Highly stereoselective and efficient synthesis of functionalized cyclohexanes with multiple stereocenters

Article abstract of DOI:10.1002/1521-3765(20020603)8:11<2585::AID-CHEM2585>3.0.CO;2-C

Chiral 7-oxo-2-enimides 2, which were readily obtained through a silyloxy-Cope rearrangement of syn-aldol products 1, have proved to be versatile substrates for a one-step, highly efficient and stereoselective synthesis of functionalized cyclohexanes. Org

Full text of DOI:10.1002/1521-3765(20020603)8:11<2585::AID-CHEM2585>3.0.CO;2-C

FULL PAPER
Highly Stereoselective and Efficient Synthesis of Functionalized
Cyclohexanes with Multiple Stereocenters
Christoph Schneider* and Oliver Reese[a]
Dedicated to Professor Lutz F. Tietze on the occasion of his 60th birthday
Abstract: Chiral 7-oxo-2-enimides 2, which were readily obtained through a silyloxy-
Cope rearrangement of syn-aldol products 1, have proved to be versatile substrates
for a one-step, highly efficient and stereoselective synthesis of functionalized
cyclohexanes. Organocopper and organoaluminum reagents have been employed as
nucleophiles that underwent a conjugate addition to the enimide structure of the
Cope products. The enolates formed in situ attacked the aldehyde or iminium ion in
an intramolecular aldol or Mannich reaction, respectively, to directly yield cyclo-
hexanols 3 and 4 and cyclohexylamines 5, respectively, in moderate to good yields
and with excellent stereocontrol.
Keywords: aldol reaction
metric synthesis ¥ Cope rearrange-
¥ asym-
ment
bases
¥ cyclohexanes ¥ Mannich
polyene macrolide antibiotics. We subsequently discovered
that highly functionalized and enantiopure cyclohexanes may
be obtained in one step from the Cope products using
organocopper and organoaluminum reagents.[6] In this article,
we detail our observations on this powerful approach towards
the assembly of six-membered carbocycles with various
functional groups and substituents attached to the ring.
In the synthesis of tetrahydropyrans and piperidines using
the Cope products 2 as substrates, we took advantage of the
ideal distance between the carbonyl group at C-7 and the
conjugate double bond at C-2 of 2 to develop the following
two-step sequence towards the oxygen and nitrogen-based
heterocycles: 1) a chemoselective, nucleophilic addition to the
aldehyde moiety, and subsequently 2) an intramolecular
hetero-conjugate addition towards the conjugate double bond
of 2 (Figure 1, top). The latter reaction furnished either
stereoisomer at will, with high stereoselectivity depending on
the carboxylic acid derivative.[2]
Introduction
The thermal silyloxy-Cope rearrangement of aldol products 1
has been developed into a useful method in stereoselective
synthesis (Scheme 1). Convergent and asymmetric synthesis
of the substrates as well as good yields and excellent
stereocontrol for the rearrangement are notable features of
this process.[1]
R4
Me3SiO
R3
O
R1
R2
O
R4
O
a)
R1
N
H
N
R3
69-86%
O
O
O
O
R2
2
#
1
OSiMe3
COXc
R1
R2
R3
Scheme 1. The silyloxy-Cope rearrangement of aldol products 1. a) tol-
uene, 1808C, 1 2 h, then pTsOH ¥ H2O, rt, 15 min.
O
O
R
R
R
Furthermore, the Cope products 2 have proved to be
versatile substrates for the straightforward synthesis of
various complex organic structures, for example polyalkyl-
substituted tetrahydropyrans,[2] piperidines,[3] terpenols,[4] and
1,3,5,... polyol chains[5] commonly found in the antifungal
O
H
N
N
X
Xc
O
Nu
2
O
X = O, NR
Nu
Nu
O
O
O
R
R
[a] Priv.-Doz. Dr. C. Schneider, Dr. O. Reese
Institut f¸r Organische Chemie
H
Xc
OH
R
O
O
der Georg-August-Universit‰t Gˆttingen
Tammannstrasse 2, 37077 Gˆttingen (Germany)
Fax : (‡49)551-399660
2
Figure 1. The two cyclization modes of the 7-oxo-2-enimides 2 to yield six-
membered heterocycles (above) and carbocycles (below).
E-mail: cschnei1@gwdg.de
Chem. Eur. J. 2002, 8, No. 11
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0811-2585 $ 20.00+.50/0
2585

C. Schneider and O. Reese
FULL PAPER
R3
O
We wondered whether we were able to reverse the order of
addition and 1) add a nucleophile to the conjugate double
bond of 2, and subsequently 2) trap the resultant enolate in
situ with the aldehyde moiety at C-7 to close the ring
(Figure 1).
O
R1
O
tBu
R2
R1
R3M, Me2AlCl
Xc
OH
H
N
R2
THF, -78 to -40°C
O
O
2
3
#
R3M
+
Results and Discussion
Al
R3
O
O
Xc
O
R2
R1
H
N
There is a significant amount of precedence in the literature
for sequential Michael aldol reactions,[7] but most of the
work reported involves reactions with Michael acceptors and
aldehydes in two different substrates. This scenario has the
advantage that the conjugate addition step can be completed
before the aldehyde, an even more reactive electrophile, is
introduced into the reaction mixture. Relatively few reports,
however, dealt with true domino Michael aldol reactions in
which both functional groups are in the same molecule. For
example, N‰f et al.[8] reported cuprate additions to w-keto
enones, and Nozaki et al.[9] introduced dialkylaluminum
thiolates as powerful nucleophiles in reactions with w-oxo
enones and enoates.
Two selectivity issues were of concern to us. Firstly, we had
to make sure that the nucleophile predominantly added to the
conjugate double bond and left the aldehyde moiety mainly
untouched. Secondly, since a new stereogenic center is
generated, the stereoselectivity of the conjugate addition is
crucial to the success of the whole process. In preliminary
experiments, we discovered that the tert-leucine-derived
oxazolidinone with a tBu substituent served this purpose
much better than the standard benzyl-substituted oxazolidi-
none.[10] With regard to the reagent choice, we concentrated
on the use of cuprate and aluminum reagents in accordance
with the results of N‰f and Nozaki.
O
O
M
tBu
B
A
Scheme 2. Domino Michael aldol reaction of 7-oxo-2-enimides 2.
Table 1. Domino Michael aldol reactions of 7-oxo-2-enimides 2a d.[a]
Entry
Substrate
Product
R1
R2
R3
Yield [%]
1
2
3
4
5
6
7
2a
2b
2a
2a
2b
2c
2d
3a
3b
3c
3d
3e
3 f
3g
CH3
Ph
CH3
CH3
Ph
H
H
H
H
H
H
CH3
nBu[b]
nBu[b]
SEt[c]
SPh[c]
SPh[c]
SPh[c]
SPh[c]
41
42
57
77
65
61
59
SiMe2Ph
CH3
[a] The stereoselectivity of the reaction was estimated to be >95:5, since
no other stereoisomer was detected in the crude product by NMR. [b] A
Yamamoto-type cuprate (nBuCu-LiI) was employed as nucleophile.
[c] The Nozaki-type ate-complex (Me3Al-SRLi) was employed as nucleo-
phile.
cyclohexanol 3a, and only resulted in a decrease in yield.
Likewise, the cyclohexanol 3b with a phenyl-substituent at
C-5 was prepared from the 7-oxo-2-enimide 2b in 42% yield
with complete stereocontrol.
Although the yield of this domino process[12] was only
moderate at best, the stereoselectivity of the overall reaction
was surely remarkable considering the formation of two new
s-bonds and three new contiguous chiral centers. In accord-
ance with our previous observations on the conjugate
additions of organocuprates to enimides,[10] it is reasonable
to assume that the addition took place on the Al-chelated
imide complex A (Scheme 2); the lower face of the double
bond is shielded by the bulky tBu group that directs the
conjugate addition towards the upper side. A directly related
Al-chelate complex has been proposed by Evans et al. for the
Me2AlCl-mediated Diels Alder reaction of unsaturated N-
acyl oxazolidinones and was later confirmed experimentally
by Castellino et al.[13] The enolate formed subsequently
attacked the aldehyde in an intramolecular aldol reaction.
The homogenous syn-stereochemistry of the aldol structure
resulted from the intramolecular transposition of the metal
ion from the enolate oxygen to the aldehyde oxygen in
transition structure B, which was presumably essential for
aldehyde activation (Scheme 2).
We synthesized the 7-oxo-2-enimides 2a d as substrates
for the envisioned process in 69 86% yield as homogenous
stereoisomers after chromatographic purification by using the
silyloxy-Cope rearrangement of syn-aldols (Figure 2). Among
O
R
O
O
O
tBu
tBu
H
N
H
N
O
O
O
O
2a: R = CH3
2b: R = Ph
2d
2c: R = SiMe2Ph
Figure 2. 7-Oxo-2-enimides 2a d used as substrates for the domino
process.
the cuprate reagents tested in this study, the mono-organo-
cuprates (RCu-LiI) introduced by Yamamoto et al.[11] in
combination with the bidentate Lewis acid Me2AlCl turned
out to be the most satisfactory. Thus, reaction of 2a with three
equivalents of BuCu-LiI/Me2AlCl in THF at À78 !À 408C
gave rise to 41% of the desired cyclohexanol 3a as a single
stereoisomer (Scheme 2 and Table 1). The principal side
product (obtained in up to 20% yield) resulted from a double
nucleophilic addition of the cuprate reagent to the aldehyde
and the conjugate double bond. Lowering the number of
equivalents of cuprate did not increase the proportion of
The assignment of product configuration was based on the
homonuclear 1H NMR coupling constants of the cyclohexane
ring protons; the correct assignment of each signal was
ascertained by 1H 13C two-dimensional spectra. The coupling
constants J(1-H,2-H) ˆ 2.0 Hz and J(2-H,3-H) ˆ 11.5 Hz in
compound 3b were fully consistent with an equatorial
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Chem. Eur. J. 2002, 8, No. 11

Functionalized Cyclohexanes
2585 2594
position of the C-2- and C-3-substituents and the axial
orientation of the C-1 OH-group (Figure 3). The coupling
constants J(4-Hax,5-H) ˆ J(5-H,6-Hax) ˆ 13.0 Hz were both
indicative of the equatorial position of the C-5 phenyl group.
Since we had previously proven that full chirality transfer
within the sigmatropic process gives rise to a homogenous
(5S)-configuration,[1] the deduction of the relative configu-
ration also constituted a reliable proof of absolute config-
uration.
aldehydes that work by the same mechanism. Subsequently,
the actual domino Michael aldol process commenced and
furnished the desired cyclohexanols.
Not unexpectedly, the Michael aldol process proceeded in
substantially higher yields when performed on the 7-keto-2-
enimides 2e and 2 f (Scheme 4 and Table 2). Here, the
carbonyl activity was attenuated and hence the chemoselec-
tivity in favor of the nucleophilic attack at the conjugate
double bond was more pronounced. The ketones 2e and 2 f
were obtained in good yields from the aldehydes 2a and 2b
through a chemoselective CH3TiCl3 addition,[16] and Swern
oxidation[17] of the resulting secondary alcohols (Scheme 3).
J = 11.5 Hz
H
H
Bu
H
6
2
4
3
J = 2.0 Hz
COXc
R1
O
O
R1
O
O
5
1
Ph
tBu
tBu
H
H
a, b)
H
H
N
H3C
N
H
O
65-70%
J = 13.0 Hz each
O
O
O
J = 2.0 Hz
O
2a: R1 = CH3
2b: R1 = Ph
2e: R1 = CH3
2f: R1 = Ph
3b
Figure 3. Assignment of product configuration for cyclohexanol 3b.
Scheme 3. Synthesis of the 7-keto-2-enimides 2e,f. a) CH3TiCl3, CH2Cl2,
À308C, 45 min; b) DMSO, (COCl)2, À788C, 30 min, then NEt3, À78 !
08C.
To improve the yield of the reaction we attempted the in
situ protection of the aldehyde moiety, because we suspected
that competing nucleophilic addition at C-7 deteriorated the
efficiency of the whole process. In this respect, various highly
oxophilic organometallic reagents such as Me2AlNR2,[14]
Me2AlSPh,[9] and Ti(NEt2)4[15] were employed in sub-stoichio-
metric and stoichiometric amounts with the intention of
converting the aldehyde reversibly into a N,O- or S,O-
hemiacetal, thereby blocking its electrophilic nature (Fig-
ure 4). The best result was obtained in the reaction of 2a with
Various types of cuprate reagents were subsequently added to
the 7-keto-2-enimides 2e and 2 f and gave rise to the tertiary
cyclohexanols 4a g in satisfactory to very good overall yields.
Again, the stereoselectivity of the domino process was
excellent furnishing the products as essentially single stereo-
isomers, presumably through the same kind of transition
structure as discussed earlier. More importantly, Grignard
reagents could be employed as cuprate precursors thus
broadening the scope of the process. In these cases, the
OAlMe2
R
OAlMe2
R
OTi(NEt2)3
Et2N R
R3
O
O
R1
O
tBu
R2N
PhS
R3M, Me2AlCl
Xc
H3C
N
Figure 4. Attempted formation of metal-substituted N,O- and S,O-hemi-
acetals as in situ protecting groups for the aldehyde moiety of 2.
THF, -78 to 0°C
R1
#
OH
CH3
O
O
2e: R1 = CH3
2f: R1 = Ph
4
R3
Xc
0.5 equivalents of Me2AlSPh in combination with three
equivalents of BuCu-LiI/Me2AlCl, which gave 48% yield of
the desired cyclohexanol 3a after 4 h at À788C. This material
was, however, contaminated with small and irremovable
amounts of the phenylthio-substituted cyclohexanol 3d (see
below) resulting from conjugate addition of the thiolate to the
enimide. Hence, no further attempts were made in this
direction.
R1
Me
O
M
O
Scheme 4. Domino Michael aldol reactions on the 7-keto-2-enimides 2e,f.
Table 2. Domino Michael aldol reactions of 7-keto-2-enimides 2e f.[a]
Entry Substrate Product R1
R3
M[b]
Yield [%]
54
Hetero substituents were incorporated into the cyclohex-
anols by employing aluminum heteronucleophiles such as
1
2
3
4
5
6
7
8
9
2e
2e
2e
2e
2e
2e
2f
2e
2f
2e
2e
4a
4b
4c
4d
4e
4f
4g
4h
4i
CH3 CH3
CH3 Et
CH3 nBu
CH3 nHex
CH3 allyl
CH3 Ph
Cu-LiI
Cu-MgBr2 71
Cu-LiI
Cu-LiI
Cu-MgBr2 81
Cu-MgBr2 53
83
62
[9]
thiolates according to Nozaki (Scheme 2 and Table 1).
