(-)-Myrtenyl N,N-diisopropylcarbamate: Stereochemistry of lithiation and electrophilic substitution directed by dynamic kinetic diastereoisomer resolution

Article abstract of DOI:10.1002/ejoc.201000390

(-)-Myrtenyl N,N-diisopropylcarbamate was lithiated by butyllithium in the presence of achiral and chiral ligands, followed by quench with several, electrophiles. The ratio of diastereomeric products allows conclusions regarding the configurational stabil

Full text of DOI:10.1002/ejoc.201000390

FULL PAPER
DOI: 10.1002/ejoc.201000390
(–)-Myrtenyl N,N-Diisopropylcarbamate: Stereochemistry of Lithiation and
Electrophilic Substitution Directed by Dynamic Kinetic Diastereoisomer
Resolution
Thérèse Hémery,[a] Jochen Becker,[a] Roland Fröhlich,[a][‡] and Dieter Hoppe*[a]
Keywords: Enantioselectivity / Diastereoselectivity / Lithiation / Aldol reactions / Kinetic resolution / Lithium/titanium
exchange
(–)-Myrtenyl N,N-diisopropylcarbamate was lithiated by
butyllithium in the presence of achiral and chiral ligands, fol-
lowed by quench with several electrophiles. The ratio of dia-
stereomeric products allows conclusions regarding the con-
figurational stability of both diastereomeric lithium interme-
diates and the influence of kinetic diastereoisomer resolution
in the substitution step.
Introduction
Metallated alk-2-en-1-yl N,N-diisopropylcarbamates like
2 turned out to be valuable homoenolate reagents,[1] in par-
ticular for enantioselective homoaldol reactions with alde-
hydes (or ketones).[2] The reagents are either accessible by
stereospecific deprotonation of enantiopure starting materi-
als by means of butyllithium/tetramethylethylenediamine
(TMEDA),[3] by deprotonation of achiral precursors with
butyllithium/(–)-sparteine[4] or chiral surrogates,[5] or by ki-
netic resolution of racemates[6] (Scheme 1).
The stereoselectivity in the formation of addition prod-
ucts 5 via a pericyclic Zimmerman–Traxler transition
state[7] is dramatically enhanced by lithium/titanium ex-
change (2 Ǟ 3),[8] which usually – but not in all cases[9]
–
proceeds with inversion of configuration from the endo-α-
lithioallyl carbamate, thus furnishing a high degree of chi-
rality transfer.
The efficiency of the enantiomeric excess depends on the
selectivity of proton transfer and the configurational sta-
bility of the lithium intermediate 2. Configurationally labile
intermediates undergo an equilibrium of the diastereo-
isomers 2 and may form essentially one diastereoisomer
in a dynamic thermodynamic resolution according to P.
Beak.[10] The stereochemical outcome is even less predicable
if the equilibrium between 2 and epi-2 is rather mobile, and
its rate is similar to that of the addition step – giving rise to
a dynamic kinetic resolution. Here, any simple relationship
between the configurational ratio in intermediates and
products is lost.
Scheme 1. Enantio- and diastereoselective homoaldol reaction
of 1.
We now studied the lithiation and the electrophilic sub-
stitution of the more complex allyl carbamate 6 more
closely.
Results and Discussion
Deprotonation, Silylation, and Related Reactions
(–)-Myrtenyl N,N-diisopropylcarbamate (6) was investi-
gated in our group on several occasions (Scheme 2).[11]
A
smooth deprotonation of 6 was already observed by A.
Brönneke during his dissertation in 1983.[12] In principle,
resulting from two diastereoisomers 7 and epi-7, the six dia-
stereoisomers/regioisomers 8–12 are possible, of which the
γ-addition products 10 and 12 are less likely since for their
[a] Organisch-Chemisches Institut, Westfälische Wilhelms-
Universität Münster,
Corrensstrasse 40, 48149 Münster, Germany
E-mail: dhoppe@uni-muenster.de
[‡] X-ray crystal structure analysis
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T. Hémery, J. Becker, R. Fröhlich, D. Hoppe
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formation the attack of the electrophile at the six-membered
Due to several previous investigations, the configuration
ring has to occur from the front face bearing the bulky iso- of the products allow for a direct conclusion on the lithium
propylidene bridge. Compounds 11 and 12 arise from the precursor: silylation and stannylation in the α-position pro-
unfavorable exo conformation of 7.
ceed with inversion.[1f,13] The stereochemistry of borylation
depends on the structure: retention for boric esters,[14] inver-
sion for trialkylboranes.[15]
Essentially complete attack of silicon electrophiles from
the more shielded top face of the enollithium component
forming 8a and 8b was observed independently of the di-
amine ligand used: TMEDA (Entries 1, 2 and 6), (–)-sparte-
ine (13) (Entry 3) or bulky C2-symmetrical bis(oxazoline)
ligand (BOX) 14[16] (Entries 4 and 7). Surprisingly, BOX li-
gand ent-14 causes a similar ratio (Entry 5), indicating that
its chiral sense has less influence on the ratio than its both
residues. The configuration of the newly formed stereogenic
centres was confirmed by derivatisation (see below).
