Stereochemistry of the Oxidation of Imines Derived from Substituted Cyclohexanones: Axial vs Equatorial Attack and Evidence for Delivery by an Adjacent Hydroxyl Group

Article abstract of DOI:10.1021/jo991928g

A set of conformationally biased imines derived from substituted cyclohexanones and benzylamine or diphenylmethylamine, respectively, were oxidized to the corresponding oxaziridines. The structures of the oxaziridines were determined via NMR comparison of two series of differently N-substituted oxaziridines. Thus, those compounds having an axially disposed nitrogen substituent displayed an upfield-shifted axial proton in a 1,3-relationship to the oxaziridine nitrogen in the N-diphenylmethyl series relative to the N-benzyl compounds. Analysis of the products obtained from these reactions suggests that (1) adjacent hydroxyl groups favor syn oxidant addition and (2) imines containing adjacent methoxy groups preferentially undergo attack anti to the resident alkoxy substituent.

Full text of DOI:10.1021/jo991928g

5120
J . Org. Chem. 2000, 65, 5120-5126
Ster eoch em istr y of th e Oxid a tion of Im in es Der ived fr om
Su bstitu ted Cycloh exa n on es: Axia l vs Equ a tor ia l Atta ck a n d
Evid en ce for Deliver y by a n Ad ja cen t Hyd r oxyl Gr ou p
Yuguang Wang,‡ Samuel Chackalamannil,‡ and J effrey Aube´*,†
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045-2506
jaube@ukans.edu
Received December 16, 1999
A set of conformationally biased imines derived from substituted cyclohexanones and benzylamine
or diphenylmethylamine, respectively, were oxidized to the corresponding oxaziridines. The
structures of the oxaziridines were determined via NMR comparison of two series of differently
N-substituted oxaziridines. Thus, those compounds having an axially disposed nitrogen substituent
displayed an upfield-shifted axial proton in a 1,3-relationship to the oxaziridine nitrogen in the
N-diphenylmethyl series relative to the N-benzyl compounds. Analysis of the products obtained
from these reactions suggests that (1) adjacent hydroxyl groups favor syn oxidant addition and (2)
imines containing adjacent methoxy groups preferentially undergo attack anti to the resident alkoxy
substituent.
Sch em e 1
Two of the most useful unifying concepts in organic
stereochemistry are the effect of conformation on the
reactions of cyclic structures1 and the delivery of reagents
through prior coordination with a nearby functional
group.2 Both of these concepts pervade the field of
chemical synthesis; in particular, the latter idea has been
a mainstay of oxidation chemistry since the early obser-
vations of Henbest on the oxidation of allylic alcohols.3
Oxaziridines are established intermediates in syntheti-
cally useful ring-expansion processes4 and are even better
known as oxidizing reagents. In particular, chiral sulfo-
nylozaziridines often afford high levels of enantioselec-
tivity in reactions with various double bonds or sulfides.5
The single most common method for oxaziridine synthesis
is the oxidation of an imine with a peracid such as
m-chloroperoxybenzoic acid (m-CPBA). These imines are
typically derived from cyclohexanone derivatives. In such
cases, equatorial attack of the oxidant is generally
favored, leading to oxaziridines bearing an axial nitrogen
substituent. However, relatively little is known about the
effect of adjacent substitution on the course of such reac-
tions, which are especially useful as they constitute the
first step in the only general route for nitrogen insertion
anti to the more substituted carbon (Scheme 1).6-8
In this paper, we examine the effect of polar substit-
uents on the stereochemistry of oxaziridine formation.
Such effects have been extensively investigated in terms
of addition to R-substituted ketones9 but have been much
less recognized in the context of imine oxidation reac-
tions. In so doing, we present evidence that polar sub-
stituents can lead to axial addition of an oxidizing agent
in favorable circumstances. In addition, the first docu-
mented case of substrate-directed delivery in the case of
an imine oxidation reaction will be presented.
Resu lts a n d Discu ssion
Ba ck gr ou n d a n d Resea r ch P la n . The observation
of equatorial attack by m-CPBA onto 4-substituted cy-
clohexylimines was first made by Oliveros, Rivie`re, and
Lattes.10 Although this course of reaction has proved
general in our experience, there have been examples that
suggest other reaction courses might be possible. Con-
sider the case presented in Scheme 2, in which the isomer
shown was the only oxaziridine isolated.7 It is reasonable
to suppose that the reaction proceeds by equatorial
* Tel: (785) 864-4496. Fax: (785) 864-5326.
† University of Kansas.
‡ At the Schering-Plough Research Institute, 2015 Galloping Hill
Road, Kenilworth, NJ 07033.
(7) For examples of the oxidation of imines containing adjacent alkyl
groups, see: (a) Oliveros, E.; Rivie`re, M.; Lattes, A. Org. Magn. Reson.
1976, 8, 601-606. (b) Oliveros, E.; Rivie`re, M.; Lattes, A. Nouv. J .
Chim. 1979, 3, 739-753. (c) Oliveros, E.; Rivie`re, M.; Lattes, A. J .
Heterocycl. Chem. 1980, 17, 107-112. (d) Aube´, J .; Hammond, M.;
Gherardini, E.; Takusagawa, F. J . Org. Chem. 1991, 56, 499-508;
correction J . Org. Chem. 1991, 56, 4086.
(8) For examples of the oxidation of imines containing adjacent
heteroatom-containing groups, see: (a) Felluga, F.; Nitti, P.; Pitacco,
G.; Valentin, E. J . Chem. Res., Synop. 1992, 86-87. (b) Czarnocki, Z.
J . Chem. Res., Synop. 1992, 334-335. (c) Wolfe, M. S.; Dutta, D.; Aube´,
J . J . Org. Chem. 1997, 62, 654-663.
(9) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191-1224.
(10) Oliveros, E.; Rivie`re, M.; Lattes, A. Org. Magn. Reson. 1976, 8,
601-606.
(1) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; J ohn Wiley & Sons: New York, 1994.
(2) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307-1370.
(3) Henbest, S. W.; Wilson, R. A. L. J . Chem. Soc. 1957, 1968-1965.
(4) Aube´, J . Chem. Soc. Rev. 1997, 26, 269-277.
(5) (a) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703-
5742. (b) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919-934.
(6) (a) Lattes, A.; Oliveros, E.; Rivie`re, M.; Belzecki, C.; Mostowicz,
D.; Abramskj, W.; Piccinni-Leopardi, C.; Germain, G.; Van Meerssche,
M. J . Am. Chem. Soc. 1982, 104, 3929-3934. (b) Aube´, J .; Wang, Y.;
Hammond, M.; Tanol, M.; Takusagawa, F.; Vander Velde, D. J . Am.