Initially we used dimethylaluminum thiolates prepared in
situ from trimethylaluminum and a thiol, but later we
discovered that the ate-complex Me3Al-SRLi[9] was a superior
reagent furnishing the thio-substituted cyclohexanols 3c g in
good yields and with high stereocontrol. Considering the high
oxophilicity of aluminum, it is very likely that these reagents
initially added to the aldehyde to reversibly form an Al-S,O-
hemiacetal that served as an in situ protecting group for the
aldehyde. Yamamoto et al.[14] have previously introduced
dimethylaluminum amides as in situ protecting groups for
Ph
CH3 SPh
Ph SPh
CH3 N3
nBu
Cu-LiI
51
76
60
59
40
Me3Al-Li
Me3Al-Li
Me2Al
10
11
4k
4l
CH3 NC5H10 Me2Al
[a] The stereoselectivity of the reaction was estimated to be >95:5, since
no other stereoisomer was detected in the crude product by NMR. [b] In
the case of the Grignard-derived cuprates and the aluminum reagents, the
external Lewis acid Me2AlCl was omitted.
Chem. Eur. J. 2002, 8, No. 11
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C. Schneider and O. Reese
FULL PAPER
Table 3. Domino Michael Mannich reactions of the 7-oxo-2-enimides
external Lewis acid (Me2AlCl) could be omitted without a
decrease in yield or selectivity. We assume that MgBr2,
formed in situ from the Grignard reagent and CuBr ¥ SMe2,
was able to act as a bidentate Lewis acid with formation of a
chelated-imide complex like the one formed with Me2AlCl.[18]
The addition of sulfur and nitrogen nucleophiles was again
accomplished in moderate to good yields using aluminum
thiolates, azides, and amides which gave rise to the cyclo-
hexanols 4h l. It should be noted at this point that
dimethylaluminum piperidide cleanly furnished the tertiary
cyclohexanol 4l in moderate yield (see below).
2a c.[a]
Entry
Substrate
Product
R1
Amine
Yield [%]
1
2
3
4
5
6
7
2a
2a
2a
2a
2b
2c
2c
5a
5b
5c
5d
5e
5 f
5g
CH3
CH3
CH3
CH3
Ph
SiMe2Ph
SiMe2Ph
morpholine
Et2NH
Bn2NH
69
46
70
65
57
59
53
Bu2NH
piperidine
piperidine
morpholine
[a] The stereoselectivity of the reaction was estimated to be >95:5, since
no other stereoisomer was detected in the crude product by NMR.
The assignment of product configuration for the tertiary
cyclohexanols 4 was complicated by the fact that the proton at
C-3 was lacking and is described here explicitly for 4i
(Figure 5). The configuration at C-1, C-2, and C-5 was again
ascertained by the large trans-diaxial coupling constants J(1-
H,2-H), J(4-Hax,5-H), and J(5-H,6-Hax) which were each
12.5 Hz indicating the equatorial position of the C-1-, C-2-,
and C-5-substituents. The configuration at C-3 was proven by
a NOESY spectrum that revealed strong NOE effects
between the axial protons at C-1, C-5, and the OH proton,
which was consistent with the axial orientation of the C-3 OH
group. In addition, a characteristic W coupling of J ˆ 2.5 Hz
between the OH proton and the axial proton at C-4 was
observed, which could only occur in the case of an axial
orientation of the hydroxyl group.
produce the iminium ion E that is then attacked by the
enolate, formed by the conjugate addition of a second amine
equivalent, in an intramolecular Mannich reaction.[19]
The anti-stereochemistry found in the Mannich products 5
was indicative of the proposed reaction path. Owing to a lack
of vacant coordination sites at the iminium nitrogen, an
intramolecular transposition of the metal cation was not
possible here. Hence, the large iminium group assumed the
sterically more favorable pro-equatorial position in transition
structure F giving rise to the anti-stereochemistry between the
COXc- and NR2-groups. The observed Michael Mannich
reaction pathway nicely supports the assumption that the
Nozaki reagents Me3Al-SRLi formed in fact in situ protecting
groups for the aldehyde moiety (Al-S,O-hemiacetals). This
behavior may also explain the exceptionally good yields when
the aldehydes 2a,b were treated with Me3Al-SRLi (Table 1,
entries 3 7).
J = 12.5 Hz
H
H
2
SPh
H
4
6
The configuration of the Mannich products 5 was again
assigned on the basis of the large trans-diaxial coupling
constants between the respective ring protons (Figure 6).
Here, all substituents adopted equatorial positions according
to J(1-H,2-H), J(2-H,3-H), J(4-Hax,5-H), and J(5-H,6-Hax)
which were in the range of 10.5 12.0 Hz.
1
COXc
5
3
Ph
CH3
H
H
OH
4i
J = 12.5 Hz each
NOE effects
Figure 5. Assignment of the product configuration for the cyclohexanol 4i.
J = 11.5 Hz each
When we attempted the synthesis of amino-substituted
cyclohexanols from the 7-oxo-2-enimides 2a c in close
analogy to the Nozaki protocol, we surprisingly isolated the
H
H
NR2
H
6
4
3
COXc
NR2
2
5
1
Me
cyclohexyldiamines 5a
g in satisfactory yields instead
H
H
H
(Scheme 5 and Table 3). Here, a nucleophilic addition of
Me2AlNR2 or the free amine to the aldehyde moiety of 2
preceded the conjugate addition, presumably forming either
an Al-N,O-hemiacetal[14] or the enamine. Either one may then
J = 11.5 Hz each
5a
Figure 6. Assignment of the product configuration for the cyclohexyl-
amine 5a.
NR2
O
O
R1
O
The domino Michael Mannich reaction may be performed
in two ways: 1) with preformed Me2AlNR2 (from Me3Al and
HNR2), or 2) with a mixture of Me2AlCl and the secondary
amine. Both procedures furnished the desired products, the
latter reaction, however, proceeded much faster giving rise to
the product within 1 2 h at 08C in yields given in the table,
whereas the former reaction required 24 h at room temper-
ature and gave the products in lower yields. This result points
to the Me2AlCl/amine mixture being the more powerful
reagent.
tBu
Me2AlCl, 2 HNR2
Xc
NR2
H
N
CH2Cl2, 0°C
R1
O
O
2
5
+
NR2
R2N
R1
O
Xc
NR2
OAlMe2
H
Xc
R1
+
E
F
This observation also suggested that an enamine formed
separately through reaction of 2 with a secondary amine
Scheme 5. Domino Michael Mannich reactions on the 7-oxo-2-enimi-
des 2.
2588
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Chem. Eur. J. 2002, 8, No. 11

Functionalized Cyclohexanes
2585 2594
and visualized with UV light and 1% aqueous KMnO4. Commercial
reagents were used directly as received, unless otherwise stated. Products
were purified by flash chromatography on Machery & Nagel silica gel 32
63 (particle size 0.032 0.063 mm). 1H and 13C NMR spectra were recorded
on a Varian VXR 200 (200 MHz), Bruker AMX 300, (300 MHz) and
Varian VXR 500 (500 MHz) in CDCl3 at 258C with TMS as internal
standard. IR spectra of evaporated films were recorded on a Bruker IFS 25
should be a good substrate for the same sequence, thereby
offering the possibility of introducing two different substitu-
ents into the cyclohexane ring. Accordingly, reaction of 2a
with piperidine and MgSO4 in toluene at 08C cleanly
furnished the enamine which was then subjected to Nozaki×s
ate-complex (Me3Al-SPhLi) to give rise to the phenylthio-
substituted cyclohexylamine 5h in 50% overall yield as a
single stereoisomer (Scheme 6).
FT-IR instrument, and UV spectra on
a Perkin Elmer Lambda 9
spectrometer. Optical rotations were measured on a Perkin Elmer 241
polarimeter. Mass spectra were taken at 70 eV (EI) or 200 eV (DCI/NH3)
on a Finnigan MAT95A spectrometer. Microanalyses were performed by
the microanalytical laboratory at the Institut f¸r Organische Chemie der
Universit‰t Gˆttingen.
PhS
O
N
O
O
tBu
a, b)
50%
Xc
H
N
7-Oxo-2-enimide 2a: The Cope product 2a was prepared from the
O
corresponding silylated aldol adduct as published.[1b] Yield: 81%. [a]2D0
ˆ
O
2a
‡57.0 (c ˆ 0.51 in CHCl3); IR (film): nÄ ˆ 2988, 2934, 2884 (CH), 1780
5h
(imide), 1722 (aldehyde), 1688 (imide), 1638 cmÀ1 (C C); 1H NMR
ˆ
Scheme 6. Synthesis of phenylthio-substituted cyclohexylamine 5h. a) Pi-
peridine, MgSO4, CH2Cl2; b) Me3Al-SPhLi, THF, À788C ! rt.
(200 MHz, CDCl3): d ˆ 0.94 (s, 9H; tBu), 1.02 (d, J ˆ 6.5 Hz, 3H; CH3),
2.15 2.45 (m, 5H; 4'-H2, 5-H, 6'-H2), 4.17 4.32 (m, 2H; 5-H2), 4.51 (dd,
J ˆ 6.5, 2.0 Hz, 1H; 4-H), 7.05 (dt, J ˆ 15.5, 7.0 Hz, 1H; 3'-H), 7.28 (d, J ˆ
15.5 Hz, 1H; 2'-H), 9.64 (t, J ˆ 1.0 Hz, 1H; 7'-H); 13C NMR (50 MHz,
CDCl3): d ˆ 20.0 (CH3), 25.6 (tBu), 27.5 (C-5'), 35.85 (tBu), 39.5, 50.2 (C-4',
C-6'), 60.79 (C-4), 65.19 (C-5), 122.4 (C-2'), 148.3 (C-3'), 154.6 (C-2), 164.9
(C-1'), 201.7 (C-7'); MS (200 eV, DCI/NH3): m/z (%): 299 (100)
Finally, cleavage of the auxiliary was addressed. After some
experimentation we found the Damon reagent, lithium
benzylthiolate,[20] most suitable for this purpose. Thus, cyclo-
hexanol 3d was treated with lithium benzylthiolate in THF at
room temperature for 15 h to furnish thioester 6 in 71% yield
(Scheme 7).
‡
[M ‡NH4]; elemental analysis calcd (%) for C15H23NO4 (281.35): C
64.06, H 8.19; found: C 64.35, H 8.19.
7-Oxo-2-enimde 2b: The Cope product 2b was prepared from the
corresponding silylated aldol adduct as published.[1b] Yield: 69%. M.p.
958C; [a]2D0 ˆ ‡36.4 (c ˆ 1.0 in CHCl3); IR (KBr): nÄ ˆ 2972 (CH), 1764
(imide), 1716 (aldehyde), 1684 (imide), 1632 cmÀ1 (C C); 1H NMR
PhS
O
PhS
O
ˆ
(200 MHz, CDCl3): d ˆ 0.90 (s, 9H; tBu), 2.63 (td, J ˆ 7.0, 1.0 Hz, 2H; 4'-
H2), 2.80 (dd, J ˆ 7.0, 1.5 Hz, 2H; 6'-H2), 3.41 (pent, J ˆ 7.0 Hz, 1H; 5'-H),
4.22 (dd, J ˆ 9.0, 7.0 Hz, 1H; 5-H), 4.29 (dd, J ˆ 9.0, 2.5 Hz, 1H; 5-H), 4.47
(dd, J ˆ 7.0, 2.5 Hz, 1H; 4-H), 6.95 (dt, J ˆ 15.5, 7.0 Hz, 1H; 3'-H), 7.15 7.37
(m, 6H, 2'-H, phenyl-H), 9.66 (t, J ˆ 1.5 Hz, 1H; 7'-H); 13C NMR (50 MHz,
CDCl3): d ˆ 25.6 (tBu), 35.9 (tBu), 39.05 (C-5'), 39.5, 49.4 (C-4', C-6'), 60.8
(C-4), 65.2 (C-5), 122.6 (C-2'), 127.0, 127.3, 128.8, 142.4 (phenyl-C), 147.7 (C-
3'), 154.6 (C-2), 164.9 (C-1'), 200.9 (C-7'); MS (70 eV, EI): m/z (%): 343
a)
Xc
OH
SBn
OH
71%
3d
6
Scheme 7. Cleavage of the chiral auxiliary. a) LiSCH2Ph, THF, rt.
‡
‡
(100) [M ], 299 (12), 211 (71) [crotonoylimide ], 182 (33), 157 (44), 144
Conclusion
‡
(60) [oxazolidinone ‡2H], 105 (100); elemental analysis calcd (%) for
C20H25NO4 (343.42): C 69.95, H 7.34; found: C 69.87, H 7.43.
A highly stereoselective and efficient process has been
developed for the de novo synthesis of enantiopure and
multiply substituted cyclohexanols and cyclohexylamines.
Acyclic 7-oxo-2-enimides 2, readily obtained through the
silyloxy-Cope rearrangement of aldol products 1, were treated
with carbon and heteronucleophiles in a domino Michael
aldol reaction and gave rise to highly substituted cyclohex-
anols 3 and 4. This process resulted in the stereoselective
formation of two new single bonds and three new stereogenic
centers and eventually in the ring-closure. With secondary
amines as nucleophiles, an iminium formation preceded the
conjugate addition and gave rise to a domino Michael
Mannich reaction and the synthesis of highly substituted
cyclohexylamines 5. Based upon these results, the synthetic
value of the bifunctional 7-oxo-2-enimides 2 for stereo-
selective synthesis has been once again demonstrated.
