR (400 MHz, CDCl3) δ 7.81
(1H, s), 7.70 (2H, s), 7.34-7.19 (10H, m), 5.94 (1H, s), 4.58 (1H,
m), 4.17 (2H, m), 3.77 (2H, m), 3.67 (1H, d, J ) 9 Hz), 3.31 (1H,
d, J ) 9 Hz), 3.28 (1H, m), 3.02 (2H, m), 2.79 (1H, m), 2.19 (2H,
m), 1.90 (2H, m) 1.43 (9H, s). 13C NMR (100 MHz, CDCl3) δ
168.91, 154.97, 152.82, 141.81, 138.38, 134.69, 131.74 (q, J C-F
) 33 Hz), 129.41, 129.06, 128.56, 128.50, 127.58, 127.15, 126.63,
123.08 (q, J C-F ) 273 Hz), 122.81 (m), 79.37, 79.21, 78.20, 66.69,
55.45, 41.63, 40 (br m, CH2N), 37.74, 31.84 (br m), 31.37 (br m),
28.42. 19F NMR (376.36 MHz, CDCl3) δ -63.14. m/e (ES+) 721
(MH+), 665 (MH+ - (CH3)2CCH2)), 621(MH+ - Boc). Anal. Calcd
for C37H38F6N2O6: C, 61.66; H, 5.31; N, 3.88%. Found: C, 61.97;
H, 5.28; N, 3.88%.
In summary we have described a practical and high-
yielding route to multigram quantities of 1, relying on a
diazo-insertion strategy which permits a highly conver-
gent synthesis, followed by an effective resolution protocol
which exploits the acyloxazolidinone moiety as a sur-
rogate for a primary alcohol.
Exp er im en ta l Section
Gen er a l P r oceed u r es. NMR spectra were recorded at 300
K. Flash column chromatography was carried out on silica gel
(E. Merck Art 7734). “Petroleum ether” refers to petroleum ether
with bp 60-80 °C. Reagents and dry solvents were purchased
from Fluka or Aldrich and used without further purification.
Glassware was dried at 130-150 °C prior to use, and reactions
were performed under an atmosphere of dry nitrogen unless
otherwise specified. Organic solvents were evaporated on a
rotary evaporator at reduced pressure. Elemental analyses were
determined by Butterworth Laboratories Ltd., Teddington,
England.
Meth yl 2-Dia zo-2-(3,5-bis(tr iflu or om eth yl)p h en yl)a ce-
t a t e (4). To a solution of methyl 3,5-bis(trifluoromethyl)-
phenylacetate (5) (53.0 g, 184 mmol) and 4-nitrobenzenesulfonyl
azide (42 g, 184 mmol) in dry acetonitrile (250 mL), cooled to
-10 °C, was added DBU (30.0 g, 196 mmol) dropwise over 30
min with stirring, and the mixture was stirred at -10 °C for a
further 0.5 h. The solvents were evaporated at reduced pressure,
and the residue was partitioned between ether and water. The
organic layer was washed with sat. NaHCO3 aq, dried (Na2SO4),
and evaporated, and residue was chromatographed on silica gel
(eluent 2.5% Et2O/ hexane) to afford 4 (52.8 g, 92%) as yellow
prisms (significant exotherm when oil crystallizes). 1H NMR (400
MHz, CDCl3) δ 7.95 (2H, s), 7.65 (1H, s), 3.91 (3H, s). 13C NMR
(100 MHz, CDCl3) δ 164.3, 132.3(q, J C-F 33 Hz), 129.1, 123.1(q,
J C-F 271 Hz), 123.0(m), 119.1(m), 52.4. 19F NMR (376.36 MHz,
CDCl3) δ -63.55. m/e (ES+) 284 (M - N2). IR (film, NaCl) 1740,
2140 cm-1. HPLC purity > 99.2% by two systems (TSKgel Super
ODS 100 × 4.6 mm column [supplied by Fisher Scientific], eluent
40% H2O/ CH3CN @ 1 mL/min; Supelco Discovery 150 × 4.6 mm
column [supplied by Supelco U.K.], eluent 35% H2O/ CH3CN @
1 mL/min monitored at 210 nM).
