Practical syntheses of enantiomerically enriched γ-lactones and γ-hydroxy ketones by the alkylation of pseudoephedrine amides with epoxides and their derivatives

Article abstract of DOI:10.1021/jo952032o

Pseudoephedrine amide enolates are shown to undergo efficient alkylation reactions with epoxides as electrophiles. Reactions with monosubstituted epoxides are subject to stereochemical matching such that the pairing leading to the 1,3-syn diastereomer is a highly selective, synthetically useful process, while the pairing forming the 1,3-anti diastereomer is not. Reactions with the 1,1-disubstituted epoxide isobutylene oxide are also highly diastereoselective and synthetically useful, but ethylene oxide exhibits poor diastereoselectivity. As an alternative to the use of ethylene oxide, 2-(tert-butyldimethylsilyloxy)ethyl iodide is shown to undergo highly diastereoselective and efficient alkylation reactions with pseudoephedrine amide enolates. Interestingly, epoxides and alkyl halides are found to attack opposite π-faces of pseudoephedrine amide enolates. The products of each of these alkylation reactions are transformed efficiently into γ-lactones by acidic hydrolysis and into methyl ketones by the addition of methyllithium. The methodology described provides useful procedures for the synthesis of enantiomerically enriched γ-lactones and γ-hydroxy ketones.

Full text of DOI:10.1021/jo952032o

2428
J . Org. Chem. 1996, 61, 2428-2440
P r a ctica l Syn th eses of En a n tiom er ica lly En r ich ed γ-La cton es a n d
γ-Hyd r oxy Keton es by th e Alk yla tion of P seu d oep h ed r in e Am id es
w ith Ep oxid es a n d Th eir Der iva tives
Andrew G. Myers* and Lydia McKinstry
Arnold and Mabel Beckman Laboratories of Chemical Synthesis, California Institute of Technology,
Pasadena, California 91125
Received November 16, 1995X
Pseudoephedrine amide enolates are shown to undergo efficient alkylation reactions with epoxides
as electrophiles. Reactions with monosubstituted epoxides are subject to stereochemical matching
such that the pairing leading to the 1,3-syn diastereomer is a highly selective, synthetically useful
process, while the pairing forming the 1,3-anti diastereomer is not. Reactions with the 1,1-
disubstituted epoxide isobutylene oxide are also highly diastereoselective and synthetically useful,
but ethylene oxide exhibits poor diastereoselectivity. As an alternative to the use of ethylene oxide,
2-(tert-butyldimethylsilyloxy)ethyl iodide is shown to undergo highly diastereoselective and efficient
alkylation reactions with pseudoephedrine amide enolates. Interestingly, epoxides and alkyl halides
are found to attack opposite π-faces of pseudoephedrine amide enolates. The products of each of
these alkylation reactions are transformed efficiently into γ-lactones by acidic hydrolysis and into
methyl ketones by the addition of methyllithium. The methodology described provides useful
procedures for the synthesis of enantiomerically enriched γ-lactones and γ-hydroxy ketones.
In tr od u ction
of amide enolates bearing an R-substituent with mono-
substituted epoxides (1,3-syn versus 1,3-anti) and the
degree of enolate π-diastereofacial selectivity possible
with the use of a chiral auxiliary. Addressing the first
issue, Sauriol-Lord and Grindley showed that the reac-
tion of achiral R-substituted N,N-dialkylamide enolates
with monosubstituted epoxides, a reaction known to favor
addition to the less-substituted epoxide terminus,5 was
inherently syn selective.6 The magnitude of the observed
diastereoselectivity was not large, with syn/anti ratios
typically between 1 and 9, and was dependent upon the
size of the epoxide substituent and the N-alkyl groups,
in both cases larger being better.6 Figure 1 below
provides a useful mnemonic device (if not a valid ratio-
nalization) that summarizes these findings. The second
stereochemical issue germane to the present work con-
cerns the extent of enolate π-facial selectivity possible
by virtue of a chiral auxiliary. Important precedence in
this regard comes from the work of Askin et al. in a study
of the reaction of epoxides with chiral amide enolates
derived from prolinol.7 Prolinol amide enolates were first
developed independently by Evans and Takacs,8a and
Sonnett and Heath,8b in new methodology for the asym-
metric alkylation of carboxylate derivatives, where it was
established that these enolates react with alkyl halides
We have shown that pseudoephedrine amides undergo
efficient and highly diastereoselective alkylation reac-
tions with a range of alkyl halides. The alkylation
products are readily transformed in a single operation
into highly enantiomerically enriched carboxylic acids,
aldehydes, ketones, or primary alcohols. Both enant-
iomers of the chiral auxiliary, pseudoephedrine, are
available in quantity and are inexpensive. This, and
desirable process features such as the crystallinity of
many pseudoephedrine amides, contribute to the prac-
ticality of the methodology.1 Recently, we have extended
the methodology to the preparation of D- and L-R-amino
acids by the alkylation of (+)- and (-)-pseudoephedrine
glycinamide, respectively.2 In this work, we explore the
use of epoxides and epoxide-derived electrophiles in the
alkylation reaction.
The importance of epoxides as electrophiles in organic
chemistry has grown collaterally with advances in meth-
odology for their synthesis in enantiomerically enriched
form.3 Despite their high reactivity, epoxides typically
do not react with lithium enolates of simple monoketones
and monoesters.4 Lithium enolates of amides, by con-
trast, are known to react readily with epoxides, presum-
ably due to their greater thermal stability (versus ester
enolates) and nucleophilicity.5 The stereochemical con-
sequences of the latter alkylation reaction are of great
interest in the context of the present study. Specific
questions concern the diastereoselectivity of the reaction
(4) Successful enolate-epoxide bond constructions typically employ
stabilized enolates (e.g., malonate derivatives) at elevated reaction
temperatures or, in the case of monoester and monoketone enolates,
utilize Lewis-acidic additives: (a) Danishefsky, S.; Kitahara, T.; Tsai,
M.; Dynak, J . J . Org. Chem. 1976, 41, 1669; and references therein.
(b) Sturm, T.; Marlewski, A. E.; Rezenka, D. S.; Taylor, S. K. J . Org.
Chem. 1989, 54, 2039. (c) Chini, M.; Crotti, P.; Favero, L.; Pineschi,
M. Tetrahedron Lett. 1991, 32, 7583. (d) Smith, A. B., III; Pasternak,
A.; Yokoyama, A.; Hirschmann, R. Tetrahedron Lett. 1994, 35, 8977.
(5) (a) Sucrow, W.; Slopianka, M.; Winkler, D. Chem. Ber. 1972, 105,
1621. (b) Sucrow, W.; Klein, U. Chem. Ber. 1975, 108, 48. (c) Hullot,
P.; Cuvigny, T.; Larcheveque, M.; Normant, H. Can. J . Chem. 1977,
55, 266. (d) Woodbury, R. P.; Rathke, M. W. J . Org. Chem. 1977, 42,
1688. (e) Woodbury, R. P.; Rathke, M. W. J . Org. Chem. 1978, 43, 1947.
(f) Takahata, H.; Wang, E.; Yamazaki, T. Synth. Commun. 1988, 18,
1159. (g) Fitzi, R.; Seebach, D. Tetrahedron 1988, 44, 5277. For the
reaction of carboxylate enolates with epoxides, see: (h) Creger, P. L.
J . Org. Chem. 1972, 37, 1907. For the reaction of chiral oxazoline
anions with epoxides, see: (i) Meyers, A. I.; Mihelich, E. D. J . Org.
Chem. 1975, 40, 1187. (j) Meyers, A. I.; Yamamoto, Y.; Mihelich, E.
D.; Bell, R. A. J . Org. Chem. 1980, 45, 2792.
X Abstract published in Advance ACS Abstracts, March 15, 1996.
(1) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J . L. J . Am. Chem.
Soc. 1994, 116, 9361.
(2) (a) Myers, A. G.; Yoon, T. Tetrahedron Lett. 1995, 36, 4555. (b)
Myers, A. G.; Gleason, J . L.; Yoon, T. J . Am. Chem. Soc. 1995, 117,
8488.
(3) (a) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102,
5974. (b) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765. (c) Zhang, W.;
Loebach, J . L.; Wilson, S. R.; J acobsen, E. N. J . Am. Chem. Soc. 1990,
112, 2801. For reviews, see also: (d) Rossiter, B. E. In Asymmetric
Synthesis; Morrison, J . D., Ed.; Academic Press: New York, 1985; Vol.
5, Chapter 7, p 193. (e) Finn, M. G.; Sharpless, K. B. In Asymmetric
Synthesis; Morrison, J . D., Ed.; Academic Press: New York, 1985; Vol.
5, Chapter 8, p 247.
(6) Sauriol-Lord, F.; Grindley, T. B. J . Org. Chem. 1981, 46, 2831.
0022-3263/96/1961-2428$12.00/0 © 1996 American Chemical Society

Enantiomerically Enriched γ-Lactones and γ-Hydroxy Ketones
J . Org. Chem., Vol. 61, No. 7, 1996 2429
the precedents summarized above and provide practical
new methodology for the synthesis of enantiomerically
enriched γ-lactones and γ-hydroxy ketones.
Resu lts
Enolization of (S,S)-pseudoephedrine propionamide (1)
or (S,S)-pseudoephedrine hydrocinnamide (2) with lithium
N,N-diisopropylamide (2.1 equiv, -78 °C for 1 h, 0 °C
for 15 min, 23 °C for 5 min) in tetrahydrofuran (THF) in
the presence of anhydrous lithium chloride (6 equiv), as
previously described,1 followed by the addition of ethylene
oxide (5 equiv) at 0 °C led to the efficient formation of a
diastereomeric mixture of alkylation products, in either
case (96-97% yield, 1 h reaction period). Accurate
F igu r e 1. Stereochemical matching in the reaction of amide
enolates with epoxides.6
determination of diastereomeric excesses was conducted
by acetylation of the crude reaction mixtures (acetic
anhydride, (dimethylamino)pyridine (DMAP)) followed by
capillary gas chromatographic analysis of the diacetates
produced. As will be apparent from the discussion below,
ethylene oxide represents a “worst-case” substrate; nei-
ther 1 nor 2 afforded synthetically useful levels of
diastereoselectivity (for 1: 49% de, for 2: 59% de). The
sense of asymmetric induction was established by acidic
hydrolysis of the alkylation products to produce the
corresponding γ-lactones (2 N aqueous sulfuric acid,
dioxane, reflux, 89-90% yield), followed by comparison
of the rotations of these products against literature values
(lactone derived from alkylation/hydrolysis of 1, ob-
served: [R]20 ) -10.2° (c ) 5.5, ethanol), literature for
D
F igu r e 2. π-Facial selectivity in the reaction of prolinol amide
(S)-(-)-2-methyl-γ-butyrolactone: [R]20 ) -21.5° (c )
enolates with alkyl halides and epoxides.7,8
D
5.5, ethanol),10 48% ee; lactone derived from alkylation/
hydrolysis of 2, observed: [R]20D ) +38.1° (c ) 5.0, carbon
tetrachloride), literature for (S)-(+)-2-phenylmethyl-γ-
with uniform and high π-facial selectivity. Askin et al.
showed that these same enolates exhibit opposite π-facial
selectivity in reactions with epoxides.7 These differing
stereochemical preferences can be summarized graphi-
cally, as shown in Figure 2. Detailed consideration of
specific examples from the work of Askin et al. shows
that in all cases, whether alkyl halides or epoxides were
used as electrophiles, the inherent π-facial selectivity of
the enolate (albeit different for the two classes of elec-
trophiles) dominated the outcome of the reaction.7 It is
interesting to note that the epoxide additions were
subject to stereochemical matching;9 the reaction favoring
the syn diastereomer was found to be the more highly
diastereoselective.7 This observation supports the notion
that the reaction of amide enolates with monosubstituted
epoxides is an inherently syn selective process.6 These
results impressively demonstrate that chiral auxiliaries
can markedly influence the π-facial selectivity of enolate
additions to epoxides. In results described herein, we
establish that pseudoephedrine is a valuable chiral
auxiliary for enolate additions to epoxides and epoxide-
derived electrophiles. Our results corroborate and extend
butyrolactone: [R]20 ) +67.7° (c ) 5.0, carbon tetra-
D
chloride),11 56% ee). Thus, the major diastereomer
produced from 1 is 3, while 2 produces 4. In both cases
the major product arises from the attack of ethylene oxide
on the opposite enolate π-face as that attacked by simple
alkyl halides, in accord with the observations of Askin
et al. in their studies of amide enolates derived from
prolinol.7 The sense of π-facial attack by alkyl halides
on enolates derived from 1 and 2 has been determined
many times over1 and was confirmed once again using
the tert-butyldimethylsilyl ether of 2-iodoethanol as the
alkyl halide; the diastereomers 5 and 6, respectively,
were formed in excellent yield and with high diastereo-
selectivity.
(7) Askin, D.; Volante, R. P.; Ryan, K. M.; Reamer, R. A.; Shinkai,
I. Tetrahedron Lett. 1988, 29, 4245.
(8) (a) Evans, D. A.; Takacs, J . M. Tetrahedron Lett. 1980, 21, 4233.
(b) Sonnet, P. E.; Heath, R. R. J . Org. Chem. 1980, 45, 3137.
(9) Masamune, S.; Choy, W.; Petersen, J . S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
Desilylation of 5 and 6 with tetra n-butylammonium
fluoride produced materials that were identical to the
minor diastereomers formed in the respective ethylene

2430 J . Org. Chem., Vol. 61, No. 7, 1996
Myers and McKinstry
Ta ble 1. Alk yla tion of P seu d oep h ed r in e Am id es w ith
“Ma tch ed ” Ep oxid esa
Ta ble 2. Alk yla tion of P seu d oep h ed r in e Am id es w ith
“Mism a tch ed ” Ep oxid esa
temp time isolated yield
de
%
temp time isolated yield
de
%
entry
R1
R2
(°C)
(h)
%
entry
R1
R2
(°C)
(h)
%
1
2
3
4
5
6
7
8
CH3 CH3
CH3 C6H5
CH3 CH2OTBS
CH3 CH2OBn
-5
-5
0
-5
-5
-5
5
6
10
21
13
10
15
26
12
86
73
78
78
79
72
64
80
73
25
12
38
45
46
17
36
1
2
3
4
5
6
7
8
CH3 CH3
CH3 C6H5
CH3 CH2OTBS
CH3 CH2OBn
-5
-5
-5
-5
-5
-5
-5
-5
4
7
10
12
9
10
11
12
88
82
84
80
86
86
81
87
93
90
96
85
Bn
Bn
Bn
Bn
CH3
C6H5
CH2OTBS
CH2OBn
Bn
Bn
Bn
Bn
CH3
C6H5
CH2OTBS
CH2OBn
g99
g95
g99
g95
-5
a
a
2 equiv of epoxide was used, except in entry 3, where 1.5 equiv
2 equiv of epoxide was used in each experiment.
was employed.
oxide alkylations. For the synthesis of simple 2-hydroxy-
ethyl alkylation products of this type, it is clear that
2-(tert-butyldimethylsilyloxy)ethyl iodide is the superior
electrophile. It is shown below that the “inverse” selec-
tivity found with ethylene oxide extends to monosubsti-
tuted and 1,1-disubstituted epoxides. It is also shown
that substituted epoxides frequently afford higher and,
often, synthetically useful levels of diastereoselectivity
and can provide products not easily obtained using alkyl
halides as electrophiles.
Ta ble 3. Alk yla tion of P seu d oep h ed r in e Am id es w ith
Ra cem ic Ep oxid es
When chiral, enantiomerically enriched (g89% ee, see
Experimental Section) monosubstituted epoxides were
used in the alkylation reaction it was found that the
inherent π-facial selectivity of the pseudoephedrine amide
enolate was the overriding feature in determining the
stereochemical outcome of the reaction (Tables 1 and 2).
Predictably, the stereochemistry of the epoxide was found
to influence the reaction as well, giving rise to matched
and mismatched combinations.9 For monosubstituted
epoxides, the matched combination is that which pro-
duces the 1,3-syn product (Table 1) while the mismatched
combination leads to a modest predominance of the 1,3-
anti products (Table 2). The stereochemistry of the
products was determined by lactonization under acidic
isolated
(()-epoxide temp yield (2S)- (2S)- (2R)- (2R)-
R1
R2
(equiv)
(°C)
%
syn anti syn anti
CH3 CH3
CH3 C6H5
CH3 CH2OTBS
Bn CH3
Bn CH2OTBS
5.0
10.0
2.0
-5
-5
0
81
84
61
78
55
72
63
73
58
62
18
19
14
23
25
6
16
12
11
13
4
2
1
8
0
5.0
2.0
-5
0
appreciable amounts of the (2S)-anti diastereomer arising
from a mismatched reaction with the contaminating
epoxide enantiomer were also formed, in addition to
minor amounts of each of the (2R)-diastereomers. The
data shows that, although the inherent π-facial selectivity
of the pseudoephedrine amide enolate dominates the
reaction, the rate ratio of matched to mismatched reac-
tions with the respective epoxide enantiomers is only
about 2.5-5, insufficient for a highly discriminating
reaction.
As an alternative to the use of monosubstituted ep-
oxides as electrophiles, alkylation reactions with the
enantiomeric iodohydrin derivatives 7 and 813 were
examined (for the specific case of propylene oxide).
Unfortunately, both iodides were exceedingly unreactive
electrophiles, deactivated both by steric hindrance and
â-oxygenation, and reacted sluggishly, inefficiently, but
highly selectively with the enolate derived from 1. When
a racemic mixture of 7 and 8 was used in the alkylation
reaction only the two 2R-isomers depicted were produced,
in a 1:1 ratio. This demonstrates that the π-facial
selectivity of the enolate exerts complete control in the
alkylation reaction; there is no discernible rate discrimi-
nation between enantiomers 7 and 8.
1
conditions (see below) followed by H NMR analysis; cis
and trans lactones were readily differentiated on the
basis of coupling constants (see Experimental Section).12
Inspection of Tables 1 and 2 reveals that matched
alkylations are synthetically useful whereas mismatched
alkylations are not. Although limited, the data suggests
that larger R-substitutents (R1 ) CH2C6H5 versus R1 )
CH3) within the enolate lead to enhanced selectivity in
the matched cases.
The diastereoselectivity of matched epoxide alkylations
versus mismatched alkylations was such that the pos-
sibility of conducting kinetic resolutions with racemic
monosubstituted epoxides as substrates was considered
(for an earlier example using chiral oxazolidinone eno-
lates, see reference 4d). As the data summarized in Table
3 reveal, the idea was sound, but did not provide a
synthetically practical procedure. In all cases, the
matched, (2S)-syn diastereomer predominated; however,
(10) Kaneko, T.; Wakabayashi, K.; Katsura, H. Bull. Chem. Soc. J pn.
1962, 35, 1149.
(11) Helmchen, G.; Nill, G.; Flockerzi, D.; Youssef, M. S. K. Angew.
Chem., Int. Ed. Engl. 1979, 18, 63.
(12) Hussain, A. M. T.; Ollis, W. D.; Smith, C.; Stoddart, J . F. J .
Chem. Soc. Perkin Trans. 1 1975, 1480.
(13) Bajwa, J . S.; Anderson, R. C. Tetrahedron Lett. 1991, 26, 3021.