Chem. Soc. 1990, 112, 4879-4891.
10.1021/jo991928g CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/02/2000

Stereochemistry of the Oxidation of Imines
J . Org. Chem., Vol. 65, No. 17, 2000 5121
Sch em e 2
Sch em e 4
Sch em e 3
the R-hydroxylated imine preferentially soaks up oxidiz-
ing agent in the presence of its less hindered, non-
hydroxylated precursor. This can be taken as circum-
stantial evidence for rate acceleration present in the
R-hydroxylated imine, which is one hallmark of delivery
of oxidizing agent.
To examine these effects systematically, a series of
ketones 1a ,b and 2a ,b were synthesized and the oxida-
tion stereochemistry of their derived imines examined.
We expected that each imine would exist predominantly
as a single chairlike conformation anchored by the 4-tert-
butyl substituent. The 2-methyl group was considered
necessary (1) to prevent enamine-mediated epimerization
of the derived imines and (2) to keep adjacent ketone and
hydroxyl groups from scrambling through a common enol.
Similar approaches have been used successfully in study-
ing steric and electronic effects in reactions of alkenes11
and ketones.12
addition of oxygen onto a conformation of imine bearing
the methoxy group in an axial position, followed by
equilibrium to the more stable oxaziridine containing an
equatorial nitrogen group.10 A possible electronic contri-
bution to the stereoselectivity was suggested by the fact
that although a series of R-substituted cyclic imines all
afforded the major stereoisomer as shown in Scheme 2,
there was a marked dependence of product ratio on the
nature of the resident substituent (Me, 1.2:1; Ph, 3.3:1,
OMe, >10:1; only the last example is shown in Scheme
2). In light of Cornforth and Felkin-Ahn considerations
that suggest that nucleophilic addition to carbonyls
occurs anti to such polar groups, the possibility of a
hitherto unobserved axial addition had to be considered
as well. However, the conformational mobility of the
product in this case did not permit us to distinguish
between these possibilities. In another study, cyclic
imines containing a 2-NHBoc substituent also appeared
to prefer attack of the oxidant anti to the polar substitu-
ent, but these results were complicated by issues of
double diastereoselectivity thus prohibiting firm mecha-
nistic conclusions.8
An additional observation bearing on the possibility of
hydroxyl group delivery is presented in Scheme 3.7 In
this interesting double oxidation reaction, the enamine
form stabilized by an adjacent carboalkoxy or phenyl
group undergoes initial oxidation and then opens to
reveal a new imine moiety. With less electrophilic oxidiz-
ing agents, such as monoperoxyphthalate, the amount
of simple imine oxidation product observed relative to the
hydroxylated ketone is diminished. The relevant observa-
tion is that in no case was any of the ketone resulting
from enamine oxidation without subsequent oxaziridina-
tion observed. Indeed, the results seem to indicate that
P r ep a r a tion of Keton es 1 a n d 2. The requisite
ketones were prepared as shown in Scheme 4. Thus,
4-tert-butyl-2-methylcyclohexanone13 was treated with
hexamethyldisilazane and trimethylsilyl iodide in pen-
tane to form the thermodynamically equilibrated enol
ether, which was then oxidized with m-CPBA.14 The
resulting epoxide was reacted with n-tetrabutylammo-
nium fluoride to generate R-hydroxycyclohexanones 1a ,b,
which were readily separated by flash column chroma-
tography. The overall yield of each ketone was about 27%.
The assignments of stereochemical structures for iso-
mers 1a ,b were based on proton NMR analysis. Because
of deshielding by the axial hydroxyl group in isomer 1b,
the axial C-6 proton was shifted downfield to 2.82 ppm,
(11) (a) Vedejs, E.; Dent, W. H., III. J . Am. Chem. Soc. 1989, 111,
6861-6862. (b) Vedejs, E.; Dent, W. H., III.; Kendall, J . T.; Oliver, P.
A. J . Am. Chem. Soc. 1996, 118, 3556-3567.
(12) Paquette, L. A.; Stepanian, M.; Mallavadhani, U. V.; Cutarelli,
T. D.; Lowinger, T. B.; Klemeyer, H. J . J . Org. Chem. 1996, 61, 7492-
7507.
(13) Stork, G.; Darling, S. D. J . Am. Chem. Soc. 1964, 86, 1761-
1768.
(14) Miller, R. D.; McKean, D. R. Synthesis 1979, 730-731.

5122 J . Org. Chem., Vol. 65, No. 17, 2000
Wang et al.
Ta ble 1. 1H NMR Com p a r ison of Keton es 1a a n d 1b
oxaziridine nitrogen can be determined from the chemical
shift of a proton having a 1,3-diaxial/syn relationship to
the nitrogen substituent (Figure 1).15 We therefore
prepared the four analogues containing N-(diphenyl)-
methyl substituents (Table 2, even-numbered entries),
with the expectation that the axial C-7 proton in such
oxaziridines with an axial nitrogen substituent would
appear at unusually high field in the 1H NMR spectrum.
axial C-4 proton
axial C-6 proton
isomer
δ (ppm)
J
vic (Hz)
δ (ppm)
J vic (Hz)
Comparison of the ratios of N-benzyl vs N-diphenyl-
methyl oxaziridines obtained from a given ketone indi-
cates that the stereochemical course is similar in each
series. Comparison of spectral data then allowed the
assignment of stereoisomers for each set of products.
Thus, three compounds exhibited a strong upfield shift
of the C-7 proton in the N-diphenylmethyl series when
compared to the N-benzyl compounds, indicating that the
nitrogen group of the oxaziridine in these compounds
occupies an axial position. The assignments of the upfield
proton as the axial C-7 proton were based on coupling
pattern analysis. For example, the upfield proton in
oxaziridine 6eq showed a clear quartet of doublets that
resulted from three large couplings (two vicinal and one
geminal) and one small coupling, consistent with only the
axial C-7 proton. Accordingly, 6eq, 8eq, and 10eq were
assigned as arising from equatorial attack by the peracid
oxidant. In contrast, both N-diphenylmethyl oxaziridines
that did not show an upfield C-7 axial proton displayed
upfield shifts of the methoxy protons on the C-4 (qua-
ternary) stereocenter (see 6a x and 12a x in Table 4). This
can be ascribed to shielding by one of the phenyl groups
attached to equatorial nitrogen as illustrated in the
minimized (MM2) conformer depicted in Figure 2 and is
absent in the products containing an axial (trans-
disposed) nitrogen.