7-Oxo-2-enimde 2c: The Cope product 2c was prepared from the
corresponding silylated aldol adduct as published.[1b] Yield: 72%.[a]2D0
ˆ
ˆ
‡34.0 (c ˆ 0.5 in CHCl3); IR (film): nÄ ˆ 2966, 2874, 2726 (CH), 1782 (C O),
1684 (C O), 1634 cm (C C); 1H NMR (200 MHz, CDCl3): d ˆ 0.33 (s,
6H; SiMe2), 0.92 (s, 9H; tBu), 1.72 (m, 1H; 5'-H), 2.07 2.55 (m, 4H; 4'-H2,
6'-H2), 4.23 (dd, J ˆ 9.0, 6.5 Hz, 1H; 5-H), 4.29 (dd, J ˆ 9.0, 2.5 Hz, 1H;
5-H), 4.49 (dd, J ˆ 6.5, 2.5 Hz, 1H; 4-H), 6.95 (ddd, J ˆ 14.5, 8.5, 6.0 Hz,
1H; 3'-H), 7.15 (d, J ˆ 14.5 Hz, 1H; 2'-H), 7.30 7.54 (m, 5H; phenyl-H),
9.64 (t, J ˆ 1.5 Hz, 1H; 7'-H); 13C NMR (50 MHz, CDCl3): d ˆ À4.7, À4.6
(SiMe2), 18.5 (C-5'), 25.3 (C(CH3)3), 33.1, 43.5 (C-4', C-6'), 35.5 (C(CH3)3),
60.4 (C-4), 64.9 (C-5), 121.5 (C-2'), 127.7, 129.1, 133.6, 136.3 (phenyl-C),
149.8 (C-3'), 154.3 (C-2), 164.5 (C-1'), 201.6 (C-7'); MS (70eV, EI): m/z (%):
À1
ˆ
ˆ
‡
‡
‡
401 (11) [M ], 386 (18) [M À CH3], 345 (14) [M À tBu], 324 (21), 278
‡
‡
(100), 191 (19) [retro-aldol-cleavage, aldehyde ], 135 (71) [PhMe2Si ], 57
‡
(8) [tBu ]; elemental analysis calcd (%) for C22H31NO4Si (401.58): C 65.80,
H 7.78; found: C 65.92, H 8.05.
7-Oxo-2-enimide 2d: The Cope product 2d was prepared from the
corresponding silylated aldol adduct as published.[1b] Yield: 86%. M.p.
708C; [a]2D0 ˆ ‡93.0 (c ˆ 1.0 in CHCl3); IR (KBr): nÄ ˆ 2966, 2883 (CH),
À1
ˆ
ˆ
1783 (imide), 1716 (C O, aldehyde), 1680 (imide), 1632 cm (C C);
1H NMR (200 MHz, CDCl3): d ˆ 0.95 (s, 9H; tBu), 0.97, 1.04 (2d, J ˆ
6.5 Hz, 6H; 2CH3), 2.10 2.58 (m, 4H; 4'-H, 5'-H, 6'-H2), 4.25 (dd, J ˆ
9.0, 2.5 Hz, 1H; 5-H), 4.31 (dd, J ˆ 9.0, 2.5 Hz, 1H; 5-H), 4.52 (dd, J ˆ 7.0,
2.5 Hz, 1H; 4-H), 6.99 (dd, J ˆ 15.5, 8.5 Hz, 1H; 3'-H), 7.25 (dd, J ˆ 15.5,
1.0 Hz, 1H; 2'-H), 9.74 (t, J ˆ 1.5 Hz, 1H; 7'-H); 13C NMR (50 MHz,
CDCl3): d ˆ 15.9, 17.1 (2CH3), 25.6 (tBu), 32.35 (C-5'), 35.9 (tBu), 41.75 (C-
4'), 48.45 (C-6'), 60.9 (C-4), 65.2 (C-5), 120.6 (C-2'), 153.9 (C-3'), 154.7 (C-
Experimental Section
General: Air and/or moisture sensitive reactions were carried out under N2
using flame-dried glassware and standard syringe/septa techniques. Sol-
vents were distilled directly prior to use from the appropriate drying
agents: THF (LiAlH4), CH2Cl2 and NEt3 (CaH2), Et2O and toluene (Na).
All reactions were monitored by thin-layer chromatography (TLC) carried
out on pre-coated silica gel SIL G/UV254 plastic plates (Machery & Nagel)
‡
2), 165.2 (C-1'), 202.0 (C-7'); MS (70 eV, EI): m/z (%): 295 (9) [M ], 252
(31), 225 (48), 153 (94) [M À oxazolidinone], 144 (77)
‡
Chem. Eur. J. 2002, 8, No. 11
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0811-2589 $ 20.00+.50/0
2589

C. Schneider and O. Reese
FULL PAPER
‡
‡
‡
[oxazolidinone ‡2H], 109 (85), 82 (100); elemental analysis calcd (%) for
[M ‡NH4], 340 (42) [M ‡H], 161 (70); elemental analysis calcd (%) for
C16H25NO4 (295.37): C 65.06, H 8.53; found: C 65.32, H 8.31.
C19H33NO4 (339.47): C 67.22, H 9.80; found: C 66.97, H 9.80.
Cyclohexanol 3b: 7-Oxo-2-enimide 2b (200 mg, 0.58 mmol) was dissolved
in THF (5 mL), and CuI (333 mg, 1.75 mmol), butyllithium (2.5m in
hexane, 0.70 mL, 1.75 mmol), and a 1m solution of Me2AlCl in hexane
(1.75 mL, 1.75 mmol) were added as described above. Flash chromatog-
raphy over silica gel (diethyl ether/pentane 1:1) gave 3b (98 mg, 42%) as a
white solid. M.p. 1338C; [a]2D0 ˆ ‡8.2 (c ˆ 1.0 in CHCl3); IR (KBr): nÄ ˆ 3549
7-Keto-2-enimide 2e: A solution of CH3TiCl3 in CH2Cl2 was prepared in
situ from a 5% solution of methyllithium in diethyl ether (4.49 mL,
7.18 mmol) and a 1m solution of TiCl4 in CH2Cl2 (7.18 mL, 7.18 mmol) at
À308C. Subsequently, the 7-oxo-2-enimide 2a (1.01 g, 3.59 mmol) was
added to this solution at À458C and the reaction mixture was stirred at this
temperature for another 30 min. The reaction was stopped by the addition
of pH 7 buffer, the phases were separated, and the aqueous layer was
extracted twice with diethyl ether. The combined organic extracts were
dried over MgSO4, filtered, and evaporated. The crude product was directly
subjected to a Swern oxidation: Oxalylchloride (3.09 mL, 3.60 mmol) was
dissolved in CH2Cl2 (50 mL) and treated with DMSO (5.54 mL, 7.80 mmol)
at À788C. After 30 min of stirring, the crude alcohol was added, and the
solution was stirred for an additional 30 min at À788C. Subsequently,
triethylamine (2.09 mL, 15.0 mmol) was added at À788C, and the reaction
mixture was warmed to RTwhereupon water was added. The layers were
separated, the aqueous phase was extracted twice with diethyl ether and the
combined organic extracts were dried over MgSO4. After filtration and
evaporation of the solvent, the crude product was purified by flash
chromatography over silica gel (diethyl ether/pentane 1:1) to give the
(OH), 2933 (CH3), 1775, 1701 (imide), 1216, 1187, 1100 cmÀ1 (C O);
À
1H NMR (500 MHz, CDCl3): d ˆ 0.85 (t, J ˆ 7.0 Hz, 1H; CH3), 0.98 (s, 9H;
tBu), 1.18 1.44 (m, 7H), 1.65 (td, J ˆ 13.0, 2.0 Hz, 1H; 6'-H), 2.05 2.12 (m,
2H; 4'-H, 6'-H), 2.27 2.36 (m, 1H; 3'-H), 3.16 (tt, J ˆ 13.0, 3.5 Hz, 1H; 5'-
H), 3.30 (s, 1H; OH), 4.00 (dd, J ˆ 11.5, 2.0 Hz, 1H; 2'-H), 4.17 (m, 1H; 1'-
H), 4.26 (dd, J ˆ 9.0, 7.5 Hz, 1H; 5-H), 4.32 (dd, J ˆ 9.0, 1.5 Hz, 1H; 5-H),
4.52 (dd, J ˆ 7.5, 1.5 Hz, 1H; 4-H), 7.15 7.33 (m, 5H; phenyl-H); 13C NMR
(50 MHz, CDCl3): d ˆ 14.0 (CH3), 22.9, 28.4, 33.7 (butyl side chain), 25.9
(tBu), 34.4 (C-3'), 35.85 (tBu), 36.7 (C-5'), 38.6, 39.2 (C-4', C-6'), 49.4 (C-2'),
61.6 (C-4), 65.2 (C-5), 67.25 (C-1'), 126.2, 127.0, 128.4, 146.3 (phenyl-C),
‡
ˆ
154.4 (C-2), 176.8 (C O); MS (70 eV, EI): m/z (%): 401 (17) [M ], 383 (59),
240 (100), 212 (75); HRMS: m/z calcd for C24H35NO4: 410.2566; found:
401.2566.
methylketone 2e (690 mg, 65% yield over 2 steps) as a viscous oil. [a]D20
ˆ
Cyclohexanol 3c: Thioethanol (13 mL, 0.17 mmol) was dissolved in THF
(2 mL), and butyllithium (2.5m in hexane, 67 mL, 0.17 mmol) was added at
08C. After for 5 min, Me3Al (2m in hexane, 84 mL, 0.17 mmol) was added to
the reaction mixture at 08C. After stirring for 1 h at 08C, the solution was
cooled to À788C, and 7-oxo-2-enimide 2a (43 mg, 0.15 mmol) in THF
(1 mL) was added. After stirring the solution for 1 h at À788C, the reaction
was quenched with water, and the layers were separated. The aqueous
phase was extracted twice with diethyl ether and the combined organic
extracts were dried over MgSO4. After filtration and evaporation of the
solvents, the crude product was purified by flash chromatography over
silica gel (diethyl ether/pentane 1:1) to give 3c (30 mg, 57%) as a colorless
oil. [a]2D0 ˆ À16.0 (c ˆ 0.35 in CHCl3); IR (film): nÄ ˆ 3477 (OH), 2960
‡66.6 (c ˆ 0.5 in CHCl3); IR (film): nÄ ˆ 2965 (CH), 1778, 1689 (imide),
1636 cmÀ1 (C C); 1H NMR (200 MHz, CDCl3): d ˆ 0.95 0.96 (m, 12H;
ˆ
tBu, CH3), 2.13 (s, 3H; CH3), 2.14 2.55 (m, 5H; 4'-H2, 5'-H, 6'-H2), 4.24
(dd, J ˆ 9.0, 7.0 Hz, 1H; 5-H), 4.30 (dd, J ˆ 9.0, 2.0 Hz, 1H; 5-H), 4.52 (dd,
J ˆ 7.0, 2.0 Hz, 1H; 4-H), 6.98 7.32 (m, 2H; 2'-H, 3'-H); 13C NMR
(50 MHz, CDCl3): d ˆ 19.9 (5'-CH3), 25.6 (tBu), 28.5, 30.5 (C-8', C-5'), 35.9
(tBu), 39.6, 50.0 (C-4', C-6'), 60.8 (C-4), 65.2 (C-5), 122.2 (C-2'), 149.0 (C-
3'), 154.6 (C-2), 165.1 (C-1'), 208.0 (C-7'); MS (70 eV, EI): m/z (%): 295 (16)
‡
‡
‡
[M ], 238 (74), 211(24) [crotonoylimide ], 153 (34) [M À oxazolidinone],
95 (100); elemental analysis calcd (%) for C16H25NO4 (295.37): C 65.06, H
8.53; found: C 65.24, H 8.56.
(CH3), 1778, 1705 (imide), 1187, 1119, 1100 cmÀ1 (C O); 1H NMR
À
7-Keto-2-enimide 2 f: 7-Oxo-2-enimide 2b (1.28 g, 3.71 mmol) was con-
verted into the title compound 2 f as described above. Yield: 70% (over
2 steps). [a]2D0 ˆ ‡46.0 (c ˆ 0.5 in CHCl3); IR (film): nÄ ˆ 2967 (CH), 1777,
(200 MHz, CDCl3): d ˆ 0.85 1.40 (m, 2H; 4'-H, 6'-H), 0.87 (d, J ˆ 6.0 Hz,
3H; CH3), 1.00 (s, 9H; tBu), 1.19 (t, J ˆ 7.5 Hz, 3H; CH3), 1.80 2.20 (m,
3H; 4'-H, 5'-H, 6'-H), 2.59 (m, 2H; 1''-H2), 3.18 (td, J ˆ 12.0, 4.0 Hz, 1H; 1'-
H), 3.25 (s, 1H; OH), 4.05 4.39 (m, 2H; 2'-H, 3'-H), 4.23 (dd, J ˆ 9.0,
7.0 Hz, 1H; 5-H), 4.31 (dd, J ˆ 9.0, 2.0 Hz, 1H; 5-H), 4.49 (dd, J ˆ 7.0,
2.0 Hz, 1H; 4-H); 13C NMR (75 MHz, CDCl3): d ˆ 14.8 (C-2''), 21.9 (C-1''),
24.5 (C-1'), 25.8 (tBu), 26.1 (C-5'), 36.2 (tBu), 39.4, 42.9 (C-4', C-6'), 40.5 (C-
1688 (imide), 1632 cmÀ1 (C C); 1H NMR (200 MHz, CDCl3): d ˆ 0.90 (s,
ˆ
9H; tBu), 2.03 (s, 3H; 8'-H3), 2.50 2.67 (m, 2H; 4'-H2), 2.70 2.86 (m, 2H;
6'-H2), 3.36 (pent, J ˆ 7.0 Hz, 1H; 5'-H), 4.22 (dd, J ˆ 9.0, 7.0 Hz, 1H; 5-H),
4.28 (dd, J ˆ 9.0, 2.0 Hz, 1H; 5-H), 4.47 (dd, J ˆ 7.0, 2.0 Hz, 1H; 4-H), 6.95
(dt, J ˆ 15.0, 7.0 Hz, 1H; 3'-H), 7.15 7.35 (m, 6H; 2'-H, phenyl-H);
13C NMR (50 MHz, CDCl3): d ˆ 25.6 (tBu), 30.6 (C-8'), 35.8 (tBu), 39.4 (C-
4'), 40.0 (C-5'), 49.4 (C-6'), 60.8 (C-4), 65.2 (C-5), 122.3 (C-2'), 126.7, 127.4,
128.6, 143.2 (phenyl-C), 148.3 (C-3'), 154.6 (C-2), 164.9 (C-1'), 207.0 (C-7');
ˆ
1'), 49.3 (C-2'), 61.5 (C-4), 65.1 (C-5), 67.5 (C-3'), 154.3 (C-2), 175.5 (C O,
‡
amide); MS (70 eV, EI): m/z (%): 343 (30) [M ], 264 (34), 182 (90), 144
‡
(100) [oxazolidinone ‡2H]; HRMS: m/z: calcd for C17H29NO4S: 343.1817;
found: 343.1817.
