Lithiated camphor-derived oxazolidinone S,N-acetals as chiral formyl anion synthons in additions to aldehydes. Asymmetric synthesis of α-hydroxy aldehydes and α-hydroxy acids

Article abstract of DOI:10.1016/S0957-4166(02)00043-5

N-(Phenylthiomethyl)oxazolidinones derived from camphor can be lithiated and added to aldehydes in good yields and stereoselectivities. The adducts are crystalline, which simplifies isolation of the major diastereomer from the product mixture. Hydrolysis affords enantiopure α-hydroxy aldehydes, which can be oxidized to α-hydroxy acids in good yields. The steric course of the reaction is analyzed in detail and a mechanistic model is presented.

Full text of DOI:10.1016/S0957-4166(02)00043-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 29–36
Lithiated camphor-derived oxazolidinone S,N-acetals as chiral
formyl anion synthons in additions to aldehydes. Asymmetric
synthesis of a-hydroxy aldehydes and a-hydroxy acids
Robert E. Gawley,* Silvio A. Campagna, Marcelina Santiago and Tong Ren†
Department of Chemistry, University of Miami, Coral Gables, FL 33124, USA
Received 7 December 2001; accepted 22 January 2002
Abstract—N-(Phenylthiomethyl)oxazolidinones derived from camphor can be lithiated and added to aldehydes in good yields and
stereoselectivities. The adducts are crystalline, which simplifies isolation of the major diastereomer from the product mixture.
Hydrolysis affords enantiopure a-hydroxy aldehydes, which can be oxidized to a-hydroxy acids in good yields. The steric course
of the reaction is analyzed in detail and a mechanistic model is presented. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Our initial efforts in this area from some years ago
involved deprotonation of N-(phenylthiomethyl)-
oxazolidinone 1, derived from valine. Addition to ben-
zaldehyde in THF at −78°C proceeded with 66% ds, but
the diastereomeric products could not be separated.
More recently, Seebach’s group showed that N-
(methylthiomethyl)oxazolidinone 2, also derived from
valine, showed very good diastereoselectivities in addi-
tions to aldehydes (typically 70–90% ds), unsymmetrical
ketones, chalcone, and imines.7 The improved
diastereoselectivity in moving from 1 to 2 is probably
due to the gem-diphenyl groups, which restrict the
motion of the isopropyl group, such that it ‘appears’ to
anything near the lithiated carbon, similar to a tert-
butyl group.8
Recent years have seen a surge of interest in the chem-
istry of functionalized organometallic reagents such as
a-aminoorganolithiums, especially those where the
metal-bearing carbon is stereogenic. Because these
organometallic reagents are chiral, they may be used in
stereoselective additions to prochiral aldehydes. This
general area has been the subject of several recent
publications, including two reviews.1,2 Herein we report
a study on the use of chiral organolithium compounds
as chiral acyl anion synthons, an asymmetric version of
the venerable Corey–Seebach reaction (Eq. (1)).3 This
synthetic transformation produces a-hydroxy acids
after oxidation, which have considerable utility in enan-
tioselective synthesis.4 Both we5 and others6–8 have
investigated this problem. The stereoselectivities
achieved in the previously reported systems range from
very low to very high, but the structural components in
the chiral anion that influence stereoselectivitity have
only recently begun to come into focus.8
Several years ago, we used a similar rationale to
improve a chiral auxiliary for tetrahydroisoquinoline
Grignard reagents, which we used as chiral nucleophiles
for additions to prochiral aldehydes in the synthesis of
some phthalideisoquinoline alkaloids. Specifically, in
additions of the Grignard reagent 4 to benzaldehyde,
we had observed 71% ds,9 but when gem-diphenyl
groups were introduced, as in 5, the selectivity
improved to 80%.10 In the same study, we found that
camphor-derived oxazoline 6 also afforded 80% ds, and
produced adducts that were highly crystalline, in some
cases obviating the need for a chromatographic separa-
tion of diastereomeric products. For this reason, we
chose to evaluate a camphor-derived chiral acyl anion
synthon, 3, in additions to aldehydes, in the hope of
improving the stereoselectivity over the results obtained
(1)
* Corresponding author. Tel.: 305-284-3279; fax: 305-668-3313;
e-mail: rgawley@miami.edu
† Author to whom inquiries regarding the X-ray structures should be
addressed. Tel.: 305-284-6617; fax: 305-284-1880; e-mail: tren@
miami.edu
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00043-5

30
R. E. Gawley et al. / Tetrahedron: Asymmetry 13 (2002) 29–36
2. Oxazolidinone synthesis
with 1 and/or the crystallinity of the addition products.
This has resulted in the present study, in which 3 is
used to prepare enantiopure a-hydroxy aldehydes and
a-hydroxy acids.
In 1991, Bonner and Thornton11 reported the synthesis
of oxazolidinone 7 in three steps from camphor qui-
none, which we followed with a slight modification. As
shown in Scheme 1, S,N-acetal 8 can be made either by
condensation of 7 with paraformaldehyde and thiophe-
nol (78% yield) or by alkylation of the sodium salt with
(phenylthio)methyl chloride (72% yield).