Discu ssion of Ster eoselectivity. Three consider-
ations could factor into the selectivity of these imine
oxidation reactions: (1) equatorial vs axial attack, of
which the former is usually favored in the absence of
additional effects,10 (2) the syn-directing effect of the
hydroxy group through hydrogen bonding, or (3) attack
anti to an electron-withdrawing substituent. As in previ-
ous studies using 2-substituted-4-cyclohexanone deriva-
tives,11,12 it is assumed that the central ring persists in
a well-behaved chair conformation throughout the reac-
tion coordinate. This supposition is supported by NMR
measurements, which are consistent with such a confor-
mation for both starting ketones and oxaziridine prod-
ucts. As noted in the Introduction, neither oxidant
delivery nor polar directing effects have been previously
demonstrated in imine oxidation reactions.
1a
1b
1.60
1.79
tt, 12.6, 2.8
tt, 12.6, 3.5
2.54
2.82
td, 1.40, 6.0
td, 13.8, 6.4
as was the axial C-4 proton to 1.79 ppm (Table 1). The
axial C-6 and C-4 protons were assigned according to
their coupling patterns. These assignments were con-
firmed by an X-ray crystallographic study of ketone 1b.
Attempts to directly methylate these hydroxyl groups
were unsuccessful, so ketones 1a ,b were separately
subjected to Wittig reaction followed by methylation and
ozonolysis. In this way, ketones 2a and 2b were obtained
in 34% and 37% overall yield, respectively. The stereo-
structures of isomers 2a ,b were deduced from those of
ketones 1a ,b.
Syn th esis of Oxa zir id in es a n d Str u ctu r e Deter -
m in a tion . The next stage of the project was to prepare
imines from ketones 1 and 2 and determine the face
selectivities of their oxidation reactions (Table 2). Ben-
zylamine 3 and diphenylmethylamine 4 were chosen as
amine components for the initial condensation reaction.
The usual method for oxaziridine synthesis was used: the
crude imine solutions were added dropwise to a suspen-
sion of m-CPBA kept at -78 °C. The reactions were
complete within a few minutes and quenched by the
addition of sodium bisulfite to the mixture at low tem-
peratures. The yields of the reactions were generally
middling compared to previously reported examples.
However, none of these examples were subjected to
extensive optimization, inasmuch as some erosion of
efficiency was expected in light of the highly hindered
substrates. The product ratios were deduced from the
1
crude H NMR spectra of the reactions, but most of the
oxaziridines were separable and their structures ana-
lyzed as pure materials.
Whereas the relative stereochemistry of the methyl,
hydroxyl, and methoxy groups in the oxaziridines could
be inferred from their precursor ketones, the relationship
between the more highly substituted C-4 carbon and the
nitrogen alkyl group was much more difficult to assess.
All of the oxaziridines were presumed to have a trans
relationship between the (nonepimerizable4) nitrogen
substituent and the more highly substituted C-position
on the basis of literature precedence (C-4, see Tables 2
and 3).6-8 In addition, this was confirmed in several cases
by nuclear Overhauser effect (NOE) studies. Thus, ir-
radiation of the benzylic protons in 5a , 7eq, and 11eq +
11a x (studied as an inseparable mixture) resulted in
enhancement of the signal corresponding to one of the
C-8 protons (Table 3). These signals were assigned to the
equatorial C-8 proton as a result of coupling with its
geminal axial proton (one large coupling) and its adjacent
C-7 protons (two small couplings).
The mechanism of the oxaziridine formation is gener-
ally considered a nucleophilic, Baeyer-Villiger type of
process rather than concerted oxygen transfer (Figure 3).
Much circumstantial evidence supports the former: (1)
the reaction being stereoselective but nonstereospecific
inasmuch as imine geometry is not reflected in the
product oxaziridines;16-18 (2) the preferential oxidation
of imines in the presence of olefins at low tempera-
tures,19,20 which is more consistent with the electron-poor
Initially, we prepared only the N-benzyl series of
oxaziridines (Table 2, odd-numbered entries) in the hope
that we would be able to assign the stereostructures
through NOE or X-ray techniques. Although these efforts
did not succeed, previous work in this laboratory has
shown that the axial or equatorial disposition of an
(15) Usuki, Y.; Wang, Y.; Aube´, J . J . Org. Chem. 1995, 60, 8028-
8035.
(16) Boyd, D. R.; Neill, D. C.; Watson, C. G.; J ennings, W. B. J .
Chem. Soc., Perkin Trans. 2 1975, 1813-1818.
(17) Belzecki, C.; Mostowicz, C. J . Org. Chem. 1975, 40, 3878-3880.
(18) Aube´, J .; Wang, Y.; Hammond, M.; Tanol, M.; Takusagawa, F.;
Vander Velde, D. J . Am. Chem. Soc. 1990, 112, 4879-4891.

Stereochemistry of the Oxidation of Imines
J . Org. Chem., Vol. 65, No. 17, 2000 5123
Ta ble 2. F a ce Selectivity of Im in e Oxid a tion Rea ction s
entry
ketone
amine
R1
R2
R3
product(s)
eq:ax ratioa
yield (%)
1
2
3
4
5
6
7
8
1a
1a
1b
1b
2a
2a
2b
2b
3
4
3
4
3
4
3
4
OH
OH
Me
Me
H
Ph
H
Ph
H
Ph
H
Ph
5a + 5b
50:50
39:61
>95:5
>95:5
>95:5
>95:5
17:83
<5:95
63
83
67
63
70
40
64
49
Me
6eq + 6a x
OH
OH
Me
Me
OMe
OMe
7eqb
Me
8eq
OMe
OMe
Me
9eqb
10eq
11eq + 11a xb,c
12a x
Me
a
b
Determined by 1H NMR examination of the crude reaction mixture. Structures assigned in analogy to the experiment summarized
in the succeeding entry. c Stereoisomers not separable by column chromatography.