Similar results are found for the stannylation (Entries 8–
10), but interestingly a second γ-isomer 11c is found, having
(E) configuration of the double bond. This fact counts for
epi-7 as the intermediate; for an anti-SEЈ attack from the
less hindered face the “carbanion” has to occupy its exo
confuguration. The configuration of both, the introduced
stereogenic centre and the double bond, was confirmed by
means of NOE experiments (Figure 1).
Scheme 2. Possible isomers formed after deprotonation of 6 in the
presence of different diamines and following reaction with electro-
philes (ElX).
Figure 1. NOE enhancements of 11c.
A further argument for the overwhelming reaction of
First, myrtenyl carbamate 6 was deprotonated in the diastereoisomer epi-7 is the formation of essentially pure
presence of different ligands, and the diastereomeric lithium boronate epi-8e (Entries 11 and 12). We recently found that
compounds were trapped with electrophiles (Scheme 2, boronic esters, such as 15, react with lithiated allyl carb-
Table 1).
amates with retention of the configuration,[14] presumably
Table 1. Metal exchange in 7/epi-7.
1
[a] Conversion, determined by H NMR analysis of the crude product. [b] Determined by GC analysis of the crude product. [c] Deter-
mined by 1H NMR analysis of the crude product. [d] Yield calculated on the isolated major isomer. [e] In addition, 16% of 17 was
isolated (see below).
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(–)-Myrtenyl N,N-Diisopropylcarbamate
due to a bonding interaction of the alkoxy group with the which means that a dynamic kinetic resolution must play a
lithium cation in the transition state. This reaction course major role either in the lithium/titanium exchange or in the
was also confirmed by Aggarwal et al.[14,15]
carbonyl addition. On the other hand, the reaction with
benzaldehyde furnished 16c in 72% yield and a dia-
stereomeric ratio of 90:10 (Scheme 4). The configuration of
the newly formed stereogenic centres, as well as the (Z) con-
figuration of the double bond, were determined by X-ray
crystallography (Figure 3).
Homoaldol Reactions
The lithium compounds add ketones, aldehydes, and
even bulky acyl chlorides onto the less hindered “rear face”
to afford the homoaldol products 16a, 16b, or 9f, which
result from the γ-syn addition reaction of diastereoisomers
epi-7 (Scheme 3). Since the reaction mixture with ketones
was warmed up to 0 °C, carboxamide 17 was formed in 10–
12% yield and a 95:5 dr. This migration of the carbamoyl
group has been observed several times and was first re-
ported by Nakai et al.[17]
Scheme 4. Titanium-mediated homoaldol reaction of myrtenyl
carbamate 6.
Scheme 3. Reaction of lithiated myrtenyl carbamate 6 with ketones
and acyl chlorides.
Figure 3. X-ray structure of 16c.[18,20]
Fortunately, 9f gave suitable crystals for X-ray analysis
(Figure 2) to allow the determination of the configuration
of the newly formed stereogenic centre (R) and of the
double bond (Z).
Stereochemistry of the Silylated Substitution Products
It was desirable to compare the stereochemical properties
of similar, but configurationally stable ion pairs with those
of unpersistent ones described below. In our previous study
we gained evidence for the fact that α-silyl groups in the
lithiated allyl carbamates enhance the configurational sta-
bility.[21] The acidic proton α to the silicon residue[22] of
8a and epi-8a was removed with sec-butyllithium, which is
expected to proceed with retention of the configuration.
This leads to the diastereoisomeric lithium carbanions 20,
endo-epi-20 and exo-epi-20, which react with pivaloyl chlo-
ride to form ketones (E)- and (Z)-21 in distinguished ratios
(92:8 and 82:18, respectively) (Scheme 5). The attack of the
Figure 2. X-ray structure of 9f.[18,19]
After titanium exchange with ClTi(NEt2)3, the reaction acyl chloride has to take place in a pericyclic reaction from
with cyclopentanone as well as with acetone led to the for- the less hindered face. The intermediate endo-epi-20 must
mation of 16a and 16b as single products in 56% and 66% turn the OCb group to the exo face. The different double-
yield, respectively (Scheme 4). These moderate yields are bond geometries as well as the relative configuration at the
probably due to the steric hindrance of the large residues in γ-C atom were proven by NOE experiments (Figure 4).
the Zimmerman–Traxler transition state TS-19. Surpris-
For comparison, (E)-21 (87%, dr Ͼ 98:2) was also
ingly, the configuration of both homoallylic alcohols arising formed from vinylsilane 22 (Scheme 6) by γ-deproton-
from the lithium and the titanium method, are identical, ation.[11b] This result and further mechanistic investi-
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T. Hémery, J. Becker, R. Fröhlich, D. Hoppe
FULL PAPER
Scheme 5. Deprotonation of 8a and epi-8a followed by reaction with pivaloyl chloride.