There is a large amount of literature on the additions of
chiral organolithium1 and organomagnesium com-
pounds2 to prochiral aldehydes, but the observed
diastereoselectivities are highly variable, and only rarely
are they outstanding. One of the more elusive goals has
been to gain insight into the reasons for the variable
stereoselectivity of additions of these chiral nucleophiles
to prochiral aldehydes. The adducts from addition of 3
to aldehydes proved to be highly crystalline, and X-ray
analysis of two of the products established the relative
and absolute configurations of the two new stereogenic
centers. Interestingly, the steric course of the addition
reaction changes for the sterically demanding pivalde-
hyde. In combination with recent results on 2 and
related systems from the Seebach group,8 knowledge of
the steric course permits a mechanistic rationale to be
constructed, and a subtle structural variable to be
identified.
3. Lithiation of 8 and additions to aldehydes
The stereoselectivity of addition of aldehydes to lithi-
ated oxazolidinone S,N-acetal 3 was evaluated. Scheme
2 illustrates the four possible diastereomeric addition
products in general form. The deprotonation of S,N-
acetal 8 with n-butyllithium in THF at −78°C, gener-
ates the a-aminoorganolithium intermediate 3 that was
added to four representative aldehydes to afford addi-
tion products 9–12 in moderate to excellent yield, as
summarized in Table 1.
SFC and/or HPLC analysis of the product mixture
revealed that, of the four possible stereoisomeric prod-
ucts, two predominated in each case. Recrystallization
of the product mixture afforded a single diastereomer
in useful yields. X-Ray crystallographic analysis
revealed that the major product in the addition of 3 to
benzaldehyde was 10a, with diastereoselectivities of 79–
86%, depending on the temperature (entry 1). The
configuration of the minor diastereomer was established
as 9a by oxidation of (R,R)-alcohol 10a to a ketone,
and sodium borohydride reduction to a mixture of
(R,S)-9a and (R,R)-10a (see Section 7 for details). This
mixture was shown by SFC and HPLC to be the same
two compounds produced in the addition reaction.
PhSH, CH2O
p-TsOH, C6H6, ∆
O
O
78%
HN
O
N
O
PhS
NaH, PhSCH2Cl
THF, RT
72%
7
8
Scheme 1.
SPh
SPh
SPh
SPh
R
S
S
R
BuLi, THF
–80°
RCHO
a: R = Ph
b: R = cyclohexyl
c: R = tert-butyl
d: R = ethyl
Xc
H
H
Xc
H
H
Xc
H
H
H
Xc
8
3
S
R
S
R
HO
H
OH
HO
OH
R
R
R
R
9
10
11
12
R,S
R,R
S,R
S,S
Scheme 2.

R. E. Gawley et al. / Tetrahedron: Asymmetry 13 (2002) 29–36
Table 1. Yield and diastereomer ratio for Scheme 2
31
Entry
R
d.r. at −78°C 9:10
Yield (%)a
d.r. at −100°C 9:10
Yield (%)a
Yield (%)b
1
2
3
4
Ph
21:79
31:61
56:44
35:65
83
81
52
80
14:86
24:76
64:34
24:76
77
74
59
71
72 10a
63 10b
51 9c
C6H11
t-Bu
Et
38 10d
a Diastereomeric mixture.
b Single diastereomer after recrystallization (ethyl acetate/hexane).
Interestingly, X-ray analysis of the major addition
product to pivaldehyde revealed it to be the (R,S)-
diastereomer 9c. An oxidation–reduction sequence fur-
ther revealed that the minor diastereomer was
(R,R)-10c. As described below, mercury-assisted
hydrolysis of 10a and 10b and 9c to the corresponding
a-hydroxy aldehydes followed by oxidation to known
a-hydroxy acids confirmed the absolute configuration
at the carbinol carbon for all three adducts. The
propanal adduct 10d was not hydrolyzed because of
anticipated solubility problems. The configuration at
the carbon bearing the auxiliary is R in 9c and 10a, so
is assigned R by analogy with 10b and 10d.
4. Conversion to a-hydroxy aldehydes and a-hydroxy
acids
Enantiomerically enriched a-hydroxy carboxaldehydes
were prepared by mercuric acetate oxidative-hydrolysis
of the isolated major diastereomers 9c, 10a and 10b.
Scheme 3 shows this hydrolysis reaction as well as the
recovery of the chiral auxiliary 7 in 72–80% yield.
Yields of a-hydroxy carboxaldehydes 13a–c, recovered
7, and optical rotations are summarized in Table 2.
As shown in Scheme 3, a-hydroxy aldehydes 13a–c
could be oxidized with pyridinium dichromate (PDC)
SPh
Hg(OAc)2, CaCO3
OH
OH
R
HOAc, H2O
80° C
Xc
H
H
PDC, CH2Cl2
S
HO
t-Bu CHO
S-13c
t-Bu CO2H
S-14c
t-Bu
9c
+ 7
SPh
Hg(OAc)2, CaCO3
HOAc, H2O
80° C
R
OH
OH
Xc
H
H
R
PDC, CH2Cl2
OH
R
CHO
R
CO2H
R
a: R = Ph
b: R = cyclohexyl
R-13
R-14
10
Scheme 3.