Ta ble 3. NOE Resu lts fr om Selected Oxa zir id in es
A theoretical study also concluded that the two-step
mechanism was more reasonable.23 A detailed analysis
of the kinetics of the oxidation reaction also supported
the two-stage mechanism and additionally indicated that
the initial addition step to the imine (or the protonated
form) is generally rate-limiting.22
In this scenario, the equatorial/axial selectivity of
oxidant delivery is established in the first step of the
mechanism, with configuration of the stereogenic nitro-
gen resulting from the minimization of nonbonded in-
teractions in the second. Since the initial step is rate-
limiting, the oxaziridine ratios reflect the equatorial/axial
ratios of this first step. The intrinsic kinetic selectivity
for imine oxidations in similar systems is for equatorial
addition of oxidant, resulting in an oxaziridine bearing
an axial nitrogen substituent (Figure 4a). In conforma-
tionally mobile systems, these products typically undergo
a ring flip to place the oxaziridine nitrogen in the more
stable equatorial position. In simple systems, the ratios
of equatorial/axial oxidation are generally quite high
(>10:1).18 Inspection of the results herein indicate that
the preference for equatorial addition selectivity has been
substantially undermined in half of the examples shown
in Table 2.
eq C-8 protona
entry
oxaziridine
5a
7eq
11eq + 11a x
R1
R2
δ (ppm) coupling data
1
2
3
OH
Me
Me
Me
OH
OMe
1.95
1.80
1.84
dt (15, 3 Hz)
dt (16, 3 Hz)
dt (15, 5 Hz)
a
Revealed through irradiation of the N-benzylic protons and
assigned from coupling and chemical shift data.
Accordingly, it appears that the hydrogen-bond-donat-
ing hydroxyl group is able to direct oxaziridination in
much the same manner as is well-known for epoxidation
reactions (Figure 4b). Although this syn-directing effect
is not strong enough to completely bias addition into the
axial direction for substrates containing an equatorially
disposed hydroxyl group, it has become competitive with
the sterically preferred addition from the equatorial
direction (Table 2, entries 1 and 2). As expected, when
the 2-hydroxyl group is itself in an axial orientation, high
equatorial addition selectivity is once again observed
(Table 2, entries 3 and 4).
F igu r e 1. Comparison of chemical shifts in (a) N-benzyl and
(b) N-diphenylmethyl oxaziridines derived from 4-substituted
ketones (R ) Me, t-Bu, Ph).15
imine acting as an electrophile rather than a nucleophile;
(3) the formation of oxaziridine in lieu of the isomeric
nitrone, which might reasonably be expected to predomi-
nate via nucleophilic attack of the imine lone pair on an
electrophilic oxidizing agent (although some exceptions
are known in special cases21); and (4) solvent effects.16,22
When the alcohol is converted into an ether substitu-
ent, the C-2 substituent exerts the opposite directing
effect (Figure 4c). In this case, however, the anti-directing
(21) Boyd, D. R.; Coulter, P. B.; McGuckin, M. R.; Sharma, N. D.;
J ennings, W. B.; Wilson, V. E. J . Chem. Soc., Perkin Trans. 1 1990,
301-306.
(22) (a) Ogata, Y.; Sawaki, Y. J . Am. Chem. Soc. 1973, 95, 4687-
4692. (b) Ogata, Y.; Sawaki, Y. J . Am. Chem. Soc. 1973, 95, 4692-
4698.
(19) Aube´, J .; Peng, X.; Wang, Y.; Takusagawa, F. J . Am. Chem.
Soc. 1992, 114, 5466-5467.
(20) Aube´, J .; Ghosh, S.; Tanol, M. J . Am. Chem. Soc. 1994, 116,
9009-9018.
(23) Azman, A.; Koller, J .; Plesnicar, B. J . Am. Chem. Soc. 1979,
101, 1107-1109.

5124 J . Org. Chem., Vol. 65, No. 17, 2000
Ta ble 4. Selected 1H NMR Da ta of Oxa zir id in es
Wang et al.
N-benzyl series (R3 ) H)
N-diphenylmethyl series (R3 ) Ph)
R1
R2
oxaziridine
δ, ax H-7 proton
δ, R2 substituent
oxaziridine
δ, ax H-7 proton
δ, R2 substituent
OH
OH
Me
OMe
Me
Me
Me
OH
Me
OMe
OMe
5a a
g0.70
g0.70
g0.70
g0.70
g0.70
g0.70
1.27
1.17
1.12
1.25
3.06
3.08
6eq
6a x
8eq
10eq
12eq
12a x
0.08
g0.70
0.18
1.23
0.96
1.24
1.25
5ba
7eq
9eq
0.21
11eqb
11a xb
ndc
Me
g0.70
2.63
a
b
Stereostructure not assigned. Stereoisomers not separable by column chromatography. c Not detected.
F igu r e 2. Proposed conformation of oxaziridine 12a x. In this
depiction, the N-diphenylmethyl substituent extends in back
of the plane of the oxaziridine ring.
F igu r e 4. Proposed transitions structures for oxaziridination
reactions. Although an initial proton transfer prior to attack
by the peracid is shown (and has been previously proposed,
as noted in the text), this step is not required by the data.
oxidations, the peracid acts as the nucleophile in these
cases rather than as an electrophile. Finally, these effects
are potent enough to surmount the normal tendency of
imine oxidation reactions to occur via equatorial attack.
These results should prove useful in the design of
asymmetric oxaziridine syntheses, of which no efficient
cases are currently known.24
F igu r e 3. Possible mechanisms for imine oxidation reactions.
effect is able to surmount the substrate’s natural prefer-
ence for equatorial attack to the extent of g5:1 in favor
of axial addition for imines containing a C-2 methoxy
group in the axial position (Table 2, entries 7 and 8).
Again, attack anti to a C-2 methoxy group in an equato-
rial position results in equatorial addition because both
directing effects are additive.
Su m m a r y. Evidence for two previously unobserved
modes of attack of nucleophilic addition of an oxidant to
imines has been obtained in a conformationally fixed
cyclic system. The stereochemical determinations were
carried out using NMR techniques previously developed
in these labs. 2-Hydroxylated imines undergo competitive
delivery of the oxidant to afford products unusually
enriched in the syn adduct. Although the results are
related to those obtained in Henbest-styled alkene ep-
Exp er im en ta l Section
Gen er a l m eth od s have been published.7d
4-(1,1-Dim et h ylet h yl)-2-h yd r oxy-2-m et h ylcycloh ex-
a n on e (1). 2-Methyl-4-tert-butylcyclohexanone (7.50 g, 47.5
mmol)13 was dissolved in pentane (250 mL) and cooled to 0 °C
under argon. Hexamethyldisilazane (12.0 mL, 57.1 mmol) was
(24) Davis, F. A.; J enkins, R. H., J r. In Asymmetric Synthesis;
Morrison, J . D., Scott, J . W., Eds.; Academic Press: Orlando, 1984;
Vol. 4, pp 313-353.