Figure 4. NOE enhancements for (E)-21 and (Z)-21.
gations[23] allow to consider the lithiated intermediate 20
as configurationally stable, which confirmed the proposed
Scheme 7. Reaction of epi-8b with pivaloyl chloride.
configuration of 8a and epi-8a.
Conclusions
Lithiation of the myrtenyl carbamate 6 leads to two dia-
stereoisomers, which are, even at –78 °C, interconverting.
Thus, the influence of ligands at the lithium cation on the
equilibrium can not be determined. The selectivity is mainly
governed by a kinetic diastereomer resolution. However, the
high diastereoselectivities (Ͼ 97:3) in the substitution reac-
tions in the presence of the bulky BOX ligand 14 point to
the following assumption: the equilibrium 7/epi-7 is shifted
to the side of the less hindered complex epi-7, and the equil-
ibration proceeds slowly. Substitution of the lithium com-
Scheme 6. Synthesis of (E)-21 by γ-deprotonation of 22.
The triethylsilane epi-8b (dr Ͼ 97:3) afforded analogously pound 7 by electrophiles proceeds in a way that can be ex-
the ketone (Z)-24 in 76% yield and a very good dia- plained by stereochemical preference of the particular elec-
stereomeric ratio of 95:5 (Scheme 7). This was a further ar- trophile. Due to the very different accessibilities of both
gument for the configuration of epi-8b and the proposed faces at the six-membered ring, γ-substitution proceeds ex-
stereochemical pathway.
clusively from the face of the methylene bridge.
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(–)-Myrtenyl N,N-Diisopropylcarbamate
raphy (Et2O/PE, 1:20) epi-8a (79 mg, 0.22 mmol, 22%) and 8a
(215 mg, 0.68 mmol, 68%) (dr = 74:26).
Experimental Section
General Remarks: All solvents were dried and purified prior to use:
toluene and Et2O were distilled from sodium/benzophenone, THF
was distilled from potassium/benzophenone, and CH2Cl2 was dis-
tilled from powdered CaH2. N,N,NЈ,NЈ-Tetramethylethylenedi-
amine (TMEDA) was distilled from powdered CaH2 and stored
under Ar in the dark. (–)-Sparteine (13) was kept under Ar in a
refrigerator after the original bottles had been opened. Solutions
of sec-butyllithium (ca. 1.3  in cyclohexane/hexane, 92:8) were fil-
tered through Celite under Ar and stored in glass bottles sealed
with septa. The exact concentration was determined by titration
with diphenylacetic acid.[24] n-Butyllithium (1.6  in hexanes) and
all other commercially available reagents were used as received. All
reactions were performed under Ar in flame-dried glassware sealed
with a rubber septum. Flash column chromatography (FCC) was
performed on Merck 60 silica gel (40–63 µm) and monitored by
thin-layer chromatography (TLC) on Merck 60 F254 TLC plates.
NMR: 1H and 13C NMR spectra were measured with Bruker
AV300, ARX300, DPX300, AV400 and ARX400 instruments and
Deprotonation with BOX Ligand 14: According to the General Pro-
cedure, 6 (87 mg, 0.31 mmol, 1.0 equiv.) was deprotonated with
nBuLi (0.25 mL, 0.4 mmol, 1.3 equiv.) and 14 (139 mg, 0.47 mmol,
1.5 equiv.) for 4 h and treated with TMSCl (97 mg, 0.89 mmol,
2.8 equiv.) for 2 h to yield after column chromatography (Et2O/PE,
1:20) 8a (87 mg, 0.25 mmol, 81%, dr Ն 97:3) as a colorless liquid.
Deprotonation with BOX Ligand ent-14: According to the General
Procedure, 6 (88 mg, 0.31 mmol, 1.0 equiv.) was deprotonated with
nBuLi (0.25 mL, 0.4 mmol, 1.3 equiv.) and ent-14 (110 mg,
0.37 mmol, 1.2 equiv.) for 4 h and treated with TMSCl (99 mg,
0.91 mmol, 2.9 equiv.) for 2 h to furnish after column chromatog-
raphy (Et2O/PE, 1:20) 8a (86 mg, 0.24 mmol, 77%) as a colorless
liquid (dr = 93:7). tR = 16.7 min (HP5). RF = 0.51 (Et2O/PE, 1:4).