Table 2. Yield and rotation data for auxiliary hydrolysis (Scheme 3)
Entry
Carbinol
R
a-Hydroxy carboxaldehyde
Yield (%)a
[h]2D5 (MeOH)b
Recovered 7 (%)
1
2
3
10a
10b
9c
Ph
C6H11
t-Bu
(R)-13a
(R)-13b
(S)-13c
78
75
67
−112
−12
−5
80
78
72
a Yields after purification by silica gel chromatography.
b Values obtained with c=1.0 except for 13c for which c=0.7.
Table 3. Rotation data for a-hydroxy acids (Scheme 3), and literature comparisons
Entry
a-Hydroxy carboxaldehyde
R
[h]2D5 (H2O) 14
[h]2D5 (H2O) (Aldrich catalog)
O.p. 14 (%)
Configuration 14
1
2
3
(R)-13a
(R)-13b
(S)-13c
Ph
−151
+154 (S)
−23 (R)
−62 (S)
98
100
97
R
R
S
C6H11 −23
t-Bu −60

32
R. E. Gawley et al. / Tetrahedron: Asymmetry 13 (2002) 29–36
to the corresponding a-hydroxy acids 14a–c in 47–68%
yield. Rotation data and literature comparisons, sum-
marized in Table 3, confirm the configurations estab-
lished by X-ray analysis for precursors to 13a and 13c,
and establish the configuration for 14b, and by extrapo-
lation, of 13b and 10b.
ing solvent molecules are deleted for clarity). The Lewis-
acidic lithium ion should coordinate to the aldehyde
oxygen trans to the aldehyde’s phenyl ring. If the
aldehyde oxygen is trans to the SMe group (on the
five-membered chelate ring), the correct (Re) face is
presented to the carbanionic carbon. Addition with
retention of configuration at the metal-bearing carbon
(SE2ret13) then gives the observed major product.
5. Discussion
The addition of 3 to aldehydes produces a mixture of 9
and 10, with the latter predominating except when
R=tert-butyl. Extrapolation of the structural features
of 2 to 3 suggest the structure for 3 shown in Scheme 5.
Specifically, the lithium ion is chelated by the carbonyl
oxygen, the lithium-bearing carbon is R, so as to place
the S-phenyl on the opposite side of the oxazolidinone
ring relative to the camphor moiety, and the S-phenyl
bond is antiperiplanar to the CꢀLi bond. Coordination
of the aldehyde as in 16 gives 17, in which the Si face
is presented to the carbanionic carbon. Addition to the
Si face, with retention at the carbanionic carbon
(SE2ret13), gives 10, the major product in three of the
four examples studied. We speculate that the reason for
the reversal of steric course, may be as follows.
Addition of 3 to benzaldehyde, cyclohexane carboxalde-
hyde, and presumably propanal, occurred predomi-
nantly to the Si face of the aldehyde. In contrast,
addition to pivaldehyde occurred with lower selectivity,
adding to the Re face of the aldehyde. Analysis of X-ray
crystal structures of adducts 9 and 10 revealed that they
had the same absolute configuration at the former
metal-bearing carbon, differing only at the carbinol
carbon. Diastereomers 11 and 12 were only present in
trace amounts at most, and could not be detected at all
in several experiments.
Analysis of the steric course of this reaction can only
begin if the configuration of the lithium-bearing carbon
of 3 is known. Although we have no direct evidence for
the configuration of this stereocenter in 3, there is
enough precedent in related systems to allow a reason-
able prediction. In particular, detailed spectroscopic
studies of 2 by the Seebach group, along with Bauer and
ourselves,8 revealed several structural features that are
likely to be present in 3 as well. Specifically (Scheme 4),
IR studies showed that the lithium in 2 is chelated by
the carbonyl oxygen, calculations showed that the S-
methyl group prefers a position antiperiplanar to the
CꢀLi bond and NMR studies established the configura-
tion of the carbanionic carbon as S.8 Even though the
barrier to inversion in a related achiral system is only 11
kcal/mol, the diastereomeric bias created by the isopro-
pyl substituent at position 4 of the oxazolidinone ring is
such that none of the minor epimer is present between
−105 and −20°C.8 Similar features apparently operate in
other a-aminoorganolithium reagents employing an
oxazolidinone chiral auxiliary.12
In structures 16 and 17, the lithium ion is in the nodal
plane of the aldehyde p bond. In order for the carbanion
to add to the carbonyl carbon, the aldehyde must rotate
to give a structure such as 18 or 19. Such a reaction
trajectory has been predicted in a theoretical investiga-
tions of the addition of methyllithium aggregates to
formaldehyde and acetaldehyde.14 Note, however, that
as this rotation occurs, the aldehyde substituent may
encounter one of the geminal methyls in the camphor
moiety in TS 19, which leads to 10. Such an encounter
may destabilize 19 relative to 18 when R is an extremely
bulky tert-butyl group, leading to a reversal in topicity
and 9 as the major product. Confirmation of this
hypothesis will require computer modeling studies that
are beyond the scope of this paper.
