Formal, Stereoselective Synthesis of Hydroxyethylene Dipeptide Isosteres Utilizing Pseudoephedrine Amides

Full text of DOI:10.1021/jo9707951

7872
J . Org. Chem. 1997, 62, 7872-7876
Sch em e 1a
F or m a l, Ster eoselective Syn th esis of
Hyd r oxyeth ylen e Dip ep tid e Isoster es
Utilizin g P seu d oep h ed r in e Am id es
Peter S. Dragovich,* Thomas J . Prins, and Ru Zhou
Agouron Pharmaceuticals Inc., 3565 General Atomics Court,
San Diego, California 92121
Received May 5, 1997
(2R,4S,5S)-Hydroxyethylene dipeptide isosteres (1) are
frequently utilized in the synthesis of nonpeptidic enzyme
inhibitors and many methods for their preparation have
been developed.1 One such method involves conversion
a
Reagents and conditions: (a) 2.1 equiv of LDA, 7.0 equiv of
LiCl, THF, -78 f 0 °C, 1 h, then 1.5 equiv of BnBr, 0 °C, 30 min,
76%; (b) 1.1 equiv of NBS, 5.0 equiv of AcOH, 4:1 THF:H2O, 0 °C,
15 min, then reflux 1 h, 65%; (c) 2.0 equiv of NaN3, DMF, 50 °C,
20 h, 52%; (d) H2, Pd/C, CH3OH, 23 °C, 2 h, then 2.0 equiv of (i-
Pr)2NEt, 1.5 equiv of (Boc)2O, 1,4-dioxane, 23 °C, 2 h, 62%.
of appropriately substituted bromo γ-lactones (2) to the
desired isosteres. The lactones, in turn, have previously
been synthesized from enantiomerically enriched γ,δ-
unsaturated dimethylamides (3a ) or acyloxazolidinones
(3b).2,3 Herein we report that optically active bromo
γ-lactone precursors of (2R,4S,5S)-hydroxyethylene dipep-
tide isosteres can also be conveniently prepared from
diastereomerically pure γ,δ-unsaturated pseudoephe-
drine amides. This method offers several potential
advantages over the previously reported syntheses of
such compounds.
with the acid chloride derived from trans-7-methyloct-4-
enoic acid4 provided the corresponding N-acylated prod-
uct 4 (93%) in accordance with literature precedent.5
Alkylation of the dianion of 4 with benzyl bromide in the
presence of excess lithium chloride afforded benzylated
product 5 in 76% yield and 98% de after purification on
silica gel.5,6 Treatment of 5 in a mixture of THF:H2O (4:
1) containing acetic acid (5 equiv) at 0 °C with a slight
excess of N-bromosuccinimide followed by reflux for 1 h
provided bromo γ-lactone 6 as a single isomer in 65%
yield after chromatographic purification.7,8 A nonpolar
intermediate was observed by TLC during the conversion
of 5 to 6, but attempts to isolate and identify this entity
were unsuccessful due to its instability on silica gel (see
below). Minor amounts of several other compounds were
also formed during the bromolactonization reaction, but
these side products were neither isolated nor character-
ized. Compound 6 was subsequently transformed2a into
aminolactone 8 (via azide 7) from which compounds of
structure 1 can be prepared by a variety of literature
methods.9
The following example illustrates the new procedure
(Scheme 1). Coupling of (1R,2R)-(-)-pseudoephedrine
The possibility of employing amides derived from
(1S,2S)-(+)-pseudoephedrine in the construction of
(1) For recent preparations of (2R,4S,5S)-hydroxyethylene dipeptide
isosteres and leading references, see: (a) Askin, D.; Wallace, M. A.;
Vacca, J . P.; Reamer, R. A.; Volante, R. P.; Shinkai, I. J . Org. Chem.
1992, 57, 2771. (b) Wuts, P. G. M.; Ritter, A. R.; Pruitt, L. E. J . Org.
Chem. 1992, 57, 6696. (c) J ones, D. M.; Nilsson, B.; Szelke, M. J . Org.
Chem. 1993, 58, 2286. (d) Ciapetti, P.; Taddei, M.; Ulivi, P. Tetrahedron
Lett. 1994, 35, 3183. (e) Pe´gorier, L.; Larcheve´que, M. Tetrahedron
Lett. 1995, 36, 2753. (f) Peyrat, J .-F.; Chaboche, C.; Figade´re, B.; Cave´,
A. Tetrahedron Lett. 1995, 36, 2757. (g) Chakraborty, T. K.; Hussain,
K. A.; Thippeswamy, D. Tetrahedron 1995, 51, 3873. (h) Dondoni, A.;
Perrone, D.; Semola, M. T. J . Org. Chem. 1995, 60, 7927.
(2) (a) Herold, P.; Duthaler, R.; Rihs, G.; Angst, C. J . Org. Chem.
1989, 54, 1178. (b) Bradbury, R. H.; Revill, J . M.; Rivett, J . E.;
Waterson, D. Tetrahedron Lett. 1989, 30, 3845. (c) Bradbury, R. H.;
Major, J . S.; Oldham, A. A.; Rivett, J . E.; Roberts, D. A.; Slater, A. M.;
Timms, D.; Waterson, D. J . Med. Chem. 1990, 33, 2335.
(3) For related studies on the electrophilic cyclization of γ,δ-
unsaturated amides, see: (a) Tamaru, Y.; Mizutani, M.; Furukawa,
Y.; Kawamura, S.-i.; Yoshida, Z.-i.; Yanagi, K.; Minobe, M. J . Am.