Stereochemistry of the Oxidation of Imines
J . Org. Chem., Vol. 65, No. 17, 2000 5125
added slowly, followed by iodotrimethylsilane (6.40 mL, 47.5
mmol). The reaction mixture was stirred at 0 °C for 10 min
and then kept at room temperature for 2 h. It was washed
with saturated NaHCO3 and dried with MgSO4. The organic
solution was concentrated and added to a solution of m-CPBA
(9.90 g, 57.1 mmol) in dichloromethane (150 mL) at -78 °C.
The reaction mixture was stirred at -78 °C for 10 min and
then at room temperature for 30 min before it was quenched
with 10% aqueous Na2S2O3. It was extracted with dichlo-
romethane, washed with saturated NaHCO3, and dried with
MgSO4. After the organic solvent was removed, the oily residue
was added to 100 mL of 1.0 N n-tetrabutylammonium fluoride
in hexane and stirred overnight. Standard aqueous workup
and separation by column chromatography (5% ethyl acetate/
hexane) afforded two known11 isomers, respectively. Isomer
1a [(2S*,4S*)-1] (Rf ) 0.40, 15% ethyl acetate/hexane): 2.30
g, 28%; isomer 1b [(2R*,4S*)-1] (Rf ) 0.33, 15% ethyl acetate/
hexane): 2.42 g, 29%. 1a : crystallization in diethyl ether at
-20 to -24 °C afforded isomer 1a as colorless crystals, mp
51-52 °C: IR (CDCl3) 3493, 2962, 1711 cm-1; 1H NMR (CDCl3,
400 MHz) δ 0.85 (s, 9H), 1.36 (s, 3H), 1.38-1.46 (m, 2H), 1.56
(tt, J ) 12.5, 2.8 Hz, 1H, C4 axial H), 2.06-2.19 (m, 2H), 2.42
(m, 1H), 2.50 (td, J ) 14.2, 6.1 Hz, 1H), 3.91 (br s, 1H, -OH);
13C NMR (CDCl3, 75.4 MHz) δ 25.8, 27.6, 28.8, 32.3, 36.9, 43.2,
44.7, 76.0, 214.7; HRMS calcd for C12H22O2 198.1620, found
198.1607; MS m/e 185 (M+ + 1), 167 (100), 141. Anal. Calcd
for C11H20O2: C, 71.70; H, 10.94. Found: C, 71.34; H, 10.80.
1b: colorless crystals, mp 80-81 °C; IR (CDCl3) 3493, 2962,
22.4, 24.4, 27.3, 28.3, 31.4, 32.7, 33.2, 37.5, 45.2, 49.3, 77.9,
106.0, 151.0; MS m/e 197 (M+ + 1), 165 (100), 149, 109, 95.
This compound was used without further purification.
(1R*,5S*)-5-(1,1-Dim eth yleth yl)-1-m eth oxy-1-m eth yl-2-
m eth ylen e-cycloh exa n e was prepared from (1S*,5S*)-5-(1,1-
dimethylethyl)-1-methyl-2-methylenecyclohexanol as described
for the preceding compound (oil, 0.540 g, 84%): IR (CDCl3)
1
2948, 1366 cm-1; H NMR (CDCl3, 300 MHz) δ 0.84 (s, 9H),
0.85-1.21 (m, 2H), 1.25 (s, 3H), 1.65 (m, 1H), 1.83 (m, 1H),
1.91 (m, 1H), 2.15 (m, 1H), 3.04 (s, 3H), 4.80 (s 1H), 4.91 (s,
1H); 13C NMR (CDCl3, 75.4 MHz) δ 21.4, 27.3, 28.6, 31.8, 32.6,
41.6, 41.7, 49.2, 76.0, 109.6, 150.8; MS m/e 197 (M+ + 1), 165
(100), 109. This compound was used without further purifica-
tion.
(2S*,4S*)-4-(1,1-Dim eth yleth yl)-2-m eth oxy-2-m eth ylcy-
cloh exa n on e (2a ). (1S*,5S*)-5-(1,1-Dimethylethyl)-1-meth-
oxy-1-methyl-2-methylenecyclohexane (0.340 g, 1.7 mmol) was
dissolved in 15 mL of a mixture of methanol and dichlo-
romethane (2:1) at -78 °C. Ozone was passed through the
solution until the deep blue color persisted. The reaction was
quenched by addition of dimethyl sulfide (2 mL). Concentration
and purification by column chromatography (5% ethyl acetate/
hexane) of the reaction mixture afforded the title compound
as a colorless oil (0.341 g, 99%): IR (CDCl3) 2957, 1718 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 0.89 (s, 9H), 1.40 (s, 3H), 1.36-
1.48 (m, 1H), 1.58 (tt, J ) 12.0, 2.9 Hz, 1H, C4 axial H), 1.70
(t, J ) 12.3 Hz, 1H), 1.91-2.05 (m, 2H), 2.32-2.49 (m, 2H),
3.33 (s, 3H); 13C NMR (CDCl3, 75.4 MHz) δ 22.4, 27.4, 27.5,
32.2, 38.7, 38.8, 44.3, 51.2, 81.1, 212.5; MS m/e 199 (M+ + 1),
167 (100), 149; HRMS calcd for C12H22O2 (M + H) 198.1620,
found 198.1607.