Because of the close similarity of 2 and 3, it is instructive
to compare the selectivities in asymmetric additions to
the same, or very similar aldehydes. For benzaldehyde,
the Re/Si facial selectivity of 2 is 90:10 at −78°C and
93:7 at −100°C. This compares with 79:21 at −78°C and
86:14 at −100°C for addition of 3 to benzaldehyde. At
−78°C, the difference in transition state energies is
therefore 340 cal/mol, and 260 cal/mole at −100°C. At
The addition products, typified by 15, result from addi-
tion of the (S)-organolithium to the Re face of the
aldehyde to give (S,S)-15.7,8 A possible coordination
complex between 2 and an aldehyde (e.g. 16) has several
structural features that are relevant (possible coordinat-
Ph
i-Pr
Ph
O
Ph
i-Pr
Ph
O
O
H
O
H
OH
PhCHO
N
N
Li
S
S
S
S
S
Me
Me
2
15
Ph
i-Pr
Ph
O
O
O
H
N
Li
16
S S
H
Me
Scheme 4.

R. E. Gawley et al. / Tetrahedron: Asymmetry 13 (2002) 29–36
33
HO
HO
O
H
O
H
O
H
O
O
O
Li
R
S
RCHO
N
N
N
R
R
R
R
R
S
S
S
3
9
10
R
O
O
Li
O
Li
H
N
R
O
H
O
O
O
Li
O
O
addition to Si
H
N
R
face gives 10
N
S
S
S
retention here
17
18
19
Scheme 5.
−100°C, 2 gave a 70:30 d.r. when added to butanal,
whereas 3 gave a 76:24 ratio when added to propanal,
corresponding to differences in transition state energies
of only 100 cal/mol. These energy differences are less
than half the energy difference between the synclinal
and antiperiplanar conformations of butane (900 cal/
mol). In other words, very subtle structural differences
in either the chiral auxiliary or the electrophile can
change the diastereoselectivity, or even the steric
course, of an electrophilic substitution to a significant
degree. Fig. 1 shows a comparison between probable
solution structures of 17 and ent-16, highlighting the
space in ent-16 that is occupied by a methyl group in
17, and which may account for the observed selectivity
differences, as well as the change in steric course
observed with 17, when R is tert-butyl.
7. Experimental
Proton NMR spectra were recorded at 400 MHz,
whereas carbon spectra were recorded at either 100
MHz or 23 MHz. Electrospray ionization mass spec-
trometry (ESI-MS) were obtained on an orthogonal
acceleration time-of-flight (oa-TOF-MS), at duPont
Pharmaceutical company, courtesy of Dr. J. Castoro.
The samples were analyzed using a MeOH/H2O eluent
without an HPLC column, and a 2 mL injection vol-
ume. The eluent was flowing at 0.2 mL/min and an
internal standard was added at 5 mL/min. Elemental
analysis was performed by Atlantic Microlabs. High
Performance Liquid Chromatography (HPLC) separa-
tions used a chiral phase (R)-DNBPG (covalent) Pirkle
column with isocratic conditions using isopropanol/
hexane. Modifier for supercritical fluid chromato-
graphic (SFC) separations was methanol, with either an
OD or AD Chiralcel column. Diode array detection
was used for both techniques. Gas chromatography was
performed with a 15 m 5% phenyl methyl silicone
vitreous silica gel capillary column. All reactions
involving air- or moisture-sensitive reagents were con-
ducted under an atmosphere of nitrogen (balloon) in
septum-stoppered flasks. Transfer of reagents was
accomplished using standard syringe techniques.
6. Summary
In conclusion, the Bonner–Thornton oxazolidinone, 7,
is a very good chiral auxiliary for generating chiral acyl
anion synthons via S,N-acetal 8, which may be used in
an asymmetric version of the Corey–Seebach reaction.
Enantiopure a-hydroxyaldehydes and a-hydroxy acids
can be prepared readily, and the auxiliary recovered in
excellent yield. A particular advantage of this system is
that the initially formed addition products are highly
crystalline, simplifying purification and diastereomeric
enrichment.
All glassware was oven dried (120°C) and cooled under
a nitrogen atmosphere. Tetrahydrofuran and diethyl
ether were distilled under nitrogen from sodium benzo-
space occupied by
methyl group in 17
R
R
Me
Me
Me
O
O
O
H
O
H
O
O
Me
Ph
Li
Li
N
N
H
S
S
Ph
Me
Me
17
ent-16
Figure 1.

34
R. E. Gawley et al. / Tetrahedron: Asymmetry 13 (2002) 29–36
phenone ketyl immediately prior to use. Triethylamine
and tetramethylethylenediamine (TMEDA) were dis-
tilled under nitrogen from calcium hydride. Commer-
cial solutions of n-butyllithium in hexanes and
sec-butyllithium in cyclohexane were titrated prior to
use with sec-butanol using 1,10-phenanthroline (mono-
hydrate) as an indicator.
BuLi. The reaction mixture was stirred at −78°C for
30 min and then the corresponding aldehyde (1.2
equiv.) was added dropwise. In the case of −100°C
addition, the solution was stirred for 30 min at −78°C,
then transferred to a liquid nitrogen/methanol slush
bath. After equilibrating for 10 min, the aldehyde was
added dropwise. In either case, the reaction was stirred
for an additional hour and then quenched with a
saturated aqueous solution of ammonium chloride.
The mixture was extracted with ether (three times).
The combined organic phases were washed with brine
and dried over MgSO4. After vacuum filtration and
concentration, the residue was dried under high vac-
uum for 24 h. The products were purified by chro-
matography for characterization only, but otherwise
were sufficiently pure for further reactions.