Enantiomerically Enriched γ-Lactones and γ-Hydroxy Ketones
J . Org. Chem., Vol. 61, No. 7, 1996 2431
Ta ble 4. La cton es by Acid ic Hyd r olysis of
P seu d oep h ed r in e Am id es
[H2SO4] isolated yield isolated de
entry R1
R2
time
1 h
(M)
%
%
A single 1,1-disubstituted epoxide substrate, isobutyl-
ene oxide, was examined in the alkylation reaction and
was found to undergo highly selective alkylations with
enolates derived from both 1 and 2. This is a useful
1
2
3
4
5
6
CH3 CH3
CH3 CH2OTBS 20 min
CH3 CH2OBn
Bn CH3
Bn CH2OTBS 30 min
Bn CH2OBn 1.5 h
0.03
0.05
0.06
0.43
0.21
0.17
83
90
90
92
92b
94
94a
g99
98
g99
g99
g99
30 min
2.5 h
a
Starting material was 94% de for entry 1, all others were
b
g99% de. Product was desilylated.
the alkylation of an achiral amide enolate with an
enantiomerically pure epoxide followed by acid-induced
hydrolysis/equilibration, the lactones derived from isobu-
tylene oxide alkylations are not.
The addition of alkyllithium reagents to the alkylation
products of this study afforded ketones in excellent yield
and with high enantiomeric excess when diastereomeri-
cally pure starting materials were employed.1 For ex-
ample, addition of 2.5 equiv of methyllithium to the
alkylation products 5 and 6 (g99% de) in ether at -78
°C followed by warming to 0 °C afforded the correspond-
ing methyl ketones as indicated in the equation below.
result, especially so given the almost certain failure of
the corresponding alkylation reactions with iodohydrin
derivatives of isobutylene oxide. In the only example of
a 1,2-disubstituted epoxide studied to date, cyclohexene
oxide was found to be completely inert toward enolates
derived from 1 and 2 under a variety of conditions.
Heating of the alkylation products of Table 1 in
aqueous dioxane at 95 °C in the presence of dilute sulfuric
acid formed the corresponding trans-lactones (Table 4)
in high yield and with high diastereomeric purity (the
diastereomeric purity of the products was determined by
1H NMR and capillary gas chromatographic analysis). In
general, the benzyl-substituted substrates were observed
to hydrolyze more slowly than the methyl-substituted
substrates and, as a consequence, the tert-butyldimeth-
ylsilyloxy group was cleaved in the product of entry 5.
Lactonization of the substrates of Table 2, by contrast,
afforded the cis-lactones as the major products. The
diastereomeric purity of these cis-lactones reflected the
diastereomeric purity of the starting materials. For
example, heating the product of entry 4, Table 2 (38%
de) with dilute sulfuric acid afforded the corresponding
cis-lactone with 36% de. Although they were not suf-
ficiently diastereomerically enriched for preparative pur-
poses, these cis-lactone products were important in
corroborating stereochemical assignments. Lactonization
of the products from alkylations with isobutylene oxide
proceeded with detectable racemization in the case of the
R-methyl substitutent, but not with the R-benzyl group
(enantiomeric excesses were determined by reduction of
the lactones with lithium aluminum hydride followed by
selective Mosher esterification15 of the primary hydroxyl
Addition of methyllithium to the diols 9 and 10 (g99%
de) was also successful, providing the corresponding
ketones in 90-97% yield, without detectable epimeriza-
tion of the R-substituent. The latter products existed as
an equilibrating mixture of open-chain and epimeric
closed forms.
Discu ssion a n d Con clu sion s
Alkyl halides and epoxides have been shown to attack
opposite enolate π-faces in alkylation reactions with
pseudoephedrine amide enolates. This represents the
second example of such reversed selectivity, the first
being that of prolinol amide enolates.7 The correlation
between the two systems is striking, and one is tempted
to search for simple, unifying explanations for these
observations. A moment’s consideration of the complex-
ity and variability of the solid state structures of lithium
1
groups and H NMR analysis). It should be noted that
whereas the trans-substituted lactones of Table 4 are
available by alternative methods, including alkylation of
enantiomerically pure 4-alkylbutyrolactones,14 or even by
(14) Tomioka, K.; Koga, K. Tetrahedron Lett. 1979, 3315.
(15) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.

2432 J . Org. Chem., Vol. 61, No. 7, 1996
Myers and McKinstry
doephedrine amide enolates with isobutylene oxide is also
a highly diastereoselective process and provides access
to products that are difficult to obtain by other means.
The products of each of these alkylation reactions readily
undergo lactonization with expulsion of the pseudoephe-
drine auxiliary upon heating with acid. They are also
readily transformed into methyl ketones in high yield and
with high enantio- or diastereoselectivity upon treatment
with methyllithium. These results should serve to
further expand the utility of pseudoephedrine as a useful
chiral auxiliary in organic synthesis.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were performed in oven-
or flame-dried glassware under an atmosphere of dry argon
unless otherwise noted. Air- and moisture-sensitive liquids
and solutions were transferred via syringe or cannula. Column
(flash) chromatography was performed using 230-400 mesh
silica gel. Analytical gas chromatography was performed with
a 25 m × 0.25 mm ID Chirasil-Val III capillary column, under
isothermal conditions, with a column head pressure of 17 psi.
Proton and carbon nuclear magnetic resonance (1H NMR and
13C NMR) spectra were recorded at 500 and 125 MHz,
respectively. Infrared (IR) spectra were obtained as neat films
unless otherwise specified.
Ma ter ia ls. Commercial reagents and solvents were used
as received with the following exceptions. Tetrahydrofuran
and diethyl ether were distilled from sodium benzophenone
ketyl. Dichloromethane, benzene, N,N-diisopropylamine, and
toluene were distilled from calcium hydride at atmospheric
pressure. The molarities of alkyllithium solutions were es-
tablished by titration with a standard solution of 2-butanol in
xylenes using 1,10-phenanthroline as indicator.17 Commercial
anhydrous lithium chloride was rigorously dried at 110 °C and
0.1 mm Hg for 12 h and was stored under an atmosphere of
dry nitrogen. (1S,2S)-N-(2-hydroxy-1-methyl-2-phenylethyl)-
N-methylpropionamide (1) and (1S,2S)-N-(2-hydroxy-1-methyl-
2-phenylethyl)-N-methylbenzenepropionamide (2) were pre-
pared by N-acylation of (1S,2S)-(+)-pseudoephedrine with
propionic anhydride or hydrocinnamoyl chloride, respectively,
as previously described.1 (R)- and (S)-2-(tert-butyldimethyl-
silyloxy)propyl iodide (7 and 8 respectively), and 2-(tert-
butyldimethylsilyloxy)ethyl iodide were prepared by silylation
of the corresponding alcohols.13 The following chiral epoxides
were commercial products; their enantiomeric purity was
F igu r e 3. Selectivity in the reaction of pseudoephedrine
amide enolates with epoxides and alkyl halides.
enolates,16 a complexity only compounded in solution, and
by the presence of lithium chloride (present study),
should quickly discourage such efforts in the absence of
further structural information. However, in simplistic
terms, the proposal of Askin et al., that the lithium
alkoxide of the chiral auxiliary directs the addition in
the case of epoxides while providing a steric blockade in
reactions with alkyl halides (see also reference 8), has
some appeal.7 Conformational analysis of both systems
reveals that favorable structures can be invoked wherein
the lithium alkoxide, and perhaps more importantly, the
solvent molecules associated with this group, can reason-
ably occupy the space above the appropriate π-face of the
Z-enolate. Figure 3 illustrates such a conformation for
a pseudoephedrine amide enolate and provides a useful
mnemonic for deriving the preferred reaction products
with alkyl halides and epoxides (cf. Figure 2). Questions
concerning the degree of aggregation of the respective
transition states, their detailed structures (to include
rotameric distributions, state of ionization, degree of
pyramidalization of nitrogen, definition of trajectories,
bond-breaking, and bond-formation) are completely un-
resolved and serve to illustrate how poorly understood
even this “simple” organic reaction is.
In practical terms, the chemistry described herein
provides useful methodology for the preparation of cer-
tain γ-lactones and γ-hydroxy ketones in enantiomeri-
cally enriched form. The alkylation reaction with ethyl-
ene oxide is insufficiently diastereoselective to be useful.
The use of 2-(tert-butyldimethylsilyloxy)ethyl iodide as
the electrophile, however, leads to a highly diastereose-
lective alkylation reaction, in accord with previous ob-
servations.1 The alkylation of pseudoephedrine amide
enolates with enantiomerically enriched, monosubsti-
tuted epoxides is an efficient method for the preparation
of diastereomerically enriched 2,4-syn-2-alkyl-4-hydroxy
amides, but not the corresponding anti products. These
results reinforce the idea that the reaction of monosub-
stituted epoxides with monosubstituted amide enolates
is inherently syn selective.6 The alkylation of pseu-
determined by optical rotation: (S)-(-)-styrene oxide [[R]20
D
) -32.5° (neat); lit. [R]20 ) -34.1° (neat),18 90% ee], (R)-(+)-
D
styrene oxide [[R]20 ) +34.3° (neat); lit. [R]20 ) +34.1°
D
D
(neat),18 99% ee], (S)-(-)-benzyl glycidyl ether [[R]20D ) -14.6°
(neat); lit. [R]20 ) -15.3° (neat),19 95% ee], (R)-(+)-benzyl
D
glycidyl ether [[R]20 ) +14.9° (neat); lit. [R]20 ) +15.0°
D
D
(neat),19 99% ee]. The enantiomeric purity of commercial (S)-
(-)-propylene oxide (97% ee) and (R)-(+)-propylene oxide (97%
ee) was determined by conversion of each to the corresponding
iodohydrin13 followed by esterification with (S)-(-)-Mosher
1
acid15 and H NMR and capillary GC analysis of the resulting
Mosher ester derivatives. (S)-(-)-tert-butyldimethylsilyl gly-
cidyl ether (89% ee) and (R)-(+)-tert-butyldimethylsilyl glycidyl
ether (89% ee) were prepared from the respective glycidols
according to the published procedures, and the enantiomeric
purity of each reagent was determined by conversion of each
to the corresponding iodohydrin13 followed by esterification
with (S)-(-)-Mosher acid15 and 1H NMR and capillary GC
analysis of the resulting Mosher ester derivatives.
[1S(S),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-4-h y-
d r oxy-N,2-d im eth ylbu ta n a m id e (3). A dry 10-mL round-
bottomed flask equipped with a magnetic stirring bar was
(16) (a) Amstutz, R.; Schweizer, W. B.; Seebach, D.; Dunitz, J . D.
Helv. Chem. Acta 1981, 64, 2617. (b) Laube, T.; Dunitz, J . D.; Seebach,
D. Helv. Chem. Acta 1985, 68, 1373. (c) Bauer, W.; Laube, T.; Seebach,
D. Chem. Ber. 1985, 118, 764. (d) Willard, P. G.; Hintze, M. J . J . Am.
Chem. Soc. 1987, 109, 5539. (e) Seebach, D. Angew. Chem., Int. Ed.
Engl. 1988, 27, 1624. (f) Willard, P. G.; MacEwan, G. J . J . Am. Chem.
Soc. 1989, 111, 7671. (g) Willard, P. G.; Hintze, M. J . J . Am. Chem.
Soc. 1990, 112, 8602.
(17) Watson, S. C.; Eastham, J . F. J . Organomet. Chem. 1967, 9,
165.
(18) (a) Eliel, E. L.; Delmonte, D. W. J . Org. Chem. 1956, 21, 596.
(b) Tomoskozi, I. Tetrahedron 1963, 19, 1969.
(19) Anisuzzaman, A. K. M.; Owen, L. N. J . Chem. Soc. (C) 1967,
1021.