Dia ster eoisom er 11B. 1H NMR (400 MHz, CDCl3) δ 7.85
(1H, s), 7.77 (2H, s), 7.34-7.16 (8H, m), 6.95 (2H, m), 5.93 (1H,
s), 4.69 (1H, m), 4.25 (1H, m), 4.17 (1H, m), 3.77 (2H, m), 3.61
(1H, d, J ) 8.7 Hz), 3.29 (1H, d, J ) 8.7 Hz), 3.04 (3H, m), 2.62
(1H, m), 2.17 (2H, m), 1.89 (2H, m) 1.43 (9H, s). 13C NMR (100
MHz, CDCl3) δ 168.97, 154.95, 152.86, 141.78, 138.43, 134.28,
131.81 (q, J C-F ) 33 Hz), 129.21, 128.88, 128.52, 127.49, 127.17,
126.61, 123.09 (q, J C-F ) 273 Hz), 122.78 (m), 79.37, 79.27, 78.24,
66.77, 55.11, 41.63, 40 (br m, CH2N), 37.31, 31.80 (br m), 31.39
(br m), 28.42. 19F NMR (376.36 MHz, CDCl3) δ -63.14. m/e (ES+)
721 (MH+), 665 (MH+ - (CH3)2CCH2)), 621 (MH+ - Boc). Anal.
Calcd for C37H38F6N2O6: C, 61.66; H, 5.31; N, 3.88%. Found:
C, 61.57; H, 5.32; N, 3.75%.
Meth yl 2-[(N-ter t-Bu toxyca r bon yl-4-p h en ylp ip er id in -4-
yl)m eth oxy]-2-(3,5-bis(tr iflu or om eth yl)p h en yl)a ceta te (3).
Slow addition (over 60 h via syringe pump) of the R-diazo ester
4 (49.26 g) as a solution in benzene (50 mL) to alcohol 27 (80 g,
1.75 equiv) in benzene (150 mL) at reflux under nitrogen, in the
presence of catalytic rhodium acetate (100 mg, 0.15 mol %),
afforded, after evaporation and chromatography of the residue
on silica gel (eluent 25% to 40% Et2O/ hexane), ester 3 (62.5 g,
70%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.79 (1H,
s), 7.70 (2H, s), 7.35 (4H, m), 7.25 (1H, m), 4.67 (1H, s), 3.79
(2H, m), 3.69 (3H, s), 3.67 (1H, d, J ) 9 Hz), 3.37 (1H, d, J ) 9
Hz), 3.04 (2H, m), 2.31 (1H, m), 2.19 (1H, m), 1.91 (2H, m), 1.44
(9H, s). 13C NMR (100 MHz, CDCl3) δ 169.87, 154.97, 141.79,
138.97, 131.73(q, J C-F ) 33 Hz), 128.58, 127.17, 126.96 (m),
126.66, 123.14 (q, J C-F ) 273 Hz), 122.37 (m), 79.96, 79.53, 79.39,
52.60, 41.72, 40 (br m, CH2N), 31.88, 31.4, 28.4. 19F NMR (376.36
Diastereomer 11A (3.0 g) and dry triethylamine (5 mL) in
DCM (50 mL) was allowed to stand at 25 °C for 16 h. The
solvents were evaporated, and the mixture was separated by
chromatography as described above to obtain diastereomer 11B
(1.85 g). Diastereomer 11A (1.0 g) was also recovered.
(+)-2-[(N-ter t-Bu toxyca r bon yl-4-p h en ylp ip er id in -4-yl)-
m eth oxy]-2-(3,5-bis(tr iflu or om eth yl)p h en yl)eth a n ol (+1).
Diastereomer 11B (1.8 g, 2.5 mmol) was dissolved in diethyl
ether (50 mL) and cooled to 0 °C under a nitrogen atmosphere.