Chem. Soc. 1984, 106, 1079. (b) Najdi, S.; Reichlin, D.; Kurth, M. J . J .
Org. Chem. 1990, 55, 6241. (c) Yokomatsu, T.; Iwasawa, H.; Shibuya,
S. J . Chem. Soc., Chem. Commun. 1992, 728. (d) Moon, H.-s.;
Eisenberg, S. W. E.; Wilson, M. E.; Schore, N. E.; Kurth, M. J . J . Org.
Chem. 1994, 59, 6504.
(4) trans-7-Methyloct-4-enoic acid was prepared in 41% yield from
isovaleraldehyde by the following sequence: (i) CH2dCHMgBr, THF,
0 °C; (ii) diethyl malonate, Ti(OEt)4, 190 °C; (iii) KOH, EtOH, reflux.
See ref 2a.
(5) (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J . L. J . Am.
Chem. Soc. 1994, 116, 9361. (b) Myers, A. G.; Yang, B. H.; Chen, H.;
McKinstry, L.; Kopecky, D. J .; Gleason, J . L. J . Am. Chem. Soc. 1997,
119, 6496. See also: Myers, A. G.; McKinstry, L. J . Org. Chem. 1996,
61, 2428.
(6) The diastereomeric excess was determined by HPLC analysis
and comparison to an independently prepared 1:1 mixture of both
diastereomers. See the Supporting Information for additional details.
(7) The assignment of the major product as bromo γ-lactone 6 is
based on IR absorbance data and the characteristic coupling pattern
in the 1H NMR spectrum. See: Tayyeb Hussain, S. A. M.; Ollis, W.
D.; Smith, C.; Stoddart, J . F. J . Chem. Soc., Perkin Trans. 1 1975,
1480 and ref 2a.
(8) No attempt was made to isolate the pseudoephedrine produced
in this step.
(9) For representative examples, see: (a) Evans, B. E.; Rittle, K.
E.; Homnick, C. F.; Springer, J . P.; Hirshfield, J .; Veber, D. F. J . Org.
Chem. 1985, 50, 4615. (b) Vacca, J . P.; Guare, J . P.; deSolms, S. J .;
Sanders, W. M.; Giuliani, E. A.; Young, S. D.; Darke, P. L.; Zugay, J .;
Sigal, I. S.; Schleif, W. A.; Quintero, J . C.; Emini, E. A.; Anderson, P.
S0022-3263(97)00795-0 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 22, 1997 7873
known2 bromo γ-lactone 14 was undertaken (Scheme 2).
Alkylation of amide 11, prepared in 96% yield from
(1S,2S)-(+)-pseudoephedrine and isovaleryl chloride, with
(trans-4-bromobut-2-enyl)cyclohexane10 provided 12 in
70% yield and 97% de after purification on silica gel.5,6
As before, treatment of 12 in a mixture of THF:H2O (4:
1) containing acetic acid (5 equiv) at 0 °C with N-
bromosuccinimide rapidly afforded a nonpolar interme-
diate which underwent subsequent conversion to the
desired bromo γ-lactone (14) at elevated temperature
(reflux). However, unlike the examples described above,
a much longer reflux period (14 h) was required to effect
complete disappearance of this intermediate (see below).
Purification of the bromolactonization products by flash
column chromatography provided an inseparable mixture
of the desired trans-lactone 14, the corresponding cis-
lactone 15, and the regioisomeric δ-lactone 16 (configu-
ration undetermined) in a 22:2:1 ratio (79% combined
yield).8,11 Similar isomer ratios and product yields were
observed in previous preparations of 14.2
Sch em e 2a
a
Reagents and conditions: (a) 2.1 equiv of LDA, 7.0 equiv of
LiCl, THF, -78 f 0 °C, 1 h, then 1.5 equiv of trans-(CH3)2CHC-
H2CHdCHCH2Br, 0 °C, 2 h, 75%; (b) 1.1 equiv of NBS, 5.0 equiv
of AcOH, 4:1 THF:H2O, 0 °C, 1 h, then reflux 2 h, 68%; (c) 2.1
equiv of LDA, 7.0 equiv of LiCl, THF, -78 f 0 °C, 1 h, then 1.4
equiv of trans-CyCH2CHdCHCH2Br, 0 °C, 15 min, 70%; (d) 1.05
equiv of NBS, 5.0 equiv of AcOH, 4:1 THF:H2O, 0 °C, 15 min, then
reflux 14 h, 79%.
Due to the greater stability of the intermediate ob-
served in the preparation of 14, it was possible to isolate
this entity by silica gel chromatography. 1H and 13C
NMR data as well as a mass spectral analysis of the
purified material were consistent with the spirocyclic
structure 13 (Scheme 2).12 The slow conversion of this
species to the desired bromo γ-lactone is presumably due
to the steric bulk of the isopropyl substituent adjacent
to the hydrolysis center. Similar intermediates are
presumably involved in the bromolactonization reactions
of γ,δ-unsaturated amides 5 and 10, but in these less-
hindered cases hydrolysis proceeds at a much more rapid
rate.