1
[α]2D0 = –31.2 (c = 0.97, CHCl3). H NMR (400 MHz, CDCl3): δ =
0.05 (s, 9 H, 2Ј-H), 0.83 (s, 3 H, 8/9-H), 1.20 (br. s and m, 13 H,
7-HA, CH3-Cb), 1.23 (s, 3 H, 8/9-H), 2.06 (m, 1 H, 5-H), 2.18 (t,
3
3JH,H = 5.4 Hz, 1 H, 1-H), 2.25 (br. s, 2 H, 4-H), 2.38 (ddd, JH,H
= 5.6, 2JH,H = 8.4 Hz, 1 H, 7-HB), 3.77, 4.04 (2 br. s, 2 H, CH-Cb),
5.03 (s, 1 H, 1Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = –2.7
(C-2Ј), 20.7, 21.6 (CH3-Cb), 21.3, 26.4 (C-8, C-9), 31.4 (C-4), 32.0
(C-7), 37.6 (C-6), 40.8 (C-5), 43.6 (C-1), 45.2, 46.3 (CH-Cb), 72.8
(C-1Ј), 117.1 (C-3), 146.1 (C-2), 155.8 (CCO-Cb) ppm. IR (ATR):
1
Varian 500 Inova and 600 Unity Plus spectrometers. H shifts are
related to SiMe4 (δH = 0.00 ppm) or to the residual content of
CHCl3 (δH = 7.24 ppm) and 13C shifts to CDCl3 (δC = 77.0 ppm).
Peak multiplicities in the 1H NMR spectra are abbreviated as s
(singlet), d (doublet), t (triplet), m (multiplet), and br. (broad). Dia-
stereotopic methylene protons with different chemical shifts are ab-
breviated as HA and HB. IR: Varian 3100 Excalibur Series with
Specac Golden Gate Single Reflection ATR. MS: Bruker MicroTof
(ESI). Optical rotations: Perkin–Elmer 341. Melting points: Stuart
Scientific SMP3. Melting points are not corrected. Elemental
analyses: Elementar-Analysensysteme Vario EL III. GC: Agilent
6890; 30 mϫ0.32 mm HP-5; 1.5 mLmin–1 H2; start at 50 °C,
10 °Cmin–1, end at 300 °C, 15 min at 300 °C.
ν = 2962, 2929, 2831 (C–H), 1699 (C=O), 1650 (C=C) cm–1. MS
˜
(ESI): m/z = 374.25 [M + Na+]. C20H37NO2Si (351.60): calcd. C
68.32, H 10.61, N 3.98; found C 68.33, H 10.70, N 3.86.
epi-8a: tR = 16.3 min (HP5). RF = 0.57 (Et2O/PE, 1:4). [α]2D0 = +15.0
1
(c = 1.04, CHCl3). H NMR (500 MHz, CDCl3): δ = 0.05 (s, 9 H,
2
2Ј-H), 0.87 (s, 3 H, 8/9-H), 1.15 (d, JH,H = 8.5 Hz, 1 H, 7-HA),
3
1.21 (d, JH,H = 6.5 Hz, 12 H, CH3-Cb), 1.26 (s, 3 H, 8/9-H), 2.03–
2
2.06 (m, 2 H, 1-H, 5-H), 2.20 (dm, JH,H = 17.4 Hz, 1 H, 4-HA),
3
2.29 (dm, 1 H, 4-HB), 2.34 (dt, JH,H = 5.6 Hz, 1 H, 7-HB), 3.92
Deprotonation of 6 and Substitution with Electrophiles
(br. s, 2 H, CH-Cb), 4.90 (s, 1 H, 1Ј-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = –2.9 (C-2Ј), 20.7, 21.5 (CH3-Cb), 21.3, 26.5 (C-8, C-
9), 31.2 (C-4), 31.5 (C-7), 38.0 (C-6), 40.8 (C-5), 44.6 (C-1), 45.7,
General Procedure: nBuLi (1.2 equiv.) was added dropwise to a
solution of myrtenyl carbamate 6 (1.0 equiv.) and the applied di-
amine ligand (1.2 equiv.) in Et2O (7 mLmmol–1) at –78 °C. After
a certain deprotonation time, the corresponding electrophile (1.5–
3.0 equiv.) was added slowly within 5 min. The mixture was stirred
for a certain additional time and was quenched by addition of a
satd. aq. NH4Cl solution (15 mLmmol–1). After warming up to
room temp. and addition of Et2O or TBME (15 mLmmol–1), the
organic layer was removed. The aqueous phase was extracted three
times with Et2O or TBME (15 mLmmol–1 each). The combined
organic layers were dried with MgSO4 and concentrated under re-
duced pressure. Purification by column chromatography yielded the
corresponding product.
46.2 (CH-Cb), 72.3 (C-1Ј), 115.0 (C-3), 147.0 (C-2), 155.4 (CCO
-
Cb) ppm. IR (ATR): ν = 2965, 2926, 2873, 2826 (C–H), 1696
˜
(C=O) cm–1. MS (ESI): m/z = 374.25 [M + Na+]. C20H37NO2Si
(351.60): calcd. C 68.32, H 10.61, N 3.98; found C 68.19, H 10.72,
N 3.80.