7.1. (1R,2S,6R,7S)-1,10,10-Trimethyl-5-phenylsulfanyl-
methyl-3-oxa-5-azatricyclo-[5.2.1.02,6]-decane-4-one 8
Procedure A: To a stirred solution of oxazolidinone
711 (2.0 g, 10.2 mmol) in benzene (25 mL) was added
p-toluenesulfonic acid (catalytic amount, 0.1 equiv.)
and paraformaldehyde (0.45 g, 10.2 mmol) at 25°C in
one portion. After stirring for 30 min at 25°C, thio-
phenol (1.06 mL, 10.2 mmol) was added. The reaction
mixture was heated under reflux using a Dean–Stark
azeotropic separation apparatus until no more water
7.2.1. (1R,2S,6R,7S)-5-((1R,2R)-2-Hydroxy-2-phenyl-1-
phenylsulfanylethyl)-1,10,10-trimethyl-3-oxo-5-azatricy-
clo-[5.2.1.02,6]-decane-4-one 10a (from addition of 3 to
benzaldehyde). Mp: 81–83°C; IR (KBr): (br) 3420,
3010, 2980, 1950, 1700, 1590, 1410, 1360, 1340, 1270,
was collected (approximately
8 h). Benzene was
removed by rotary evaporation and the crude product
purified by column chromatography (ethyl acetate/hex-
ane, 1:4 v/v) to afford 8 as a white solid (2.51 g, 78%).
Mp=74–75°C; IR (KBr): 3080, 2985, 2944, 1760,
1580, 1485, 1420, 1320, 1290, 1240, 1090, 1050, 1030,
1
1220, 1100, 1040, 980, 820 cm−1. H NMR (400 MHz,
CDCl3): l 7.5–7.2 (m, 10H), 5.4 (d, J=6 Hz, 1H), 5.1
(m, 1H), 4.1 (d, J=8 Hz, 1H), 3.8 (br, s, 1H), 3.6 (d,
J=8 Hz, 1H), 2.7–2.2 (m, 4H), 2.1 (m, 1H), 0.90 (s,
3H), 0.77 (s, 3H), 0.68 (s, 3H). 13C NMR (90 MHz,
CDCl3): l 4.0, 5.3, 11.2, 27.9, 29.2, 33.3, 34.6, 38.2,
38.6, 48.6, 88.2, 92.0, 127.2, 128.2, 128.8, 129.9, 130.2,
132.4, 134.8, 135.2, 184.2. ESI-MS calcd for
C25H30NO3S (MH+): 424.1946; found 424.1946. Anal.
calcd for C25H29NO3S: C, 70.89%, H, 6.90%; found:
C, 70.91%, H, 7.07%. Crystal data: C25H29NO3S, M=
423.6, monoclinic, space group P21, a=10.028(1), b=
1
980, 900 cm−1; H NMR (400 MHz, CDCl3): l 7.4–7.2
(m, 5H), 5.6 (d, J=8 Hz, 1Ha), 4.4 (d, J=8 Hz, 1Hb),
4.2 (d, J=6 Hz, 1H), 3.8 (d, J=6 Hz, 1H), 1.90 (m,
1H), 1.7 (m, 2H), 1.5 (m, 2H), 1.1 (s, 3H), 0.87 (s,
3H), 0.84 (s, 3H). 13C NMR (90 MHz, CDCl3): l 4.0,
5.3, 11.2, 27.9, 29.2, 33.3, 34.6, 38.2, 48.6, 88.3, 92.0,
129.9, 130.2, 134.3, 134.8, 184.2. ESI-MS calcd for
C18H24NO2S (MH+): 318.1528; found 318.1519. Anal.
calcd for C18H23NO2S: C, 68.10%, H, 7.30%, N,
4.41%; found: C, 67.99%, H, 7.30%, N, 4.36%.
,
11.080(1),
c=11.003(1)
A,
i=115.360(1)°,
3
,
V=1104.7(1) A , Z=2; Data were collected on a
Bruker SMART1000 CCD diffractometer at 27°C with
Procedure B: To stirred solution of oxazolidinone 7
(6.60 g, 37.0 mmol) in THF (25 mL) was added
sodium hydride (60% dispersion in mineral oil, 1.78 g,
44.4 mmol) at 0°C. After stirring the suspension for 30
min, Bu4NI (catalytic amount) and phenylthiomethyl
chloride (4.90 mL, 37.0 mmol) were added. The reac-
tion mixture was heated under reflux for 6 h, cooled
to room temperature and carefully quenched with
brine (10 mL). The mixture was extracted with diethyl
ether (3×25 mL). The organic layers were combined
and dried over MgSO4. After filtration and concentra-
tion by rotary evaporation, the product was purified
by column chromatography (ethyl acetate/hexane, 1:4
v/v) to yield 8 (8.5 g, 72%).
,
MoKa radiation (u=0.71073 A). R1=0.0305, wR2=
0.0778, absolute structure (Flack) parameter=0.04(6).
Further details have been deposited with the Cam-
bridge Crystallographic Data Centre (CCDC 175200,
UM168).
7.2.2.