As demonstrated above, γ,δ-unsaturated pseudoephe-
drine amides can be efficiently transformed into the
bromo γ-lactone precursors of (2R,4S,5S)-hydroxyethyl-
ene dipeptide isosteres. Some potential advantages of
the current method over previous syntheses of such
bromo γ-lactones include (1) the ready availability and
relatively low cost of either enantiomer of pseudoephe-
drine, (2) the ability of pseudoephedrine amide enolates
to undergo high-yielding, highly diastereoselective al-
kylations with a wide variety of electrophiles,5 and (3)
the ability to utilize either pseudoephedrine enantiomer
as a chiral auxiliary and thus involve either γ,δ-unsatur-
ated amide diastereomer in isostere synthesis. We
believe that the above methodology represents a reliable
and general means to prepare peptidomimetic compounds
and expect that it will find use in organic synthesis.
(2R,4S,5S)-hydroxyethylene dipeptide isosteres was also
investigated (Scheme 2). Specifically, we sought to
prepare compound 6 utilizing (1S,2S)-(+)-pseudoephe-
drine, although such preparation necessitated nucleo-
philic and electrophilic species which differed from those
described in the example above. Thus, coupling of
(1S,2S)-(+)-pseudoephedrine with hydrocinnamoyl chlo-
ride afforded amide 9 in good yield (71%) after purifica-
tion by recrystallization.5 Alkylation of the dianion of 9
with trans-1-bromo-5-methylhex-2-ene10 using the condi-
tions described previously for the preparation of 5
provided 10 (the diastereomer of 5) in 75% yield and 96%
de after purification on silica gel.5,6 This material was
subjected to the bromolactonization conditions outlined
above and afforded bromo γ-lactone 6 in 68% yield
(contaminated with 5% of an isomeric lactone of unde-
termined configuration) after flash column chromatog-
raphy.8 Thus, it appears that either enantiomer of
pseudoephedrine may be utilized for bromo γ-lactone
synthesis, although some minor variability in yield and
purity of the desired products may be observed.
In order to more rigorously quantitate the amounts of
side products formed during the above bromolactoniza-
tion reaction and to better compare the new procedure
with existing literature methods, the synthesis of the
Exp er im en ta l Section 13
S.; Huff, J . R. J . Med. Chem. 1991, 34, 1225. (c) Lyle, T. A.; Wiscount,
C. M.; Guare, J . P.; Thompson, W. J .; Anderson, P. S.; Darke, P. L.;
Zugay, J . A.; Emini, E. A.; Schleif, W. A.; Quintero, J . C.; Dixon, R. A.
F.; Sigal, I. S.; Huff, J . R. J . Med. Chem. 1991, 34, 1228. (d) Reference
2.
(10) trans-1-Bromo-5-methylhex-2-ene and (trans-4-bromobut-2-
enyl)cyclohexane were prepared from isovaleraldehyde (52%) and
cyclohexylacetaldehyde (63%), respectively, by the following se-
quence: (i) CH2dCHMgBr, THF, 0 °C; (ii) SOBr2, 1,5-hexadiene,
ClCH2CH2Cl, 0 °C. Each product contained 10% of an isomeric
bromide. See ref 2a.
All reactions were performed in septum-sealed flasks under
a slight positive pressure of argon unless otherwise noted. All
(11) The product ratios and identities were determined from 1H
NMR signals (CDCl3) as follows: 14: 4.43 ppm (m); 15: 4.30 ppm (m),
16: 4.52 ppm (m). See ref 2a.
(12) The stereochemistry of the spirocyclic center is assumed to
result from kinetic addition of the pseudoephedrine hydroxyl moiety
opposite the isopropyl substituent.

7874 J . Org. Chem., Vol. 62, No. 22, 1997
Notes
commercial reagents were used as received from their respective
suppliers with the following exceptions. Tetrahydrofuran (THF)
was distilled from sodium benzophenone ketyl prior to use.
Dichloromethane (CH2Cl2) was distilled from calcium hydride
prior to use. Anhydrous lithium chloride was prepared by
heating at 110 °C under vacuum overnight. 1H NMR and 13C
NMR spectra were recorded at 300 and 75 MHz, respectively,
and chemical shifts are reported in ppm (δ) relative to internal
tetramethylsilane. Melting points (uncorrected) were deter-
mined using a Mel-Temp II apparatus.
min at 0 °C and then was warmed to 23 °C and subsequently
refluxed for 1 h. After being cooled to 23 °C, the reaction mixture
was partitioned between half-saturated NaHCO3 (300 mL) and
a 1:1 mixture of EtOAc and hexanes (2
200 mL). The
combined organic layers were dried over Na2SO4 and were
concentrated. Careful flash chromatographic purification of the
residue (5% EtOAc in hexanes) gave 6 (7.09 g, 65%) as a pale
yellow oil: Rf ) 0.79 (30% EtOAc in hexanes); [R]25 ) +25.2 (c
D
) 0.84, CH3OH); IR (cm-1) 1777; 1H NMR (CDCl3, coupling
constants were obtained from a homonuclear 2DJ spectrum) δ
0.87 (d, 3 H, J ) 6.5 Hz), 0.94 (d, 3 H, J ) 6.9 Hz), 1.53-1.72
(m, 2 H), 1.82-1.93 (m, 1 H), 2.15 (ddd, 1 H, J ) 15.0, 8.3, 6.8
Hz), 2.30 (ddd, 1 H, J ) 15.0, 9.9, 5.1 Hz), 2.83 (dd, 1 H, J )
13.9, 9.0 Hz), 3.10 (dddd, 1 H, J ) 9.9, 8.8, 6.8, 5.0 Hz), 3.18
(dd, 1 H, J ) 13.9, 5.0 Hz), 4.08 (ddd, 1 H, J ) 9.7, 6.1, 3.7 Hz),
4.27 (ddd, 1 H, J ) 8.1, 6.1, 3.7 Hz), 7.20-7.36 (m, 5 H); 13C
NMR (CDCl3) δ 20.7, 23.1, 25.8, 30.6, 36.8, 41.0, 43.1, 56.2, 79.9,
126.9, 128.7, 128.9, 137.8, 178.0. Anal. Calcd for C16H21BrO2:
C, 59.09; H, 6.51. Found C, 59.01; H, 6.53.