‡
MS (70 eV, EI): m/z (%): 357 (17) [M ], 300 (39), 211 (100)
Cyclohexanol 3d: 7-Oxo-2-enimide 2a (49 mg, 0.17 mmol) was dissolved in
THF (3 mL), and thiophenol (20 mL, 0.19 mmol), butyllithium (2.5m in
hexane, 77 mL, 0.19 mmol), and Me3Al (2m in hexane, 96 mL, 0.19 mmol)
were added as described above. Flash chromatography over silica gel
‡
‡
[crotonoylimide ], 157 (85), 144 (61) [oxazolidinone ‡2H], 105 (27);
elemental analysis calcd (%) for C21H27NO4 (357.44): C 70.56, H 7.61;
found: C 70.26, H 7.37.
(diethyl ether/pentane 1:1) gave 3d (51 mg, 77%) as a colorless oil. [a]D20
ˆ
Cyclohexanol 3a: CuI (125 mg, 0.66 mmol) was suspended in dry THF
(3 mL), and butyllithium (2.5m in hexane, 0.26 mL, 0.66 mmol) was added
at À308C whereupon the mixture immediately turned black. After 20 min,
the solution was cooled to À788C, and a 1m solution of Me2AlCl in hexane
(0.66 mL, 0.66 mmol) and then 2a (62 mg, 0.22 mmol) dissolved in THF
(1 mL) were added. The solution was allowed to warm to À408C over 3 h.
At that temperature, saturated NH4Cl solution was added, the layers were
separated, and the aqueous phase was extracted twice with diethyl ether.
The combined organic extracts were dried over MgSO4, filtered, and
evaporated. The crude product was purified by flash chromatography over
silica gel (diethyl ether/pentane 1:1) to give cyclohexanol 3a (30 mg, 41%)
as a colorless oil. [a]2D0 ˆ ‡6.6 (c ˆ 1.67 in CHCl3); IR (film): nÄ ˆ 3515
‡3.3 (c ˆ 1.21 in CHCl3); IR (film): nÄ ˆ 3471 (OH), 2960 (CH3), 1779, 1705
(imide), 1187, 1118, 1057 cmÀ1 (C O); 1H NMR (500 MHz, CDCl3): d ˆ
À
0.85 (d, J ˆ 6.5 Hz, 3H; 5'-CH3), 1.02 (s, 9H; tBu), 1.08 (ddd, J ˆ 13.5, 12.0,
2.0 Hz, 1H; 4'-H), 1.18 (dt, J ˆ 13.5, 12.0 Hz, 1H; 6'-H), 1.85 (dtd, J ˆ 13.5,
3.5, 2.0 Hz, 1H; 4'-H), 1.90 2.02 (m, 1H; 5'-H), 2.07 (dtd, J ˆ 13.5, 3.5,
2.0 Hz, 1H; 6'-H), 3.22 (brs, 1H; OH), 3.61 (td, J ˆ 12.0, 3.5 Hz, 1H; 1'-H),
4.13 (brs, 1H; 3'-H), 4.22 (dd, J ˆ 12.0, 2.0 Hz, 1H; 2'-H), 4.26 (dd, J ˆ 9.0,
7.5 Hz, 1H; 5-H), 4.32 (dd, J ˆ 9.0, 1.5 Hz, 1H; 5-H), 4.52 (dd, J ˆ 7.5,
1.5 Hz, 1H; 4-H), 7.22 7.45 (m, 5H; phenyl-H); 13C NMR (75 MHz,
CDCl3): d ˆ 21.5 (C-1''), 25.8 (C-5'), 25.8 (tBu), 36.2 (tBu), 39.4, 42.6 (C-4',
C-6'), 45.0 (C-1'), 48.9 (C-2'), 61.6 (C-4), 65.2 (C-5), 67.6 (C-3'), 127.4, 128.8,
ˆ
(OH), 2927 (CH3), 1779, 1704 (imide), 1183, 1101, 1058 cmÀ1 (C O);
132.9, 134.0 (phenyl-C), 154.3 (C-2), 175.3 (C O); MS (70 eV, EI): m/z (%):
À
‡
‡
1H NMR (200 MHz, CDCl3): d ˆ 0.73 (q, J ˆ 12.5 Hz, 1H; 4'-H), 0.80 0.95
(m, 6H; 2CH3), 0.97 (s, 9H; tBu), 0.98 1.41 (m, 7H; 4'-H, 6'-H2, 2''-H2, 3''-
H2), 1.80 2.20 (m, 4H; 3'-H, 5'-H, 1''-H2), 3.05 (s, 1H; OH), 3.79 (dd, J ˆ
11.5, 2.0 Hz, 1H; 2'-H), 4.00 (brs, 1H, 1'-H), 4.20 (dd, J ˆ 9.0, 7.0 Hz, 1H;
5-H), 4.27 (dd, J ˆ 9.0, 2.0 Hz, 1H; 5-H), 4.46 (dd, J ˆ 7.0, 2.0 Hz, 1H; 4-H);
13C NMR (50 MHz, CDCl3): d ˆ 14.0 (CH3), 22.1 (CH3), 22.9 (butyl side
chain), 25.2 (C-5'), 25.8 (tBu), 28.4, 33.7 (butyl side chain), 33.85 (C-3'), 35.9
(tBu), 40.0, 40.3 (C-4', C-6'), 49.6 (C-2'), 61.5 (C-4), 65.1 (C-5), 67.3 (C-1'),
391 (95) [M ], 264 (77), 230 (80), 144 (70) [oxazolidinone ‡2H], 121
(100); elemental analysis calcd (%) for C21H29NO4S (391.53): C 64.42, H
7.47; found: C 64.65, H 7.76.
Cyclohexanol 3e: 7-Oxo-2-enimide 2b (107 mg, 0.31 mmol) was dissolved
in THF (5 mL), and thiophenol (33 mL, 0.33 mmol), butyllithium (2.5m in
hexane, 131 mL, 0.33 mmol), and Me3Al (2m in hexane, 164 mL, 0.33 mmol)
were added as described above. Flash chromatography over silica gel
(diethyl ether/pentane 1:1) gave 3e (92 mg, 65%) as a white solid. M.p.
1728C; [a]2D0 ˆ À48.7 (c ˆ 1.0 in CHCl3); IR (KBr): nÄ ˆ 3420 (OH), 2943
ˆ
154.4 (C-2), 176.7 (C O); MS (200 eV, DCI/NH3): m/z (%): 357 (100)
2590
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0811-2590 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 11

Functionalized Cyclohexanes
2585 2594
(CH3), 1775, 1699 (imide), 1217, 1196, 1112 cmÀ1 (C O); 1H NMR
(300 MHz, CDCl3): d ˆ 1.06 (s, 9H; tBu), 1.65 (td, J ˆ 13.0, 2.0 Hz, 1H;
4'-H), 1.77 (q, J ˆ 13.0 Hz, 1H; 6'-H), 2.08 (dtd, J ˆ 13.0, 4.0, 1.5 Hz, 1H; 4'-
H), 2.30 (dtd, J ˆ 13.0, 4.0, 1.5 Hz, 1H; 6'-H), 3.16 (tt, J ˆ 13.0, 4.0 Hz, 1H;
5'-H), 3.76 (td, J ˆ 12.0, 4.0 Hz, 1H; 1'-H), 4.25 4.36 (m, 1H; 3'-H), 4.30
(dd, J ˆ 9.0, 7.5 Hz, 1H; 5-H), 4.36 (dd, J ˆ 9.0, 1.5 Hz, 1H; 5-H), 4.40 (dd,
J ˆ 12.0, 2.0 Hz, 1H; 2'-H), 4.57 (dd, J ˆ 7.5, 1.5 Hz, 1H; 4-H), 7.10 7.48 (m,
10H; phenyl-H); 13C NMR (50 MHz, CDCl3): d ˆ 25.9 (tBu), 36.3 (tBu),
37.0 (C-5'), 38.6, 41.5 (C-4', C-6'), 45.6 (C-1'), 48.6 (C-2'), 61.7 (C-4), 65.3 (C-
ethylmagnesium bromide (3m in diethyl ether, 0.24 mL, 0.72 mmol) was
added. The solution was stirred for 1 h at À408C, cooled to À788C, and
then treated with 7-keto-2-enimide 2e (42 mg, 0.14 mmol) dissolved in
THF (1 mL). The reaction mixture was slowly warmed to RT over 3 4 h
and eventually stopped through the addition of saturated NH4Cl solution.
The layers were separated, and the aqueous phase was extracted twice with
diethyl ether. The combined organic extracts were dried over MgSO4,
filtered, and evaporated. The crude product was purified by flash
chromatography over silica gel (diethyl ether/pentane 1:1) to give 4b
(33 mg, 71%) as a white solid. M.p. 888C; [a]2D0 ˆ ‡39.8 (c ˆ 1.0 in CHCl3);
IR (KBr): nÄ ˆ 3499 (OH), 2967 (CH3), 1777, 1674 (imide), 1229, 1185,
À
5), 67.5 (C-3'), 126.4, 127.0, 127.6, 128.5, 129.0, 133.1, 133.8, 145.0 (phenyl-
C), 154.4 (C-2), 175.4 (C O); MS (70 eV, EI): m/z (%): 453 (76) [M ], 326
‡
ˆ
‡
1105 cmÀ1 (C O); 1H NMR (200 MHz, CDCl3): d ˆ 0.68 (q, J ˆ 12.5 Hz,
À
(43), 292 (47), 183 (100), 144 (63) [oxazolidinone ‡2H]; elemental analysis
calcd (%) for C26H31NO4S (453.59): C 68.85, H 6.89; found: C 69.10, H 7.06.
1H; 4'-H), 0.90 (d, J ˆ 7.0 Hz, 3H; 5'-CH3), 0.98 (s, 9H; tBu), 1.06 (s, 3H; 1'-
CH3), 0.73 2.14 (m, 10H; 3'-H, 4'-H, 5'-H, 6'-H2, CH2H3), 3.65 (s, 1H;
OH), 3.79 (d, J ˆ 11.5 Hz, 1H; 2'-H), 4.19 (dd, J ˆ 9.0, 7.5 Hz, 1H; 5-H),
4.33 (dd, J ˆ 9.0, 1.5 Hz, 1H; 5-H), 4.53 (dd, J ˆ 7.5, 1.5 Hz, 1H; 4-H);
13C NMR (50 MHz, CDCl3): d ˆ 10.8 (CH3), 22.0 (CH3), 25.9 (tBu), 26.7
(CH3), 26.7 (C-1''), 29.15 (C-3'), 35.8 (tBu), 38.05 (C-5'), 38.4, 46.8 (C-4',
C-6'), 52.65 (C-2'), 61.9 (C-4), 65.3 (C-5), 70.8 (C-1'), 154.5 (C-2), 178.1
Cyclohexanol 3 f: 7-Oxo-2-enimide 2c (40 mg, 0.10 mmol) was dissolved in
THF (3 mL), and thiophenol (11 mL, 0.11 mmol), butyllithium (2.5m in
hexane, 44 mL, 0.11 mmol), and Me3Al (2m in hexane, 55 mL, 0.11 mmol)
were added as described above. Flash chromatography over silica gel
(diethyl ether/pentane 1:1) gave 3 f (31 mg, 61%) as a white solid. M.p.
1118C; [a]2D0 ˆ À28.0 (c ˆ 0.5 in CHCl3); IR (KBr): nÄ ˆ 3472 (OH), 2965
‡
‡
ˆ
(CH3), 1780, 1704 (imide), 1222, 1186, 1113, 1071, 1027 cmÀ1 (C O);
(C O); MS (70 eV, EI): m/z (%): 325 (25) [M ], 310 (28) [M À Me], 296
À
‡
1H NMR (500 MHz, CDCl3): d ˆ 0.24, 0.25 (2s, 6H; SiMe2), 1.03 (s, 9H;
tBu), 1.30 (td, J ˆ 13.5, 2.0 Hz, 1H; 4'-H), 1.38 (td, J ˆ 13.5, 12.0 Hz, 1H; 2'-
H), 1.50 (tt, J ˆ 13.5, 3.0 Hz, 1H; 3'-H), 1.84, 2.12 (2m, 2H; 4'-H, 2'-H), 3.59
(td, J ˆ 12.0, 4.0 Hz, 1H; 1'-H), 4.12 (m, 1H; 5'-H), 4.25 (dd, J ˆ 12.0,
2.0 Hz, 1H; 6'-H), 4.29 (dd, J ˆ 9.0, 7.5 Hz, 1H; 5-H), 4.35 (dd, J ˆ 9.0,
1.5 Hz, 1H; 5-H), 4.55 (dd, J ˆ 7.5, 1.5 Hz, 1H; 4-H), 7.24 7.47 (m, 10H,
phenyl-H); 13C NMR (50 MHz, CDCl3): d ˆ À5.3, À5.1 (SiMe2), 17.9 (C-
3'), 25.8 (tBu), 31.95, 35.0 (C-4', C-6'), 36.2 (tBu), 45.8 (C-1'), 49.3 (C-6'),
61.6 (C-4), 65.2 (C-5), 67.1 (C-5'), 127.3, 127.8, 128.8, 129.0, 132.5, 133.9,
(25) [M À Et], 226 (71), 185 (63), 167 (77), 144 (100)
‡
[oxazolidinone ‡2H]; elemental analysis calcd (%) for C18H31NO4
(325.44): C 66.43, H 9.60; found: C 66.48, H 9.30.
Cyclohexanol 4c: 7-Keto-2-enimide 2e (100 mg, 0.34 mmol) was dissolved
in THF (5 mL), and CuI (323 mg, 1.70 mmol), butyllithium (2.5m in
hexane, 0.68 mL, 1.70 mmol), and Me2AlCl (1m in hexane, 1.70 mL,
1.70 mmol) were added as described above. Flash chromatography over
silica gel (diethyl ether/pentane 1:1) gave 4c (99 mg, 83%) as a white solid.
M.p. 748C; [a]2D0 ˆ ‡24.8 (c ˆ 0.5 in CHCl3); IR (KBr): nÄ ˆ 3502 (OH),
2961 (CH3), 1780, 1674 (imide), 1183, 1105 cmÀ1 (C O); 1H NMR
ˆ
134.1, 137.1 (phenyl-C), 154.3 (C-2), 175.1 (C O); MS (70 eV, EI): m/z (%):
511 (87) [M ], 278 (89), 135 (100); HRMS: m/z: calcd for C28H37NO4SSi:
À
‡
(200 MHz, CDCl3): d ˆ 0.68 (q, J ˆ 12.0 Hz, 1H; 4'-H), 0.81 0.97 (m,
3H; CH3), 0.89 (d, J ˆ 6.5 Hz, 3H; CH3), 0.99 (s, 9H; tBu), 1.06 (s, 3H; 1'-
CH3), 1.15 2.19 (m, 11H; 3'-H, 4'-H, 5'-H, 6'-H2, butyl side chain), 3.69 (d,
J ˆ 2.0 Hz, 1H; OH), 3.78 (d, J ˆ 11.0 Hz, 1H; 2'-H), 4.19 (dd, J ˆ 9.5,
7.5 Hz, 1H; 5-H), 4.33 (dd, J ˆ 9.5, 1.5 Hz, 1H; 5-H), 4.53 (dd, J ˆ 7.5,
1.5 Hz, 1H; 4-H); 13C NMR (50 MHz, CDCl3): d ˆ 14.0 (CH3), 22.0 (CH3),
22.9, 25.9 (tBu), 26.7 (CH3), 28.6, 29.2 (C-3'), 33.85, 35.8 (tBu), 36.8 (C-5'),
39.2, 46.8 (C-4', C-6'), 52.9 (C-2'), 61.9 (C-4), 65.3 (C-5), 70.8 (C-1'), 154.5
511.2212, found: 511.2212.