(1R,2S,6R,7S)-5-((1R,2R)-2-Hydroxy-2-cyclo-
hexyl-1-phenylsulfanylethyl)-1,10,10-trimethyl-3-oxo-5-
aza-tricyclo-[5.2.1.02,6]-decane-4-one 10b (from addition
of 3 to cyclohexanecarboxaldehyde). Mp: 164–165°C;
IR (KBr): (br) 3430, 3100, 3010, 2980, 1695, 1480,
1410, 1340, 1270, 1220, 1100, 1030, 970, 930, 820
1
cm−1. H NMR (400 MHz, CDCl3): l 7.6–7.2 (m, 5H),
5.3 (d, J=8 Hz, 1H), 5.1 (d, J=8 Hz, 1H), 4.2 (d,
J=8 Hz, 1H), 3.8 (m, 1H), 3.7 (m, 1H), 3.6 (br, s,
1H), 2.2 (m, 1H), 1.8–1.6 (m, 3H), 1.3–0.92 (m, 11H),
1.0 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H). 13C NMR (90
MHz, CDCl3): l 3.9, 4.2, 4.5, 4.8, 4.9, 5.0, 5.3, 11.2,
27.9, 29.2, 33.3, 34.6, 38.2, 48.6, 88.2, 92.0, 127.2,
128.2, 128.8, 129.8, 185.2. ESI-MS calcd for
C25H36NO3S (MH+): 430.2416; found 430.2430. Anal.
calcd for C25H35NO3S: C, 69.89%, H, 8.21%; found:
C, 69.62%, H, 8.26%.
7.2. General procedure for deprotonation of
(1R,2S,6R,7S)-1,10,10-trimethyl-5-phenylsulfanylmethyl-
3-oxa-5-aza-tricyclo-[5.2.1.02,6]-decane-4-one 8 and its
addition reaction to aldehydes
To a stirred solution of 8 (0.1 M) in THF at −78°C
(CO2/acetone) was added n-BuLi (1.1 equiv., 1.6 M in
hexanes) dropwise over 5 min. The color of solution
changed to dark orange–red after the addition of n-

R. E. Gawley et al. / Tetrahedron: Asymmetry 13 (2002) 29–36
35
1
7.2.3. (1R,2S,6R,7S)-5-((1R,2R)-2-Hydroxy-1-phenyl-
sulfanylbutyl)-1,10,10-trimethyl-3-oxo-5-aza-tricyclo-
[5.2.1.02,6]-decane-4-one 10d (from addition of 3 to
propanal). Mp: 67–69°C; IR (KBr): (br) 3450, 3010,
2990, 1700, 1490, 1410, 1360, 1340, 1270, 1220, 1100,
1360, 1340, 1270, 1220, 1100, 1040, 980, 820 cm−1. H
NMR (400 MHz, CDCl3): l 7.7–7.2 (m, 10H), 5.1 (s,
1H), 4.8 (m, 1H), 3.8 (m, 1H), 2.7–2.2 (m, 3H), 2.1 (m,
2H), 0.90 (s, 3H), 0.77 (s, 3H), 0.68 (s, 3H). 13C NMR
(90 MHz, CDCl3): l 4.0, 5.3, 11.2, 27.7, 29.2, 33.3, 34.6,
38.2, 48.6, 88.2, 92.0, 127.2, 128.8, 129.9, 130.2, 132.4,
134.8, 134.3, 134.8, 179.4, 184.2. ESI-MS calcd for
C25H28NO3S (MH+): 422.1790; found 422.1798. Anal.
calcd for C25H27NO3S: C, 71.23%, H, 6.46%; found: C,
71.16%, H, 6.54%.
1
1030, 970, 930, 820 cm−1. H NMR (400 MHz, CDCl3):
l 7.6–7.2 (m, 5H), 5.1 (d, J=6 Hz, 1H), 4.2 (d, J=6
Hz, 1H), 4.1 (m, 1H), 3.9 (m, 2H), 3.8 (br, s, 1H), 3.6
(m, 2H), 2.0 (m, 1H), 1.8–1.7 (m, 3H), 1.5 (t, 3H), 1.0
(s, 3H), 0.90 (s, 3H), 0.88 (s, 3H). 13C NMR (90 MHz,
CDCl3): l 3.9, 4.6, 5.3, 11.2, 27.9, 28.0, 29.2, 33.3, 34.6,
38.2, 48.6, 88.3, 92.0, 127.2, 128.2, 128.8, 129.8, 132.4,
184.2. ESI-MS calcd for C21H30NO3S (MH+): 376.1946;
found 376.1953. Anal. calcd for C21H29NO3S: C,
67.17%, H, 7.78%. Found: C, 67.32%, H, 7.94%.
7.3.2. (1R,2S,6R,7S)-1,10,10-Trimethyl-5-((1R)-2-oxo-2-
cyclohexyl-1-phenylsulfanyl-ethyl)-3-oxa-5-aza-tricyclo
[5.2.1.02,6]decane-4-one (from 9b/10b). Mp: 158–160°C;
IR (KBr): 3100, 3010, 2980, 1720, 1695, 1480, 1410,
1
1340, 1270, 1220, 1100, 1030, 970, 930, 820 cm−1. H
7.2.4.