1
2872, 1711 cm-1; H NMR (CDCl3, 400 MHz) δ 0.86 (s, 9H),
1.27 (s, 3H), 1.36-1.50 (m, 2H), 1.78 (tt, J ) 12.6, 3.4 Hz, 1H,
C4 axial H), 1.96-2.09 (m, 2H), 2.31 (dq, J ) 14.0, 3.2 Hz,
1H), 2.74-2.85 (m, 1H); 13C NMR (CDCl3, 75.4 MHz) δ 24.9,
27.2, 27.3, 31.8, 36.6, 41.4, 41.6, 74.9, 213.9; MS m/e 185 (M+
+ 1), 167, 141 (100). Anal. Calcd for C11H20O2: C, 71.70; H,
10.94. Found: C, 71.68; H, 10.71.
(2R*,4S*)-4-(1,1-Dim et h ylet h yl)-2-m et h oxy-2-m et h yl-
cycloh exan on e (2b). (1R*,5S*)-5-(1,1-Dimethylethyl)-1-meth-
oxy-1-methyl-2-methylenecyclohexane (0.210 g, 1.1 mmol) was
reacted as described for the preceding compound to afford a
1
(1S*,5S*)-5-(1,1-Dim et h ylet h yl)-1-m et h yl-2-m et h yle-
n ecycloh exan ol. Methyltriphenyl phosphonium bromide (9.66
g, 26.5 mmol) and potassium tert-butoxide (3.02 g, 25.6 mmol)
in THF (30 mL) were allowed to reflux for 30 min. Ketone 1a
(1.57 g, 9.0 mmol) was added, and the reaction mixture was
allowed to reflux for 10 min. Standard aqueous workup and
purification by column chromatography (5% ethyl acetate/
hexane) gave the title product (1.47 g, 95%): IR (CDCl3) 3595,
colorless oil (0.189 g, 89%): IR (CDCl3) 2934, 1715 cm-1; H
NMR (CDCl3, 300 MHz) δ 0.83 (s, 9H), 1.13 (s, 3H), 1.15-
1.39 (m, 2H), 1.89 (tt, J ) 12.4, 3.3 Hz, 1H, C4 axial H), 1.96-
2.23 (m, 3H), 2.65-2.76 (m, 2H), 3.08 (s, 3H); 13C NMR (CDCl3,
75.4 MHz) δ 17.8, 27.3, 28.6, 31.7, 37.9, 40.8, 41.8, 50.7, 79.9,
213.8; MS m/e 199 (M+ + 1, 100), 167, 141, 84; HRMS calcd
for C12H22O2 (M + H) 198.1620, found 198.1626.
Gen er a l P r oced u r e for Oxa zir id in e Syn th esis. A solu-
tion of ketone (1.0 equiv) and amine (1.2-1.5 equiv) in toluene
was allowed to reflux for 5-7 h in a round-bottom flask that
was equipped with a condenser connected via a Dean-Stark
trap. The solution was then cooled to room temperature and
added dropwise to a suspension of m-CPBA (1.2 equiv) in CH2-
Cl2 kept at -78 °C (dry ice/acetone bath). The oxidation
reaction was usually completed within 20 min (TLC analysis)
and quenched with saturated Na2S2O4 at low temperature. The
reaction mixture was poured into a separation funnel and
partitioned between saturated Na2S2O4 and diethyl ether. The
organic layer was washed with saturated NaHCO3 and brine
and dried with Na2SO4. Products were isolated by concentra-
tion followed by column chromatography (1:9 ethyl acetate/
hexane).
1
2953, 1646 cm-1; H NMR (CDCl3, 300 MHz) δ 0.85 (s, 9H),
0.95-1.34 (m, 3H), 1.32 (s, 3H), 1.64-1.71 (br s, 1H), 1.78-
1.91 (m, 2H), 2.05-2.17 (m, 1H), 2.32-2.41 (m, 1H), 4.69 (d,
J ) 1.7 Hz, 1H), 4.96 (d, J ) 1.7 Hz, 1H); 13C NMR (CDCl3,
75.4 MHz) δ 26.8, 27.3, 28.6, 32.0, 33.2, 43.9, 45.8, 73.9, 104.2,
155.4; MS m/e 182 (M+), 165 (100, M+ - OH), 109. This
compound was used without further purification.
(1R*,5S*)-5-(1,1-Dim et h ylet h yl)-1-m et h yl-2-m et h yle-
n ecycloh exa n ol was prepared as described for the preceding
compound (1.60 g, 90%): 1H NMR (CDCl3, 300 MHz) δ 0.85
(s, 9H), 0.95-1.15 (m, 2H), 1.47 (s, 3H), 1.63 (tt, J ) 12.4, 3.2
Hz, 1H, C5 axial H), 1.81-1.91 (m, 2H), 2.21 (dt, J ) 13.3, 3.1
Hz, 1H), 2.45 (m, 1H), 4.74 (s, 1H), 4.84 (s, 1H); 13C NMR
(CDCl3, 75.4 MHz) δ 27.3, 27.9, 28.6, 31.8, 32.3, 41.6, 42.5,
71.4, 106.6, 153.2; MS m/e 182 (M+), 165 (100, M+ - OH), 149,
125, 109, 95. This compound was used without further
purification.
[2S*,3S*,4S*,6S*]-6-(1,1-Dim et h ylet h yl)-4-h yd r oxy-4-
m eth yl-2-(ph en ylm eth yl)-1-oxa-2-azaspir o[2.5]octan e an d
[2R*,3R*,4S*,6S*]-6-(1,1-Dim eth yleth yl)-4-h ydr oxy-4-m eth -
yl-2-(p h en ylm eth yl)-1-oxa -2-a za sp ir o[2.5]octa n e (5a a n d
5b). According to the general procedure, ketone 1a (0.423 g,
2.4 mmol) afforded two oxaziridines in a combined 63% yield
isomers (1:1 ratio determined by 1H NMR of the crude
mixture). The isomer with high Rf value is designated as 5a ,
and the low Rf value isomer is assigned as 5b. 5a : Rf ) 0.48,
10% ethyl acetate/hexane, colorless oil; IR (CDCl3) 3477, 2960
(1S*,5S*)-5-(1,1-Dim eth yleth yl)-1-m eth oxy-1-m eth yl-2-
m eth ylen e- cycloh exa n e. (1S*,5S*)-5-(1,1-Dimethylethyl)-
1-methyl-2-methylenecyclohexanol (0.810 g, 4.5 mmol) was
added to 60% NaH (0.23 g, 5.9 mmol) in THF (15 mL), and
the reaction mixture was allowed to reflux for 1 h. The reaction
mixture was cooled to room temperature, iodomethane (1.14
g, 8.00 mmol) added, and the reaction mixture was stirred at
room temperature for 3 h. It was worked up by addition of
hexane (10 mL) and filtration through a pad of Celite. The
filtrate was concentrated and purified by column chromatog-
raphy (4% ethyl acetate/hexane) to afford the title product as
cm-1 1H NMR (CDCl3, 300 MHz) δ 0.76 (s, 9H), 0.81-0.95
;
(m, 2H), 1.11 (t, J ) 12.8 Hz, 1H), 1.27 (s, 3H), 1.75-1.80 (m,
1H), 1.89-1.99 (m, 2H), 2.12 (td, J ) 14.2, 4.4 Hz, 1H), 3.25
(s, 1H), 4.03 (AB q, J ) 14.2 Hz, ∆v ) 42.9 Hz, 2H), 7.21-
7.42 (m, 5H); 13C NMR (CDCl3, 75.4 MHz) δ 21.7, 24.0, 25.1,
27.2, 31.9, 41.8, 44.3, 56.9, 69.8, 87.2, 127.9, 128.6, 128.8, 136.1;
1
an oil (0.610 g, 75%): IR (CDCl3) 2952, 1368 cm-1; H NMR
(CDCl3, 300 MHz) δ 0.84 (s, 9H), 0.89-1.19 (m, 2H), 1.28 (s,
3H), 1.75 (m, 2H), 2.12 (m, 1H), 2.34 (m, 1H), 3.28 (s, 3H),
4.72 (s, 1H), 4.89 (s, 1H); 13C NMR (CDCl3, 75.4 MHz) δ 13.8,
MS m/e 290 (M+), 246, 168, 106 (100); HRMS calcd for C18H28
-
NO2 (M + H) 290.2120, found 290.2126. 5b: Rf ) 0.35, 10%

5126 J . Org. Chem., Vol. 65, No. 17, 2000
Wang et al.