Cyclohexanol 3g: 7-Oxo-2-enimide 2d (75 , 0.25 mmol) was dissolved in
THF (4 mL), and thiophenol (27 mL, 0.27 mmol), butyllithium (2.5m in
hexane, 107 mL, 0.27 mmol), and Me3Al (2m in hexane, 134 mL, 0.27 mmol)
were added as described above. Flash chromatography over silica gel
(diethyl ether/pentane 1:1) gave 3g (61 mg, 59%) as a white solid. M.p.
668C; [a]2D0 ˆ ‡59.3 (c ˆ 0.3 in CHCl3); IR (KBr): nÄ ˆ 3478 (OH), 2965
‡
(CH3), 1779, 1704 (imide), 1220, 1102, 1058 cmÀ1 (C O); 1H NMR
ˆ
(C-2), 178.2 (C O); MS (70 eV, EI): m/z (%): 353 (27) [M ], 338 (30)
À
‡
‡
‡
[M À Me], 296 (53) [M À Bu], 254 (100), 211 (29) [M À oxazolidinone],
(500 MHz, CDCl3): d ˆ 0.91 (d, J ˆ 6.5 Hz, 3H; CH3), 0.95 (s, 9H; tBu),
1.08 (d, J ˆ 6.5 Hz, 3H; CH3), 1.20 1.30 (m, 2H; 4'-H, 6'-H), 1.70 1.81 (m,
1H; 5'-H), 1.84 (dt, J ˆ 14.0, 3.5 Hz, 1H; 4'-H), 2.84 (brs, 1H; OH), 3.40
(dd, J ˆ 12.5, 11.0 Hz, 1H; 1'-H), 4.09 (brs, 1H; 3'-H), 4.26 (dd, J ˆ 9.0,
7.5 Hz, 1H; 5-H), 4.32 (dd, J ˆ 9.0, 1.5 Hz, 1H; 5-H), 4.48 (dd, J ˆ 12.5,
2.0 Hz, 1H; 2'-H), 4.52 (dd, J ˆ 7.5, 1.5 Hz, 1H; 4-H), 7.18 7.48 (m, 5H;
phenyl-H); 13C NMR (50 MHz, CDCl3): d ˆ 17.0 (CH3), 20.1 (CH3), 25.7
(tBu), 31.9 (C-5'), 36.0 (tBu), 40.0, 45.6 (C-4', C-6'), 50.8 (C-1'), 51.7 (C-2'),
61.5 (C-4), 65.1 (C-5), 67.2 (C-3'), 126.7, 128.7, 131.6, 135.8 (phenyl-C), 154.3
‡
195 (79) [M À oxazolidinone À O], 186 (58), 185 (67), 144 (98)
‡
[oxazolidinone ‡2H]; elemental analysis calcd (%) for C20H35NO4
(353.50): C 67.95, H 9.98; found: C 68.29, H 9.79.
Cyclohexanol 4d: 7-Keto-2-enimide 2e (35 mg, 0.12 mmol) was dissolved
in THF (3 mL), and CuI (113 mg, 0.59 mmol), hexyllithium (2.5m in
hexane, 0.24 mL, 0.59 mmol), and Me2AlCl (1m in hexane, 0.59 mL,
0.59 mmol) were added as described above. Flash chromatography over
silica gel (diethyl ether/pentane 1:2) gave 4d (28 mg, 62%) as a colorless
oil. [a]2D0 ˆ ‡28.5 (c ˆ 0.4 in CHCl3); IR (film): nÄ ˆ 3500 (OH), 2927 (CH3),
‡
ˆ
(C-2), 174.6 (C O); MS (70 eV, EI): m/z (%): 405 (90) [M ], 278 (29), 244
‡
1783, 1673 (imide), 1266, 1182, 1104 cmÀ1 (C O); 1H NMR (200 MHz,
(20), 144 (45) [oxazolidinone ‡2H], 135 (100); elemental analysis calcd
À
(%) for C22H31NO4S (405.55): C 65.15, H 7.70; found: C 65.23, H 7.82.
CDCl3): d ˆ 0.68 (q, J ˆ 11.5 Hz, 1H; 4'-H), 0.70 2.20 (m, 24H; 1'-CH3, 5'-
CH3, 3'-H, 4'-H, 5'-H, 6'-H2, hexyl side chain), 0.99 (s, 9H; tBu), 3.69 (d, J ˆ
2.0 Hz, 1H; OH), 3.79 (d, J ˆ 11.5 Hz, 1H; 2'-H), 4.19 (dd, J ˆ 9.0, 7.5 Hz,
1H; 5-H), 4.33 (dd, J ˆ 9.0, 1.5 Hz, 1H; 5-H), 4.53 (dd, J ˆ 7.5, 1.5 Hz, 1H;
4-H); 13C NMR (75 MHz, CDCl3): d ˆ 14.1 (CH3), 22.0 (CH3), 25.95 (tBu),
26.7 (C-1'-Me), 29.2 (C-3'), 22.6, 26.35, 29.5, 31.8, 34.1 (hexyl side chain),
35.8 (tBu), 36.8 (C-5'), 39.2, 46.9 (C-4', C-6'), 52.9 (C-2'), 61.9 (C-4), 65.3 (C-
Cyclohexanol 4a: 7-Keto-2-enimide 2e (56 mg, 0.19 mmol) was dissolved
in THF (3 mL), and a solution of MeCu-LiI freshly prepared from CuI
(181 mg, 0.95 mmol), MeLi (1.6m in diethyl ether, 0.59 mL, 0.95 mmol),
and Me2AlCl (1m in hexane, 0.95 mL, 0.95 mmol) was added as described
above. Flash chromatography over silica gel (diethyl ether/pentane 1:1)
gave 4a (32 mg, 54%) as a colorless oil. [a]2D0 ˆ ‡49.2 (c ˆ 1.0 in CHCl3);
IR (film): nÄ ˆ 3498 (OH), 2960 (CH3), 1782, 1673 (imide), 1272, 1183,
ˆ
5), 70.8 (C-1'), 154.5 (C-2), 178.2 (C O); MS (70 eV, EI): m/z (%): 381 (8)
‡
‡
‡
1104 cmÀ1 (C O); 1H NMR (200 MHz, CDCl3): d ˆ 0.68 1.10, 1.67 1.80
À
[M ], 366 (14) [M À Me], 296 (48) [M À Hexyl], 282 (58), 223 (53), 185
‡
(49), 144 (100) [oxazolidinone ‡2H]; HRMS: m/z: calcd for C22H39NO4:
(2m, 7H; CH3, 4'-H2, 6'-H2), 0.88 (d, J ˆ 6.5 Hz, 3H; CH3), 0.98 (s, 9H;
tBu), 1.07 (s, 3H; 1'-CH3), 1.86 2.29 (m, 2H; 3'-H, 5'-H), 3.70 (d, J ˆ
11.5 Hz, 1H; 2'-H), 3.76 (s, 1H; OH), 4.20 (dd, J ˆ 9.5, 7.5 Hz, 1H; 5-H),
4.34 (dd, J ˆ 9.5, 1.5 Hz, 1H; 5-H), 4.52 (dd, J ˆ 7.5, 1.5 Hz, 1H; 4-H);
13C NMR (50 MHz, CDCl3): d ˆ 19.9 (CH3), 21.85 (CH3), 25.9 (tBu), 26.8
(CH3), 29.2 (C-3'), 32.0 (C-5'), 35.8 (tBu), 42.9 (C-4'), 46.6 (C-6'), 53.7 (C-
381.2879; found: 381.2879.
Cyclohexanol 4e: 7-Keto-2-enimide 2e (41 mg, 0.14 mmol) was dissolved
in THF (3 mL), and CuBr/dimethylsulfide complex (143 mg, 0.69 mmol)
and allylmagnesium chloride (2m in hexane, 0.35 mL, 0.70 mmol) were
added as described above. Flash chromatography over silica gel (diethyl
ether/pentane 1:2) gave 4e (38 mg, 81%) as a colorless oil. [a]2D0 ˆ ‡33.0
(c ˆ 0.5 in CHCl3); IR (film): nÄ ˆ 3501 (OH), 2963 (CH3), 1783, 1672
ˆ
2'), 61.9 (C-4), 65.35 (C-5), 70.75 (C-1'), 154.6 (C-2), 178.2 (C O); MS
‡
‡
(70 eV, EI): m/z (%): 311 (17) [M ], 296 (38) [M À CH3], 212 (67), 153
‡
‡
(imide), 1263, 1183, 1104 cmÀ1 (C O); 1H NMR (200 MHz, CDCl3): d ˆ
(69) [M À oxazolidinone À O], 144 (100) [oxazolidinone ‡2H]; HRMS:
m/z: calcd for C17H29NO4: 311.2096; found: 311.2096.
À
0.68 (q, J ˆ 12.0 Hz, 1H; 4'-H3), 0.88 (d, J ˆ 6.5 Hz, 3H; 5'-CH3), 0.99 (s,
9H; tBu), 1.08 (s, 3H; 1'-CH3), 1.20 2.30 (m, 7H; 3'-H, 4'-H, 5'-H, 6'-H2,
1''-H2), 3.65 (d, J ˆ 2.0 Hz, 1H; OH), 3.80 (d, J ˆ 10.5 Hz, 1H; 2'-H), 4.20
Cyclohexanol 4b: CuBr/dimethylsulfide complex (146 mg, 0.72 mmol) was
suspended in dry THF (3 mL) and cooled to À408C at which temperature
Chem. Eur. J. 2002, 8, No. 11
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0811-2591 $ 20.00+.50/0
2591

C. Schneider and O. Reese
FULL PAPER
(dd, J ˆ 9.5, 7.5 Hz, 1H; 5-H), 4.34 (dd, J ˆ 9.5, 1.5 Hz, 1H; 5-H), 4.52 (dd,
were added as described above. Purification by flash chromatography over
silica gel (diethyl ether/pentane 1:1) gave 4i (100 mg, 60%) as a white solid.
M.p. 1988C; [a]2D0 ˆ À49.8 (c ˆ 1.0 in CHCl3); IR (KBr): nÄ ˆ 3466 (OH),
ˆ
J ˆ 7.5, 1.5 Hz, 1H; 4-H), 4.95 5.09 (m, 2H; CH CH2), 5.67 5.90 (m, 1H;
CH CH2); 13C NMR (50 MHz, CDCl3): d ˆ 21.9 (CH3), 26.0 (tBu), 26.6,
ˆ
2966 (CH3), 1775, 1689 (imide), 1258, 1215, 1192, 1104 cmÀ1 (C O);
À
29.1, 36.6 (C-3', C-5', C-1'-Me), 35.8 (tBu), 38.55, 39.05, 49.8 (C-4', C-1'',
C-6'), 52.45 (C-2'), 62.0 (C-4), 65.4 (C-5), 70.8 (C-1'), 116.8 (CH CH2),
1H NMR (200 MHz, CDCl3): d ˆ 1.05 (s, 9H; tBu), 1.20 (s, 3H; 3'-CH3), 1.53
(td, J ˆ 12.5, 2.5 Hz, 1H; 4'-H), 1.76 (q, J ˆ 12.5 Hz, 1H; 6'-H), 1.93 (ddd,
J ˆ 12.5, 3.5, 1.0 Hz, 1H; 4'-H), 2.27 (m, 1H; 6'-H), 3.13 (tt, J ˆ 12.5, 3.5 Hz,
1H; 5'-H), 3.71 (td, J ˆ 12.5, 2.5 Hz, 1H; 1'-H), 3.97 (d, J ˆ 2.5 Hz, 1H;
OH), 4.25 (dd, J ˆ 9.0, 7.5 Hz, 1H; 5-H), 4.37 (d, J ˆ 12.5 Hz, 1H; 2'-H),
4.38 (dd, J ˆ 9.0, 1.0 Hz, 1H; 5-H), 4.62 (dd, J ˆ 7.5, 1.0 Hz, 1H; 4-H), 7.13
7.45 (m, 10H; phenyl-H); 13C NMR (50 MHz, CDCl3): d ˆ 25.9 (tBu), 29.1
(C-3'-Me), 36.3 (tBu), 38.3 (C-5'), 41.1, 45.2 (C-4', C-6'), 47.8 (C-1'), 51.6 (C-
2'), 62.0 (C-4), 65.4 (C-5), 71.7 (C-3'), 126.3, 127.0, 127.5, 128.5, 128.9, 132.8,
ˆ
ˆ
ˆ
136.1 (CH CH2), 154.5 (C-2), 177.9 (C O); MS (70 eV, EI): m/z (%): 337
‡
‡
‡
(3) [M ], 322 (15) [M À Me], 296 (100) [M À allyl], 144 (72)
‡
[oxazolidinone ‡2H]; HRMS: m/z: calcd for C19H31NO4: 337.2253; found:
337.2253.
Cyclohexanol 4 f: 7-Keto-2-enimide 2e (63 mg, 0.21 mmol) was dissolved
in THF (4 mL), and CuBr/dimethylsulfide complex (66 mg, 0.32 mmol) and
phenylmagnesium chloride (2m in hexane, 0.32 mL, 0.64 mmol) were
added as described above. Flash chromatography over silica gel (diethyl
ether/pentane 1:1) gave 4 f (42 mg, 53%) as a white solid. M.p. 1308C;
[a]2D0 ˆ ‡24.0 (c ˆ 0.5 in CHCl3); IR (KBr): nÄ ˆ 3541 (OH), 2963 (CH3),
ˆ
134.0, 145.0 (phenyl-C), 154.4 (C-2), 176.3 (C O); MS (70 eV, EI): m/z (%):
‡
‡
467 (88) [M ], 358 (53) [M À SPh], 340 (82), 197 (93), 157 (100), 144 (86)
‡
1772, 1701 (imide), 1268, 1225, 1186, 1102 cmÀ1 (C O); 1H NMR
[oxazolidinone ‡2H]; HRMS: m/z: calcd for C27H33NO4S: 467.2130;
À
found: 467.2130.