Enantiomerically Enriched γ-Lactones and γ-Hydroxy Ketones
J . Org. Chem., Vol. 61, No. 7, 1996 2433
charged with anhydrous lithium chloride (0.254 g, 6.00 mmol,
6.00 equiv), N,N-diisopropylamine (0.275 mL, 2.10 mmol, 2.10
equiv), and tetrahydrofuran (1.00 mL). The resulting suspen-
sion was cooled to -78 °C and n-butyllithium (2.40 M in
hexanes, 0.921 mL, 2.21 mmol, 2.21 equiv) was added by
syringe. The suspension was warmed to 0 °C for 10 min, then
was cooled to -78 °C. A solution of (1S,2S)-N-(2-hydroxy-1-
methyl-2-phenylethyl)-N-methylpropionamide (1) (0.221 g,
1.00 mmol, 1 equiv) in tetrahydrofuran (2.00 mL) was added
dropwise to the reaction flask by syringe. The transfer was
quantitated with an additional portion of tetrahydrofuran (0.50
mL). Upon completion of the addition, 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 finally was cooled to 0 °C. Ethylene oxide was
condensed into a dry 5-mL round-bottomed flask at -78 °C.
The condensed liquid (0.250 mL, 5.00 mmol, 5.00 equiv) was
slowly transferred to the reaction vessel via a dry ice-jacketed
syringe. After 1 h, saturated aqueous ammonium chloride
solution (2 mL) was added, and the resulting biphasic mixture
was partitioned between water (2.5 mL) and ethyl acetate (2.5
mL). The aqueous layer was separated and extracted further
with three 2-mL portions of ethyl acetate. The combined
organic layers were dried over anhydrous sodium sulfate and
then were concentrated to give a viscous yellow oil. Purifica-
tion of the oily residue by flash column chromatography (ethyl
acetate) provided 2.57 g (97%) of 3 (an inseparable mixture of
diastereomers) as a viscous, colorless oil. Capillary GC
analysis of the corresponding O,O-diacetate, formed from the
product diol by acetylation with excess acetic anhydride and
DMAP, established a diastereomeric excess (de) of 49% for this
product. Spectroscopic and analytical data for the diastereo-
meric mixture follow (assignments are secured unambiguously
by the preparation of an authentic sample of the pure minor
diastereomer, see below): 1H NMR (C6D6) major diastereomer
(3) (5:1 rotamer ratio, * denotes minor rotamer peaks): δ 7.37
(d, 2H, J ) 7.5 Hz), 7.29* (d, 2H, J ) 7.6 Hz), 7.14 (m, 3H),
7.09* (m, 3H), 5.23 (br s, 1H), 4.73 (br s, 1H), 4.43 (d, 1H, J )
7.4 Hz), 4.38* (d, 1H, J ) 7.4 Hz), 4.16 (m, 1H), 3.87 (br s,
1H), 3.66 (m, 1H), 3.58 (m, 1H), 3.54* (m, 1H), 3.07* (m, 1H),
2.86* (s, 3H), 2.74 (m, 1H), 2.51 (s, 3H), 2.07 (m, 1H), 2.00*
(m, 1H), 1.59* (m, 1H), 1.55 (m, 1H), 1.29* (d, 3H, J ) 6.6
Hz), 0.99 (d, 3H, J ) 6.8 Hz), 0.79 (d, 3H, J ) 6.0 Hz), 0.78*
(d, 3H, J ) 6.3 Hz); minor diastereomer (2.5:1 rotamer ratio,
* denotes minor rotamer peaks): δ 7.32* (d, 2H, J ) 7.2 Hz),
7.26 (d, 2H, J ) 7.3 Hz), 7.18 (m, 3H), 7.10* (m, 3H), 5.96 (br
s, 1H), 5.30* (br s, 1H), 4.74 (br s, 1H), 4.63* (d, 1H, J ) 9.3
Hz), 4.42 (d, 1H, J ) 9.4 Hz), 4.06 (dq, 1H, J ) 9.3, 6.7 Hz),
3.79 (dt, 1H, J ) 8.9, 3.3 Hz), 3.63 (dt, 1H, J ) 11.5, 4.9 Hz),
3.51* (m, 1H), 3.22 (m, 1H), 2.82 (s, 3H), 2.72* (m, 1H), 2.59*
(s, 3H), 2.19 (m, 1H), 1.97* (m, 1H), 1.62 (m, 1H), 1.51* (m,
1H), 1.01 (d, 3H, J ) 6.6 Hz), 1.00* (d, 3H, J ) 6.0 Hz), 0.97*
(d, 3H, J ) 6.9 Hz), 0.58 (d, 3H, J ) 6.7 Hz); 13C NMR (C6D6)
major diastereomer (3): δ 178.46, 178.21*, 143.18, 142.90*,
128.58, 128.45, 127.67, 127.48, 127.35, 76.03, 75.33*, 60.54,
60.34*, 58.40*, 57.03, 37.69*, 37.36, 33.63, 33.02*, 31.12,
27.35*, 17.88, 15.51*, 14.34; minor diastereomer: δ 178.41*,
177.82, 143.41*, 142.93, 128.71, 128.52, 128.38, 127.53, 127.43,
127.13, 75.77*, 75.17, 60.58, 60.28*, 58.48, 37.62, 37.03*,
33.61*, 32.41, 27.02, 19.02, 17.45*, 15.72, 14.25*; IR 3378 (br,
s, OH), 2966 (m), 2931 (m), 2872 (m), 1614 (s, CdO), 1455 (m),
1049 (m) cm-1; HRMS (CI) calcd for C15H24NO3 (MH+) 266.1756,
found 266.1757.
by the preparation of an authentic sample of the pure minor
diastereomer, see below): 1H NMR (C6D6) major diastereomer
(4) (20:1 rotamer ratio, * denotes minor rotamer peaks): δ 7.36
(d, 2H, J ) 7.4 Hz), 7.20-7.10 (m, 3H), 7.10-7.05 (m, 4H),
6.99 (m, 1H), 5.04 (br s, 1H), 4.77 (br s, 1H), 4.29 (br d, 1H, J
) 8.9 Hz), 3.74 (m, 1H), 3.59 (m, 1H), 3.07 (m, 1H), 3.02 (dd,
2H, J ) 12.4, 10.4 Hz), 2.79* (s, 3H), 2.59 (dd, 1H, J ) 12.2,
4.2 Hz), 2.33 (s, 3H), 2.21 (m, 1H), 1.65 (m, 1H), 0.79* (d, 3H,
J ) 6.7 Hz), 0.49 (d, 3H, J ) 6.8 Hz); minor diastereomer (∼3:1
rotamer ratio, * denotes minor rotamer peaks): δ 7.29* (d, 2H,
J ) 7.5 Hz), 7.26 (d, 2H, J ) 7.5 Hz), 7.22-7.04 (m, 10H),
7.01 (d, 2H, J ) 7.2 Hz), 6.93 (t, 2H, J ) 7.4 Hz), 6.89* (t, 2H,
J ) 7.2 Hz), 5.52 (br s, 1H), 4.61 (br s, 1H), 4.23 (d, 1H, J )
9.6 Hz), 3.94 (dq, 1H, J ) 9.2, 6.8 Hz), 3.81 (dt, 1H, J ) 11.8,
2.6 Hz), 3.68 (dt, 1H, J ) 11.6, 4.6 Hz), 3.49 (m, 1H), 3.32*
(m, 1H), 2.97 (dd, 1H, J ) 12.6, 11.1 Hz), 2.74 (s, 3H), 2.56
(dd, 1H, J ) 12.7, 4.4 Hz), 2.27* (s, 3H), 2.20 (m, 1H), 1.94*
(m, 1H), 1.72 (m, 1H), 1.51* (m, 1H), 0.91* (d, 3H, J ) 6.7
Hz), -0.03 (d, 3H, J ) 6.6 Hz); 13C NMR (C6D6) major
diastereomer (4): δ 177.35, 176.50*, 142.83, 140.34, 129.76,
129.36, 128.65, 128.46, 128.38, 127.52, 126.37, 76.18, 75.40*,
60.87, 60.60*, 55.68, 42.22, 41.00*, 40.31, 39.70*, 36.49, 36.00*,
29.82, 15.30*, 14.05; minor diastereomer: δ 177.06*, 176.16,
143.37*, 142.85, 140.45, 140.22*, 129.45, 129.36, 128.71,
128.57, 127.44, 127.31, 127.04, 126.55, 126.34, 75.56*, 75.43,
60.63, 60.47*, 58.76, 42.01*, 41.40, 41.19, 39.76*, 37.47, 36.28*,
26.80, 23.80*, 14.81, 14.06*; IR 3378 (br, s, OH), 2966 (w), 2931
(m) 2872 (m), 1614 (s, CdO), 1496 (m), 1455 (s), 1414 (m), 1049
(s) cm-1; HRMS (CI) calcd for C21H28NO3 (MH+) 342.2069,
found 342.2064.
[1S(R),2S]-N-(2-H yd r oxy-1-m et h yl-2-p h en ylet h yl)-4-
(ter t-bu tyldim eth ylsilyloxy)-N,2-dim eth ylbu tan am ide (5).
A dry 25-mL round-bottomed flask equipped with a magnetic
stirring bar was charged with anhydrous lithium chloride
(0.508 g, 12.0 mmol, 6.00 equiv), N,N-diisopropylamine (0.590
mL, 4.50 mmol, 2.25 equiv), and tetrahydrofuran (2.00 mL).
The resulting suspension was cooled to -78 °C, and n-
butyllithium (2.38 M in hexanes, 1.76 mL, 4.20 mmol, 2.10
equiv) was added by syringe. The suspension was warmed to
0 °C for 10 min and then was cooled to -78 °C. A solution of
amide 1 (0.442 g, 2.00 mmol, 1 equiv) in tetrahydrofuran (4.50
mL) was transferred dropwise to the reaction flask by syringe.
The transfer was then quantitated with an additional portion
of tetrahydrofuran (0.50 mL). Upon completion of the addition,
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 finally was cooled to 0 °C.
2-(tert-Butyldimethylsilyloxy)ethyl iodide (1.15 g, 4.00 mmol,
2.00 equiv) was added to the reaction flask by microliter
syringe. After 5.5 h, saturated aqueous ammonium chloride
solution (5 mL) was added and the resulting biphasic mixture
was partitioned between water (3 mL) and ethyl acetate (5
mL). The aqueous layer was separated and extracted further
with three 5-mL portions of ethyl acetate. The combined
organic layers were dried over anhydrous sodium sulfate and
then were concentrated. Purification of the residue by flash
column chromatography (30% ethyl acetate in hexanes) pro-
vided 0.691 g (91%) of 5 as a highly viscous, colorless oil.
Desilylation of 5, as follows, produced a diol that was identical
to the minor diastereomer formed by the alkylation of 1 with
ethylene oxide. A solution of 5 (0.236 g, 0.621 mmol, 1 equiv)
in tetrahydrofuran (2.00 mL) at 23 °C was treated with tetra-
n-butylammonium fluoride (1.00 M in tetrahydrofuran, 0.745
mL, 0.745 mmol, 1.20 equiv). After 15 min, water (1 mL) was
added and the solution was partitioned between water (2 mL)
and ethyl acetate (5 mL). The aqueous layer was separated
and extracted further with three 1-mL portions of ethyl
acetate. The combined organic layers were dried over anhy-
drous sodium sulfate and then were concentrated. The result-
ing oil was purified by flash column chromatography (ethyl
acetate) to furnish 0.153 g (93%) of the diol (spectroscopic data
is included in the experimental procedure for 3). Acetylation,
as described above, followed by capillary GC analysis of the
resulting O,O-diacetate, established a diastereomeric excess
(de) of 97% for product 5: 1H NMR (∼3:1 rotamer ratio, *
denotes minor rotamer peaks, C6D6) δ 7.34 (d, 2H, J ) 7.2
Hz), 7.28* (d, 2H, J ) 7.2 Hz), 7.16 (m, 3H), 7.08* (m, 3H),
[1S(S),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-4-h y-
d r oxy-N-m eth yl-2-(p h en ylm eth yl)bu ta n a m id e (4). The
alkylation of (1S,2S)-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-
methylbenzenepropionamide (2) (0.297 g, 1.00 mmol, 1 equiv)
with ethylene oxide (0.250 mL, 5.00 mmol, 5.00 equiv) in
tetrahydrofuran (0.400 M, 0 °C for 1 h) was carried out as
described for 3. Purification of the product by flash column
chromatography (50% ethyl acetate in hexanes) provided 0.328
g (96%) of 4 (an inseparable mixture of diastereomers) as a
highly viscous, colorless oil. Acetylation, as described above,
and capillary GC analysis of the resulting O,O-diacetate
established a diastereomeric excess (de) of 59% for this
product. Spectroscopic and analytical data for the diastereo-
meric mixture follow (assignments are secured unambiguously

2434 J . Org. Chem., Vol. 61, No. 7, 1996
Myers and McKinstry
4.55 (dd, 1H, J ) 7.2, 7.1 Hz), 4.28* (dd, 1H, J ) 5.9, 3.0 Hz),
4.03* (m, 1H), 3.68 (m, 1H), 3.46 (m, 1H), 3.37 (m, 1H), 3.11*
(m, 1H), 2.81* (s, 3H), 2.78 (m, 1H), 2.48 (s, 3H), 2.44* (m,
1H), 1.91 (m, 1H), 1.62* (m, 1H), 1.46 (m, 1H), 1.09* (d, 3H, J
) 6.8 Hz), 1.03 (d, 3H, J ) 6.8 Hz), 0.99 (d, 3H, J ) 6.9 Hz),
0.97* (s, 9H), 0.91 (s, 9H), 0.65* (d, 3H, J ) 6.7 Hz), 0.09* (s,
3H), 0.08* (s, 3H), -0.01 (s, 3H), -0.03 (s, 3H); 13C NMR (C6D6)
δ 178.00, 176.72*, 143.79, 142.71*, 128.59, 128.31, 127.49,
127.37, 126.80, 76.38, 75.50*, 61.87*, 60.87, 58.90, 58.23*,
37.41, 32.73, 32.62*, 26.27* 26.09, 18.37*, 18.13, 17.30, 15.52*,
14.34, -5.03*, -5.15*, -5.30; IR 3377 (br, s, OH), 2954 (s),
2919 (s), 2860 (s), 1613 (s, CdO), 1472 (m), 1461 (m), 1443
(m), 1249 (s), 1090 (s), 838 (s) cm-1; HRMS (CI) calcd for
C21H38NO3Si (MH+) 380.2621, found 380.2624.
anes) afforded 0.123 g (88%) of product as a white crystalline
solid. Acetylation followed by capillary GC analysis of the
resulting O,O-diacetate established a diastereomeric excess
(de) of 93% for this product: mp 75-79 °C; 1H NMR (∼5:1
rotamer ratio, * denotes minor rotamer peaks, C6D6) δ 7.37
(d, 2H, J ) 7.4 Hz), 7.26* (d, 2H, J ) 7.4 Hz), 7.19-7.12 (m,
3H), 7.11-7.06* (m, 3H), 5.30 (br s, 1H), 4.75 (br s, 1H), 4.41
(d, 1H, J ) 8.5 Hz), 4.35* (d, 1H, J ) 8.4 Hz), 3.89 (m, 1H),
3.78* (m, 1H), 3.20* (m, 1H), 2.94 (m, 1H), 2.88* (s, 3H), 2.54
(s, 3H), 2.00 (ddd, 1H, J ) 13.3, 10.4, 2.6 Hz), 1.39 (ddd, 1H,
J ) 13.5, 9.8, 3.8 Hz), 1.29* (d, 3H, J ) 6.8 Hz), 1.21 (d, 3H,
J ) 5.6 Hz), 1.06* (d, 3H, J ) 6.1 Hz), 0.99 (d, 3H, J ) 6.9
Hz), 0.86* (d, 3H, J ) 6.6 Hz), 0.78 (d, 3H, J ) 6.5 Hz); 13C
NMR (C6D6) δ 178.37, 143.16, 128.44, 127.67, 127.37, 127.25,
76.13, 75.55*, 67.99*, 65.38, 58.50*, 57.12, 44.32*, 43.74,
34.50*, 33.13, 33.00*, 31.20, 27.40*, 24.55, 18.58*, 18.15,
15.98*, 14.41; IR 3378 (br, s, OH), 2964 (s), 2929 (m), 2871
(w), 1612 (s, CdO), 1451 (s), 1410 (m), 1376 (m), 1111 (m),
1082 (s), 1047 (m) cm-1; HRMS (FAB) calcd for C16H26NO3
[1S(R),2S]-N-(2-H yd r oxy-1-m et h yl-2-p h en ylet h yl)-4-
(ter t-b u t yld im et h ylsilyloxy)-N-et h yl-2-(p h en ylm et h yl)-
bu ta n a m id e (6). The alkylation of 2 (1.19 g, 4.00 mmol, 1
equiv) with 2-(tert-butyldimethylsilyloxy)ethyl iodide (2.30 g,
8.00 mmol, 2.00 equiv) in tetrahydrofuran (8.00 mL, 0 °C for
6 h) was carried out as described above for compound 5. The
product was obtained as a viscous, light yellow oil (1.64 g, 90%)
after purification by flash column chromatography (30% ethyl
acetate in hexanes). Desilylation of 6, as described for 5,
produced a diol (92%; spectroscopic data is included in the
experimental procedure for 4) that was identical to the minor
diastereomer formed in the alkylation of 2 with ethylene oxide.
Acetylation, as described above, followed by capillary GC
analysis of the resulting O,O-diacetate established that prod-
uct 6 had been formed with a diastereomeric excess (de) of
g99%: 1H NMR (3.5:1 rotamer ratio, * denotes minor rotamer
peaks, C6D6) δ 7.23 (d, 2H, J ) 7.2 Hz), 7.20* (m, 2H), 7.16-
6.99 (m, 14H), 6.95 (m, 1H), 6.91* (m, 1H), 4.49 (br d, 1H, J )
6.8 Hz), 4.14* (dd, 1H, J ) 9.2, 2.7 Hz), 3.99 (br s, 1H), 3.87*
(dq, 1H, J ) 9.8, 5.8 Hz), 3.75 (m, 1H), 3.41 (dt, 1H, J ) 10.4,
5.1 Hz), 3.20 (dt, 1H, J ) 10.0, 3.9 Hz), 3.15 (m, 1H), 3.07*
(dd, 1H, J ) 12.9, 10.4 Hz), 3.04 (dd, 1H, J ) 12.9, 9.9 Hz),
2.72* (s, 3H), 2.67* (dd, 1H, J ) 12.8, 4.8 Hz), 2.61 (dd, 1H, J
) 12.9, 4.8 Hz), 2.45* (m, 1H), 2.28 (s, 3H), 1.91 (m, 1H), 1.66*
(m, 1H), 1.61 (m, 1H), 0.96* (s, 9H), 0.93 (d, 3H, J ) 7.0 Hz),
0.89 (s, 9H), 0.14* (d, 3H, J ) 6.5 Hz), 0.10* (s, 3H), 0.09* (s,
3H), -0.04 (s, 3H), -0.07 (s, 3H); 13C NMR (C6D6) δ 176.87,
175.59*, 143.57, 142.82*, 140.68*, 140.47, 129.42, 128.63,
128.56, 127.43, 127.32, 126.84, 126.51, 126.32, 75.86, 75.42*,
62.22*, 60.65, 60.45, 58.71*, 41.21*, 40.98, 40.28*, 39.36,
36.88*, 36.58, 33.81, 26.88*, 26.30*, 26.06, 18.69*, 18.31,
14.87*, 14.18, -4.94*, -5.09*, -5.28; IR 3389 (br, s, OH), 2955
(s), 2931 (s), 2884 (s), 2861 (s), 1619 (s, CdO), 1455 (s), 1255
(m), 1084 (s), 838 (m) cm-1; HRMS (FAB) calcd for C27H41NO3Si
(M+) 455.2857, found 455.2856.
(MH+) 280.1914, found 280.1913. Anal. Calcd for C16H25
-
NO3‚1/2H2O (288.19): C, 66.62; H, 9.09; N, 4.86. Found: C,
66.58; H, 9.03; N, 4.88.
[1S(2S,4S),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
4-h yd r oxy-N,2-d im eth yl-4-p h en ylbu ta n a m id e (Ta ble 1,
en tr y 2). The alkylation of 1 (0.111 g, 0.500 mmol, 1 equiv)
with (S)-(-)-styrene oxide (0.120 g, 1.00 mmol, 2.00 equiv) in
tetrahydrofuran (0.500 M, -5 °C for 7 h) was carried out as
described above for entry 1 (Table 1). The product was
obtained as a white crystalline solid (0.139 g, 82%) after
recrystallization from benzene (3.00 mL). Acetylation and
capillary GC analysis of the resulting O,O-diacetate estab-
lished a diastereomeric excess (de) of 90% for this product: mp
122-126 °C; 1H NMR (∼4:1 rotamer ratio, * denotes minor
rotamer peaks, CDCl3) δ 7.36-7.26 (m, 10H), 7.26 -7.14* (m,
10H), 4.71 (dd, 1H, J ) 9.2, 3.1 Hz), 4.56 (m and d, 2H, J )
7.7 Hz), 4.51* (d, 1H, J ) 7.8 Hz), 4.04* (m, 1H), 3.70-3.11
(br s, 1H), 2.93 (m and s*, 1H and 3H), 2.82 (s, 3H), 2.15 (ddd,
1H, J ) 13.8, 10.1, 3.1 Hz), 2.12* (m, 1H), 1.77* (m, 1H), 1.75
(ddd, 1H, J ) 13.6, 9.2, 3.6 Hz), 1.21* (d, 3H, J ) 6.8 Hz),
1.06 (d, 3H, J ) 6.2 Hz), 1.03 (d, 3H, J ) 6.9 Hz), 0.93* (d,
3H, J ) 6.7 Hz); 13C NMR (CDCl3) δ 178.88, 145.03, 142.28,
128.73, 128.36, 127.73, 127.20, 126.58, 125.66, 125.53, 76.44,
72.00*, 71.73, 58.55, 43.89*, 43.30, 33.13, 32.35, 18.50*, 17.79,
15.70*, 14.41; IR 3378 (br, s, OH), 2975 (m), 2929 (m), 2871
(m), 1612 (s, CdO), 1491 (m), 1451 (s), 1410 (m), 1111 (m),
1088 (m), 1047 (m), 1030 (m) cm-1; HRMS (FAB) calcd for
C21H28NO3 (MH+) 342.2070, found 342.2069. Anal. Calcd for
C21H27NO3‚H2O (359.21): C, 70.15; H, 8.14; N, 3.90. Found:
C, 70.45; H, 7.73; N, 3.94.
[1S(2S,4S),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
4-h yd r oxy-N,2-d im eth ylp en ta n a m id e (Ta ble 1, en tr y 1).
A dry 10-mL round bottomed flask equipped with a magnetic
stirring bar was charged with anhydrous lithium chloride
(0.127 g, 3.00 mmol, 6.00 equiv), N,N-diisopropylamine (0.138
mL, 1.05 mmol, 2.10 equiv), and tetrahydrofuran (0.50 mL).
The resulting suspension was cooled to -78 °C, and n-
butyllithium (2.30 M in hexanes, 0.480 mL, 1.11 mmol, 2.21
equiv) was added by syringe. The suspension was warmed to
0 °C for 10 min and then was cooled to -78 °C. A solution of
1 (0.111 g, 0.500 mmol, 1 equiv) in tetrahydrofuran (1.80 mL)
was transferred dropwise to the reaction flask by syringe. The
transfer was quantitated with an additional portion of tet-
rahydrofuran (0.20 mL). Upon completion of the addition, the
reaction mixture was stirred at -78 °C for 1 h, at 0 °C for 15
min, at 23 °C for 5 min, and finally was cooled to 0 °C. (S)-
(-)-Propylene oxide (0.0581 g, 1.00 mmol, 2.00 equiv) was
added to the reaction vessel by microliter syringe, and the
resulting solution was stirred at -5 °C for 4 h. Saturated
aqueous ammonium chloride solution (2 mL) was added, and
the resulting biphasic mixture was partitioned between water
(5 mL) and ethyl acetate (5 mL). The aqueous layer was
separated and extracted further with three 5-mL portions of
ethyl acetate and one 5-mL portion of dichloromethane. The
combined organic layers were dried over anhydrous sodium
sulfate and then were concentrated. Purification of the residue
by flash column chromatography (75% ethyl acetate in hex-
[1S(2S,4R),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
5-(ter t-bu tyld im eth ylsilyloxy)-4-h yd r oxy-N,2-d im eth yl-
p en ta n a m id e (Ta ble 1, en tr y 3). The alkylation of 1 (0.221
g, 1.00 mmol, 1 equiv) with (S)-(-)-tert-butyldimethylsilyl
glycidyl ether (0.377 g, 2.00 mmol, 2.00 equiv) in tetrahydro-
furan (1.00 M, -5 °C for 10 h) was carried out as described
above for entry 1 (Table 1). The product was obtained as a
viscous, colorless oil (0.344 g, 84%) after purification by flash
column chromatography (50% ethyl acetate in hexanes).
Capillary GC analysis of the corresponding O,O,O-triacetate,
prepared from the alkylated amide by sequential desilylation
and acetylation (as described above for 5), established a
diastereomeric excess (de) of 96% for this product: 1H NMR
(4:1 rotamer ratio, * denotes minor rotamer peaks, C6D6) δ
7.33 (d, 2H, J ) 7.3 Hz), 7.22* (d, 2H, J ) 7.3 Hz), 7.17 (m,
3H), 7.07* (m, 3H), 4.49 (d, 1H, J ) 7.3 Hz), 4.42 (br s, 1H),
4.28 (m, 1H), 3.78 (m, 1H), 3.53 (dd, 1H, J ) 9.9, 4.1 Hz), 3.49*
(dd, 1H, J ) 9.9, 3.8 Hz), 3.39 (dd, 1H, J ) 9.9, 6.6 Hz), 3.33*
(dd, 1H, J ) 9.9, 7.2 Hz), 3.10 (br s, 1H), 2.95 (m, 1H), 2.88*
(s, 3H), 2.49 (s, 3H), 2.01 (ddd, 1H, J ) 13.0, 10.7, 2.2 Hz),
1.45* (ddd, 1H, J ) 13.7, 10.3, 3.6 Hz), 1.42 (ddd, 1H, J )
13.7, 10.3, 3.6 Hz), 1.34* (d, 3H, J ) 6.8 Hz), 0.98 (d, 3H, J )
6.8 Hz), 0.90 (s and d, 9H and 3H, J ) 6.8 Hz), 0.87* (s, 9H),
0.81* (d, 3H, J ) 6.4 Hz), 0.03 (s, 6H), -0.04* (s, 6H); 13C NMR
(C6D6) δ 178.44, 143.65, 128.19, 127.40, 126.81, 76.48, 69.88,
68.02, 59.85, 37.89, 33.98, 33.05, 26.04, 18.35, 14.42, -5.27,
-5.36; IR 3389 (br, s, OH), 2955 (s), 2931 (s), 2861 (s), 1614