tr a n s-(1′R,2′R)-7-Meth yloct-4-en oic Acid (2′-Hyd r oxy-1′-
m eth yl-2′-p h en yleth yl)m eth yl Am id e (4). Oxalyl chloride
(2.71 mL, 31.1 mmol, 1.05 equiv) was added to a solution of
trans-7-methyloct-4-enoic acid4 (4.62 g, 29.6 mmol, 1 equiv) and
N,N-dimethylformamide (0.03 mL, 0.39 mmol, 0.012 equiv) in
benzene (100 mL) at 23 °C. The reaction mixture was stirred
at 23 °C for 2 h and then was concentrated under reduced
pressure. The resulting oil was dissolved in THF (20 mL) and
was added via cannula to a solution of (1R,2R)-(-)-pseudoephe-
drine (4.45 g, 26.9 mmol, 0.91 equiv) and triethylamine (4.50
mL, 32.3 mmol, 1.1 equiv) in THF (200 mL) at 0 °C. The reaction
mixture was stirred at 0 °C for 30 min, then was partitioned
(1′S,3R,5S)-5-(1′-Azid o-3′-m eth ylbu tyl)-3-ben zyld ih yd r o-
fu r a n -2-on e (7). A suspension of sodium azide (2.83 g, 43.5
mmol, 2.0 equiv) and 6 (7.09 g, 21.8 mmol, 1 equiv) in N,N-
dimethylformamide (50 mL) was heated at 50 °C for 20 h. The
reaction mixture was cooled to 23 °C and was partitioned
between water (200 mL) and a 1:1 mixture of EtOAc and hexanes
between half-saturated NH4Cl (150 mL) and EtOAc (2
150
mL). The combined organic layers were dried over Na2SO4 and
concentrated, and the residue purified by flash column chroma-
tography (gradient elution 40 f 50% EtOAc in hexanes) to afford
4 (7.55 g, 93%) as a viscous oil: Rf ) 0.27 (50% EtOAc in
(2
200 mL). The combined organic layers were dried over
Na2SO4 and concentrated, and the residue was purified by flash
column chromatography (10% EtOAc in hexanes) to give 7 (3.26
g, 52%) as a colorless oil: Rf ) 0.47 (20% EtOAc in hexanes);
[R]25D ) +10.2 (c ) 1.2, CH3OH); IR (cm-1) 2109, 1775; 1H NMR
(CDCl3) δ 0.93 (d, 3 H, J ) 6.5 Hz), 0.94 (d, 3 H, J ) 6.5 Hz),
1.32-1.41 (m, 1 H), 1.55-1.65 (m, 1 H), 1.70-1.85 (m, 1 H),
2.03-2.18 (m, 2 H), 2.80 (dd, 1 H, J ) 13.5, 8.9 Hz), 3.05-3.22
(m, 2 H), 3.27-3.33 (m, 1 H), 4.22-4.27 (m, 1 H), 7.18-7.36 (m,
5 H); 13C NMR (CDCl3) δ 21.6, 22.8, 24.6, 29.8, 36.7, 38.8, 40.6,
62.8, 79.2, 126.8, 128.6, 128.8, 137.8, 178.0. Anal. Calcd for
C16H21N3O2: C, 66.88; H, 7.37; N, 14.62. Found: C, 66.68; H,
7.29; N, 14.47.
hexanes); [R]25 ) -70.3 (c ) 0.97, CH3OH); IR (cm-1) 3382,
D
1
1622; H NMR (CDCl3, mixture of rotamers) δ 0.87 (d, J ) 6.5
Hz), 0.99 (d, J ) 6.8 Hz), 1.11 (d, J ) 7.2 Hz), 1.53-1.66 (m),
1.86 (t, J ) 6.1 Hz), 2.26-2.54 (m), 2.82 (s), 2.92 (s), 3.99-4.04
(m), 4.29 (s, br), 4.42-4.47 (m), 4.56-4.62 (m), 5.37-5.51 (m),
7.26-7.36 (m); 13C NMR (CDCl3, mixture of rotamers) δ 14.4,
15.3, 22.2, 26.7, 28.0, 28.3, 28.4, 32.7, 33.7, 34.4, 41.8, 58.3, 75.4,
76.4, 126.4, 126.8, 127.5, 128.2, 128.3, 128.6, 129.6, 129.9, 130.0,
130.1, 141.3, 142.4, 173.6, 174.8. Anal. Calcd for C19H29NO2:
C, 75.21; H, 9.63; N, 4.62. Found: C, 75.31; H, 9.63; N, 4.55.