ethyl acetate/hexane, colorless oil; IR (CDCl3) 3533, 2959 cm-1
;
3.99 (AB q, J ) 14.3 Hz, ∆v ) 12.8 Hz, 2H), 7.25-7.47 (m,
5H); 13C NMR (CDCl3, 50.3 MHz) δ 18.6, 24.5, 25.1, 27.2, 27.4,
32.1, 37.6, 43.6, 51.2, 57.4, 74.6, 88.6, 127.5, 128.6, 128.6, 137.1;
MS m/e 304 (M+ + 1, 100), 288; HRMS calcd for C19H29NO2 +
Na (M) 326.2096, found 326.2091.
1H NMR (CDCl3, 300 MHz) δ 0.87 (s, 9H), 1.18 (s, 3H), 1.25-
1.41 (m, 3H), 1.81-2.05 (m, 4H), 2.56 (s, 1H), 4.03 (AB q, J )
13.7 Hz, ∆v ) 64.3 Hz, 2H), 7.29-7.42 (m, 5H); 13C NMR
(CDCl3, 75.4 MHz) δ 23.8, 24.7, 25.1, 27.2, 32.0, 39.1, 44.1,
56.8, 69.6, 87.1, 127.9, 128.7, 128.9, 135.9; MS. m/e 290 (M+),
246, 168, 106 (100); HRMS calcd for C18H28NO2 (M + H)
290.2120, found 290.2128.
[2S*,3S*,4S*,6S*]-6-(1,1-Dim et h ylet h yl)-4-m et h oxy-4-
m e t h y l-2-(d i p h e n y lm e t h y l)-1-o x a -2-a z a s p i r o [2.5]-
octa n e (10eq). According to the general procedure, ketone 2a
afforded the title compound as a solid (0.88 g, 40%, a single
isomer as determined by 1H NMR of the crude reaction
[2R*,3R*,4S*,6S*]-6-(1,1-Dim et h ylet h yl)-4-h yd r oxy-4-
m e t h y l-2-(d i p h e n y lm e t h y l)-1-o x a -2-a z a s p i r o [2.5]-
octa n e (6a x) a n d [2S*,3S*,4S*,6S*]-6-(1,1-Dim eth yleth yl)-
4 -h y d r o x y -4 -m e t h y l -2 -(d i p h e n y l m e t h y l )-1 -o x a -2 -
azaspir o[2.5]octan e (6eq). According to the general procedure,
ketone 1a (0.190 g, 1.1 mmol) afforded the title compound as
an oil (0.330 g, 83%, 61:39 as determined by 1H NMR of the
mixture): mp 116-118 °C, IR (CDCl3) 2957, 1494 cm-1 1H
;
NMR (CDCl3, 400 MHz) δ 0.21 (m, 1H, axial C-7 proton), 0.58
(s, 9H), 1.16-1.21 (m, 2H), 1.26 (s, 3H), 1.39 (m, 1H), 1.64 (m,
1H), 1.92-1.98 (m, 2H), 3.36 (s, 3H), 4.62 (s, 1H), 7.12-7.55
(m, 10H); 13C NMR (CDCl3, 75.4 MHz) δ 19.0, 24.2, 25.4, 27.2,
32.0, 37.9, 43.3, 51.8, 70.2, 74.4, 89.6, 127.1, 127.2, 127.7, 128.4,
128.8, 140.2, 142.5; MS m/e 379 (M+), 349, 322, 167 (100);
HRMS calcd for C25H33NO2 379.2511, found 379.2506.
crude mixture). Mixtu r e: IR (CDCl3) 3521, 2959, 2889 cm-1
MS m/e 366 (M+ + 1, 100), 182, 167; HRMS calcd for C24H31
;
-
NO2 365.2355, found 365.2343. 6a x: 1H NMR (CDCl3, 400
MHz) δ 0.79 (s, 9H), 0.96 (s, 3H), 1.13-1.36 (m, 3H), 1.71-
2.11 (m, 4H), 2.69 (s, 1H), 4.81 (s, 1H), 7.21-7.49 (m, 10H);
13C NMR (CDCl3, 75.4 MHz) δ 22.0, 23.0, 24.6, 27.3, 32.0, 39.2,
44.0, 69.0, 69.7, 87.7, 127.0, 127.6, 128.2, 128.6, 138.7, 141.2.
6eq: 1H NMR (CDCl3, 400 MHz) δ 0.13 (qd, J ) 13.2, 3.6 Hz,
1H, axial C-7 proton), 0.53 (s, 9H), 1.23 (s, 3H), 3.49 (s, 1H),
4.69 (s, 1H), 7.21-7.49 (m, 10H); 13C NMR (CDCl3, 75.4 MHz)
δ 24.2, 27.1, 31.8, 41.2, 43.8, 69.6, 69.9, 87.7, 127.1, 127.3,
128.0, 128.3, 128.9, 139.1, 141.3.