Reaction with TMSOTf: According to the General Procedure, 6
(84 mg, 0.30 mmol, 1.0 equiv.) was deprotonated with nBuLi
(0.25 mL, 0.4 mmol, 1.3 equiv.) and TMEDA (40 mg, 0.34 mmol,
1.2 equiv.) for 4 h and treated with TMSOTf (0.18 mL, 0.9 mmol,
3.0 equiv.) for 1 h to furnish after column chromatography (Et2O/
PE, 1:20) 8a (61 mg, 0.17 mmol, 55%) as a colorless liquid (dr =
90:10). For analytical data, see above.
Reaction with TMSCl: (S)- and (R)-{(1R,5R)-6,6-Dimethylbicyclo-
[3.1.1]hept-2-en-2-yl}(trimethylsilyl)methyl
amate (8a and epi-8a)
N,N-Diisopropylcarb-
Reaction with TESCl: (S)- and (R)-{(1R,5R)-6,6-Dimethylbicy-
clo[3.1.1]hept-2-en-2-yl}(triethylsilyl)methyl N,N-Diisopropylcarb-
amate (8b and epi-8b)
Deprotonation with TMEDA: According to the General Procedure,
6 (422 mg, 1.5 mmol, 1.0 equiv.) was deprotonated with nBuLi
(1.1 mL, 1.8 mmol, 1.3 equiv.) and TMEDA (208 mg, 1.8 mmol,
1.2 equiv.) for 2 h and treated with TMSCl (485 mg, 4.4 mmol,
3.0 equiv.) for 4 h. Conversion and dr were determined by 1H NMR
analysis of the crude product (87% conversion, dr = 56:44).
Deprotonation with TMEDA: According to the General Procedure,
6 (143 mg, 0.51 mmol, 1.0 equiv.) was deprotonated with nBuLi
(0.38 mL, 0.61 mmol, 1.2 equiv.) and TMEDA (75 mg, 0.65 mmol,
1.3 equiv.) for 2 h and treated with TESCl (235 mg, 1.56 mmol,
3.1 equiv.) for 2 h to yield after column chromatography (Et2O/PE,
1:15) epi-8b (136 mg, 0.35 mmol, 69%) as a colorless liquid (dr =
92:8).
Deprotonation with (–)-Sparteine (13): According to the General
Procedure, 6 (279 mg, 1.3 mmol, 1.0 equiv.) was deprotonated with
nBuLi (0.81 mL, 1.3 mmol, 1.3 equiv.) and 13 (305 mg, 1.3 mmol,
1.3 equiv.) for 30 min and treated with TMSCl (163 mg, 1.5 mmol,
1.5 equiv.) for 1 h to yield after purification by column chromatog-
Deprotonation with BOX Ligand 14: According to the General Pro-
cedure, 6 (85 mg, 0.31 mmol, 1.0 equiv.) was deprotonated with
nBuLi (0.25 mL, 0.40 mmol, 1.3 equiv.) and 14 (113 mg,
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T. Hémery, J. Becker, R. Fröhlich, D. Hoppe
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0.38 mmol, 1.2 equiv.) for 4 h and treated with TESCl (145 mg,
0.96 mmol, 3.1 equiv.) for 2 h to yield after purification by column
chromatography (Et2O/PE, 1:20) 8b (136 mg, 0.20 mmol, 87%) as
a colorless liquid (dr = 93:7).
(100 MHz, CDCl3): δ = 10.3 (C-2Ј), 13.7 (C-5Ј), 20.6 (CH3-Cb),
21.4 (CH3-Cb), 21.4 (C-8), 26.3 (C-9), 27.5 (C-4Ј), 29.1 (C-3Ј), 31.2
(C-4), 31.9 (C-7), 37.9 (C-6), 40.9 (C-1/5), 43.8 (C-1/5), 45.2, 46.0
(CH-Cb), 73.4 (C-1Ј), 113.0 (C-3), 148.5 (C-2), 155.6 (CCO-Cb)
ppm. IR (ATR): ν = 2955, 2919 (C–H), 2872, 1673 (NC=O), 1434,
˜
8b: tR = 19.0 min (HP5). RF = 0.59 (Et2O/PE, 1:4). [α]2D0 = –33.8
1335, 1308, 1047 cm–1. MS (ESI): m/z = 592.32 [M + Na+].
C29H55NO2Sn (568.46): calcd. C 61.27, H 9.75, N 2.46; found C
61.34, H 9.48, N 2.43.