tr a n s-(1′R,2S,2′R)-2-Ben zyl-7-m eth yloct-4-en oic Acid (2′-
Hyd r oxy-1′-m eth yl-2′-p h en yleth yl)m eth yl Am id e (5). n-
Butyllithium (52.6 mL of a 1.6 M solution in hexanes, 84.2 mmol,
2.1 equiv) was added to a suspension of anhydrous lithium
chloride (11.9 g, 282 mmol, 7.0 equiv) and diisopropylamine (12.7
mL, 90.3 mmol, 2.25 equiv) in THF (300 mL) at -78 °C. The
reaction mixture was stirred for 20 min at -78 °C maintained
at 0 °C for 5 min, and subsequently cooled again to -78 °C. A
solution of 4 (12.2 g, 40.1 mmol, 1 equiv) in THF (40 mL) was
added via cannula, and the resulting solution was stirred at -78
°C for 1 h, was maintained at 0 °C for 15 min, was stirred at 23
°C for 5 min, and then was cooled again to 0 °C. Benzyl bromide
(7.15 mL, 60.1 mmol, 1.5 equiv) was added, and the reaction
mixture was stirred at 0 °C for 30 min and then was partitioned
between half-saturated NH4Cl (200 mL) and a 1:1 mixture of
EtOAc and hexanes (2 200 mL). The combined organic layers
were dried over Na2SO4 and were concentrated. Purification of
the residue by flash column chromatography (gradient elution
20 f 40% EtOAc in hexanes) provided 5 (12.0 g, 76%) as a
(1S,2′S,4′R)-[1-(4′-Ben zyl-5′-oxo-t et r a h yd r ofu r a n -2′-yl)-
3-m eth ylbu tyl]ca r ba m ic Acid ter t-Bu tyl Ester (8). A sus-
pension of 7 (3.26 g, 11.3 mmol, 1 equiv) and Pd/C (10%, 0.40 g)
in CH3OH (60 mL) was stirred under a hydrogen atmosphere
(balloon) for 2 h. The reaction mixture was filtered through
Celite and concentrated and the residue dissolved in 1,4-dioxane
(80 mL). N,N-Diisopropylethylamine (3.94 mL, 22.6 mmol, 2.0
equiv) and di-tert-butyl dicarbonate (3.70 g, 17.0 mmol, 1.5 equiv)
were added sequentially, and the resulting solution was stirred
at 23 °C for 2 h. The reaction mixture was then partitioned
between water (150 mL) and a 1:1 mixture of EtOAc and hexanes
(2
150 mL). The combined organic layers were dried over
Na2SO4 and were concentrated. Purification of the residue by
flash column chromatography (gradient elution, 10 f 15%
EtOAc in hexanes) provided 8 (2.53 g, 62%) as a white solid:
mp ) 84-86 °C; Rf ) 0.66 (30% EtOAc in hexanes); [R]25
)
D
-19.9 (c ) 1.4, CH3OH); IR (cm-1) 3338, 1767, 1704; H NMR
(CDCl3) δ 0.89 (d, 3 H, J ) 6.5 Hz), 0.90 (d, 3 H, J ) 6.5 Hz),
1.18-1.32 (m, 1 H), 1.40 (s, 9 H), 1.43-1.56 (m, 1 H), 1.98-2.07
(m, 1 H), 2.20-2.29 (m, 1 H), 2.78 (dd, 1 H, J ) 13.7, 9.0 Hz),
2.91-3.01 (m, 1 H), 3.15 (dd, 1 H, J ) 13.7, 4.4 Hz), 3.71-3.81
(m, 1 H), 4.23-4.28 (m, 1 H), 4.34 (d, 1 H, J ) 9.7 Hz), 7.16-
7.33 (m, 6 H); 13C NMR (CDCl3) δ 21.6, 22.8, 24.5, 28.1, 29.3,
36.7, 41.4, 51.2, 66.8, 79.4, 80.5, 126.6, 128.5, 128.6, 137.9, 155.8,
178.9. Anal. Calcd for C21H31NO4: C, 69.77; H, 8.64; N, 3.87.
Found: C, 69.78; H, 8.70; N, 3.81.
1
viscous oil: Rf ) 0.54 (50% EtOAc in hexanes); [R]25 ) -18.6
D
(c ) 0.86, CH3OH); IR (cm-1) 3382, 1617; 1H NMR (CDCl3,
mixture of rotamers) δ 0.81-0.90 (m), 1.42-1.61 (m), 1.80-1.95
(m), 2.17-2.25 (m), 2.33-2.54 (m), 2.55 (s), 2.73-2.99 (m), 3.05-
3.16 (m), 3.93-4.00 (m), 4.31-4.51 (m), 5.25-5.56 (m), 7.14-
7.37 (m); 13C NMR (CDCl3, mixture of rotamers) δ 14.2, 15.5,
22.2, 22.3, 27.0, 28.3, 32.2, 36.2, 36.5, 39.0, 41.9, 44.6, 45.3, 58.3,
75.1, 76.2, 126.2, 126.4, 126.6, 126.9, 127.6, 127.8, 128.3, 128.3,
128.5, 128.6, 128.9, 129.2, 132.1, 132.2, 139.8, 140.4, 140.9, 142.1,
176.0, 177.3. Anal. Calcd for C26H35NO2: C, 79.35; H, 8.96; N,
3.56. Found: C, 79.35; H, 9.01; N, 3.50.
(1′S,2′S)-N-(2′-Hydr oxy-1′-m eth yl-2′-ph en yleth yl)-N-m eth -
yl-3-p h en ylp r op ion a m id e (9). A solution of hydrocinnammoyl
chloride (15.7 mL, 106 mmol, 1.15 equiv) in THF (20 mL) was
added via cannula over 10 min to a solution of (1S,2S)-(+)-
pseudoephedrine (15.22 g, 92 mmol, 1 equiv) and triethylamine
(16.7 mL, 119.6 mmol, 1.3 equiv) in THF (200 mL) at 0 °C. After
being stirred at 0 °C for 30 min, the reaction mixture was
quenched with H2O (10 mL) and was partitioned between EtOAc
(100 mL) and brine (3 100 mL). The organic layer was dried
over Na2SO4 and was concentrated to afford a yellow solid.