(300 MHz, CDCl3): d ˆ 0.38 (s, 9H; tBu), 0.89 (d, J ˆ 7.5 Hz, 3H; 5'-CH3),
0.80 1.25, 1.76 1.90 (m, 4H; 4'-H2, 6'-H2), 1.14 (s, 3H; 1'-CH3), 2.02 2.21
(m, 1H; 5'-H), 3.30 (td, J ˆ 11.5, 3.5 Hz, 1H; 3'-H), 3.54 (d, J ˆ 2.0 Hz, 1H;
OH), 4.06 (dd, J ˆ 9.0, 7.5 Hz, 1H; 5-H), 4.15 (dd, J ˆ 9.0, 1.5 Hz, 1H; 5-H),
4.31 (dd, J ˆ 7.5, 1.5 Hz, 1H; 4-H), 4.55 (d, J ˆ 11.5 Hz, 1H; 2'-H), 7.08 7.35
(m, 5H; phenyl-H); 13C NMR (50 MHz, CDCl3): d ˆ 21.7 (CH3), 25.0 (tBu),
27.4 (C-1'-Me), 29.15 (C-3'), 35.1 (tBu), 43.9 (C-4'), 44.4 (C-5'), 46.4 (C-6'),
51.6 (C-2'), 61.2 (C-4), 64.9 (C-5), 70.9 (C-1'), 126.7, 128.0, 128.6, 143.5
Cyclohexanol 4k: Trimethylsilyl azide (84 mL, 0.63 mmol) was dissolved in
THF (2 mL), and methanol (25 mL, 0.63 mmol) was added at 08C. After
1 h, Me3Al (2m in hexane, 0.32 mL, 0.64 mmol) was added. After stirring
for 1 h, 7-keto-2-enimide 2e (59 mg, 0.21 mmol) dissolved in THF (1 mL)
was added. The solution was stirred at 08C and then allowed to warm to RT
over 5 h. The reaction was quenched by the addition of saturated NH4Cl
solution, the layers were separated, and the aqueous phase was extracted
twice with diethyl ether. The combined organic extracts were dried over
MgSO4, filtered, and evaporated. The crude product was purified by flash
chromatography over silica gel (diethyl ether/pentane 1:1) to give 4k
(38 mg, 60%) as a white solid. M.p. 1648C; [a]2D0 ˆ À9.4 (c ˆ 0.5 in CHCl3);
ˆ
(phenyl-C), 154.3 (C-2), 176.7 (C O); MS (70 eV, EI): m/z (%): 373 (45)
‡
‡
[M ], 274 (72), 212 (50), 144 (65) [oxazolidinone ‡2H], 131 (100);
elemental analysis calcd (%) for C22H31NO4 (373.49): C 70.75, H 8.37;
found: C 70.52, H 8.47.
IR (film): nÄ ˆ 3523 (OH), 2969 (CH3), 2106 (azide), 1776, 1687 (imide),
Cyclohexanol 4g: 7-Keto-2-enimide 2 f (103 mg, 0.29 mmol) was dissolved
in THF (5 mL), and CuI (274 mg, 1.44 mmol), butyllithium (2.5m in
hexane, 0.58 mL, 1.44 mmol), and Me2AlCl (1m in hexane, 1.44 mL,
1.44 mmol) were added as described above. Flash chromatography over
silica gel (diethyl ether/pentane 1:2) gave 4g (61 mg, 51%) as a white solid.
M.p. 1248C; [a]2D0 ˆ ‡20.6 (c ˆ 0.5 in CHCl3), IR (KBr): nÄ ˆ 3492 (OH),
1
1216, 1189, 1109, 1052 cmÀ1 (C O); H NMR (500 MHz, CDCl3): d ˆ 0.96
À
(d, J ˆ 6.5 Hz, 3H; 5'-CH3), 0.97 (s, 9H; tBu), 1.01 (dd, J ˆ 13.5, 11.5 Hz,
1H; 6'-H), 1.11 (s, 3H; 1'-CH3), 1.23 (q, J ˆ 11.5 Hz, 1H; 4'-H), 1.72 (ddd,
J ˆ 13.5, 4.0, 1.5 Hz, 1H; 6'-H), 2.03 2.13 (m, 1H; 5'-H), 2.13 (dtd, J ˆ 11.5,
4.0, 1.5 Hz, 1H; 4'-H), 3.65 (brs, 1H; OH), 3.87 (td, J ˆ 11.5, 4.0 Hz, 1H; 3'-
H), 4.12 (d, J ˆ 11.5 Hz, 1H; 2'-H), 4.19 (dd, J ˆ 9.0, 7.5 Hz, 1H; 5-H), 4.32
(dd, J ˆ 9.0, 1.5 Hz, 1H; 5-H), 4.55 (dd, J ˆ 7.5, 1.5 Hz, 1H; 4-H); 13C NMR
(50 MHz, CDCl3): d ˆ 21.4 (CH3), 25.6 (tBu), 26.1 (CH3), 32.8 (C-5'), 36.05
(tBu), 38.4, 45.9 (C-4', C-6'), 52.0 (C-2'), 60.1 (C-3'), 61.3 (C-4), 65.2 (C-5),
2963 (CH3), 1769, 1670 (imide), 1219, 1105 cmÀ1 (C O); 1H NMR
À
(300 MHz, CDCl3): d ˆ 0.85 (t, J ˆ 7.0 Hz, 3H; CH3), 0.88 0.95 (m, 1H;
6'-H), 1.00 (s, 9H; tBu), 1.12 (s, 3H; 1'-CH3), 1.15 1.55 (m, 7H; 4'-H, butyl
side chain), 1.94 (ddd, J ˆ 13.5, 3.5, 1.5 Hz, 1H; 6'-H), 2.08 (dtd, J ˆ 13.0,
3.5, 1.5 Hz, 1H; 4'-H), 2.24 (m, 1H; 3'-H), 3.16 (tt, J ˆ 13.0, 3.5 Hz, 1H; 5'-
H), 3.85 (d, J ˆ 2.5 Hz, 1H; OH), 3.96 (d, J ˆ 11.5 Hz, 1H; 2'-H), 4.22 (dd,
J ˆ 9.5, 7.5 Hz, 1H; 5-H), 4.35 (dd, J ˆ 9.5, 1.5 Hz, 1H; 5-H), 4.56 (dd, J ˆ
7.5, 1.5 Hz, 1H; 4-H), 7.15 7.34 (m, 5H; phenyl-H); 13C NMR (50 MHz,
CDCl3): d ˆ 14.0 (CH3), 22.9, 28.6, 33.8 (butyl side chain), 25.9 (tBu), 29.2
(C-1'-Me), 35.8 (tBu), 37.0 (C-3'), 38.1 (C-5'), 38.2, 45.7 (C-4', C-6'), 52.8 (C-
2'), 61.9 (C-4), 65.35 (C-5), 70.8 (C-1'), 126.1, 127.0, 128.4, 146.3 (phenyl-C),
ˆ
71.5 (C-1'), 154.1 (C-2), 176.1 (C O); MS (200 eV, DCI/NH3): m/z (%): 695
‡
‡
‡
(15) [2M ‡NH3], 373 (100) [M ‡2NH3], 356 (76) [M ‡NH3]; elemental
analysis calcd (%) for C16H26N4O4 (338.40): C 56.79, H 7.74; found: C 57.12,
H 7.75.
Cyclohexanol 4l: 7-Keto-2-enimide 2e (51 mg, 0.17 mmol) was dissolved in
CH2Cl2 (3 mL) and cooled to 08C. Piperidine (51 mL, 0.52 mmol) and then
Me2AlCl (1m in hexane, 0.52 mL, 0.52 mmol) were added. Stirring was
continued for 1 h at 08C, and the reaction was then stopped by the addition
of saturated NaHCO3 solution. The layers were separated, the aqueous
phase was extracted twice with diethyl ether, and the combined organic
extracts were dried over MgSO4. After filtration and evaporation of the
solvents, the crude product was purified by flash chromatography over
silica gel (diethyl ether/pentane 1:1) to give 4l (26 mg, 40%) as a white
solid. M.p. 1458C; [a]2D0 ˆ ‡20.6 (c ˆ 0.5 in CHCl3); IR (KBr): nÄ ˆ 3538
‡
ˆ
154.5 (C-2), 178.0 (C O); MS (70 eV, EI): m/z (%): 415 (3) [M ], 397 (52),
254 (34), 226 (100), 169 (61); elemental analysis calcd (%) for C25H37NO4
(415.57): C 72.26, H 8.97; found: C 72.22, H 8.71.
Cyclohexanol 4h: 7-Keto-2-enimide 2e (100 mg, 0.34 mmol) was dissolved
in THF (5 mL), and thiophenol (36 mL, 0.36 mmol), butyllithium (2.5m in
hexane, 142 mL, 0.36 mmol), and Me3Al (2m in hexane, 178 mL, 0.36 mmol)
were added as described above. Purification by flash chromatography over
silica gel (diethyl ether/pentane 1:1) gave 4h (108 mg, 76%) as a white
solid. M.p. 478C; [a]2D0 ˆ ‡23.0 (c ˆ 0.4 in CHCl3); IR (KBr): nÄ ˆ 3486, 2960
(OH), 2943 (CH3), 1777, 1708 (imide), 1276, 1217, 1182, 1100, 1059 cmÀ1
1
À
(C O); H NMR (200 MHz, CDCl3): d ˆ 0.80 2.09 (m, 11H; 4'-H2, 5'-H,
(CH3), 1782, 1673 (imide), 1263, 1228, 1104 cmÀ1 (C O); 1H NMR
À
6'-H2, piperidine ring protons), 0.92 (d, J ˆ 7.5 Hz, 3H; 5'-CH3), 1.03 (s, 9H;
tBu), 1.08 (s, 3H; 1'-CH3), 2.28 2.42, 2.74 2.88 (2m, 4H; NCH), 3.16 (td,
J ˆ 11.5, 3.5 Hz, 1H; 3'-H), 3.88 (d, J ˆ 2.0 Hz, 1H; OH), 4.18 (dd, J ˆ 9.5,
7.5 Hz, 1H; 5-H), 4.24 (d, J ˆ 11.5 Hz, 1H; 2'-H), 4.31 (dd, J ˆ 9.5, 1.5 Hz,
1H; 5-H), 4.55 (dd, J ˆ 7.5, 1.5 Hz, 1H; 4-H); 13C NMR (50 MHz, CDCl3):
d ˆ 21.9 (CH3), 25.6 (tBu), 24.9, 26.3 (piperidine ring), 26.4 (C-1'-Me), 29.3
(C-5'), 31.4 (C-4'), 36.1 (tBu), 46.75 (C-6'), 50.3 (NCH2), 50.75 (C-2'), 61.5
(500 MHz, CDCl3): d ˆ 0.84 (d, J ˆ 6.5 Hz, 3H; 5'-CH3), 1.00 (dd, J ˆ
13.5, 12.0 Hz, 1H; 4'-H), 1.04 (s, 9H; tBu), 1.14 (s, 3H; 3'-CH3), 1.20 (q,
J ˆ 12.0 Hz, 1H; 6'-H), 1.72 (dd, J ˆ 13.5, 3.5 Hz, 1H; 4'-H), 1.96 (m, 1H; 5'-
H), 2.07 (dt, J ˆ 12.0, 4.0 Hz, 1H; 6'-H), 3.58 (td, J ˆ 12.0, 4.0 Hz, 1H; 1'-H),
4.22 (d, J ˆ 12.0 Hz, 1H; 2'-H), 4.24 (dd, J ˆ 9.0, 7.5 Hz, 1H; 5-H), 4.36 (dd,
J ˆ 9.0, 1.0 Hz, 1H; 5-H), 4.58 (dd, J ˆ 7.5, 1.0 Hz, 1H; 4-H), 7.23 7.32 (m,
5H; phenyl-H); 13C NMR (50 MHz, CDCl3): d ˆ 21.4 (CH3), 25.9 (tBu),
27.1 (CH3), 29.1 (C-5'), 36.3 (tBu), 42.4, 46.0 (C-4', C-6'), 47.35 (C-1'), 51.8
(C-2'), 62.0 (C-4), 65.35 (C-5), 71.7 (C-3'), 127.3, 128.9, 132.6, 134.3 (phenyl-
ˆ
(C-4), 64.15 (C-3'), 65.1 (C-5), 71.5 (C-1'), 154.6 (C-2), 177.5 (C O); MS
(70 eV, EI): m/z (%): 380 (54) [M ], 138 (100); HRMS: m/z: calcd for
‡
C21H36N2O4: 380.2675; found: 380.2675.
ˆ
ˆ
C), 154.4 (C O, urethane), 176.4 (C O, amide); MS (70 eV, EI): m/z (%):
Cyclohexylamine 5a: 7-Oxo-2-enimide 2a (56 mg, 0.20 mmol) was dis-
solved in CH2Cl2 (3 mL) and cooled to 08C. Morpholine (52 mL,
0.60 mmol) and then Me2AlCl (1m in hexane, 0.40 mL, 0.40 mmol) were
added. After 1 h, the reaction was stopped by the addition of saturated
NaHCO3 solution. The layers were separated, the aqueous phase was
extracted twice with diethyl ether, and the combined organic extracts were
dried over MgSO4. After filtration and evaporation of solvents, the crude
‡
‡
‡
405 (100) [M ], 296 (77) [M À SPh], 278 (98) [M À OH À H], 144 (44)
‡
[oxazolidinone ‡2H], 135 (50); elemental analysis calcd (%) for
C22H31NO4S (405.55): C 65.40, H 7.88; found: C 65.15, H 7.70.