Enantiomerically Enriched γ-Lactones and γ-Hydroxy Ketones
J . Org. Chem., Vol. 61, No. 7, 1996 2435
(s, CdO), 1472 (s), 1461 (s), 1455 (s), 1255 (s), 1108 (s), 1085
(s) cm-1; HRMS (FAB) calcd for C22H40NO4Si (MH+) 410.2728,
found 410.2727. Anal. Calcd for C22H39NO4Si‚H2O (427.28):
C, 61.79; H, 9.67; N, 3.28. Found: C, 61.57; H, 9.26; N, 3.15.
[1S(2S,4R),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
5-ben zyloxy-4-h ydr oxy-N,2-d im eth ylp en ta n a m id e (Ta ble
1, en tr y 4). The alkylation of 1 (0.221 g, 1.00 mmol, 1 equiv)
with (S)-(-)-benzyl glycidyl ether (0.328 g, 2.00 mmol, 2.00
equiv) in tetrahydrofuran (1.00 M, -5 °C for 12 h) was carried
out as described above for entry 1 (Table 1). The product was
obtained as a highly viscous, colorless oil (0.310 g, 80%) after
purification by flash column chromatography (2.5% methanol
in dichloromethane). Acetylation followed by capillary GC
analysis of the resulting O,O-diacetate established a diaster-
eomeric excess (de) of 85% for this product: 1H NMR (∼5:1
rotamer ratio, * denotes minor rotamer peaks, C6D6) δ 7.32
(d, 2H, J ) 7.4 Hz), 7.24 (d, 2H, J ) 7.5 Hz), 7.19-7.05 (m,
16H), 4.48 (br d, 1H, J ) 7.9 Hz), 4.32 (br s, 1H), 4.24 (2d, 2H,
J ) 12.0 Hz), 4.19* (s, 2H), 4.09* (br d, 1H, J ) 8.0 Hz), 3.93
(m, 1H), 3.88* (m, 1H), 3.27 (dd, 1H, J ) 9.4, 3.6 Hz), 3.23*
(dd, 1H, J ) 9.4, 3.6 Hz), 3.17 (dd, 1H, J ) 9.3, 7.4 Hz), 3.14*
(dd, 1H, J ) 9.4, 7.3 Hz), 2.94 (m, 1H), 2.84* (s, 3H), 2.73* (br
s, 1H), 2.45 (s, 3H), 2.06* (m, 1H), 2.00 (ddd, 1H, J ) 13.3,
10.8, 2.5 Hz), 1.42* (m, 1H), 1.37 (ddd, 1H, J ) 13.5, 10.4, 3.4
Hz), 1.31* (d, 3H, J ) 6.8 Hz), 0.97 (d, 3H, J ) 6.9 Hz), 0.94
(s, 3H), 0.77* (d, 3H, J ) 6.7 Hz); 13C NMR (C6D6) δ 178.14,
177.87*, 143.22, 139.01, 138.87*, 128.56, 128.21, 127.71,
127.62, 127.52, 127.25, 75.91, 75.51, 75.34*, 73.33, 68.52*,
68.29, 58.54*, 57.42, 38.70*, 38.16, 32.79, 32.38*, 31.11, 27.46*,
18.89*, 18.29, 15.69*, 14.41; IR 3383 (br, s, OH), 2965 (m),
2934 (m), 2871 (m), 1611 (s, CdO), 1454 (s), 1105 (s), 1084 (s),
1047 (m), 1026 (m) cm-1; HRMS (FAB) calcd for C23H32NO4
(MH+) 386.2333, found 386.2331.
[1S(2S,4S),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
4-h y d r o x y -N -m e t h y l-2-(p h e n y lm e t h y l)p e n t a n a m id e
(Ta ble 1, en tr y 5). The alkylation of 2 (0.149 g, 0.500 mmol,
1 equiv) with (S)-(-)-propylene oxide (0.0581 g, 1.00 mmol,
2.00 equiv) in tetrahydrofuran (0.500 M, -5 °C for 9 h) was
carried out as described above for entry 1 (Table 1). The
product was obtained as a white crystalline solid (0.152 g, 86%)
after purification by flash column chromatography (ethyl
acetate). Acetylation followed by capillary GC analysis of the
resulting O,O-diacetate established a diastereomeric excess
(de) of g99% for this product: mp 112-114 °C; 1H NMR (∼15:1
rotamer ratio, * denotes minor rotamer peaks, C6D6) δ 7.35
(d, 2H, J ) 7.3 Hz), 7.24-7.00 (2m, 7H), 6.97 (m, 1H), 5.02
(br s, 1H), 4.67 (br s, 1H), 4.27 (d, 1H, J ) 9.3 Hz), 3.89 (m,
1H), 3.35 (m, 1H), 3.29 (m, 1H), 2.97 (dd, 1H, J ) 12.9, 9.7
Hz), 2.78* (s, 3H), 2.57 (dd, 1H, J ) 12.9, 5.6 Hz), 2.34 (s, 3H),
2.08 (ddd, 1H, J ) 13.3, 11.0, 2.4 Hz), 1.48 (ddd, 1H, J ) 13.5,
10.2, 3.5 Hz), 1.15 (d, 3H, J ) 6.1 Hz), 0.88* (d, 3H, J ) 6.2
Hz), 0.80* (d, 3H, J ) 6.7 Hz), 0.54 (d, 3H, J ) 6.8 Hz); 13C
NMR (C6D6) δ 177.30, 142.93, 140.40, 129.73, 129.37, 128.51,
128.45, 127.36, 126.42, 76.39, 65.42, 55.87, 42.58, 41.24, 40.44,
30.02, 24.52, 14.19; IR 3357 (br, s, OH), 2962 (m), 2930 (m),
1612 (s, CdO), 1494 (m), 1452 (s), 1126 (m), 1078 (m), 1046
(m), 1030 (m) cm-1; HRMS (FAB) calcd for C22H30NO3 (MH+)
356.2227, found 356.2226.
9.8 Hz), 2.64 (dd, 1H, J ) 13.1, 5.5 Hz), 2.47 (s, 3H), 2.15 (ddd,
1H, J ) 13.8, 10.7, 3.1 Hz), 1.82 (ddd, 1H, J ) 13.6, 9.8, 3.6
Hz), 1.00* (d, 3H, J ) 6.9 Hz), 0.64 (d, 3H, J ) 6.8 Hz); 13C
NMR (CDCl3) δ 177.09, 145.17, 141.65, 139.37, 129.08, 128.81,
128.23, 128.12, 128.08, 128.05, 127.62, 126.85, 126.80, 126.44,
126.10, 125.42, 75.73, 71.09, 54.91, 42.37, 40.81, 39.73, 29.70,
13.88; IR 3383 (br, s, OH), 2925 (m), 1613 (s, CdO), 1490 (s),
1450 (s), 1411 (m), 1048 (m), 1026 (m) cm-1; HRMS (FAB) calcd
for C27H32NO3 (MH+) 418.2384, found 418.2382. Anal. Calcd
for C27H31NO3‚1/2H2O (426.24): C, 76.01; H, 7.57; N, 3.29.
Found: C, 76.34; H, 7.69; N, 3.39.
[1S(2S,4R),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
5-(ter t-bu tyldim eth ylsilyloxy)-4-h ydr oxy-N-m eth yl-2-(ph e-
n ylm et h yl)p en t a n a m id e (9) (Ta ble 1, en t r y 7). The
alkylation of 2 (0.297 g, 1.00 mmol, 1 equiv) with (S)-(-)-tert-
butyldimethylsilyl glycidyl ether (0.377 g, 2.00 mmol, 2.00
equiv) in tetrahydrofuran (1.00 M, -5 °C for 11 h) was carried
out as described above for entry 1 (Table 1). The product 9
was obtained as a white crystalline solid (0.393 g, 81%) after
purification by flash column chromatography (30% ethyl
acetate in hexanes). Capillary GC analysis of the correspond-
ing O,O,O-triacetate (prepared by desilylation/acetylation, as
described above) established a diastereomeric excess (de) of
g99% for 9: mp 79-81 °C; 1H NMR (10:1 rotamer ratio, *
denotes minor rotamer peaks, C6D6) δ 7.35* (d, 2H, J ) 7.3
Hz), 7.32 (d, 2H, J ) 7.3 Hz), 7.16-7.12 (m, 6H), 7.07-7.03
(m 5H), 6.99* (m, 5H), 4.85 (br s, 1H), 4.34 (dd, 1H, J ) 8.3,
4.2 Hz), 4.21 (br s, 1H), 4.14* (dd, 1H, J ) 8.5, 3.0 Hz), 3.83
(m, 1H), 3.72* (m, 1H), 3.50 (dd, 1H, J ) 10.0, 3.9 Hz), 3.39
(m, 1H,), 3.33 (dd, 1H, J ) 9.9, 6.6 Hz), 3.17* (dd, 1H, J ) 9.9,
6.6 Hz), 3.02 (dd, 1H, J ) 12.8, 9.9 Hz), 2.84* (s, 3H), 2.63
(dd, 1H, J ) 12.9, 5.4 Hz), 2.41 (s, 3H), 2.07 (ddd, 1H, J )
13.2, 11.1, 2.1 Hz), 2.02* (m, 1H), 1.59 (ddd, 1H, J ) 13.5,
10.2, 3.5 Hz), 0.91 (s, 9H), 0.86* (d, 3H, J ) 6.6 Hz), 0.82* (s,
9H), 0.60 (d, 3H, J ) 6.6 Hz), 0.01 (s, 6H), -0.09* (s, 6H); 13
C
NMR (C6D6) δ 177.37, 143.12, 140.26, 129.75, 129.35, 128.76,
128.63, 128.46, 127.43, 127.28, 126.44, 76.42, 69.69, 67.96,
41.06, 40.60, 36.85, 26.07, 25.98, 18.47, 14.17, -5.23, -5.34;
IR 3381 (br, s, OH), 2956 (s), 2926 (s), 2855 (s), 1612 (s), 1451
(m), 1253 (m), 1122 (s), 1081 (s), 838 (s) cm-1. Anal. Calcd
for C28H43NO4Si: C, 69.24; H, 8.93; N, 2.89. Found: C, 69.02;
H, 8.90; N, 2.62.
[1S(2S,4R),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
5-(ben zyloxy)-4-h yd r oxy-N-m eth yl-2-(p h en ylm eth yl)p en -
ta n a m id e (10) (Ta ble 1, en tr y 8). The alkylation of 2 (0.297
g, 1.00 mmol, 1 equiv) with (S)-(-)-benzyl glycidyl ether (0.328
g, 2.00 mmol, 2.00 equiv) in tetrahydrofuran (1.00 M, -5 °C
for 12 h) was carried out as described above for entry 1 (Table
1). The product 10 was obtained as a white solid (0.420 g,
87%) after purification by flash column chromatography (1%
methanol, 29.7% ethyl acetate, 69.3% hexanes). Analysis by
500 MHz 1H NMR, as described above (Table 1, entry 6),
established a diastereomeric excess (de) of g95% for this
product. A single recrystallization from toluene (20.0 mL)
provided 10 as white needles: mp 126-128 °C; 1H NMR (∼8:1
rotamer ratio, * denotes minor rotamer peaks, CDCl3) δ 7.34-
7.13 (m, 15H), 4.65 (br s, 1H), 4.52 (d, 1H, J ) 12.0 Hz), 4.49
(d, 1H, J ) 11.9 Hz), 4.47* (s, 2H), 4.41 (d, 1H, J ) 8.9 Hz),
4.33* (d, 1H, J ) 8.9 Hz), 3.78 (m, 1H), 3.62* (m, 1H), 3.46
(dd, 1H, J ) 9.5, 3.1 Hz), 3.42* (dd, 1H, J ) 9.5, 3.1 Hz), 3.32
(m, 1H), 3.28 (dd, 1H, J ) 9.4, 7.5 Hz), 3.20* (dd, 1H, J ) 9.4,
7.5 Hz), 3.10* (dd, 1H, J ) 12.9, 9.9 Hz), 2.85 (dd, 1H, J )
12.9, 9.9 Hz), 2.84* (s, 3H), 2.69 (dd, 1H, J ) 13.0, 5.3 Hz),
2.58 (s, 3H), 1.90 (ddd, 1H, J ) 13.7, 11.1, 2.7 Hz), 1.83* (ddd,
1H, J ) 13.7, 11.1, 2.7 Hz), 1.58 (ddd, 1H, J ) 13.9, 10.6, 3.6
Hz), 1.50* (ddd, 1H, J ) 13.9, 10.6, 3.6 Hz), 0.91* (d, 3H, J )
6.4 Hz), 0.68 (d, 3H, J ) 6.8 Hz); 13C NMR (CDCl3) δ 177.66,
142.14, 139.75, 138.19, 129.50, 129.20, 128.85, 128.67, 128.62,
128.52, 128.07, 128.01, 127.26, 127.06, 126.59, 74.76, 73.51,
68.22, 56.80, 40.95, 40.37, 36.47, 31.22, 14.40; IR 3386 (br, s,
OH), 2920 (m), 2858 (m), 1612 (s, CdO), 1493 (m), 1451 (s),
1415 (m), 1120 (s), 1079 (s), 1048 (m), 1027 (m) cm-1. Anal.
Calcd for C29H35NO4: C, 75.45; H, 7.65; N, 3.04. Found: C,
75.36; H, 7.68; N, 2.84.
[1S(2S,4S),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
4-h yd r oxy-N-m eth yl-4-p h en yl-2-(p h en ylm eth yl)bu ta n a -
m id e (Ta ble 1, en tr y 6). The alkylation of 2 (0.149 g, 0.500
mmol, 1 equiv) with (S)-(-)-styrene oxide (0.120 g, 1.00 mmol,
2.00 equiv) in tetrahydrofuran (1.00 M, -5 °C for 10 h) was
carried out as described above for entry 1 (Table 1). The
product was obtained as a white crystalline solid (0.178 g, 86%)
after purification by flash column chromatography (2.5%
methanol in dichloromethane). The diastereomeric excess (de)
of the product was quantified by integration of the proton
1
resonances (500 MHz H NMR) corresponding to the methyl
groups of the pseudoephedrine auxiliary (N-methyl and C-
methyl) and was determined to be g95%. Recrystallization
from benzene (2.00 mL) afforded very fine, white needles: mp
1
136-139 °C; H NMR (∼18:1 rotamer ratio, * denotes minor
rotamer peaks, CDCl3) δ 7.38-7.03 (m, 15H), 4.73 (br s, 1H),
4.63 (dd, 1H, J ) 9.8, 3.1 Hz), 4.35 (d, 1H, J ) 9.1 Hz), 3.24
(m, 1H), 2.86 (m, 1H), 2.83* (s, 3H), 2.80 (dd, 1H, J ) 13.0,
[1S(2S,4R),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
4-h yd r oxy-N,2-d im eth ylp en ta n a m id e (Ta ble 2, en tr y 1).