1
(c = 0.95, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.61 (dddd,
3
4
2JH,H = 11.6, JH,H = 7.9, JH,H = 3.1 Hz, 6 H, 2Ј-H), 0.81 (s, 3 H,
8-H), 0.97 (t, 3 H, 3Ј-H), 1.19 (m, 13 H, CH3-Cb, 7-HA), 1.23 (s, 3
11c: RF = 0.64 (Et2O/PE, 1:4). [α]2D0 = +178.3 (c = 1.06, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 0.74 (s, 3 H, 8-H), 0.86 (m, 15
H, 2Ј-H, 5Ј-H), 1.28 (m, 18 H, 4Ј-H, CH3-Cb), 1.47 (m, 7 H, 7-HA,
3Ј-H), 2.02 (m, 2 H, 1/5-H, 4-HA), 2.21 (m, 1 H, 4-HB), 2.30 (m, 2
3
H, 9-H), 2.06 (m, 2 H, 5-H), 2.17 (dt, JH,H = 5.6 Hz, 1 H, 1-H),
2.25 (m, 2 H, 4-H), 2.38 (dt, 2JH,H = 8.5 Hz, 1 H, 7-HB), 3.85, 3.93
4
(2 br. s, 2 H, CH-Cb), 5.20 (d, JH,H = 0.9 Hz, 1 H, 1Ј-H), 5.34
3
3
(dd, JH,H = 2.6, JH,H = 1.4 Hz, 1 H, 3-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 2.6 (C-2Ј), 7.5 (C-3Ј), 20.7 (CH3-Cb), 21.3
(C-8), 21.4 (CH3-Cb), 26.4 (C-9), 31.4 (C-4), 32.0 (C-7), 37.6 (C-
6), 40.7 (C-5), 43.4 (C-1), 45.6 (CH-Cb), 45.8 (CH-Cb), 70.6 (C-
3
4
2
H, 1/5-H, 7-HB), 2.55 (dd, JH,H = 9.7, JH,H = 1.6, JH,Sn
=
42.2 Hz, 1 H, 3-H), 3.68, 4.16 (2 br. s, 2 H, CH-Cb), 6.56 (dd,
4JH,Sn = 12.6 Hz, 1 H, 1Ј-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 9.9 (C-2Ј, 1JH,Sn = 151.4 Hz), 13.7 (C-5Ј), 16.6 (C-3), 20.8 (CH3-
Cb), 21.8 (C-8), 25.6 (C-9), 26.5 (C-7), 27.4 (C-4), 27.6 (C-3Ј/4Ј),
29.1 (C-3Ј/4Ј), 41.5 (C-1/5), 41.6 (C-6), 45.6 (CH-Cb), 46.4 (CH-
Cb), 46.8 (C-1/5), 124.4 (C-1Ј), 129.0 (C-2), 152.2 (CCO-Cb) ppm.
1Ј), 117.5 (C-3), 146.3 (C-2), 155.2 (CCO-Cb) ppm. IR (ATR): ν =
˜
2953 (C–H), 1698 (C=O), 1427, 1322, 1157, 1046, 633 cm–1. MS
(ESI): m/z = 416.30 [M + Na+]. C23H43NO2Si (393.68): calcd. C
70.17, H 11.01, N 3.56; found C 69.80, H 11.23, N 3.47.
IR (ATR): ν = 2956, 2919 (C–H), 2871, 1712 (NC=O), 1430, 1328,
˜
epi-8b: tR = 18.8 min (HP5). RF = 0.66 (Et2O/PE, 1:4). [α]2D0 = +20.0
(c = 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.61 (q, 3JH,H
= 7.9 Hz, 6 H, 2Ј-H), 0.87 (s, 3 H, 8-H), 0.94 (t, 3 H, 3Ј-H), 1.16
(d, 2JH,H = 8.5 Hz, 1 H, 7-HA), 1.22 (d, 3JH,H = 6.7 Hz, 12 H, CH3-
Cb), 1.27 (s, 3 H, 9-H), 2.02 (m, 2 H, 1-H, 5-H), 2.22 (m, 2 H, 4-
H), 2.34 (m, 1 H, 7-HB), 3.78, 4.06 (2 br. s, 2 H, CH-Cb), 5.00 (d,
1302, 1143, 1095, 1045 cm–1. MS (ESI): m/z = 592.31 [M + Na+].
C29H55NO2Sn (568.46): calcd. C 61.27, H 9.75, N 2.46; found C
61.25, H 9.59, N 2.38.
Reaction with Ph3SnCl: (S)-{(1R,5R)-6,6-Dimethylbicyclo[3.1.1]-
hept-2-ylidene)(triphenylstannyl)methyl N,N-Diisopropylcarbamate
(8d): According to the General Procedure, 6 (89 mg, 0.32 mmol,
1.0 equiv.) was deprotonated with nBuLi (0.25 mL, 0.44 mmol,
1.4 equiv.) and 14 (140 mg, 0.48 mmol, 1.5 equiv.) for 4 h and
treated with Ph3SnCl (347 mg, 0.90 mmol, 2.8 equiv.) dissolved in
Et2O (1.5 mL) for 3 h to yield after purification by column
chromatography (Et2O/PE, 1:50) 8d (89 mg, 0.22 mmol, 65%) as a
colorless oil (dr Ն 97:3).