Recrystallization from toluene afforded 9 (19.5 g, 71%) as a white
solid: mp ) 102-104 °C; Rf ) 0.48 (50% EtOAc in hexane); IR
(1′R,3R,5S)-3-Ben zyl-5-(1′-b r om o-3′-m et h ylb u t yl)d ih y-
d r ofu r a n -2-on e (6). N-Bromosuccinimide (5.97 g, 33.5 mmol,
1.1 equiv) was added in small portions over 5 min to a solution
of 5 (12.0 g, 30.5 mmol, 1 equiv) and glacial acetic acid (8.73
mL, 152 mmol, 5.0 equiv) in a 4:1 mixture of THF and H2O (250
mL) at 0 °C. The resulting yellow solution was stirred for 15
(13) General experimental procedures and instrumentation are
described in the following: Dragovich, P. S.; Prins, T. J .; Zhou, R. J .
Org. Chem. 1995, 60, 4922.

Notes
J . Org. Chem., Vol. 62, No. 22, 1997 7875
1
(KBr pellet, cm-1) 3396, 1814, 1450; H NMR (CDCl3, mixture
of rotamers) δ 0.92 (d, J ) 6.9 Hz), 1.08 (d, J ) 6.9 Hz), 2.57-
2.67 (m), 2.77 (s), 2.94-3.02 (m), 7.21-7.35 (m); 13C NMR
(CDCl3, mixture of rotamers) δ 14.4, 15.2, 26.9, 31.1, 31.5, 32.4,
35.4, 36.1, 58.2, 75.4, 76.4, 126.0, 126.1, 126.4, 126.8, 127.6,
128.3, 128.3, 128.4, 128.4, 128.4, 128.6, 141.1, 141.2, 141.5, 142.2,
173.2, 174.4. Anal. Calcd for C19H23NO2: C, 76.74; H, 7.79; N,
4.71. Found: C, 76.82; H, 7.83; N, 4.67.
tr a n s-(1′S,2S,2′S)-6-Cycloh exyl-2-isop r op ylh ex-4-en oic
Acid (2′-H yd r oxy-1′-m et h yl-2′-p h en ylet h yl)m et h yla m id e
(12). n-Butyllithium (6.67 mL of a 1.6 M solution in hexanes,
10.7 mmol, 2.1 equiv) was added to a suspension of anhydrous
lithium chloride (1.52 g, 35.9 mmol, 7.0 equiv) and diisopropyl-
amine (1.60 mL, 11.4 mmol, 2.25 equiv) in THF (10 mL) at -78
°C. The reaction mixture was stirred for 20 min at -78 °C,
maintained at 0 °C for 5 min, and subsequently cooled again to
-78 °C. A solution of 11 (1.27 g, 5.09 mmol, 1 equiv) in THF
(15 mL) was added dropwise via cannula over 10 min. After
the mixture was stirred for 1 h, the reaction vessel was warmed
to 0 °C for 15 min, then to 23 °C for 5 min, and then cooled
again to 0 °C. (trans-4-Bromobut-2-enyl)cyclohexane10 (1.43 g,
7.12 mmol, 1.4 equiv) was added dropwise, and the reaction
mixture was stirred for 15 min at 0 °C and then was subse-
quently partitioned between saturated NH4Cl (45 mL) and
tr a n s-(1′S,2S,2′S)-2-Ben zyl-7-m eth yloct-4-en oic Acid (2′-
Hyd r oxy-1′-m eth yl-2′-p h en yleth yl)m eth yl Am id e (10). n-
Butyllithium (11.42 mL of a 1.6 M solution in hexanes, 18.27
mmol, 2.1 equiv) was added to a solution of anhydrous lithium
chloride (2.57 g, 60.6 mmol, 7.0 equiv) and diisopropylamine
(2.74 mL, 19.58 mmol, 2.25 equiv) in THF (100 mL) at -78 °C.