2436 J . Org. Chem., Vol. 61, No. 7, 1996
Myers and McKinstry
The alkylation of 1 (0.111 g, 0.500 mmol, 1 equiv) with (R)-
(+)-propylene oxide (0.0581 g, 1.00 mmol, 2.00 equiv) in
tetrahydrofuran (0.500 M, -5 °C for 6 h) was carried out as
described above for entry 1 (Table 1). The product was
obtained as a viscous, colorless oil (0.121 g, 86%, an insepa-
rable mixture of diastereomers) after purification by flash
column chromatography (75% ethyl acetate in hexanes).
Acetylation followed by capillary GC analysis of the resulting
O,O-diacetates established a diastereomeric excess (de) of 73%
for this product. Spectroscopic and analytical data for the
diastereomeric mixture follow (assignments are secured un-
ambiguously by the preparation of an authentic sample of the
pure minor diastereomer, see the alkylation of 1 with 7,
described below): 1H NMR (C6D6) major diastereomer (∼11:1
rotamer ratio, * denotes minor rotamer peaks): δ 7.38 (d, 2H,
J ) 7.4 Hz), 7.26* (d, 2H, J ) 7.4 Hz), 7.20-7.11 (m, 4H),
7.09* (t, 1H, J ) 7.1 Hz), 7.08 (t, 1H, J ) 7.1 Hz), 5.00 (br s,
1H), 4.60 (br s, 1H), 4.49 (2d, 2H, J ) 5.3 Hz), 3.57 (m, 1H),
2.84* (s, 3H), 2.69 (m, 1H), 2.54 (m, 1H), 2.41 (s, 3H), 2.03
(ddd, 1H, J ) 13.9, 9.2, 9.0 Hz), 1.25 (ddd, 1H, J ) 8.1, 4.8,
3.2 Hz), 1.05 (d, 3H, J ) 6.1 Hz), 1.00* (d, 3H, J ) 6.1 Hz),
0.99* (d, 3H, J ) 6.6 Hz), 0.96 (d, 3H, J ) 6.7 Hz), 0.85 (d,
3H, J ) 6.5 Hz), 0.71* (d, 3H, J ) 6.6 Hz); minor diastereomer
(4:1 rotamer ratio, * denotes minor rotamer peaks): δ 7.36*
(d, 2H, J ) 7.6 Hz), 7.22 (d, 2H, J ) 7.6 Hz), 7.20-7.12 (m,
3H), 7.10-7.04* (m, 3H), 5.61 (br s, 1H), 4.62* (d, 1H, J ) 7.1
Hz), 4.51 (br s, 1H), 4.27 (d, 1H, J ) 9.5 Hz), 4.13 (m, 1H),
4.03 (m, 1H), 3.61* (m, 1H), 3.34 (m, 1H), 2.81 (s, 3H), 2.78*
(m, 1H), 2.53* (s, 3H), 2.38* (m, 1H), 2.14 (ddd, 1H, J ) 13.2,
10.9, 2.3 Hz), 1.84* (ddd, 1H, J ) 13.2, 10.9, 2.3 Hz), 1.37 (ddd,
1H, J ) 13.3, 10.4, 2.9 Hz), 1.27* (ddd, 1H, J ) 13.4, 10.0, 3.4
Hz), 1.21 (d, 3H, J ) 6.2 Hz), 1.02 (d, 3H, J ) 6.7 Hz), 0.98*
(d, 3H, J ) 6.7 Hz), 0.97* (d, 3H, J ) 6.8 Hz), 0.59 (d, 3H, J
) 6.6 Hz); 13C NMR (C6D6) major diastereomer: δ 178.54,
143.06, 128.26, 127.57, 127.33, 127.20, 127.05, 75.87, 66.63,
57.33, 43.77, 34.18, 31.41, 24.19, 17.75, 14.02; minor dia-
stereomer: δ 178.00, 177.20*, 143.30*, 142.25, 128.49, 128.34,
126.82, 75.09, 66.00*, 65.24, 60.00*, 58.01, 44.28, 44.21*, 33.70,
33.25*, 31.91, 27.62*, 26.80*, 23.55, 18.97, 15.55, 15.35*; IR
3376 (br, s, OH), 2965 (s), 2933 (m), 2881 (w), 1613 (s, CdO),
1047 (m), 1030 (m) cm-1. Anal. Calcd for C21H27NO3‚1/2H2O
(350.20): C, 71.96; H, 8.06; N, 4.00. Found: C, 71.71; H, 8.21;
N, 3.61.
[1S(2S,4S),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
5-(ter t-bu tyld im eth ylsilyloxy)-4-h yd r oxy-N,2-d im eth yl-
p en ta n a m id e (Ta ble 2, en tr y 3). The alkylation of 1 (0.221
g, 1.00 mmol, 1 equiv) with (R)-(+)-tert-butyldimethylsilyl
glycidyl ether (0.283 g, 1.50 mmol, 1.50 equiv) in tetrahydro-
furan (0.800 M, 0 °C for 21 h) was carried out as described
above for entry 1 (Table 1). The product was obtained as a
viscous, colorless oil (0.320 g, 78%, an inseparable mixture of
diastereomers) after purification by flash column chromatog-
raphy (50% ethyl acetate in hexanes). Capillary GC analysis
of the corresponding O,O,O-triacetates (prepared by desilyla-
tion/acetylation, as described above) established a diastereo-
meric excess (de) of 12% for this product: 1H NMR (∼1.5:1
rotamer ratio for each diastereomer, C6D6) δ 7.35 (d, 2H, J )
7.4 Hz), 7.34 (d, 2H, J ) 7.4 Hz), 7.30 (d, 2H, J ) 7.4 Hz),
7.22-7.15 (m, 11H), 7.12-7.06 (m, 3H), 4.60 (br s, 1H), 4.55
(br d, 1H, J ) 5.9 Hz), 4.51 (br s, 1H), 4.31 (m, 1H), 4.22 (m,
1H), 4.12 (m, 1H), 4.00 (m, 1H), 3.75 (m, 1H), 3.65 (m, 1H),
3.63 (dd, 1H, J ) 10.2, 4.4 Hz), 3.57-3.34 (m, 6H), 3.32 (dd,
1H, J ) 10.2, 7.0 Hz), 3.21 (m, 1H), 3.05 (br s, 1H), 2.97 (m,
1H), 2.87 (m, 2H), 2.84 (s, 3H), 2.75 (ap q, 1H, J ) 6.6 Hz),
2.53 (s, 3H), 2.49 (s, 3H), 2.42 (s, 3H), 2.24 (ddd, 1H, J ) 12.8,
10.4, 2.3 Hz), 1.97 (m, 2H), 1.89 (m, 1H), 1.58 (ddd, 1H, J )
12.2, 9.3, 2.3 Hz), 1.51 (ddd, 1H, J ) 14.0, 6.2, 2.8 Hz), 1.41
(ddd, 1H, J ) 12.8, 11.0, 4.6 Hz), 1.37 (d, 3H, J ) 6.8 Hz),
1.35 (ddd, 1H, J ) 13.9, 11.6, 4.6 Hz), 1.10 (d, 3H, J ) 6.9
Hz), 1.03 (d, 3H, J ) 7.4 Hz), 0.99 (d, 3H, J ) 6.8 Hz), 0.98 (d,
3H, J ) 6.6 Hz), 0.95 (s, 9H), 0.93 (s, 9H), 0.91 (s, 9H), 0.89 (s,
9H), 0.84 (d, 3H, J ) 6.7 Hz), 0.82 (d, 3H, J ) 6.8 Hz), 0.77 (d,
3H, J ) 6.5 Hz), 0.62 (d, 3H, J ) 6.8 Hz), 0.06 (s, 6H), 0.04 (s,
6H), 0.00 (2 s, 6H), -0.01 (s, 3H), -0.02 (s, 3H); 13C NMR
(C6D6) δ 178.72, 178.26, 176.81, 143.73, 143.50, 142.95, 142.58,
128.70, 128.53, 128.31, 127.47, 127.37, 127.07, 126.93, 126.81,
76.32, 76.17, 75.55, 71.20, 70.99, 70.05, 69.79, 68.11, 67.99,
59.00, 58.36, 58.10, 38.30, 37.72, 33.98, 33.14, 32.88, 31.86,
27.45, 27.00, 26.15, 26.07, 19.29, 18.47, 18.27, 17.74, 16.22,
15.78, 14.26, -5.27; IR 3378 (br, m, OH), 2955 (s), 2931 (s),
2884 (m), 2861 (s), 1619 (s, CdO), 1472 (m), 1461 (m), 1455
(m), 1255 (s), 1114 (s), 1085 (s), 838 (s), 779 (s), 703 (s) cm-1
.
1455 (s), 1408 (m), 1087 (m), 1045 (m) cm-1
.
[1S(2S,4S),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
5-(ben zyloxy)-4-h ydr oxy-N,2-dim eth ylpen tan am ide (Table
2, en tr y 4). The alkylation of 1 (0.221 g, 1.00 mmol, 1 equiv)
with (R)-(+)-benzyl glycidyl ether (0.328 g, 2.00 mmol, 2.00
equiv) in tetrahydrofuran (1.00 M, -5 °C for 13 h) was carried
out as described above for entry 1 (Table 1). The product was
obtained as a highly viscous, colorless oil (0.301 g, 78%, an
inseparable mixture of diastereomers) after purification by
flash column chromatography (2.5% methanol in dichlo-
romethane). Acetylation followed by capillary GC analysis of
the resulting O,O-diacetates established a diastereomeric
excess (de) of 38% for this product: 1H NMR (∼3:1 rotamer
ratio for each diastereomer, C6D6) δ 7.37 (d, 2H, J ) 7.4 Hz),
7.32-7.00 (m, 16H), 7.26 (d, 2H, J ) 7.5 Hz), 4.60 (br s, 1H),
4.50 (2 d, 2H, J ) 7.0 Hz), 4.38-4.13 (m, 2H), 4.30 (s, 2H),
4.25 (s, 2H), 3.77 (2 m, 2H), 3.24 (d, 2H, J ) 5.0 Hz), 3.21 (d,
2H, J ) 5.5 Hz), 2.88 (s, 3H), 2.85 (s, 3H), 2.71 (m, 1H), 2.51
(s, 3H), 2.41 (s, 3H), 2.04 (ddd, 1H, J ) 14.3, 9.9, 7.5 Hz), 1.93
(m, 1H), 1.52 (m, 1H), 1.47 (ddd, 1H, J ) 9.1, 6.1, 3.2 Hz),
1.34 (d, 3H, J ) 6.6 Hz), 1.09 (d, 3H, J ) 6.9 Hz), 1.01 (d, 3H,
J ) 6.9 Hz), 0.99 (d, 3H, J ) 6.8 Hz), 0.95 (d, 3H, J ) 6.1 Hz),
0.87 (d, 3H, J ) 6.6 Hz), 0.78 (d, 3H, J ) 6.9 Hz), 0.72 (d, 3H,
J ) 6.5 Hz); 13C NMR (C6D6) δ 178.41, 177.60, 143.31, 138.67,
128.34, 127.56, 127.23, 126.84, 126.57, 76.16, 76.15, 75.14,
75.12, 73.24, 69.38, 69.00, 58.64, 57.80, 38.60, 37.92, 33.64,
33.00, 32.13, 21.80, 20.00, 17.48, 14.03; IR 3382 (br, s, OH),
2967 (m), 2928 (m), 2869 (m), 1614 (s, CdO), 1451 (m), 1106
(m), 1086 (m) cm-1; HRMS (FAB) calcd for C23H32NO4 (MH+)
386.2333, found 386.2331. Anal. Calcd for C23H31NO4‚1/2H2O
(394.23): C, 70.01; H, 8.18; N 3.55. Found: C, 69.66; H, 8.16;
N, 3.64.
[1S(2S,4R),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
4-h yd r oxy-N,2-d im eth yl-4-p h en ylbu ta n a m id e (Ta ble 2,
en tr y 2). The alkylation of 1 (0.111 g, 0.500 mmol, 1 equiv)
with (R)-(+)-styrene oxide (0.120 g, 1.00 mmol, 2.00 equiv) in
tetrahydrofuran (0.500 M, -5 °C for 10 h) was carried out as
described above for entry 1 (Table 1). The product was
obtained as a viscous, light yellow oil (0.124 g, 73%, an
inseparable mixture of diastereomers) after purification by
flash column chromatography (2.5% methanol in dichlo-
romethane). Acetylation followed by capillary GC analysis of
the resulting O,O-diacetates established a diastereomeric
excess (de) of 25% for this product: 1H NMR (∼2:1 rotamer
ratio for each diastereomer, C6D6) δ 7.35 (d, 2H, J ) 7.9 Hz),
7.32 (d, 2H, J ) 7.9 Hz), 7.31 (d, 2H, J ) 7.4 Hz), 7.28 (d, 2H,
J ) 7.9 Hz), 7.25-6.99 (m, 32H), 5.32 (br s, 1H), 5.01 (br d,
1H, J ) 8.8 Hz), 4.70 (br s, 1H), 4.62 (dd and m, 2H, J ) 8.1,
6.8 Hz), 4.59 (d,1H, J ) 9.6 Hz), 4.47 (d, 1H, J ) 8.2 Hz), 4.30
(br s, 1H), 4.24 (d, 1H, J ) 9.6 Hz), 4.18 (d, 1H, J ) 8.2 Hz),
4.14 (m, 1H), 4.00 (m, 1H), 3.44 (m, 1H), 3.26 (br s, 1H), 2.95
(m, 1H), 2.82 (s, 3H), 2.79 (s, 3H), 2.59 (s, 3H), 2.53-2.39 (m
and ddd, 2H, J ) 13.1, 8.8, 4.7 Hz), 2.47 (ddd, 1H, J ) 13.2,
10.4, 2.8 Hz), 2.37 (s, 3H), 2.31 (s, 3H), 2.21 (ddd, 1H, J )
13.3, 10.4, 2.9 Hz), 1.73 (m, 1H), 1.63 (ddd, 1H, J ) 13.1, 9.6,
4.3 Hz), 1.53 (m, 1H), 1.31 (d, 3H, J ) 6.7 Hz), 1.01 (d, 3H, J
) 6.9 Hz), 0.96 (d, 3H, J ) 6.7 Hz), 0.89 (d, 3H, J ) 6.9 Hz),
0.84 (d, 3H, J ) 6.4 Hz), 0.64 (d, 3H, J ) 6.6 Hz), 0.56 (d, 3H,
J ) 6.6 Hz); 13C NMR (C6D6) δ 178.41, 178.36, 177.37, 175.31,
146.22, 145.85, 143.42, 143.14, 142.82, 142.69, 128.76, 128.53,
128.42, 128.38, 127.60, 127.55, 127.43, 127.38, 127.21, 127.05,
126.82, 126.60, 126.31, 126.15, 126.00, 76.02, 75.21, 73.09,
71.81, 58.20, 45.47, 44.25, 34.34, 32.48, 27.40, 26.87, 19.10,
17.88, 15.69, 14.32; IR 3378 (s, OH), 2974 (m), 2928 (m), 1612
(s, CdO), 1490 (m), 1451 (s), 1410 (m), 1110 (m), 1087 (m),
[1S(2S,4R),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
4-h y d r o x y -N -m e t h y l-2-(p h e n y lm e t h y l)p e n t a n a m id e
(Ta ble 2, en tr y 5). The alkylation of 2 (0.149 g, 0.500 mmol,