3
4JH,H = 1.7 Hz, 1 H, 1Ј-H), 5.23 (dd, JH,H = 2.9 Hz, 1 H, 3-H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 2.3 (C-2Ј), 7.4 (C-3Ј), 20.9
(CH3-Cb), 21.2 (C-8, CH3-Cb), 26.4 (C-9), 31.3 (C-7), 31.5 (C-4),
38.1 (C-6), 40.8, 44.6 (C-1,C-5), 45.8 (CH-Cb), 69.8 (C-1Ј), 114.7
(C-3), 147.0 (C-2), 154.8 (CCO-Cb) ppm. IR (ATR): ν = 2953, 2913
˜
(C–H), 1699 (NC=O), 1427, 1377, 1321, 1046, 1030, 723 cm–1. MS
(ESI): m/z = 416.30 [M + Na+]. C23H43NO2Si (351.60): calcd. C
70.17, H 11.01, N 3.56; found C 69.94, H 11.13, N 3.37.
8d: RF = 0.64 (Et2O/PE, 1:4). [α]2D0 = +17.3 (c = 0.93, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 0.46 (d, 2JH,H = 8.7 Hz, 1 H, 7-HA),
0.77 (s, 3 H, 8-H), 1.03 (m, 12 H, CH3-Cb), 1.15 (s, 3 H, 9-H), 1.90
Reaction with Bu3SnCl: (S)-{(1R,5R)-6,6-Dimethylbicyclo[3.1.1]-
hept-2-en-2-yl}(tributylstannyl)methyl N,N-Diisopropylcarbamate
(8c) and {(1R,2E,3S,5R)-6,6-Dimethyl-3-(tributylstannyl)bicyclo-
[3.1.1]hept-2-ylidene}methyl N,N-Diisopropylcarbamate (11c)
3
(m, 1 H, 5-H), 1.97 (dt, JH,H = 5.7 Hz, 1 H, 7-HB), 2.18 (m, 3 H,
1-H, 4-H), 3.68, 3.88 (2 br. s, CH-Cb), 5.38 (m, 1 H, 1Ј-H), 5.40
4
(d, JH,H = 1.0 Hz, 1 H, 3-H), 7.32 (m, 9 H, HAr), 7.59 (br. m, 6
H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.3 (CH3-Cb),
20.3 (CH3-Cb), 21.2 (CH3-Cb), 21.2 (CH3-Cb), 21.4 (C-8), 26.2 (C-
9), 31.0 (C-7), 31.1 (C-4), 37.9 (C-6), 40.4 (C-5), 44.1 (C-1), 45.2
(CH-Cb), 46.3 (CH-Cb), 76.1 (C-3), 116.8 (C-1Ј), 128.0 (CHAr),
Deprotonation with TMEDA: According to the General Procedure,
6 (1.410 g, 5.05 mmol, 1.0 equiv.) was deprotonated with nBuLi
(3.9 mL, 6.24 mmol, 1.2 equiv.) and TMEDA (705 mg, 6.06 mmol,
1.2 equiv.) for 2 h and treated with Bu3SnCl (2.489 g, 7.65 mmol,
1.5 equiv.) for 3 h to yield after purification by column chromatog-
raphy (Et2O/PE, 1:50) 8c and 11c as two yellowish liquids: (i) pure
8c (354 mg, 0.62 mmol, 12%); (ii) mixtures 8c/11c (ratio = 77:23)
(1.200 g, 2.11 mmol, 42%) and 11c/8c (ratio = 81:19) (1.012 g
1.78 mmol, 35%). Total yield: 2.212 g, 3.89 mmol, 89%, 8c/11c =
74:26. 11c was purified by a second column chromatography for
analysis.
128.4 (CHAr), 137.4 (CHAr), 141.1 (CAr), 146.8 (C-2), 156.2 (CCO
-
Cb) ppm. IR (ATR): ν = 3063 (C–HAr), 2970, 2916 (C–H), 1656
˜
(NC=O), 1480, 1428, 1330, 1308, 1157, 1073, 1046, 726 (C–HAr),
697 (C–HAr
) = 652.22 [M +
cm–1. MS (ESI): m/z Na+].
C35H43NO2Sn (628.43): calcd. C 66.89, H 6.90, N 2.23; found C
67.03, H 7.24, N 2.18.