The reaction mixture was stirred for 20 min at -78 °C,
maintained at 0 °C for 5 min, and subsequently cooled again to
-78 °C. An ice-cooled solution of 9 (2.59 g, 8.7 mmol, 1 equiv)
in THF (20 mL) was added via cannula over 5 min. The reaction
mixture was stirred at -78 °C for 1 h, at 0 °C for 15 min, and
at 23 °C for 5 min and then was cooled to 0 °C. A solution of
trans-1-bromo-5-methylhex-2-ene10 (2.31 g, 13.05 mmol, 1.5
equiv) in THF (5 mL) was added via cannula, and the reaction
mixture was stirred at 0 °C for 2 h and then was partitioned
between half-saturated NH4Cl (200 mL) and a 1:1 mixture of
EtOAc and hexanes (2 200 mL). The combined organic layers
were dried over Na2SO4, concentrated, and purified by flash
column chromatography (25% EtOAc in hexane) to afford 10
(2.44 g, 75%) as a viscous, yellow oil: Rf ) 0.72 (50% EtOAc in
EtOAc (3
30 mL). The combined organic layers were dried
over Na2SO4 and concentrated. Purification of the residue by
flash column chromatography (25% EtOAc in hexanes) afforded
12 (1.38 g, 70%) as a thick oil: Rf ) 0.76 (50% EtOAc in hexanes);
[R]25 ) +47.5 (c ) 1.1, CHCl3); IR (cm-1) 3378, 1614; 1H NMR
D
(CDCl3, mixture of rotamers) δ 0.75-0.99 (m), 0.92 (d, J ) 6.8
Hz), 0.95 (d, J ) 6.8 Hz), 1.07-1.26 (m), 1.09 (d, J ) 6.8 Hz),
1.57-1.71 (m), 1.75-1.94 (m), 2.16-2.41 (m), 2.86 (s), 2.88 (s),
4.34-4.64 (m), 5.11-5.23 (m), 5.36-5.48 (m), 7.24-7.40 (m); 13
C
NMR (CDCl3, mixture of rotamers) δ 14.5, 15.2, 19.8, 19.9, 21.1,
21.2, 26.2, 26.2, 26.4, 26.7, 28.1, 30.7, 30.8, 30.8, 30.9, 32.9, 33.0,
33.1, 33.5, 33.7, 34.8, 37.9, 37.9, 38.1, 40.4, 48.3, 49.1, 49.7, 58.4,
75.0, 76.2, 126.3, 127.0, 127.2, 127.4, 128.2, 128.2, 128.5, 128.8,
129.9, 130.8, 131.6, 140.9, 142.5, 176.3, 177.8. Anal. Calcd for
hexane); [R]23 ) +65.8 (c )1.0, CHCl3); IR (cm-1) 3379, 2955,
1614; H NMR (CDCl3, mixture of rotamers) δ 0.24 (d, J ) 6.6
D
1
C
25H39NO2: C, 77.87; H, 10.19; N, 3.63. Found: C, 77.76; H,
Hz), 0.84-0.86 (m), 0.94 (d, J ) 6.9 Hz), 1.49-1.60 (m), 1.79-
1.91 (m), 2.13-2.40 (m), 2.48-2.55 (m), 2.76-2.94 (m), 3.72-
3.77 (m), 4.27-4.31 (m), 4.44-4.49 (m), 5.18-5.29 (m), 5.41-
5.55 (m), 7.10-7.38 (m); 13C NMR (CDCl3, mixture of rotamers)
δ 14.1, 14.3, 22.1, 22.7, 26.9, 28.2, 28.3, 28.5, 30.8, 33.0, 36.2,
36.5, 38.8, 39.1, 41.8, 41.9, 44.4, 45.0, 45.3, 58.2, 59.2, 75.1, 75.3,
76.0, 126.0, 126.4, 126.5, 126.6, 127.4, 128.1, 128.3, 128.4, 128.9,
131.0, 131.9, 132.1, 139.7, 140.0, 141.2, 142.0, 175.9, 176.9.
Anal. Calcd for C26H35NO2: C, 79.35; H, 8.96; N, 3.56. Found:
C, 79.25; H, 8.91; N, 3.59.
10.22; N, 3.55.
(1′R,3S,5S)-5-(1′-Br om o-2′-cycloh exyleth yl)-3-isop r op yl-
d ih yd r ofu r a n -2-on e (14). N-Bromosuccinimide (0.294 g, 1.65
mmol, 1.05 equiv) was added in small portions over 5 min to a
solution of 12 (0.606 g, 1.57 mmol, 1 equiv) and glacial acetic
acid (0.450 mL, 7.86 mmol, 5.0 equiv) in a 4:1 mixture of THF
and H2O (18 mL) at 0 °C. The resulting yellow solution was
stirred for 15 min at 0 °C, warmed to 23 °C, and subsequently
refluxed for 14 h. After being cooled to 23 °C, the reaction
mixture was partitioned between half-saturated NaHCO3 (20
mL) and a 1:1 mixture of EtOAc and hexanes (3 20 mL). The
combined organic layers were dried over Na2SO4 and were
concentrated. Flash chromatographic purification of the residue
(50% CH2Cl2 in hexanes) gave 14 (0.392 g, 79%) as a white solid
(containing minor amounts of other isomers by 1H NMR): mp
) 86-90 °C; Rf ) 0.32 (7% acetone in hexanes); IR (cm-1) 1772;
1H NMR (CDCl3, major isomer) δ 0.73-0.90 (m, 1H), 0.92-1.09
(m, 1H), 0.95 (d, 3H, J ) 6.8 Hz), 1.03 (d, 3H, J ) 6.8 Hz), 1.11-
1.36 (m, 3H), 1.54-1.81 (m, 8H), 2.12-2.32 (m, 3H), 2.64-2.73
(m, 1H), 4.12-4.20 (m, 1H), 4.39-4.47 (m, 1H); 13C NMR (CDCl3,
major isomer) δ 18.2, 20.1, 25.6, 25.9, 26.2, 27.0, 29.0, 31.3, 33.6,
34.9, 41.5, 45.4, 56.1, 79.9, 177.7.