Enantiomerically Enriched γ-Lactones and γ-Hydroxy Ketones
J . Org. Chem., Vol. 61, No. 7, 1996 2437
1 equiv) with (R)-(+)-propylene oxide (0.0581 g, 1.00 mmol,
2.00 equiv) in tetrahydrofuran (0.500 M, -5 °C for 10 h) was
carried out as described above for entry 1 (Table 1). The
product was obtained as a viscous, colorless oil (0.141 g, 79%,
an inseparable mixture of diastereomers) after purification by
flash column chromatography (50% ethyl acetate in hexanes).
Acetylation followed by capillary GC analysis of the resulting
O,O-diacetates established a diastereomeric excess (de) of 45%
for this product: 1H NMR (20:1 rotamer ratio for major
diastereomer and 4:1 rotamer ratio for minor diastereomer, *
denotes rotamer peaks, C6D6) δ 7.39 (d, 2H, J ) 7.9 Hz), 7.32*
(d, 2H, J ) 7.9 Hz), 7.28* (d, 2H, J ) 7.8 Hz), 7.22 (d, 2H, J
) 7.8 Hz), 7.18-7.02 (m, 29 H), 6.98* (t, 1H, J ) 7.8 Hz), 6.94
(t, 1H, J ) 7.8 Hz), 6.87* (t, 1H, J ) 7.8 Hz), 5.05 (br s, 1H),
4.61 (br s, 2H), 4.33 (d, 1H, J ) 9.2 Hz), 4.14 (d, 1H, J ) 9.0
Hz), 4.06 (m, 1H), 3.98 (dq, 1H, J ) 9.5, 7.0 Hz), 3.60 (m, 2H),
3.35 (m, 2H), 3.01 (dd, 1H, J ) 12.4, 10.7 Hz), 2.88 (m, 1H),
2.77 (s, 3H), 2.71* (s, 3H), 2.61 (dd, 1H, J ) 12.9, 4.6 Hz),
2.53 (dd, 1H, J ) 12.6, 4.6 Hz), 2.32* (s, 3H), 2.27 (s and m,
3H and 1H), 2.18 (ddd, 1H, J ) 13.8, 10.0, 10.0 Hz), 1.89* (ddd,
1H, J ) 13.4, 10.3, 3.1 Hz), 1.56 (ddd, 1H, J ) 13.4, 10.3, 3.1
Hz), 1.37 (ddd, 1H, J ) 13.8, 5.5, 2.7 Hz), 1.22 (d, 3H, J ) 6.2
Hz), 1.08 (d, 3H, J ) 6.3 Hz), 0.92* (d, 3H, J ) 6.4 Hz), 0.77*
(d, 3H, J ) 6.8 Hz), 0.49 (d, 3H, J ) 6.8 Hz), 0.05* (d, 3H, J
) 6.4 Hz), -0.06 (d, 3H, J ) 6.4 Hz); 13C NMR (C6D6) δ 177.59,
175.98, 142.96, 142.73, 140.61, 140.30, 129.87, 129.46, 128.73,
128.60, 128.44, 127.57, 127.40, 127.05, 126.87, 126.46, 126.32,
76.10, 75.42, 68.04, 65.24, 58.50, 55.46, 44.41, 43.40, 43.30,
41.59, 40.73, 40.62, 29.64, 26.78, 24.50, 23.99, 14.85, 13.97;
IR 3380 (br, s, OH), 2971 (m), 2928 (m), 1610 (s, CdO), 1492
[1S(2S,4S),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
5-(ter t-bu tyldim eth ylsilyloxy)-4-h ydr oxy-N-m eth yl-2-(ph e-
n ylm eth yl)p en ta n a m id e (Ta ble 2, en tr y 7). The alkylation
of 2 (0.297 g, 1.00 mmol, 1 equiv) with (R)-(+)-tert-butyldi-
methylsilyl glycidyl ether (0.377 g, 2.00 mmol, 2.00 equiv) in
tetrahydrofuran (0.400 M, 5 °C for 26 h) was carried out as
described above for entry 1 (Table 1). The product was
obtained as a viscous, colorless oil (0.312 g, 64%, an insepa-
rable mixture of diastereomers) after purification by flash
column chromatography (30% ethyl acetate in hexanes).
Capillary GC analysis of the corresponding O,O,O-triacetates
(prepared by desilylation/acetylation, as described above)
established a diastereomeric excess (de) of 17% for this
product: 1H NMR (20:1 rotamer ratio for major diastereomer
and 1.5:1 rotamer ratio for minor diastereomer, * denotes
rotamer peaks, C6D6) δ 7.41* (d, 2H, J ) 8.8 Hz), 7.36 (d, 2H,
J ) 8.8 Hz), 7.29* (d, 2H, J ) 8.8 Hz), 7.24 (d, 2H, J ) 8.8
Hz), 7.21-7.01 (m, 23H), 7.00 (t, 3H, J ) 8.7 Hz), 6.95* (t,
3H, J ) 8.6 Hz), 6.87* (t, 3H, J ) 8.8 Hz), 4.95 (br s, 1H),
4.56* (br d, 1H, J ) 5.8 Hz), 4.38 (d, 1H, J ) 8.9 Hz), 4.19 (d,
1H, J ) 9.5 Hz), 4.04 (m, 2H), 3.68 (m, 1H), 3.65 (m, 1H), 3.62
(dd, 1H, J ) 10.3, 4.5 Hz), 3.53 (dd, 1H, J ) 10.3, 5.6 Hz),
3.49 (dd, 1H, J ) 9.7, 6.1 Hz), 3.44 (dd, 1H, J ) 9.7, 5.5 Hz),
3.33* (m, 1H), 3.21* (dd, 1H, J ) 7.2, 5.4 Hz), 3.11 (dd, 1H, J
) 12.5, 10.8 Hz), 3.05 (m, 2H), 3.01 (dd, 1H, J ) 13.2, 9.8 Hz),
2.81 (s, 3H), 2.77* (s, 3H), 2.64 (m, 2H), 2.36* (s, 3H), 2.29 (s,
3H), 2.17 (ddd, 1H, J ) 13.6, 9.5, 4.4 Hz), 1.92* (ddd, 1H, J )
13.2, 11.1, 2.1 Hz), 1.74 (m, 2H), 1.44* (ddd, 1H, J ) 13.5,
10.2, 3.5 Hz), 0.94 (2 s, 18H), 0.90* (s, 9H), 0.87* (s, 9H), 0.80*
(d, 3H, J ) 6.5 Hz), 0.53 (d, 3H, J ) 6.6 Hz), 0.06 (2 s, 6H),
0.04 (2 s, 6H), 0.03* (d, 3H, J ) 6.5 Hz), 0.00 (d, 3H, J ) 6.5
Hz), -0.01* (2 s, 6H), -0.04* (s, 6H); 13C NMR (C6D6) δ 177.54,
177.06*, 175.53, 143.62*, 143.05, 142.83, 140.53, 140.20,
140.05*, 129.82, 129.45, 129.41, 129.20, 128.71, 128.62, 128.59,
128.53, 128.44, 128.42, 127.62, 127.49, 127.28, 126.81, 126.58,
126.47, 126.33, 76.25, 75.72*, 75.63, 72.32, 69.81, 69.41*, 67.96,
67.89, 67.78, 58.54, 56.08, 42.76, 41.57, 41.02, 40.47, 40.35,
38.25, 37.32, 36.88*, 29.93, 26.71, 26.15, 26.09, 26.02*, 18.57,
18.46, 14.86, 14.24*, 13.99, -5.19, -5.27, -5.40*; IR 3378 (br,
m, OH), 2938 (s), 2926 (s), 2858 (s), 1616 (s, CdO), 1452 (m),
1255 (m), 1125 (s), 1080 (s), 1051 (m), 837 (s), 775 (m), 701 (s)
(m), 1454 (s), 1411 (m), 1121 (m), 1083 (m), 1046 (m) cm-1
.
[1S(2S,4R),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
4-h yd r oxy-N-m eth yl-4-p h en yl-2-(p h en ylm eth yl)bu ta n a -
m id e (Ta ble 2, en tr y 6). The alkylation of 2 (0.149 g, 0.500
mmol, 1 equiv) with (R)-(+)-styrene oxide (0.120 g, 1.00 mmol,
2.00 equiv) in tetrahydrofuran (0.500 M, -5 °C for 15 h) was
carried out as described above for entry 1 (Table 1). The
product was obtained as a white solid (0.151 g, 72%, an
inseparable mixture of diastereomers) after purification by
flash column chromatography (2.5% methanol in dichlo-
romethane). Analysis by 500 MHz 1H NMR, as described
above (Table 1, entry 6), established a diastereomeric excess
(de) of 46% for this product. A single recrystallization of the
product from benzene (2.00 mL) afforded a pure sample of the
major diastereomer as white needles (mp 134-136 °C) allow-
ing assignments to be made within the diastereomeric mixture,
as follows: 1H NMR (CDCl3) major diastereomer (10:1 rotamer
ratio, * denotes minor rotamer peaks): δ 7.24-7.02 (m, 15H),
4.63 (br s, 1H), 4.58 (dd, 1H, J ) 9.5, 4.5 Hz), 4.31 (d, 1H, J )
9.1 Hz), 2.96 (m, 1H), 2.77 (m and dd, 1H and 1H, J ) 13.1,
9.9 Hz), 2.74* (s, 3H), 2.62 (dd, 1H, J ) 13.1, 5.6 Hz), 2.41 (s,
3H), 2.34 (ddd, 1H, J ) 14.0, 9.5, 4.6 Hz), 1.78 (ddd, 1H, J )
14.0, 8.2, 3.9 Hz), 0.80* (d, 3H, J ) 6.6 Hz), 0.58 (d, 3H, J )
6.1 Hz); minor diastereomer (∼2:1 rotamer ratio, * denotes
minor rotamer peaks): δ 7.43-7.00 (m, 15H), 4.57 (m, 1H),
4.34 (d, 1H, J ) 9.5 Hz), 3.99* (m, 1H), 3.62 (m, 1H), 3.19*
(m, 1H), 2.82 (dd, 1H, J ) 13.3, 9.9 Hz), 2.81 (s, 3H), 2.72 (dd,
1H, J ) 13.3, 5.6 Hz), 2.54* (s, 3H), 2.18 (ddd, 1H, J ) 14.0,
12.8, 2.5 Hz), 2.09* (ddd, 1H, J ) 14.0, 11.5, 2.6 Hz), 1.79*
(ddd, 1H, J ) 14.0, 11.5, 2.5 Hz), 1.05 (m, 1H), 1.03 (d, 3H, J
) 6.9 Hz), 0.43* (d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3) major
diastereomer: δ 177.42, 176.75*, 144.32, 141.85, 141.20*,
139.37, 129.27, 129.05, 128.52, 128.32, 127.80, 127.69, 126.41,
127.00, 126.41, 126.00, 125.80, 76.21, 75.65*, 74.16, 73.20*,
56.15, 42.74, 42.31, 41.45*, 40.08, 39.20*, 30.34, 15.50*, 14.09;
minor diastereomer: δ 175.46, 144.53, 144.50*, 142.20*,
141.53, 140.20*, 139.99, 129.24, 129.19, 128.43, 128.19, 127.13,
126.85, 126.75, 126.25, 126.14, 125.54, 125.34, 75.39*, 74.98,
71.65*, 70.68, 57.87, 53.50*, 44.10, 42.40*, 41.52*, 40.81, 40.49,
40.00*, 27.56*, 26.48, 15.25*, 14.53; IR 3381 (br, s, OH), 3057
(m), 3026 (m), 2976 (m), 2925 (m), 1610 (s, CdO), 1494 (s),
1453 (s), 1413 (s), 1119 (m), 1048 (m), 910 (m) cm-1; HRMS
(FAB) calcd for C27H32NO3 (MH+) 418.2384, found 418.2382.
Anal. Calcd for C27H31NO3‚H2O (426.24): C, 76.01; H, 7.57;
N, 3.29. Found: C, 76.07; H, 7.53; N, 3.32.
cm-1
.
[1S(2S,4S),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
5-(ben zyloxy)-4-h yd r oxy-N-m eth yl-2-(p h en ylm eth yl)p en -
ta n a m id e (Ta ble 2, en tr y 8). The alkylation of 2 (0.297 g,
1.00 mmol, 1 equiv) with (R)-(+)-benzyl glycidyl ether (0.328
g, 2.00 mmol, 2.00 equiv) in tetrahydrofuran (1.00 M, -5 °C
for 12 h) was carried out as described above for entry 1 (Table
1). The product was obtained as a white crystalline solid
(0.369 g, 80%) after purification by flash column chromatog-
raphy (1% methanol, 29.7% ethyl acetate, 69.3% hexanes).
Analysis by 500 MHz 1H NMR, as described above (Table 1,
entry 6), established a diastereomeric excess (de) of 36% for
this product. A single recrystallization from toluene (20.0 mL)
afforded a pure sample of the minor diastereomer as white
needles (mp 153-155 °C) allowing spectroscopic assignments
to be made within the diastereomeric mixture, as follows: 1H
NMR (CDCl3) major diastereomer (∼15:1 rotamer ratio, *
denotes minor rotamer peaks): δ 7.34-7.11 (m, 15H), 4.78 (br
s, 1H), 4.52 (d, 2H, J ) 6.8 Hz), 4.38 (d, 1H, J ) 9.4 Hz), 3.90
(m, 1H), 3.43 (dd, 1H, J ) 9.2, 5.8 Hz), 3.35 (m and dd, 1H
and 1H, J ) 9.4, 7.8 Hz), 3.15 (m, 1H), 2.93 (dd, 1H, J ) 12.9,
9.9 Hz), 2.82* (s, 3H), 2.74 (dd, 1H, J ) 12.8, 5.5 Hz), 2.58 (s,
3H), 2.11 (ddd, 1H, J ) 14.0, 10.2, 3.9 Hz), 1.65 (ddd, 1H, J )
13.9, 9.9, 4.0 Hz), 0.92* (d, 3H, J ) 6.9 Hz) 0.63 (d, 3H, J )
6.7 Hz); minor diastereomer (1.3:1 rotamer ratio, * denotes
minor rotamer peaks): δ 7.34-7.11 (m, 30H), 4.52 (s, 2H),
4.51* (s, 2H), 4.48* (d, 1H, J ) 7.4 Hz), 4.30 (d, 1H, J ) 9.7
Hz), 4.19 (m, 1H), 3.92 (m, 1H), 3.87 (m, 1H), 3.55* (m, 1H),
3.51 (dd, 1H, J ) 6.6, 3.3 Hz), 3.44* (m, 1H), 3.41 (dd, 1H, J
) 10.3, 2.9 Hz), 3.36 (dd, 1H, J ) 9.7, 6.6 Hz), 3.29 (m, 1H),
3.22* (dd, 1H, J ) 9.1, 7.9 Hz), 2.91 (dd, 1H, J ) 12.9, 10.5
Hz), 2.88* (dd, 1H, J ) 13.2, 10.0 Hz), 2.78 (s, 3H), 2.72 (dd,
1H, J ) 12.9, 4.7 Hz), 2.68* (dd, 1H, J ) 12.6, 5.3 Hz), 2.58*
(s, 3H), 2.00 (ddd, 1H, J ) 13.4, 13.4, 2.2 Hz), 1.82* (ddd, 1H,
J ) 13.1, 13.1, 1.6 Hz), 1.70 (ddd, 1H, J ) 13.6, 11.6, 3.6 Hz),