Cyclohexanol 4i: 7-Keto-2-enimide 2 f (127 mg, 0.36 mmol) was dissolved
in THF (5 mL), and thiophenol (40 mL, 0.39 mmol), butyllithium (2.5m in
hexane, 156 mL, 0.36 mmol), and Me3Al (2m in hexane, 196 mL, 0.36 mmol)
2592
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0811-2592 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 11

Functionalized Cyclohexanes
2585 2594
product was purified by column chromatography over silica gel (diethyl
ether/pentane 1:2) to give 5a (60 mg, 69%) as a white solid. M.p. 1788C;
[a]2D0 ˆ ‡40.0 (c ˆ 0.8 in CHCl3); IR (KBr): nÄ ˆ 2956 (CH), 2852 (N-CH2),
31.9, 32.4 (C-4', C-6'), 35.6 (tBu), 47.4 (C-2'), 50.3, 50.6 (NCH2), 61.8 (C-4),
ˆ
62.3, 63.3 (C-1', C-3'), 65.0 (C-5), 155.1 (C-2), 176.0 (C O); MS (70 eV, EI):
‡
‡
m/z (%): 521 (2) [M ], 393 (97) [M À NBu2], 222 (36), 182 (100);
elemental analysis calcd (%) for C31H59N3O3 (521.46): C 71.40, H 11.40;
found: C 71.64, H 11.50.
1769, 1703 (imide), 1213, 1187, 1118, 1070, 1034 cmÀ1 (C O); 1H NMR
À
(500 MHz, CDCl3): d ˆ 0.85, 0.89 (2q, J ˆ 11.5 Hz, 2H; 4'-H, 6'-H), 0.98 (d,
J ˆ 6.5 Hz, 3H; 5'-Me), 0.99 (s, 9H; tBu), 1.34 1.45 (m, 1H; 5'-H), 1.77 (m,
2H; 4'-H, 6'-H), 2.31, 2.39 (2ddd, J ˆ 11.0, 6.0, 3.0 Hz, 4H; NCH), 2.64
2.70 (m, 2H; NCH), 2.74 (td, J ˆ 11.5, 3.5 Hz, 1H; 3'-H), 2.82 2.90 (m, 2H;
NCH), 2.86 (td, J ˆ 11.5, 3.5 Hz, 1H; 1'-H), 3.42 3.65 (m, 8H; OCH), 4.19
(dd, J ˆ 9.0, 7.5 Hz, 1H; 5-H), 4.25 (t, J ˆ 11.5 Hz, 1H; 2'-H), 4.28 (dd, J ˆ
9.0, 1.5 Hz, 1H; 5-H), 4.52 (dd, J ˆ 7.5, 1.5 Hz, 1H; 4-H); 13C NMR
(50 MHz, CDCl3): d ˆ 22.3 (C-5'-Me), 25.7 (tBu), 29.8 (C-5'), 31.5, 32.6 (C-
4', C-6'), 36.0 (tBu), 46.7 (C-2'), 49.15, 49.9 (NCH2), 61.6 (C-4), 65.15 (C-5),
Cyclohexylamine 5e: 7-Oxo-2-enimide 2b (116 mg, 0.34 mmol) was
dissolved in CH2Cl2 (5 mL), and piperidine (100 mL, 1.01 mmol) and
Me2AlCl (1m in hexane, 0.68 mL 0.68 mmol) were added as described
above. Column chromatography over silica gel (diethyl ether/pentane 1:2)
gave the cyclohexylamine 5e (95 mg, 57%) as a white solid. M.p. 1718C;
[a]2D0 ˆ ‡40.4 (c ˆ 0.5 in CHCl3); IR (KBr): nÄ ˆ 2933 (CH), 1778, 1703
(imide), 1254, 1187, 1105, 1061, 1035 cmÀ1 (C O); 1H NMR (500 MHz,
À
CDCl3): d ˆ 1.02 (s, 9H; tBu), 1.25 1.55 (m, 14H; 4'-H, 6'-H, 6CH2
(piperidine)), 1.91 2.01 (m, 2H; 4'-H, 6'-H), 2.31, 2.34 (2m, 4H; NCH),
2.51 (tt, J ˆ 12.5, 3.0 Hz, 1H; 5'-H), 2.66, 2.85 (2m, 4H; NCH), 2.88, 2.99
(2td, J ˆ 11.5, 3.5 Hz, 2H; 1'-H, 3'-H), 4.18 (dd, J ˆ 9.0, 7.5 Hz, 1H; 5-H),
4.28 (dd, J ˆ 9.0, 1.0 Hz, 1H; 5-H), 4.42 (t, J ˆ 11.5 Hz, 1H; 2'-H), 4.54 (dd,
J ˆ 7.5, 1.0 Hz, 1H; 4-H), 7.18 7.33 (m, 5H; phenyl-H); 13C NMR (50 MHz,
CDCl3): d ˆ 24.8, 25.0 (C-4'' (piperidine)), 25.8 (tBu), 26.5 (C-3'' (piper-
idine)), 27.3 (C-5'' (piperidine)), 30.9, 32.0 (C-4', C-6'), 35.9 (tBu), 41.5 (C-
5'), 47.1 (C-2'), 50.2, 50.9 (piperidine-NCH), 61.6 (C-4), 65.1 (C-5), 67.1, 67.8
ˆ
66.2, 67.0 (C-1', C-3'), 67.4, 68.1 (OCH2), 155.3 (C-2), 176.1 (C O); MS
‡
‡
(70 eV, EI): m/z (%): 438 (13) [M ], 351 (25) [M À C4H8NO], 180 (46),
165, 140 (100); HRMS: m/z: calcd for C23H39N3O5: 437.2889; found:
437.2889.
Cyclohexylamine 5b: 7-Oxo-2-enimide 2a (58 mg, 0.21 mmol) was dis-
solved in CH2Cl2 (3 mL), and diethylamine (53 mL, 0.62 mmol) and
Me2AlCl (1m in hexane, 0.41 mL, 0.41 mmol) were added as described
above. Column chromatography over silica gel (diethyl ether/pentane 1:2)
gave the cyclohexylamine 5b (39 mg, 46%) as a white solid. M.p. 1288C;
ˆ
(C-1', C-3'), 126.2, 126.8, 128.5, 146.4 (phenyl-C), 155.1 (C-2), 176.3 (C O);
‡
‡
[a]2D0 ˆ ‡65.8 (c ˆ 0.5 in CHCl3); IR (KBr): nÄ ˆ 2870 (CH), 1776, 1704
MS (70 eV, EI): m/z (%): 495 (24) [M ], 411 (43) [M À piperidine], 240
(38), 200 (100); elemental analysis calcd (%) for C30H45N3O3 (495.70): C
72.69, H 9.15; found: C 72.91, H 9.19.
1
(imide), 1264, 1184, 1130, 1096 cmÀ1 (C O); H NMR (500 MHz, CDCl3):
À
d ˆ 0.80 1.11 (m, 2H; 4'-H, 6'-H), 0.88 (t, J ˆ 7.0 Hz, 6H; 2N-CH2-CH3),
0.94 (t, J ˆ 7.0 Hz, 6H; 2N-CH2-CH3), 0.97 (s, 9H; tBu), 1.36 (m, 1H; 5'-H),
1.65 1.76 (m, 2H; 4'-H, 6'-H), 2.23, 2.30 (2dq, J ˆ 13.0, 6.5 Hz, 4H; NCH),
2.50, 2.70 (2dq, J ˆ 13.0, 7.0 Hz, 4H; NCH), 2.88, 3.02 (2ddd, J ˆ 12.0, 11.0,
3.5 Hz, 2H; 1'-H, 3'-H), 4.11 (dd, J ˆ 9.0, 7.5 Hz, 1H; 5-H), 4.23 (dd, J ˆ 9.0,
1.5 Hz, 1H; 5-H), 4.25 (t, J ˆ 11.0 Hz, 1H; 2'-H), 4.44 (dd, J ˆ 7.5, 1.5 Hz,
1H; 4-H); 13C NMR (50 MHz, CDCl3): d ˆ 14.1, 14.5 (2NCH2CH3), 22.45
(C-5'-Me), 25.8 (tBu), 30.2 (C-5'), 32.05, 32.8 (C-4', C-6'), 35.6 (tBu), 43.5,
43.6 (2NCH2), 47.6 (C-2'), 61.1 (C-4), 61.6, 62.6 (C-1', C-3'), 62.05 (C-5),
Cyclohexylamine 5 f: 7-Oxo-2-enimide 2c (43 mg, 0.11 mmol) was dis-
solved in CH2Cl2 (3 mL), and piperidine (53 mL, 0.54 mmol) and Me2AlCl
(1m in hexane, 0.32 mL, 0.32 mmol) were added as described above.
Column chromatography over silica gel (diethyl ether/pentane 1:2) gave
the cyclohexylamine 5 f (35 mg, 59%) as a white solid. M.p. 788C; [a]D20
ˆ
‡32.0 (c ˆ 0.5 in CHCl3); IR (KBr): nÄ ˆ 2932 (CH), 1778, 1702 (imide),
1
1262, 1230, 1187, 1104, 1060 cmÀ1 (C O); H NMR (300 MHz, CDCl3): d ˆ
À
0.23 (s, 6H; SiMe2), 0.67 (tt, J ˆ 13.0, 2.5 Hz, 1H; 1'-H), 0.97 (s, 9H; tBu),
0.88 1.51 (m, 14H; 2'-H, piperidine ring protons), 1.65 1.81 (m, 2H; 4'-H,
6'-H), 2.52 2.82 (m, 8H; N-CH), 2.64, 2.76 (2td, J ˆ 11.5, 3.5 Hz, 2H; 3'-H,
5'-H), 4.13 (dd, J ˆ 9.0, 7.5 Hz, 1H; 5-H), 4.22 (dd, J ˆ 9.0, 1.5 Hz, 1H; 5-H),
4.24 (t, J ˆ 11.5 Hz, 1H; 4'-H), 4.58 (dd, J ˆ 7.5, 1.5 Hz, 1H; 4-H), 7.31 7.52
(m, 5H; phenyl-H); 13C NMR (75 MHz, CDCl3): d ˆ À4.8, À4.8 (SiMe2),
21.5 (C-1'), 23.2, 24.3, 24.8, 25.0 (piperidine ring), 25.75 (tBu), 26.5, 27.3 (C-
2', C-6'), 35.8 (tBu), 47.6 (C-4'), 50.1, 50.8 (piperidine-NCH), 61.5 (C-4), 65.0
(C-5), 68.8, 69.6 (C-3', C-5'), 127.8, 128.9, 133.8, 137.9 (phenyl-C), 155.1 (C-
‡
ˆ
155.1 (C-2), 175.2 (C O); MS (70 eV, EI): m/z (%): 409 (6) [M ], 337 (35)
‡
‡
[M À NEt2], 307 (16), 166 (20) [M À (NBn2)2 À CH3], 151 (26), 126 (100);
elemental analysis calcd (%) for C23H43N3O3 (409.61): C 67.44, H 10.58;
found: C 67.49, H 10.50.
Cyclohexylamine 5c: 7-Oxo-2-enimide 2a (64 mg, 0.23 mmol) was dis-
solved in CH2Cl2 (3 mL), and dibenzylamine (131 mL, 0.68 mmol) and
Me2AlCl (1m in hexane, 0.45 mL, 0.45 mmol) were added as described
above. Column chromatography over silica gel (diethyl ether/pentane 1:2)
gave the cyclohexylamine 5c (105 mg, 70%) as a white solid. M.p. 1488C;
[a]2D0 ˆ ‡14.7 (c ˆ 1.0 in CHCl3); IR (KBr): nÄ ˆ 3027 (phenyl-H), 2956
‡
‡
ˆ
2), 176.4 (C O); MS (70 eV, EI): m/z (%): 553 (40) [M ], 469 (40) [M
À
piperidine], 333 (59), 281 (49), 258 (100), 138 (77), 111 (49); HRMS: m/z
(CH), 1776, 1702 (imide), 1187, 1068 cmÀ1 (C O); 1H NMR (500 MHz,
calcd for C32H51N3O3Si: 553.3699; found: 553.3699.
À
CDCl3): d ˆ 0.87 (d, J ˆ 6.5 Hz, 3H; 5'-Me), 0.87 1.01 (m, 2H; 4'-H, 6'-H),
1.04 (s, 9H; tBu), 1.15 1.31 (m, 1H; 5'-H), 1.48 1.54, 1.76 1.82 (2m, 2H;
4'-H, 6'-H), 3.07, 3.26 (2ddd, J ˆ 12.0, 10.5, 3.5 Hz, 2H; 1'-H, 3'-H), 3.46,
3.47, 3.83, 3.94 (4d, J ˆ 14.0 Hz, 8H; N-Bn-H), 4.15 (dd, J ˆ 9.0, 7.5 Hz, 1H;
5-H), 4.21 (dd, J ˆ 9.0, 1.5 Hz, 1H; 5-H), 4.44 (dd, J ˆ 7.5, 1.5 Hz, 1H; 4-H),
4.54 (t, J ˆ 10.5 Hz, 1H; 2'-H), 7.14 7.28 (m, 20H; phenyl-H); 13C NMR
(50 MHz, CDCl3): d ˆ 22.4 (C-5'-Me), 26.0 (tBu), 29.4 (C-5'), 32.9, 33.5 (C-
4', C-6'), 35.7 (tBu), 47.1 (C-2'), 53.8, 54.1 (benzyl-C), 62.0, 62.5 (C-1', C-3'),
62.65 (C-4), 65.1 (C-5), 126.6, 126.7, 127.9, 128.0, 128.1, 129.2, 139.1, 139.5
Cyclohexylamine 5g: 7-Oxo-2-enimide 2c (45 mg, 0.11 mmol) was dis-
solved in CH2Cl2 (3 mL), and morpholine (59 mL, 0.67 mmol) and Me2AlCl
(1m in hexane, 0.45 mL, 0.45 mmol) were added as described above.
Column chromatography over silica gel (diethyl ether/pentane 1:2) gave
the cyclohexylamine 5g (33 mg, 53%) as a white solid. M.p. 888C; [a]D20
ˆ
‡32.0 (c ˆ 0.5 in CHCl3); IR (KBr): nÄ ˆ 2959 (CH), 1775, 1701 (imide),
1270, 1216, 1186, 1117, 1069 cmÀ1 (C O); H NMR (500 MHz, CDCl3): d ˆ
1
À
0.26 (s, 6H; SiMe2), 0.67 (tt, J ˆ 12.5, 2.5 Hz, 1H; 1'-H), 0.88 1.02 (m, 2H;
2'-H, 6'-H), 0.97 (s, 9H; tBu), 1.71 1.85 (m, 2H; 2'-H, 6'-H), 2.24 2.40 (m,
4H; N-CH), 2.60 2.67 (m, 2H; N-CH), 2.79 2.86 (m, 2H; N-CH), 2.68,
2.80 (td, J ˆ 11.5, 3.5 Hz, 2H; 3'-H, 5'-H), 3.39 3.64 (m, 8H; OCH), 4.17
(dd, J ˆ 9.0, 7.5 Hz, 1H; 5-H), 4.23 (t, J ˆ 11.5 Hz, 1H; 4'-H), 4.27 (dd, J ˆ
9.0, 1.5 Hz, 1H; 5-H), 4.51 (dd, J ˆ 7.5, 1.5 Hz, 1H; 4-H), 7.35 7.42 (m, 5H;
phenyl-H); 13C NMR (50 MHz, CDCl3): d ˆ À4.75 (SiMe2), 21.7 (C-1'),
23.6, 24.7 (C-2', C-6'), 26.0 (tBu), 36.2 (tBu), 47.4 (C-4'), 49.3, 50.0 (N-CH),
61.8 (C-4), 65.4 (C-5), 67.6, 68.25 (OCH), 68.4, 69.2 (C-3', C-5'), 128.1, 129.4,
ˆ
(phenyl-C), 155.1 (C-2), 175.1 (C O); MS (70 eV, EI): m/z (%): 657 (2)
‡
‡
‡
‡
[M ], 567 (95) [M À Bn], 462 (48) [M À NBn2], 250 (61) [M
À
(NBn2)2 À CH3], 91 (100); HRMS: m/z: calcd for C43H51N3O5: 657.3930;
found: 657.3930.