(1R,2S,6R,7S)-5-((1R,2S)-2-Hydroxy-3,3-
NMR (400 MHz, CDCl3): l 7.6–7.2 (m, 5H), 3.8 (m,
1H), 3.7 (m, 2H), 2.2 (m, 2H), 1.8–1.6 (m, 3H), 1.3–0.92
(m, 11H), 1.0 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H). 13C
NMR (90 MHz, CDCl3): l 3.90, 4.2, 4.4, 4.8, 5.0, 5.2,
11.2, 27.9, 29.2, 33.3, 34.6, 38.2, 48.6, 88.3, 92.0, 127.2,
128.2, 129.8, 132.4, 178.4, 185.2. ESI-MS calcd for
C25H34NO3S (MH+): 428.2259; found 428.2271. Anal.
calcd for C25H33NO3S: C, 70.22%, H, 7.78%, N, 3.28%;
found: C, 70.53%, H, 8.08%, N, 3.14%.
dimethyl-1-phenylsulfanylbutyl)-1,10,10-trimethyl-3-oxo-
5-aza-tricyclo-[5.2.1.02,6]-decane-4-one 9c (from addition
of 3 to pivaldehyde). Mp: 135–136°C; IR: (br) 3450,
3010, 2990, 1700, 1490, 1410, 1340, 1270, 1220, 1100,
1
1030, 970, 930, 820 cm−1. H NMR (400 MHz, CDCl3):
l 7.6–7.2 (m, 5H), 4.2 (d, J=6 Hz, 1H), 4.0 (m, 1H),
3.7 (m, 2H), 3.2 (br, s, 1H), 1.8 (m, 2H), 1.7–1.6 (m,
3H), 1.1 (s, 3H), 0.90 (s, 3H), 0.80 (d, J=6 Hz, 9H),
0.76 (s, 3H). 13C NMR (90 MHz, CDCl3): l 3.98 (3C),
4.6, 5.3, 5.4, 11.2, 27.1, 28.3, 28.5, 29.2, 33.3, 34.6, 38.2,
48.6, 52.2, 88.3, 92.0, 127.8, 128.2, 128.8, 129.8, 185.2.
ESI-MS calcd for C25H34NO3S (MH+): 404.2259; found
404.2258. Anal. calcd for C23H33NO3S: C, 68.45%, H,
8.24%; found: C, 68.61%, H, 8.23%. Crystal data:
C23H33NO3S, M=403.6, orthorhombic, space group
7.3.3. (1R,2S,6R,7S)-1,10,10-Trimethyl-5-((1R)-2-oxo-
3,3-dimethyl-1-phenylsulfanyl-butyl)-3-oxa-5-aza-tricy-
clo-[5.2.1.02,6]-decane-4-one
(from
9c/10c).
Mp:
66–68°C; IR (KBr): 3010, 2990, 1700, 1690, 1490, 1410,
1
1340, 1270, 1220, 1100, 1030, 970, 930, 820 cm−1. H
,
P212121, a=6.8616(5), b=12.011(1), c=27.465(2) A,
V=2263.4(3) A , Z=4; Data were collected on a
NMR (400 MHz, CDCl3): l 7.6–7.2 (m, 5H), 4.0 (m,
1H), 3.7 (m, 2H), 1.8 (m, 2H), 1.7–1.6 (m, 3H), 1.1 (s,
3H), 0.90 (s, 3H), 0.80 (s, 9H), 0.76 (s, 3H). 13C NMR
(90 MHz, CDCl3): l, 3.98 (3C), 4.6, 5.2, 5.7, 11.2, 28.0,
29.2, 33.3, 34.6, 38.2, 48.6, 88.2, 127.8, 128.2, 128.8,
129.8, 132.4, 178.8, 185.2. Anal. calcd for C23H31NO3S:
C, 68.79%, H, 7.78%. Found: C, 68.94%, H, 7.91%.
3
,
Bruker SMART1000 CCD diffractometer at 27°C with
MoKa radiation (u=0.71073 A). R1=0.0325, wR2=
0.0727, absolute structure (Flack) parameter=−0.04(6).
Further details have been deposited with the Cam-
bridge Crystallographic Data Centre (CCDC 175201,
UM169).
,
7.3.4. (1R,2S,6R,7S)-1,10,10-Trimethyl-5-((1R)-2-oxo-1-
phenylsulfanyl-butyl)-3-oxa-5-aza-tricyclo-[5.2.1.02,6]-
decane-4-one (from 9d/10d). Mp: 82°–84°C; IR (KBr):
3010, 2990, 1710, 1690, 1490, 1410, 1360, 1340, 1270,
7.3. General procedure for the oxidation of carbinol
products 9/10 with pyridinium chlorochromate (PCC)
To a stirred suspension of pyridinium chlorochromate
(23.3 g, 0.15 mol) in anhydrous dichloromethane (150
mL) at 25°C was added the corresponding carbinols
9/10 (0.1 mol) dissolved in dichloromethane (20 mL) in
one portion. After stirring the mixture for 1.5 h, dry
diethyl ether (200 mL) was added and the supernatant
liquid decanted from a black gum. The insoluble
residue was washed with ether (3×30 mL) until it
became a granular black solid. The combined ether
solution was passed through a short pad of florisil
under vacuum. The solvent was removed by rotary
evaporation, affording the ketone product in 85–95%
yield. The ketones were purified by recrystallization
(diethyl ether/hexane, 3:2) for characterization.