2438 J . Org. Chem., Vol. 61, No. 7, 1996
Myers and McKinstry
1.51* (ddd, 1H, J ) 13.5, 10.8, 3.3 Hz), 0.94* (d, 3H, J ) 6.5
Hz), 0.04 (d, 3H, J ) 6.6 Hz); 13C NMR (CDCl3) major
diastereomer: δ 177.71, 140.89, 139.67, 138.04, 129.27, 128.90,
128.82, 128.53, 128.38, 128.05, 127.09, 126.63, 76.36, 74.65,
73.66, 70.93, 55.75, 42.69, 40.33, 36.83, 30.98, 14.25; minor
diastereomer: δ 177.17*, 175.39, 142.32*, 141.88, 139.83,
139.45, 138.03, 129.06, 128.70, 128.47, 128.24, 127.78, 127.74,
127.52, 126.88, 126.54, 126.40, 126.33, 75.73, 74.78*, 74.13,
73.46*, 73.37, 68.17, 68.05*, 58.18, 41.02, 40.83*, 40.10*, 39.99,
37.61, 36.59*, 26.58, 14.82, 14.29*; IR 3381 (br, s, OH), 2915
(m), 2854 (m), 1605 (s, CdO), 1453 (s), 1124 (s), 1078 (s), 1048
(m), 1027 (m) cm-1; HRMS (FAB) calcd for C29H36NO4 (MH+)
462.2646, found 462.2644. Anal. Calcd for C29H35NO4: C,
75.45; H, 7.65; N, 3.04. Found: C, 75.00; H, 7.70; N, 2.80.
[1S(2R,4R),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
4-(t er t -b u t yld im e t h ylsilyloxy)-N ,2-d im e t h ylp e n t a n a -
m id e. A dry 10-mL round-bottomed flask equipped with a
magnetic stirring bar was charged with anhydrous lithium
chloride (0.559 g, 13.2 mmol, 13.2 equiv), N,N-diisopropy-
lamine (0.606 mL, 4.62 mmol, 4.62 equiv), and tetrahydrofuran
(2.00 mL). The resulting suspension was cooled to -78 °C,
and n-butyllithium (3.25 M in hexanes, 1.50 mL, 4.86 mmol,
4.86 equiv) was added by syringe. The suspension was
warmed to 0 °C for 10 min and then was cooled to -78 °C. A
solution of 1 (0.487 g, 2.20 mmol, 2.20 equiv) in tetrahydro-
furan (1.70 mL) was transferred dropwise to the reaction flask
by syringe. The transfer was quantitated with an additional
portion of tetrahydrofuran (0.50 mL). Upon completion of the
addition, the reaction mixture was stirred at -78 °C for 1 h,
at 0 °C for 15 min, at 23 °C for 5 min, and finally was cooled
to 0 °C. To the reaction vessel was added (R)-2-(tert-butyldi-
methylsilyloxy)propyl iodide (7, 0.300 g, 1.00 mmol, 1 equiv)
by microliter syringe. The resulting mixture was warmed
briefly to 23 °C and then was heated to 45 °C. After 14 h the
suspension was cooled to 23 °C and subsequently was parti-
tioned between water (5 mL) and ethyl acetate (5 mL). The
aqueous layer was separated and extracted further with three
3-mL portions of ethyl acetate and one 5-mL portion of
dichloromethane. The combined organic layers were dried
over anhydrous sodium sulfate and then were concentrated.
Purification of the residue by flash column chromatography
(25% ethyl acetate in hexanes) afforded the product as a
viscous, light yellow oil (0.140 g, 36%). Desilylation of the
product, as described for 5, produced a diol (92%; spectroscopic
data is included in the procedure for the amide of Table 2,
entry 1) that was identical to the minor diastereomer (2R-syn)
formed in the alkylation of 1 with (R)-(+)-propylene oxide.
Acetylation followed by capillary GC analysis of the resulting
O,O-diacetate established a diastereomeric excess (de) of g99%
for this product: 1H NMR (10:1 rotamer ratio, * denotes minor
rotamer peaks, C6D6) δ 7.37 (d, 2H, J ) 7.4 Hz), 7.28* (d, 2H,
J ) 7.4 Hz), 7.19-7.16 (m, 3H), 7.10-7.00* (m, 3H), 4.77 (br
s, 1H), 4.65 (br s, 1H), 4.53 (dd, 1H, J ) 6.8 Hz), 3.78 (m, 1H),
2.81* (s, 3H), 2.76 (m, 1H), 2.56 (s, 3H), 2.09 (ddd, 1H, J )
13.2, 9.7, 3.2 Hz), 1.37 (ddd, 1H, J ) 13.2, 8.9, 3.9 Hz), 1.27*
(d, 3H, J ) 6.1 Hz), 1.08 (d, 3H, J ) 6.0 Hz), 1.05* (d, 3H, J
) 6.9 Hz), 1.01* (s, 9H), 0.99 (d, 3H, J ) 7.0 Hz), 0.96 (d, 3H,
J ) 7.0 Hz), 0.95 (s, 9H), 0.66* (d, 3H, J ) 6.8 Hz), 0.18* (s,
3H), 0.16* (s, 3H), 0.02 (s, 3H), -0.06 (s, 3H); 13C NMR (C6D6)
δ 177.73, 143.65, 128.40, 127.50, 126.98, 76.44, 75.65*, 68.88*,
67.62, 57.29, 44.59, 43.75*, 33.56, 31.64, 26.15, 24.63, 23.50*,
19.35*, 18.40, 18.20, 15.66*, 14.17, -3.80, -4.55; IR 3386 (br,
m, OH), 2954 (s), 2933 (s), 2859 (s), 1619 (s, CdO), 1471 (m),
denotes minor rotamer peaks, C6D6) δ 7.34 (d, 2H, J ) 7.5
Hz), 7.24-7.02 (m, 8H), 4.56 (dd, 1H, J ) 6.4 Hz), 4.30 (br s,
1H), 4.15* (m, 1H), 3.93* (m, 1H), 3.73 (m, 1H), 3.10* (m, 1H),
2.86* (s, 3H), 2.70 (m, 1H), 2.49 (s, 3H), 2.45* (m, 1H), 1.70
(ddd, 1H, J ) 13.4, 8.2, 4.9 Hz), 1.56* (m, 1H), 1.35 (ddd, 1H,
J ) 13.3, 9.2, 4.6 Hz), 1.21* (d, 3H, J ) 6.1 Hz), 1.19* (d, 3H,
J ) 6.7 Hz), 1.06 (d, 3H, J ) 6.7 Hz), 1.01 (d, 3H, J ) 6.8 Hz),
0.96 (d, 3H, J ) 6.1 Hz), 0.95* (s, 9H), 0.94 (s, 9H), 0.69* (d,
3H, J ) 6.7 Hz), 0.11* (s, 3H), 0.09* (s, 3H), 0.04 (s, 6H); 13C
NMR (C6D6) δ 178.28, 143.83, 128.63, 128.29, 127.35, 126.78,
76.47, 75.85*, 66.80*, 66.29, 59.47, 57.50*, 44.00, 33.20*, 32.89,
26.32*, 26.08, 24.18, 18.17, 17.55*, 16.68, 15.50*, 14.30, -4.15,
-4.60; IR 3372 (br, m, OH), 2961 (s), 2928 (s), 2852 (m), 1619
(s), 1462 (m), 1256 (m), 1088 (m), 1045 (m) cm-1
.
[1S(2S),2S]-N-(2-H yd r oxy-1-m et h yl-2-p h en ylet h yl)-4-
h ydr oxy-N,2,4-tr im eth ylpen tan am ide. A dry 10-mL round-
bottomed flask equipped with a magnetic stirring bar was
charged with anhydrous lithium chloride (0.127 g, 3.00 mmol,
6.00 equiv), N,N-diisopropylamine (0.138 mL, 1.05 mmol, 2.10
equiv), and tetrahydrofuran (0.50 mL). The resulting suspen-
sion was cooled to -78 °C, and n-butyllithium (2.30 M in
hexanes, 0.480 mL, 1.11 mmol, 2.21 equiv) was added by
syringe. The suspension was warmed to 0 °C for 10 min and
then was cooled to -78 °C. A solution of 1 (0.111 g, 0.500
mmol, 1 equiv) in tetrahydrofuran (0.80 mL) was transferred
dropwise to the reaction flask by syringe. The transfer was
quantitated with an additional portion of tetrahydrofuran (0.20
mL). Upon completion of the addition, the reaction mixture
was stirred at -78 °C for 1 h, at 0 °C for 15 min, at 23 °C for
5 min, and finally was cooled to 0 °C. Isobutylene oxide (0.108
g, 1.50 mmol, 3.00 equiv) was added to the reaction vessel by
microliter syringe, and the resulting solution was stirred at 0
°C for 4 h. Saturated aqueous ammonium chloride solution
(2 mL) was added, and the resulting biphasic mixture was
partitioned between water (5 mL) and ethyl acetate (5 mL).
The aqueous layer was separated and extracted further with
three 5-mL portions of ethyl acetate and one 5-mL portion of
dichloromethane. The combined organic layers were dried
over anhydrous sodium sulfate and then were concentrated.
Purification of the residue by flash column chromatography
(2.5% methanol in dichloromethane) afforded 0.123 g (84%) of
product as a white crystalline solid. Acetylation, followed by
capillary GC analysis of the resulting O,O-diacetate, estab-
lished a diastereomeric excess (de) of 95% for this product: mp
89-92 °C; 1H NMR (∼10:1 rotamer ratio, * denotes minor
rotamer peaks, C6D6) δ 7.35 (d, 2H, J ) 7.5 Hz), 7.21-7.05
(m, 3H), 4.53 (br d, 1H, J ) 6.5 Hz), 4.39 (br s, 1H), 4.08* (br
s, 1H), 2.78* (s, 3H), 2.61 (m, 1H), 2.52* (m, 1H), 2.41 (dd,
1H, J ) 13.9, 10.8 Hz), 2.37 (s, 3H), 2.00 (br s, 1H), 1.31* (d,
3H, J ) 6.5 Hz), 1.18* (s, 3H), 1.13 (dd, 1H, J ) 14.2, 2.1 Hz),
1.08 (s, 3H), 1.05* (s, 3H), 1.03 (s, 3H), 0.95 (d, 3H, J ) 6.5
Hz), 0.88 (d, 3H, J ) 6.8 Hz), 0.78* (d, 3H, J ) 6.7 Hz); 13C
NMR (C6D6) δ 179.19, 143.47, 128.53, 128.30, 127.48, 127.16,
76.29, 70.17, 59.58, 47.65, 32.53, 32.50, 31.47, 28.72, 19.33,
15.61, 14.22; IR 3378 (br, s, OH), 2975 (s), 2929 (m), 2883 (w),
1618 (s, CdO), 1451 (m), 1410 (m), 1376 (m), 1134 (m), 1047
(m) cm-1. Anal. Calcd for C17H27NO3: C, 69.57; H, 9.28; N,
4.78. Found: C, 69.63; H, 9.25; N, 4.67.
[1S(2S),2S]-N-(2-H yd r oxy-1-m et h yl-2-p h en ylet h yl)-4-
h ydr oxy-N,4-dim eth yl-2-(ph en ylm eth yl)pen tan am ide. The
alkylation of 2 (0.149 g, 0.500 mmol, 1 equiv) with isobutylene
oxide (0.108 g, 1.50 mmol, 3.00 equiv) in tetrahydrofuran
(0.500 M, 0 °C for 4.5 h) was carried out as described for the
alkylation of 1 with isobutylene oxide. The product was
obtained as a white crystalline solid (0.131 g, 71%) after
purification by flash column chromatography (2.5% methanol
in dichloromethane). Acetylation followed by capillary GC
analysis of the resulting O,O-diacetate established a diaster-
eomeric excess (de) of g99% for this product: mp 96-99 °C;
1H NMR (∼25:1 rotamer ratio, * denotes minor rotamer peaks,
C6D6) δ 7.45 (d, 2H, J ) 7.4 Hz), 7.21-6.97 (m, 8H), 5.08 (m,
1H), 4.55 (br s, 1H), 4.40 (d, 1H, J ) 9.2 Hz), 3.15 (br s, 1H),
3.11 (m, 1H), 2.97 (dd, 1H, J ) 12.5, 10.0 Hz), 2.88* (s, 3H),
2.54 (d, 1H, J ) 12.1 Hz), 2.52 (dd, 1H, J ) 10.7, 8.0 Hz), 2.33
(s, 3H), 1.37 (dd, 1H, J ) 13.9, 1.7 Hz), 1.18 (s, 3H), 1.12 (s,
3H), 0.98* (d, 3H, J ) 7.0 Hz), 0.54 (d, 3H, J ) 6.9 Hz); 13C
1461 (m), 1455 (m), 1255 (s), 1092 (m), 1050 (s) cm-1
.
[1S(2R,4S),2S]-N-(2-Hyd r oxy-1-m eth yl-2-p h en yleth yl)-
4-(t er t -b u t yld im e t h ylsilyloxy)-N ,2-d im e t h ylp e n t a n a -
m id e. The alkylation of 1 (0.487 g, 2.20 mmol, 2.20 equiv)
with (S)-2-(tert-butyldimethylsilyloxy)propyl iodide (8) (0.300
g, 1.00 mmol, 1 equiv) in tetrahydrofuran (2.20 mL, 45 °C for
14 h) was carried out as described for the alkylation of 1 with
7. The product was obtained as a viscous, colorless oil (0.0590
g, 15%) after purification by flash column chromatography
(25% ethyl acetate in hexanes). Capillary GC analysis of the
corresponding O,O-diacetate (prepared by desilylation/acetyl-
ation, as described above) established a diastereomeric excess
(de) of g99% for this product: 1H NMR (3:1 rotamer ratio, *

Enantiomerically Enriched γ-Lactones and γ-Hydroxy Ketones
J . Org. Chem., Vol. 61, No. 7, 1996 2439
Ta ble 5. Cou p lin g Con sta n ts for Tr a n s-La cton e
Der iva tives of Alk yla ted Am id esa
NMR (C6D6) δ 178.02, 142.88, 140.08, 129.45, 128.76, 128.47,
128.41, 126.54, 76.26, 70.45, 55.94, 46.85, 41.37, 40.47, 31.77,
29.59, 28.44, 13.97; IR 3389 (br, s, OH), 2966 (m), 2931 (m),
2872 (w), 1614 (s, CdO), 1455 (m), 1132 (m), 1049 (m) cm-1
.
Anal. Calcd for C23H31NO3: C, 74.75; H, 8.46; N, 3.79.
Found: C, 74.33; H, 8.64; N, 3.74.
P r ep a r a tion of tr a n s-γ-Bu tyr ola cton es by th e Acid ic
Hyd r olysis of Alk yla ted P seu d oep h ed r in e Am id es. The
following provides a representative procedure:
(2S,4R)-tr a n s-4-[(Ben zyloxy)m eth yl]-2-m eth yl-γ-bu ty-
r ola cton e (Ta ble 4, en tr y 3). An oven-dried test tube (16 ×
125 mm) equipped with a magnetic stirring bar was charged
with [1S(2S,4R),2S]-N-(2-hydroxy-1-methyl-2-phenylethyl)-5-
(benzyloxy)-4-hydroxy-N,2-dimethylpentanamide (Table 1, en-
try 4, g99% de, 0.136 g, 0.353 mmol, 1 equiv), aqueous sulfuric
acid solution (2 N, 1.00 M, 0.706 mL, 0.706 mmol), and dioxane
(3.00 mL). The solution was heated at 95 °C for 30 min. After
cooling to 23 °C, the reaction mixture was partitioned between
saturated aqueous sodium bicarbonate solution (2 mL) and
ethyl acetate (2 mL). The aqueous layer was separated and
extracted further with three 1-mL portions of ethyl acetate.
The combined organic extracts were dried over anhydrous
sodium sulfate and were concentrated. Purification of the
residue by flash column chromatography (50% ethyl acetate
in hexanes) provided 0.0719 g (90%) of the product as a viscous,
colorless oil. The diasteromeric excess (de) of the product was
quantified by capillary GC analysis and was found to be 98%:
1H NMR (C6D6) δ 7.21-7.15 (m, 3H), 7.09 (m, 2H), 4.22 (d,
1H, J ) 12.1 Hz), 4.17 (d, 1H, J ) 12.1 Hz), 3.99 (m, 1H), 3.12
(dd, 1H, J ) 10.4, 3.6 Hz), 2.96 (dd, 1H, J ) 10.5, 3.9 Hz),
2.40 (m, 1H), 1.67 (ddd, 1H, J ) 12.7, 9.3, 3.2 Hz), 1.17 (ddd,
1H, J ) 12.7, 8.8, 8.8 Hz), 0.91 (d, 3H, J ) 7.4 Hz); 13C NMR
(C6D6) δ 178.88, 138.40, 128.64, 127.81, 75.83, 73.50, 71.84,
33.89, 32.39, 16.03; IR 2972 (s), 2931 (s), 2869 (s), 1767 (s,
CdO), 1451 (m), 1379 (m), 1364 (m), 1348 (m), 1198 (m), 1172
(s), 1100 (s), 1027 (s), 955 (m), 924 (m) cm-1; HRMS (FAB)
calcd for C13H17O3 (MH+) 221.1178, found 221.1177.
J (Hz) J (Hz) J (Hz) J (Hz) J (Hz)
entry
R1
CH3
CH3
CH3
CH3
R2
H2,H3R H2,H3â
H
3R,H4
H
3â,H4
H
3R,H3â
b
1
2
3
4
5
6
7
8
C6H5
7.0
8.0
8.9
8.8
7.5
8.1
8.7
9.0
9.0
8.6
9.4
9.3
8.4
8.5
9.5
9.4
7.5
8.1
8.9
8.8
7.5
8.1
8.7
9.0
5.5
4.6
2.9
3.2
4.3
4.2
3.6
3.3
12.8
12.9
12.5
12.7
12.8
12.9
13.0
12.8
C6H5
CH2OTBS
CH2OBn
CH2C6H5 CH3
CH2C6H5 C6H5
CH2C6H5 CH2OH
CH2C6H5 CH2OBn
a
Spectroscopic data were measured in C6D6, except in entries
b
1 and 2, where CDCl3 was used. Literature values, see reference
12.
as a white crystalline solid (92%). Analysis of this product by
capillary GC established a diastereomeric excess (de) of
g99%: mp 79-80 °C (toluene); 1H NMR (C6D6) δ 7.08 (m, 2H),
7.02 (m, 1H), 6.94 (d, 2H, J ) 7.1 Hz), 3.79 (m, 1H), 3.32 (m,
1H), 3.00 (dd and m, 2H, J ) 13.5, 4.6 Hz), 2.82 (ddt, 1H, J )
9.3, 9.3, 4.6 Hz), 2.45 (dd, 1H, J ) 13.9, 9.3 Hz), 2.36 (br t, J
) 6.0 Hz), 1.58 (ddd, 1H, J ) 13.0, 9.5, 3.6 Hz), 1.38 (ddd, 1H,
J ) 13.0, 8.7, 8.7 Hz); 13C NMR (C6D6) δ 178.41, 138.95, 129.20,
128.74, 126.74, 78.21, 64.31, 41.20, 36.96, 28.85; IR 3409 (s,
OH), 1729 (s, CdO), 1218 (m), 1186 (m), 1154 (m), 1052 (m),
978 (m) cm-1. Anal. Calcd for C12H14O3: C, 69.87; H, 6.84.
Found: C, 69.73; H, 6.99.
(2S,4R)-tr a n s-4-[(Ben zyloxy)m eth yl]-2-(ph en ylm eth yl)-
γ-bu tyr ola cton e (Ta ble 4, en tr y 6). Hydrolysis of the
alkylation product of Table 1 entry 8 (g99% de) with 0.17 M
sulfuric acid in dioxane (95 °C, 1.5 h) afforded the lactone
product as a viscous, colorless oil (94%). Analysis of this
product by capillary GC established a diastereomeric excess
(de) of g99%: 1H NMR (C6D6) δ 7.18-7.10 (m, 4H), 7.09-7.00
(m, 4H), 6.93 (d, 2H, J ) 7.0 Hz), 4.16 (d, 1H, J ) 12.1 Hz),
4.10 (d, 1H, J ) 12.2 Hz), 3.85 (m, 1H), 3.08 (dd, 1H, J ) 9.9,
3.4 Hz), 3.02 (dd, 1H, J ) 13.9, 4.5 Hz), 2.86 (dd, 1H, J ) 10.5,
3.8 Hz), 2.83 (dd, 1H, J ) 9.3, 4.5 Hz), 2.47 (dd, 1H, J ) 13.9,
9.3 Hz), 1.57 (ddd, 1H, J ) 12.8, 9.4, 3.3 Hz), 1.41 (ddd, 1H, J
) 12.8, 9.0, 9.0 Hz); 13C NMR (C6D6) δ 177.68, 139.13, 138.36,
129.23, 128.75, 128.62, 127.72, 126.73, 76.22, 73.46, 71.82,
67.77, 40.97, 36.93, 29.66, 25.78; IR 2919 (w), 2861 (w), 1772
(s, CdO), 1455 (m), 1149 (m), 1114 (m) cm-1. Anal. Calcd for
C19H20O3: C, 76.99; H, 6.81. Found: C, 76.60; H, 7.15.
Cis- and trans-isomers of 2,4-disubstituted γ-butyrolactones
are easily distinguishable by the magnitude of their vicinal
coupling constants (reference 12 and Tables 5 and 6). Key
resonances are summarized in Tables 5 and 6.
(2S,4S)-tr a n s-2,4-Dim eth yl-γ-bu tyr ola cton e (Ta ble 4,
en tr y 1). Hydrolysis of the alkylation product of Table 1 entry
1 (94% de) with 0.03 M sulfuric acid in dioxane (95 °C, 1 h)
afforded the known12 product lactone as a light yellow, volatile
oil (83%). Analysis of this product by capillary GC established
a diastereomeric excess (de) of 94%.
(2S,4R)-tr a n s-2-Meth yl-4-[(ter t-bu tyld im eth ylsilyloxy)-
m eth yl]-γ-bu tyr ola cton e (Ta ble 4, en tr y 2). Hydrolysis of
the alkylation product of Table 1 entry 3 (g99% de) with 0.05
M sulfuric acid in dioxane (95 °C, 20 min) afforded the lactone
product as a viscous, colorless oil (90%). Analysis of this
product by capillary GC established a diastereomeric excess
(de) of g99%: 1H NMR (C6D6) δ 3.93 (ddd, 1H, J ) 9.8, 6.7,
3.4 Hz), 3.42 (dd, 1H, J ) 11.2, 3.5 Hz), 3.17 (dd, 1H, J ) 11.1,
3.2 Hz), 2.49 (m, 1H), 1.82 (ddd, 1H, J ) 12.5, 9.4, 2.9 Hz),
1.23 (dt, 1H, J ) 12.3, 8.9 Hz), 0.98 (d, 3H, J ) 7.3 Hz), 0.89
(s, 9H), -0.01 (s, 3H), -0.02 (s, 3H); 13C NMR (C6D6) δ 178.85,
76.87, 65.19, 34.10, 32.05, 25.93, 18.37, 16.34, -5.45,-5.57;
IR 2951 (s), 2931 (s), 2879 (m), 2858 (s), 1777 (s, CdO), 1472
(m), 1462 (m), 1255 (s), 1203 (s), 1172 (s), 1131 (s), 1069 (s),
1022 (s), 955 (m), 934 (m), 836 (s), 779 (s) cm-1. Anal. Calcd
for C12H24O3Si: C, 58.98; H, 9.91. Found: C, 59.00; H, 10.03.
(2S,4S)-tr a n s-4-Meth yl-2-(p h en ylm eth yl)-γ-bu tyr ola c-
ton e (Ta ble 4, en tr y 4). Hydrolysis of the alkylation product
of Table 1 entry 5 (g99% de) with 0.43 M sulfuric acid in
dioxane (95 °C, 2.5 h) afforded the lactone product as a viscous,
colorless oil (92%). Analysis of this product by capillary GC
established a diastereomeric excess (de) of g99%: 1H NMR
(C6D6) δ 7.22-7.15 (m, 2H), 7.11 (m, 1H), 7.01 (d, 2H, J ) 7.0
Hz), 3.90 (m, 1H), 3.05 (m, 1H), 2.54 (m, 2H), 1.48 (ddd, 1H, J
) 12.8, 7.5, 7.5 Hz), 1.15 (ddd, 1H, J ) 12.8, 8.4, 4.3 Hz), 0.79
(d, 3H, J ) 6.4 Hz); 13C NMR (C6D6) δ 177.25, 139.10, 129.20,
128.75, 126.77, 73.86, 40.85, 36.54, 33.91, 20.82; IR 2979 (w),
2934 (w), 1770 (s, CdO), 1155 (s) cm-1; HRMS (FAB) calcd
for C12H14O2 (M+) 190.0994, found 190.0994.
(S)-2,4,4-Tr im eth yl-γ-bu tyr ola cton e. Hydrolysis of the
product (95% de) from the alkylation of 1 with isobutylene
oxide in 0.19 M aqueous sulfuric acid in dioxane (70 °C, 1 h)
afforded (S)-2,4,4-trimethyl-γ-butyrolactone as a white, low-
melting solid (94%). Reduction of the lactone with lithium
aluminum hydride in ether at 0 °C and selective esterification
of the primary hydroxyl groups of the resulting mixture of diols
with (S)-(-)-Mosher acid15 (with care to ensure complete
conversion) provided the corresponding Mosher ester deriva-
tives. An accurate evaluation of the diastereomeric ratio and,
therefore, the enantiomeric excess (85% ee) for the starting
lactone was provided by analysis of the Mosher esters by high
resolution H NMR spectroscopy. Lactone: mp 47-49 °C; lit.20
1
mp for racemic lactone: 48-50 °C; 1H NMR (CCl4) δ 2.67-
2.57 (m, 1H), 2.16 (dd, 1H, J ) 11.7, 10.2 Hz), 1.58 (dd, 1H, J
) 12.2, 11.7 Hz), 1.41 (s, 3H), 1.32 (s, 3H), 1.22 (d, 3H, J ) 7.0
(2S,4R)-tr a n s-4-(Hyd r oxym eth yl)-2-(p h en ylm eth yl)-γ-
bu tyr ola cton e (Ta ble 4, en tr y 5). Hydrolysis of the alkyl-
ation product of Table 1 entry 7 (g99% de) with 0.21 M sulfuric
acid in dioxane (95 °C, 30 min) afforded the lactone product
(20) Cannon, G. W.; Santilli, A. A.; Shenian, P. J . Am. Chem. Soc.
1959, 81, 1660.