Water (0.05 mL, 2.75 mmol) was added, followed by lithium
borohydride (0.054 g, 2.5 mmol). The reaction was stirred at 0
°C for 0.75 h and quenched by addition of 1 N NaOH (50 mL).
The mixture was extracted with ethyl acetate, and the organic
solutions were washed with brine, dried (MgSO4), filtered and
evaporated in vacuo. The residue was purified by chromatog-
raphy on silica gel eluting with 20% ethyl acetate/hexane to
obtain (+)-1 (1.2 g, 88%, 97% ee) as a white foam: RD +31.1° (c
) 1; CH2Cl2), 1H NMR (400 MHz, CDCl3) δ 7.78 (1H, s), 7.52
(2H, s), 7.40-7.32 (4H, m), 7.27 (1H, m), 4.29 (1H, m), 3.76 (2H,
m), 3.50 (2H, m), 3.41 (1H, d, J ) 8.8 Hz), 3.34 (1H, d, J ) 8.8
Hz), 3.04 (2H, m), 2.24 (2H, m), 1.83 (3H, m), 1.44 (9H, s). 13C
NMR (100 MHz, CDCl3) δ 154.94, 142.03, 141.53, 131.88 (q, J C-F
MHz, CDCl3) δ -63.29. m/e (ES+) 576 (MH+), 520 (MH+
-
(CH3)2CCH2)), 476 (MH+ - Boc). HPLC purity > 97.8% by two
systems (TSKgel Super ODS 100 × 4.6 mm column [supplied
by Fisher Scientific], eluent 70% CH3CN/0.1% aqueous trifluo-
roacetic acid @ 1 mL/min; ACE 3C18 150 × 4.6 mm column
(17) As yet we have been unable to prepare crystalline derivatives
of 11 or 1 suitable for X-ray structural determination of the absolute
configuration.
) 33 Hz), 128.70, 126.95, 126.78, 126.68 (m), 123.13 (q, J C-F
)

2618 J . Org. Chem., Vol. 65, No. 8, 2000
Additions and Corrections
273 Hz), 122.06 (m), 82.30, 79.49, 79.06, 66.82, 41.71, 40 (br m,
CH2N), 31.92 (br m), 28.42 ppm. 19F NMR (376.36 MHz, CDCl3)
δ -63.26. m/e (ES+) 548 (MH+), 492 (MH+ - (CH3)2CCH2)), 448
(MH+ - Boc). HPLC purity > 99.5% by two systems (Hypersil
Hypurity 150 × 4.6 mm column, eluent 62% CH3CN/H2O @ 1
mL/min; Supelco Discovery 150 × 4.6 mm column, eluent 50%
CH3CN/H2O @ 1 mL/min monitored at 210 nM). Anal. Calcd for
C27H31F6N1O4: C, 59.23; H, 5.71; N, 2.56%. Found: C, 59.32;
H, 5.80; N, 2.46%.
Ack n ow led gm en t. We thank Mr. J ames McCabe
for his valuable assistance with obtaining differential
scan calorimetric measurements on diazo compound 4.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 1, 3, 4, 11A, and 11B. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O9918246
Additions and Corrections
Vol. 64, 1999
Yva n Le Hu e´r ou , J u lien Doyon , a n d Ren e´ L. Gr e´e*.
Stereocontrolled Synthesis of Key Advanced Intermediates
toward Simplified Acetogenin Analogues.
Page 6784, Scheme 2. (+)-Solketal and subsequent
derivatives have been represented with the configuration
opposite to that of the optical rotation shown. The
experimental section which describes the synthesis of
both enantiomers is, however, correct. Scheme 2 and all
subsequent pictorial material should be corrected as
shown below. We thank Dr. R. E. Dardis for bringing this
mistake to our attention and we apologize to the readers
for this error.
Sch em e 2
J O994015V
10.1021/jo994015v
Published on Web 03/30/2000