1
1220, 1100, 1030, 970, 930, 820 cm−1. H NMR (400
MHz, CDCl3): l 7.6–7.2 (m, 5H), 4.1 (m, 1H), 3.9 (q,
2H), 3.6 (m, 2H), 2.0 (m, 2H), 1.8–1.7 (m, 3H), 1.4 (t,
3H), 1.0 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H). 13C NMR
(90 MHz, CDCl3): l 3.9, 4.6, 5.3, 5.7, 11.2, 28.0, 29.2,
33.2, 34.6, 38.2, 48.6, 88.2, 92.0, 128.8, 129.8, 132.4,
134.8, 180.2, 184.2. ESI-MS calcd for C21H28NO3S
374.1790 (MH+): found 374.1785. Anal. calcd for
C21H27NO3S: C, 67.53%, H, 7.29%. Found: C, 67.90%,
H, 7.54%.
7.4. General procedure for the reduction of above
ketones to 9/10 epimeric carbinol mixture with sodium
borohydride
7.3.1. (1R,2S,6R,7S)-1,10,10-Trimethyl-5-((1R)-2-oxo-
2-phenyl-1-phenylsulfanyl-ethyl)-3-oxa-5-aza-tricyclo-
[5.2.1.02,6]-decane-4-one (from 9a/10a). Mp: 96–98°C;
IR (KBr): 3020, 2980, 1950, 1720, 1695, 1590, 1410,
To a stirred solution of the ketone (1 mmol) in
methanol (15 mL) at 25°C was added a solution of
NaBH4 (2 mmol) in water/methanol (1:1 v/v) in one

36
R. E. Gawley et al. / Tetrahedron: Asymmetry 13 (2002) 29–36
portion. The reaction mixture was stirred for 1 h and
then quenched with dilute aqueous acetic acid (3 mL).
The mixture was extracted with diethyl ether (3×20
mL), washed with brine and dried over MgSO4. After
filtration and concentration by rotary evaporation the
corresponding mixture of carbinol epimers was
obtained in 67–73% yield. No further purification was
needed for these compounds.
Acknowledgements
This work was generously supported by the National
Institutes of Health (GM 56271). We thank the Univer-
sity of Miami for the purchase of the CCD diffractome-
ter used in this work.
References
7.5. General procedure for the oxidative hydrolysis of
carbinols 10a, 10b and 9c to a-hydroxy carboxalde-
hydes 13a, 13b and 13c, respectively
1. Gawley, R. E. In Advances in Asymmetric Synthesis;
Hassner, A., Ed. Stereoselective addition of chiral a-
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2. Gawley, R. E. In Grignard Reagents: New Developments;
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To a stirred solution of the corresponding carbinol 10a,
10b and 9c (1.0 mmol) in aqueous 80% acetic acid (10
mL) at 25°C was added a solution of mercuric acetate
(2.2 mmol) in acetic acid (10 mL). Powdered calcium
carbonate (2.2 mmol) was added to buffer the reaction
mixture near pH 7. The stirred mixture was heated to
80°C under nitrogen for 4–6 h. After this period of
time, the reaction was complete as indicated by TLC
(CH2Cl2/MeOH, 1:1). The mixture was allowed to cool
to room temperature and filtered through a Celite bed.
The filter cake was washed with hexane/
dichloromethane (1:1). The organic phase was sepa-
rated from the filtrate and washed with aqueous
ammonium acetate (5 M, 5 mL), water (5 mL) and
brine (5 mL). After drying the organic solution over
MgSO4, filtration and concentration by rotary evapora-
tion, crude a-hydroxy aldehyde 13a–28 was obtained in
72–80% yields. Purification of 13a–c was accomplished
by silica chromatography (hexane/ethyl acetate, 1:9).
7.6. General procedure for the oxidation of a-hydroxy
aldehydes 13a, 13b and 13c to a-hydroxy carboxylic
acids 14a, 14b and 14c, respectively
8. Gaul, C.; Arvidsson, P. I.; Bauer, W.; Gawley, R. E.;
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To a stirred suspension of (C5H5N)2Cr2O7 (1.2 mmol)
in dichloromethane (20 mL) at 25°C was added a
solution of the correspond a-hydroxy aldehydes 13a–c
(1.0 mmol) in dichloromethane (10 mL) in one portion.
The mixture was stirred for 2 h at room temperature.
At that time, no starting material was observed by TLC
(dichloromethane/methanol, 1:1). Phosphoric acid (1
mL) was added and the insoluble residue was filtered
through a short pad of Florisil. The cake was washed
with dichloromethane (5 mL). The dark filtrate was
filtered through a silica gel plug and washed with
dichloromethane (ꢀ5 mL). After concentration, the
crude a-hydroxy carboxylic acid was obtained in 47–
68% yield. Purification of the a-hydroxy carboxylic acid
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1
boxylic acids 13a–c were made by comparison of H
and 13C NMR, and specific rotation, with commercially
available (R)-(+)-mandelic acid 14a, (S)-(+)-hexahydro-
mandelic acid 14b and (S)-(−)-2-hydroxy-3,3-dimethyl-
butyric acid 14c.