2440 J . Org. Chem., Vol. 61, No. 7, 1996
Myers and McKinstry
Ta ble 6. Cou p lin g Con sta n ts for Cis-La cton e
Der iva tives of Alk yla ted Am id esa
pared as described above, established an enantiomeric excess
(ee) of g95% for this product. Ketone: 1H NMR (C6D6) δ 7.09
(m, 2H), 7.06 (m, 3H), 3.42 (m, 2H), 2.86 (m, 1H), 2.82 (dd,
1H, J ) 12.9, 8.2 Hz), 2.49 (dd, 1H, J ) 12.7, 6.0 Hz), 1.82 (m,
1H), 1.76 (s, 3H), 1.49 (m, 1H), 0.93 (s, 9H), -0.01 (2 s, 6H);
13C NMR (C6D6) δ 209.37, 140.13, 129.21, 128.66, 126.46, 61.17,
53.25, 51.31, 38.25, 34.74, 29.91, 26.07, 18.41, -5.40; IR 2953
(s), 2930 (s), 2895 (m), 2860 (s), 1715 (s, CdO), 1255 (s), 1104
(s), 836 (s), 778 (s) cm-1; HRMS (FAB) calcd for C18H31O2Si
(MH+) 307.2094, found 307.2093.
J (Hz) J (Hz) J (Hz) J (Hz) J (Hz)
(3S,5R)-6-(ter t-Bu tyldim eth ylsilyloxy)-5-h ydr oxy-3-(ph e-
n ylm eth yl)-2-h exa n on e. The reaction of 9 (g99% de) with
methyllithium (5.00 equiv, ether, -78 f 0 °C) provided the
product ketone as a viscous, colorless oil (97%; an equilibrating
mixture of open-chain and epimeric closed forms): 1H NMR
(C6D6) δ 7.12-6.94 (m, 15H), 4.22 (m, 1H), 4.10 (m, 1H), 3.64
(dd, 1H, J ) 9.6, 4.5 Hz), 3.62 (m, 1H), 3.46 (dd, 1H, J ) 10.6,
4.5 Hz), 3.39 (dd, 1H, J ) 10.5, 4.3 Hz), 3.34 (dd, 1H, J ) 10.5,
3.8 Hz), 3.23-3.19 (m, 2H), 2.90 (dd, 1H, J ) 13.6, 5.5 Hz),
2.81 (dd, 1H, J ) 13.6, 8.0 Hz), 2.73 (dd, 1H, J ) 13.6, 9.5
Hz), 2.60 (br s, 1H), 2.53 (dd, 1H, J ) 13.6, 7.2 Hz), 2.48 (m,
1H), 2.23 (m, 1H), 2.15 (m, 1H), 2.05 (ddd, 1H, J ) 13.6, 12.5,
7.2 Hz), 1.96 (ddd, 1H, J ) 11.6, 11.6, 9.1 Hz), 1.83 (s, 3H),
1.79 (ddd, 1H, J ) 11.6, 8.4, 2.8 Hz), 1.76 (ddd, 1H, J ) 13.3,
8.9, 2.8 Hz), 1.55 (s, 3H), 1.48 (ddd, 1H, J ) 13.3, 6.0, 2.4 Hz),
1.41 (ddd, 1H, J ) 13.8, 10.1, 3.6 Hz), 1.36 (s, 3H), 0.91 (s,
9H), 0.89 (s, 9H), 0.86 (s, 9H), 0.00 (s, 3H), -0.01 (s, 3H), -0.02
(s, 3H), -0.04 (s, 3H), -0.05 (s, 6H); 13C NMR (C6D6) δ 210.89,
141.67, 139.82, 129.21, 129.14, 128.69, 128.55, 126.52, 126.11,
105.03, 77.99, 77.18, 69.74, 67.91, 66.34, 65.51, 51.21, 50.23,
49.56, 39.12, 37.11, 36.35, 34.98, 33.26, 30.64, 29.44, 26.08,
26.01, 22.84, 18.46, -5.25; IR 3417 (m, OH), 2953 (s), 2928
(s), 2857 (s), 1713 (m, CdO), 1496 (m), 1472 (m), 1462 (m),
1455 (m), 1255 (s), 1146 (s), 1107 (s), 1014 (m), 928 (m), 838
entry
R1
CH3
CH3
CH3
CH3
R2
H2,H3R H2,H3â
H
3R,H4
H
3â,H4
H
3R,H3â
b
1
2
3
4
5
6
7
8
C6H5
8.1
8.2
9.2
8.9
9.3
8.0
9.0
9.0
12.9
11.9
11.9
11.9
11.9
12.9
11.8
11.6
5.8
5.5
6.3
6.2
5.6
5.7
6.3
6.3
10.8
10.9
10.2
10.3
10.6
10.6
10.0
10.1
12.4
11.6
12.5
12.4
12.2
12.2
12.9
12.6
C6H5
CH2OTBS
CH2OBn
CH2C6H5 CH3
CH2C6H5 C6H5
CH2C6H5 CH2OH
CH2C6H5 CH2OBn
a
Spectroscopic data were measured in C6D6, except in entries
b
1 and 2, where CDCl3 was used. Literature values, see reference
12.
Hz); lit.5a δ 2.8-2.5 (m, 1H), 2.22 (dd, 1H, J ) 12, 9 Hz), 1.63
(t, 1H, J ) 12, 12 Hz), 1.44 (s, 3H), 1.35 (s, 3H), 1.23 (d, 3H).
(S)-4,4-Dim eth yl-2-(ph en ylm eth yl)-γ-bu tyr olacton e. Hy-
drolysis of the product (g99% de) from the alkylation of 2 with
isobutylene oxide in 0.17 M aqueous sulfuric acid in dioxane
(95 °C, 2 h) afforded (S)-4,4-dimethyl-2-(phenylmethyl)-γ-
butyrolactone as a white crystalline solid (94%). High resolu-
tion 1H NMR analysis of the corresponding Mosher ester
derivative (prepared by reduction/esterification, as described
above) established an enantiomeric excess (ee) of g99% for this
1
product. Lactone: mp 78-79 °C; H NMR (C6D6) δ 7.09 (m,
(s) cm-1
.
2H), 7.04 (m, 1H), 6.94 (d, 2H, J ) 7.1 Hz), 3.17 (dd, 1H, J )
13.7, 4.1 Hz), 2.57 (m, 1H), 2.48 (dd, 1H, J ) 13.7, 9.6 Hz),
1.36 (dd, 1H, J ) 12.6, 8.7 Hz), 1.22 (dd, 1H, J ) 11.6 Hz),
0.93 (s, 3H), 0.77 (s, 3H); 13C NMR (C6D6) δ 176.22, 139.46,
129.18, 128.75, 126.69, 80.63, 42.57, 40.62, 36.86, 28.71, 26.78;
IR 2975 (s), 2930 (s), 1766 (s, CdO), 1604 (m), 1496 (s), 1455
(3S,5R)-6-(Ben zyloxy)-5-h yd r oxy-3-(p h en ylm eth yl)-2-
h exa n on e. The reaction of 10 (g99% de) with methyllithium
(4.00 equiv, ether, -78 f 0 °C) afforded the product ketone
as a viscous, colorless oil (90%; an equilibrating mixture of
open-chain and epimeric closed forms): 1H NMR (C6D6) δ
7.22-6.91 (m, 30H), 4.30 (m and d, 3H, J ) 6.4 Hz), 4.16 (d,
1H, J ) 12.3 Hz), 4.14 (d and m, 2H, J ) 12.2 Hz), 3.71 (m,
1H), 3.38 (dd, 1H, J ) 9.9, 3.1 Hz), 3.24 (d, 2H, J ) 4.9 Hz),
3.18 (m, 1H), 3.06 (m, 2H), 2.96 (dd, 1H, 9.3, 7.5 Hz), 2.84 (dd,
1H, J ) 13.7, 5.5 Hz), 2.78 (dd, 1H, J ) 13.3, 8.2 Hz), 2.68
(dd, 1H, J ) 13.6, 9.5 Hz), 2.50 (dd, 1H, J ) 13.5, 6.9 Hz),
2.22-2.10 (m, 2H), 2.06 (ddd, 1H, J ) 12.8, 9.1 Hz), 1.92 (ddd,
1H, J ) 12.1, 9.0 Hz), 1.78 (s, 3H), 1.76 (ddd, 1H, J ) 11.8,
8.3, 3.0 Hz), 1.72 (ddd, 1H, J ) 13.5, 10.4, 2.9 Hz), 1.52 (s,
3H), 1.48 (ddd, 1H, J ) 12.6, 10.4, 2.9 Hz), 1.37 (ddd, 1H, J )
13.7, 10.1, 3.6 Hz), 1.25 (s, 3H); 13C NMR (C6D6) δ 210.71,
141.58, 140.90, 139.81, 139.22, 138.62, 129.16, 129.12, 128.62,
128.53, 128.40, 127.57, 127.48, 126.45, 126.06, 106.70, 104.92,
76.65, 75.69, 75.03, 73.44, 73.27, 72.84, 68.22, 50.85, 50.10,
49.31, 39.09, 36.98, 36.28, 35.24, 33.81, 30.65,30.48, 26.01,
23.07; IR 3422 (br, s, OH), 2918 (s), 2957 (s), 1709 (m, C)O),
1496 (m), 1454 (s), 1377 (m), 1260 (m), 1098 (br s), 1028 (m),
(s), 1375 (s), 1265 (s), 1181 (s), 1129 (s) 955 (s) cm-1
.
P r ep a r a tion of Meth yl Keton es fr om Alk yla ted P seu -
d oep h ed r in e Am id es. Methyl ketones derived from alkyl-
ation products 5, 6, 9, and 10 were prepared according to the
procedure previously described.1 Enantiomeric excesses of the
ketones derived from products 5 and 6 were determined by
the reduction of each ketone with lithium aluminum hydride
in ether at 0 °C (producing a ∼1:1 mixture of diastereomeric
alcohols). The diastereomeric mixture of alcohols was esteri-
fied with (S)-(-)-Mosher acid15 (with care to ensure complete
conversion), and the resulting Mosher esters were analyzed
by high resolution 1H NMR spectroscopy and capillary GC.
(R)-5-(ter t-Bu t yld im et h ylsilyloxy)-3-m et h yl-2-p en t a -
n on e. The reaction of 5 (g99% de) with methyllithium (2.50
equiv, ether, -78 f 0 °C) provided the product ketone as a
colorless oil (89%). Capillary GC and 500 MHz 1H NMR
analysis of the Mosher ester derivatives, prepared as described
above, established an enantiomeric excess (ee) of g95% for this
product. Ketone: 1H NMR (C6D6) δ 3.46 (m, 2H), 2.47 (m, 1H),
1.85 (m, 1H), 1.79 (s, 3H), 1.36 (m, 1H), 0.95 (s, 9H), 0.88 (d,
3H, J ) 7.1 Hz), 0.02 (s, 6H); 13C NMR (C6D6) δ 209.90, 61.01,
43.65, 35.98, 27.71, 26.07, 18.40, 16.25, -5.38; IR 2953 (s),
2930 (s), 2883 (m), 2860 (s), 1715 (s, CdO), 1464 (m), 1360
(m), 1255 (s), 1098 (s), 836 (s), 778 (s) cm-1. Anal. Calcd for
C12H26O2Si: C, 62.56; H, 11.38. Found: C, 62.77; H, 11.63.
(R)-5-(ter t-Bu tyld im eth ylsilyloxy)-3-(p h en ylm eth yl)-2-
p en ta n on e. The reaction of 6 (g99% de) with methyllithium
(2.50 equiv, ether, -78 f 0 °C) provided the product ketone
913 (m), 801 (m) cm-1
.
Ack n ow led gm en t . Support of this research from
the National Science Foundation is acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of compounds (39 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.
1
as a colorless oil (92%). Capillary GC and 500 MHz H NMR
analysis of the corresponding Mosher ester derivatives, pre-
J O952032O