[2R*,3R*,4R*,6S*]-6-(1,1-Dim eth yleth yl)-4-m eth oxy-4-
m e t h yl-2-(p h e n ylm e t h yl)-1-oxa -2-a za sp ir o[2.5]oct a n e
(11a x) a n d [2S*,3S*,4R*,6S*]-6-(1,1-Dim et h ylet h yl)-4-
m et h oxy-4-m et h yl-2-(p h en ylm et h yl)-1-oxa -2-a za sp ir o-
[2.5]octa n e (11eq). According to the general procedure,
ketone 2b (0.312 g, 1.7 mmol) afforded the title products (0.321
g, 64%) as an 83:17 mixture of isomers (1H NMR of the crude
reaction mixture). Mixtu r e: IR (CDCl3) 2953, 1462 cm-1; MS
m/e 304 (M+ + 1, 100), 272, 246, 197; HRMS calcd for C19H29
-
[2S*,3S*,4R*,6S*]-6-(1,1-Dim et h ylet h yl)-4-h yd r oxy-4-
m e t h yl-2-(p h e n ylm e t h yl)-1-oxa -2-a za sp ir o[2.5]oct a n e
(7eq). According to the general procedure, ketone 1b (0.533
g, 3.1 mmol) afforded a single isomer (1H NMR of crude
reaction mixture) as colorless solid (0.593 g, 67%): mp 86-87
NO2 (M + H) 304.2277, found 304.2277. 11a x: 1H NMR
(CDCl3, 400 MHz) δ 0.89 (s, 9H), 1.03 (s, 3H), 1.21 (m, 1H),
1.34 (qd, J ) 13.4, 3.7 Hz, 1H, C7 axial H), 1.59 (tt, J ) 12.5,
3.3 Hz, 1H), 1.87 (tt, J ) 13.9, 3.1 Hz, 1H), 1.98 (dt, J ) 12.8,
3.2 Hz, 1H), 2.27 (td, J ) 13.4, 4.3 Hz, 1H), 3.06 (s, 3H), 4.00
°C (CH3CN); IR (CDCl3) 2941, 1480 cm-1 1H NMR (CDCl3,
;
(AB q, J ) 14.5 Hz, ∆v ) 10.7 Hz, 2H), 7.25-7.47 (m, 5H); 13
C
400 MHz) δ 0.79 (s, 9H), 0.88 (m, 2H), 1.12 (s, 3H), 1.15 (t
(partially obscured), J ) 13.4 Hz, 1H, C5 axial H), 1.62 (tt, J
) 12.5, 3.4 Hz, 1H, C6 axial H), 1.53 (br d, 1H), 1.78-1.88 (m,
2H), 2.54 (td, J ) 13.8, 4.4 Hz, 1H), 4.04 (AB q, J ) 14.4 Hz,
∆v ) 62.4 Hz, 2H), 7.31-7.42 (m, 5H); 13C NMR (CDCl3, 50.3
MHz) δ 22.7, 23.6, 24.9, 27.2, 31.7, 39.3, 41.3, 57.3, 73.5, 87.0,
127.7, 128.4, 128.7, 136.9. Anal. Calcd for C18H27NO2: C, 74.70;
H, 9.40; N, 4.84. Found: C, 74.82; H, 9.49; N, 4.99.
NMR (CDCl3, 50.3 MHz) δ 16.8, 23.7, 25.2, 27.3, 31.8, 37.5,
40.9, 49.4, 56.8, 77.5, 85.1, 127.7, 128.7, 128.9, 136.9. 11eq:
1H NMR (CDCl3, 300 MHz, diagnostic peaks only) δ 0.77 (s,
9H), 1.06 (s, 3H), 3.21 (s, 3H); 13C NMR (CDCl3, 75.4 MHz,
diagnostic peaks only) δ 17.9, 23.1, 28.7, 86.5.
[2R*,3R*,4R*,6S*]-6-(1,1-Dim eth yleth yl)-4-m eth oxy-4-
m e t h y l-2-(d i p h e n y lm e t h y l)-1-o x a -2-a z a s p i r o [2.5]-
octa n e (12a x). According to the general procedure, ketone 2b
afforded the title product (0.198 g, 49%) as an oil (a single
isomer by 1H NMR of crude reaction mixture): IR (CDCl3)
[2S*,3S*,4R*,6S*]-6-(1,1-Dim et h ylet h yl)-4-h yd r oxy-4-
m e t h y l-2-(d i p h e n y lm e t h y l)-1-o x a -2-a z a s p i r o [2.5]-
octa n e (8eq). According to the general procedure, ketone 1b
afforded the title compound as an oil (0.230 g, 63%, a single
isomer, as determined by 1H NMR of the crude reaction
1
2954, 1462 cm-1; H NMR (CDCl3, 300 MHz) δ 0.78 (s, 9H),
1.05 (s, 3H) CH3), 1.15 (t, J ) 13.2, 1H), 1.25 (qd, J ) 12.9,
4.0 Hz, 1H), 1.48 (tt, J ) 12.5, 3.2 Hz,), 1.75 (dt, J ) 14.0, 3.0
Hz, 1H), 1.82-1.95 (m, 2H), 2.08 (td, J ) 13.0, 4.3 Hz,), 2.63
(s, 3H), 4.79 (s, 1H), 7.25-7.57 (m, 10H); 13C NMR (CDCl3,
50.3 MHz) δ 16.9, 24.2, 25.5, 27.4, 31.9, 38.1, 40.8, 49.2, 69.0,
76.6, 86.6, 127.0, 127.2, 127.9, 128.3, 128.4, 128.7, 139.0, 142.4;
MS m/e 279 (M+), 322, 167 (100); HRMS calcd for C25H33NO2
379.2511, found 379.2511.
1
mixture): IR (CDCl3) 3589, 2957 cm-1; H NMR (CDCl3, 400
MHz) δ 0.18 (qd, J ) 14.0, 3.6 Hz, 1H, axial C-7 proton), 0.63
(s, 9H), 1.02 (t, J ) 13.3 Hz, 1H), 1.24 (s, 3H), 1.43-1.58 (m,
2H), 1.75 (br s, 1H), 1.80-1.93 (m, 2H), 2.52 (td, J ) 14.3, 4.3
Hz, 1H), 4.71 (s, 1H), 7.21-7.59 (m, 10H); 13C NMR (CDCl3,
75.4 MHz) δ 23.1, 24.1, 24.5, 27.2, 31.6, 38.9, 40.8, 69.9, 87.3,
127.1, 127.1, 127.6, 127.7, 128.4, 128.8, 140.1, 142.3; MS m/e
365 (M+), 182, 167 (100), 84; HRMS calcd for C24H31NO2
365.2355, found 365.2343.
Ack n ow led gm en t. We thank the National Insti-
[2S*,3S*,4S*,6S*]-6-(1,1-Dim et h ylet h yl)-4-m et h oxy-4-
m e t h yl-2-(p h e n ylm e t h yl)-1-oxa -2-a za sp ir o[2.5]oct a n e
(9eq). According to the general procedure, ketone 2a (0.188
g, 1.0 mmol) afforded a single isomer (1H NMR of the crude
reaction mixture) as colorless oil (0.212 g, 70%): IR (CDCl3)
tutes of Health for support of this work.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR for
compounds 1a , 1b, 2a , 2b, 5a , 5b, 6eq + 6a x, 7eq, 8eq, 9eq,
10eq, 11eq + 11a x, and 12a x. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
2954, 1463 cm-1; H NMR (CDCl3, 400 MHz) δ 0.77 (s, 9H),
0.96 (m, 1H), 1.26 (s, 3H), 1.22-1.37(m, 3H), 1.72 (br d, 1H),
1.82 (d, J ) 11.9 Hz, 1H), 1.92-1.98 (m, 2H), 3.25 (s, 3H),
J O991928G