(1′R,3R,5S)-3-Ben zyl-5-(1′-b r om o-3′-m et h ylb u t yl)d ih y-
d r ofu r a n -2-on e (6, Alter n a te Syn th esis). N-Bromosuccin-
imide (1.54 g, 8.64 mmol, 1.1 equiv) was added in small portions
over 5 min to a solution of 10 (3.09 g, 7.85 mmol, 1 equiv) and
glacial acetic acid (2.25 mL, 39.25 mmol, 5.0 equiv) in a 4:1
mixture of THF and H2O (50 mL) at 0 °C. The resulting yellow
solution was stirred for 1 h at 0 °C and then was warmed to 23
°C and subsequently refluxed for 2 h. After being cooled to 23
°C, the reaction mixture was partitioned between half-saturated
NaHCO3 (200 mL) and a 1:1 mixture of EtOAc and hexanes (2
200 mL). The combined organic layers were dried over
Na2SO4 and were concentrated. Purification of the residue by
flash column chromatography (5% EtOAc in hexane) provided
6 as yellow oil (1.73 g, 68% yield, contaminated with 5% of an
isomeric lactone of undetermined configuration as observed by
1H NMR).
(1′R,2S,3S,5S,7S,9S)-7-(1′-Br om o-2′-cycloh exylet h yl)-9-
isop r op yl-3,4-d im eth yl-2-p h en yl-1,6-d ioxa -4-a za sp ir o[4.4]-
n on a n e (13). N-Bromosuccinimide (0.047 g, 0.26 mmol, 1.05
equiv) was added in small portions to a solution of 12 (0.097 g,
0.25 mmol, 1 equiv) and glacial acetic acid (0.072 mL, 1.26 mmol,
5.0 equiv) in a 4:1 mixture of THF and H2O (2.5 mL) at 0 °C.
The resulting yellow solution was stirred for 15 min at 0 °C and
then partitioned between half-saturated NaCl (4 mL) and a 1:1
(1′S,2′S)-N-(2′-H yd r oxy-1′-m et h yl-2′-p h en ylet h yl)-N,3-
d im eth ylbu tyr a m id e (11). A solution of (1S,2S)-(+)-pseu-
doephedrine (2.00 g, 12.1 mmol, 1 equiv) and triethylamine (2.19
mL, 15.7 mmol, 1.3 equiv) in THF (30 mL) was cooled to 0 °C.
A solution of isovaleryl chloride (1.70 mL, 13.9 mmol, 1.15 equiv)
in THF (6 mL) was added dropwise over a 5 min period,
producing a white precipitate. After 10 min of stirring at 0 °C,
H2O (2 mL) and EtOAc (70 mL) were added. The mixture was
transferred to a separatory funnel and washed with brine (3
60 mL). The organic phase was dried over Na2SO4 and concen-
trated. The residue was dried under vacuum for 3 h to give 11
(2.90 g, 96%) as a white solid: mp ) 66-68 °C; Rf ) 0.31 (50%
EtOAc in hexanes); IR (cm-1) 3378, 1614; 1H NMR (CDCl3,
mixture of rotamers) δ 0.92-1.00 (m), 1.13 (d, J ) 7.2 Hz), 2.07-
2.33 (m), 2.81 (s), 2.92 (s), 3.98-4.08 (m), 4.37-4.64 (m), 7.23-
7.40 (m); 13C NMR (CDCl3, mixture of rotamers) δ 14.4, 15.3,
22.5, 22.6, 22.7, 22.8, 25.4, 25.5, 26.7, 33.0, 42.4, 42.9, 58.2, 75.3,
76.3, 126.2, 126.8, 127.4, 128.0, 128.2, 128.5, 141.5, 142.4, 173.5,
174.8. Anal. Calcd for C15H23NO2: C, 72.25; H, 9.30; N, 5.62.
Found: C, 72.31; H, 9.34; N, 5.67.
mixture of EtOAc and hexanes (3
5 mL). The combined
organic layers were dried over Na2SO4 and were concentrated.
The residue was passed through a plug of silica gel (eluting with
4% EtOAc in hexanes) and then purified by preparative thin
layer chromatography (10% EtOAc in hexanes) to give 13 (0.067
g, 57%) as a clear, colorless glass (containing minor impurities
by 1H NMR): Rf ) 0.91 (25% EtOAc in hexanes); 1H NMR
(CDCl3) δ 0.74-1.38 (m, 6H), 0.92 (d, 3H, J ) 6.5 Hz), 1.04 (d,
3H, J ) 6.5 Hz), 1.10 (d, 3H, J ) 5.9 Hz), 1.61-2.25 (m, 11H),
2.35 (s, 3H), 2.83-2.93 (m, 1H), 4.06-4.21 (m, 2H), 4.46 (d, 1H,
J ) 8.9 Hz), 7.24-7.43 (m, 5H); 13C NMR (CDCl3) δ 15.5, 21.3,
22.3, 26.0, 26.2, 26.5, 28.9, 31.4, 31.8, 32.3, 34.0, 35.2, 42.4, 45.6,
58.7, 65.6, 76.3, 86.4, 122.0, 127.1, 127.8, 128.3, 140.6; HRMS
calcd for C25H38BrNO2 [MCs+] 596.1140, found 596.1161.
Ack n ow led gm en t. We would like to thank the
following people: David Stirling and Kathleen Tucker

7876 J . Org. Chem., Vol. 62, No. 22, 1997
Notes
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
preparation of both relevant diastereomers corresponding to
compounds 5, 10, and 12 and conditions for HPLC analyses
of these mixtures (4 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.
for performing the HPLC measurements, Dr. Barbara
Potts for obtaining the homonuclear 2DJ spectrum of
compound 6, Terence Moran and Dr. Srinivasan Babu
for optimization of several experimental procedures,
Prof. Andrew G. Myers and Dr. Hou Chen of the
California Institute of Technology for advice on conduct-
ing the alkylation of pseudoephedrine amides, and Dr.
Steven Bender for helpful discussions.
J O9707951