Cyclohexylamine 5d: 7-Oxo-2-enimide 2a (38 mg, 0.135 mmol) was
dissolved in CH2Cl2 (3 mL), and dibutylamine (68 mL, 0.41 mmol) and
Me2AlCl (1m in hexane, 0.27 mL 0.27 mmol) were added as described
above. Column chromatography over silica gel (diethyl ether/pentane 1:2)
gave the cyclohexylamine 5d (46 mg, 65%) as a white solid. M.p. 1088C;
ˆ
134.0, 137.6 (phenyl-C), 155.5 (C-2), 176.1 (C O); MS (70 eV, EI): m/z (%):
‡
‡
557 (74) [M ], 471 (31) [M À morpholine], 335 (73), 300 (80), 283 (83),
260 (100), 140 (73); HRMS: m/z: calcd for C30H47N3O5Si: 557.3285; found:
557.3285.
[a]2D0 ˆ ‡56.0 (c ˆ 0.5 in CHCl3); IR (KBr): nÄ ˆ 2870 (CH), 1780, 1704
1
(imide), 1262, 1211, 1184, 1095 cmÀ1 (C O); H NMR (500 MHz, CDCl3):
À
d ˆ 0.83, 0.86 (2t, J ˆ 7.0 Hz, 6H; CH3), 0.97 (s, 9H; tBu), 1.02 1.48 (m,
19H; 4'-H, 5'-H, 6'-H, butyl side chain), 1.71 (m, 2H; 4'-H, 6'-H), 2.19, 2.33.
2.57 (3m, 8H; NCH), 2.77, 2.95 (2ddd, J ˆ 12.0, 11.0, 3.5 Hz, 2H; 1'-H, 3'-
H), 4.09 (dd, J ˆ 9.0, 7.0 Hz, 1H; 5-H), 4.21 (dd, J ˆ 9.0, 1.0 Hz, 1H; 5-H),
4.23 (t, J ˆ 11.0 Hz, 1H; 2'-H), 4.38 (dd, J ˆ 7.0, 1.0 Hz, 1H; 4-H); 13C NMR
(50 MHz, CDCl3): d ˆ 14.2, 14.2 (NCH2CH3), 20.6, 20.85 (N-butyl side
chain), 22.45 (C-5'-Me), 25.7 (tBu), 30.1 (C-5'), 31.5 (N-butyl side chain),
Cyclohexylamine 5h: 7-Oxo-2-enimide 2a (79 mg, 0.28 mmol) was dis-
solved in CH2Cl2 (4 mL), and piperidine (28 mL, 0.28 mmol) and a small
amount of MgSO4 were added. After stirring for 1 h, the MgSO4 was
filtered off, and the solvent was evaporated in vacuo. In a second flask,
thiophenol (35 mL, 0.34 mmol) was dissolved in THF (10 mL), and
butyllithium (2.5m in hexane, 0.27 mL, 0.67 mmol) and Me3Al (2m in
hexane, 0.17 mL, 0.34 mmol) were added. After stirring for 1 h at 08C, the
Chem. Eur. J. 2002, 8, No. 11
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C. Schneider and O. Reese
FULL PAPER
solution was cooled to À508C, and the enamine dissolved in THF (1 mL)
was added by syringe. After another 10 min, Me2AlCl (1m in hexane,
0.34 mL, 0.34 mmol) was added and the reaction mixture was stirred for 8 h
(at which time the reaction temperature had reached RT). Saturated NaCl
solution was added, the layers were separated, and the aqueous phase was
extracted twice with ether. The combined organic extracts were dried over
MgSO4, filtered, and evaporated. Chromatographic purification over silica
gel (diethyl ether/pentane 1:1) gave cyclohexylamine 5h (64 mg, 50%) as a
colorless oil. [a]2D0 ˆ ‡35.3 (c ˆ 0.3 in CHCl3); IR (KBr): nÄ ˆ 2930 (CH),
[2] a) C. Schneider, Synlett 1997, 815 817; b) C. Schneider, A. Schuffen-
hauer, Eur. J. Org. Chem. 2000, 73 82.
[3] a) C. Schneider, C. Bˆrner, Synlett 1998, 652 654; b) C. Schneider, C.
Bˆrner, A. Schuffenhauer, Eur. J. Org. Chem. 1999, 3353 3362.
[4] C. Schneider, Eur. J. Org. Chem. 1998, 1661 1663.
[5] a) C. Schneider, M. Rehfeuter, Tetrahedron Lett. 1998, 39, 9 12; b) C.
Schneider, M. Rehfeuter, Chem. Eur. J. 1999, 5, 2850 2858.
[6] C. Schneider, O. Reese, Angew. Chem. 2000, 112, 3074 3076; Angew.
Chem. Int. Ed. 2000, 39, 2948 2950.
1780, 1696 (imide), 1260, 1223, 1186, 1119, 1096 cmÀ1 (C O); 1H NMR
[7] For a review, see: R. J. K. Taylor, Synthesis 1985, 364 392; for an
elegant application towards a prostaglandin synthesis, see: R. Noyori,
M. Suzuki, Angew. Chem. 1984, 96, 854 882; Angew. Chem. Int. Ed.
Engl. 1984, 23, 847 875; for some recent work, see: K. Takasu, K.
Misawa, M. Yamada, Y. Furuta, T. Taniguchi, M. Ihara, Chem.
Commun. 2000, 1739 1740; H. Paulsen, S. Antons, A. Brandes, M.
Lˆgers, S. N. M¸ller, P. Naab, C. Schmeck, S. Schneider, J. Stoltefu˚,
Angew. Chem. 1999, 111, 3574 3576; Angew. Chem. Int. Ed. 1999, 38,
3373 3375; M. Ono, K. Nishimura, Y. Nagaoka, K. Tomioka,
Tetrahedron Lett. 1999, 40, 1509 1512; F. Dinon, E. Richards, P. J.
Murphy, D. E. Hibbs, M. B. Hursthouse, K. M. A. Malik, Tetrahedron
Lett. 1999, 40, 3279 3282; B. L. Feringa, M. Pineschi, L. A. Arnold, R.
Imbos, A. H. M. de Vries, Angew. Chem. 1997, 109, 2733 2736;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2620 2623; S. G. Davies, D. R.
Fenwick, Chem. Commun. 1997, 565 566; A. G. M. Barrett, A.
Kamimura, J. Chem. Soc. Chem. Commun. 1995, 1755 1756; Y.
Yamamoto, N. Asao, T. Yuehara, J. Am. Chem. Soc. 1992, 114, 5427
5428.
[8] F. N‰f, R. Decorzant, W. Thommen, Helv. Chim. Acta 1975, 58, 1808
1812.
[9] A. Itoh, S. Ozawa, K. Oshima, H. Nozaki, Bull. Chem. Soc. Jpn. 1981,
54, 274 278.
[10] C. Schneider, O. Reese, Synthesis 2000, 1689 1694.
[11] a) Y. Yamamoto, K. Maruyama, J. Am. Chem. Soc. 1978, 100, 3240
3241; b) Y. Yamamoto, S. Yamamoto, H. Yatagai, Y. Ishihara, K.
Maruyama, J. Org. Chem. 1982, 47, 119 126.
[12] For reviews, see: a) L. F. Tietze, Chem. Rev. 1996, 96, 115 136;
b) L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137 170; Angew.
Chem. Int. Ed. Engl. 1993, 32, 131 164.
À
(500 MHz, CDCl3): d ˆ 0.89 (d, J ˆ 6.5 Hz, 3H; 5'-CH3), 0.94 (q, J ˆ
12.5 Hz, 1H; 4'-H), 1.02 (s, 9H; tBu), 1.08 (q, J ˆ 13.0 Hz, 1H; 6'-H),
1.20 1.70 (m, 7H; 5'-H, piperidine-CH2), 1.74 (ddt, J ˆ 12.5, 3.5, 1.5 Hz,
1H, 4'-H), 1.97 (dtd, J ˆ 13.0, 3.5, 1.5 Hz, 1H; 6'-H), 2.25, 2.63 (2m, 4H;
NCH), 2.75 (ddd, J ˆ 12.5, 11.5, 3.5 Hz, 1H; 3'-H), 3.31 (ddd, J ˆ 13.0, 11.5,
3.5 Hz, 1H; 1'-H), 4.22 (dd, J ˆ 9.0, 7.5 Hz, 1H; 5-H), 4.24 (t, J ˆ 11.5 Hz,
1H; 2'-H), 4.31 (dd, J ˆ 9.0, 1.5 Hz, 1H; 5-H), 4.54 (dd, J ˆ 7.5, 1.5 Hz, 1H;
4-H), 7.19 7.56 (m, 5H; phenyl-H); 13C NMR (50 MHz, CDCl3): d ˆ 21.95
(C-5'-Me), 24.7, 27.2 (piperidine-CH2), 25.8 (tBu), 31.2 (C-5'), 32.1 (C-4'),
35.9 (tBu), 42.0 (C-6'), 48.5, 49.4 (C-1', C-2'), 51.05 (piperidine-NCH), 62.0
(C-4), 65.2 (C-5), 68.8 (C-3'), 127.5, 128.7, 133.1, 134.3 (phenyl-C), 154.9 (C-
‡
‡
ˆ
2), 175.8 (C O); MS (70 eV, EI): m/z (%): 458 (<1) [M ], 457 (<1) [M
À
‡
‡
H], 443 (<1) [M À Me], 349 (100) [M À SPh]; elemental analysis calcd
(%) for C26H38N2O3S (458.66): C 68.09, H 8.35; found: C 67.91, H 8.28.
Cyclohexanol thioester 6: Benzyl mercaptan (23 mL, 0.20 mmol) was
dissolved in THF (0.5 mL), and butyllithium (2.5m in hexane, 64 mL,
0.16 mmol) was added at 08C. After 10 min, cyclohexanol 3d (25 mg,
0.064 mmol) dissolved in THF (0.5 mL) was added at 08C, and the reaction
mixture was stirred for 15 h at RT. 2m NaOH solution was added, the layers
were separated, and the aqueous phase was extracted with ether. The
combined organic extracts were dried over MgSO4, filtered, and evapo-
rated. Column chromatography over silica gel (diethyl ether/pentane 1:1)
gave thioester 6 (17 mg, 71%) as a colorless oil. IR (film): nÄ ˆ 3460 (OH),
À1
2960 (CH3), 1682 (C O), 1125, 1042 cm (C O); 1H NMR (300 MHz,
CDCl3): d ˆ 0.88 (d, J ˆ 6.5 Hz, 3H; 5-CH3), 1.02 1.30 (m, 2H), 1.80 2.40
(m, 4H), 2.87 (dd, J ˆ 11.5, 2.0 Hz, 1H; 2-H), 3.68 (td, J ˆ 11.5, 3.5 Hz, 1H;
1-H), 3.90 (brs, 1H; 3-H), 4.07 (d, J ˆ 14.0 Hz, 1H; S-CH2-Ph), 4.12 (d, J ˆ
14.0 Hz, 1H; S-CH2-Ph), 7.13 7.45 (m, 10H; phenyl-H); 13C NMR
(50 MHz, CDCl3): d ˆ 21.5 (CH3), 26.0 (C-5), 33.1 (C-2), 39.25, 42.1 (C-4,
C-6), 45.3, 51.97 (C-1, SCH2), 68.0 (C-3), 127.1, 127.4, 128.0, 128.8, 129.2,
ˆ
À
[13] a) D. A. Evans, K. T. Chapman, J. Bisaha,J. Am. Chem. Soc. 1988, 110,
1238 1256; b) S. Castellino, W. J. Dwight, J. Am. Chem. Soc. 1993,
115, 2986 2987.
[14] K. Maruoka, Y. Araki, H. Yamamoto, Tetrahedron Lett. 1988, 29,
3101 3104.
ˆ
132.9, 134.0, 135.2 (phenyl-C), 202.1 (C O); MS (200 eV, DCI/NH3): m/z
(%): 390 (100) [M ‡NH4 ]; elemental analysis calcd (%) for C21H24O2S2
‡
‡
(372.42): C 67.73, H 6.50; found: C 67.95, H 6.48.
[15] M. T. Reetz, B. Wenderoth, R. Peter, J. Chem. Soc. Chem. Commun.
1983, 406 408.
[16] M. T. Reetz, S. H. Kyung, M. H¸llmann, Tetrahedron 1986, 42, 2931
2935.
Acknowledgement
[17] D. Swern, S.-L. Huang, A. J. Mancuso, J. Org. Chem. 1978, 43, 2480
2482.
[18] D. R. Williams, W. S. Kissel, J. J. Li, Tetrahedron Lett. 1998, 39, 8593
8596.
[19] For an excellent review, see: M. Arend, B. Westermann, N. Risch,
Angew. Chem. 1998, 110, 1096 1122; Angew. Chem. Int. Ed. 1998, 37,
1044 1070.
Support for this work has been provided by the Deutsche Forschungsge-
meinschaft (Schn 441/1-2), the Fonds der Chemischen Industrie (doctoral
fellowship to O.R.), Degussa AG, and BASF AG. We would also like to
thank Andrew Hodgson (Socrates program) for carrying out some
experiments.
[20] R. E. Damon, G. M. Coppola, Tetrahedron Lett. 1990, 31, 2849 2852.
[1] For a review, see: a) C. Schneider, Synlett 2001, 1079 1091; b) C.
Schneider, M. Rehfeuter, Tetrahedron 1997, 53, 133 144.
Received: December 3, 2001 [F3718]
2594
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0811-2594 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 11