Reaction with 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane:
(R)-{(1R,5R)-6,6-Dimethyl-bicyclo[3.3.1]hept-2-en-2-yl)(4,4,5,5-tet-
ramethyl-1,3,2-dioxaborolan-2-yl)methyl N,N-Diisopropylcarbamate
(epi-8e)
Deprotonation with BOX Ligand 14: According to the General Pro-
cedure, 6 (152 mg, 0.52 mmol, 1.0 equiv.) was deprotonated with
nBuLi (0.41 mL, 0.66 mmol, 1.3 equiv.) and 14 (191 mg,
0.65 mmol, 1.3 equiv.) for 4 h and treated with Bu3SnCl (256 mg,
0.79 mmol, 1.5 equiv.) for 2 h to yield after purification by column
chromatography (Et2O/PE, 1:50) 8c (212 mg, 0.37 mmol, 71%) as
a colorless liquid (8c/11c = 85:15).
Deprotonation with TMEDA: According to the General Procedure,
6 (289 mg, 2.97 mmol, 1.0 equiv.) was deprotonated with nBuLi
(2.3 mL, 3.68 mmol, 1.2 equiv.) and TMEDA (407 mg, 3.50 mmol,
1.2 equiv.) for 2 h and treated with 15 (1.665 g, 8.95 mmol,
3.0 equiv.) for 2 h to furnish after column chromatography (Et2O/
PE, 1:2) epi-8e (816 mg, 2.01 mmol, 67%) as a colorless solid (dr
Ն 97:3) and side product 17 (132 mg, 0.47 mmol, 16%) as a color-
less solid.
8c: RF = 0.80 (Et2O/PE, 1:4). [α]2D0 = –6.6 (c = 1.33, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 0.89 (m, 18 H, 8-H, 2Ј-H, 5Ј-H),
3
1.20 (d, JH,H = 6.9 Hz, 13 H, 7-HA, CH3-Cb), 1.29 (m, 9 H, 9-H,
4Ј-H), 1.49 (m, 6 H, 3Ј-H), 2.09 (m, 2 H, 1-H, 5-H), 2.27 (m, 2 H,
4
4-H), 2.38 (m, 1 H, 7-HB), 3.86 (br. s, 2 H, CH-Cb), 5.20 (d, JH,H
Deprotonation with BOX Ligand 14: According to the General Pro-
cedure, 6 (95 mg, 0.34 mmol, 1.0 equiv.) was deprotonated with
= 1.4 Hz, 1 H, 3-H), 5.32 (m, 1 H, 1Ј-H) ppm. 13C NMR
3716
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3711–3720

(–)-Myrtenyl N,N-Diisopropylcarbamate
nBuLi (0.28 mL, 0.45 mmol, 1.3 equiv.) and 14 (142 mg, 1.3 equiv.) for 2 h and treated with cyclopentanone (756 mg,
0.48 mmol, 1.4 equiv.) for 4 h and treated with 15 (171 mg,
0.92 mmol, 2.7 equiv.) for 2 h to furnish after purification by col-
umn chromatography (Et2O/PE, 1:2) epi-8e (89 mg, 0.22 mmol,
65%) as a colorless solid (dr Ն 97:3).
9.0 mmol, 3.0 equiv.) to yield after column chromatography (twice:
TBME/PE, 1:2 then 1:4) products 16a and 17 (674 mg, 16a/17 =
82:18, dr = 95:5). Calculated yield: 16a: 552 mg, 1.5 mmol, 53%;
17: 122 mg, 0.44 mmol, 12%.
epi-8e: RF = 0.33 (Et2O/PE, 1:1). M.p. 73–75 °C (Et2O). [α]2D0
=
16a: tR = 19.8 min (HP5). RF = 0.13 (Et2O/PE, 1:4). [α]2D0 = –17.9
(c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.71 (s, 3 H,
–13.5 (c = 0.98, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 0.91 (s,
3 H, 8-H), 1.16 (s, 6 H, 3Ј-H), 1.18 (s, 6 H, 3Ј-H), 1.26 (m, 15 H,
1
8/9-H), 1.26 (br. s, 12 H, CH3-Cb), 1.24 (s, 3 H, 8/9-H), 1.55–1.87
(m, 9 H, 5-H, 3Ј-H, 4Ј-H), 1.90–2.05 (m, 3 H, 4-H, 7-HA), 2.16–
2
9-H, CH3-Cb), 1.41 (d, JH,H = 8.6 Hz, 1 H, 7-HA), 2.05 (m, 2 H,
1-H, 5-H), 2.20 (m, 1 H, 4-HA), 2.33 (m, 2 H, 4-HB, 7-HB), 3.93,
3
3
2.38 (m, 2 H, 1-H, 7-HB), 2.99 (ddd, JH,H = 10.3, JH,H = 3.0, J
= 1.6 Hz, 1 H, 3-H), 3.78, 4.10 (2 br. s, 2 H, CH-Cb), 6.72 (d, JH,H
= 1.7 Hz, 1 H, 1Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.8
(CH3-Cb), 21.7, 25.7 (C-8, C-9), 23.0, 23.2 (C-4Ј), 26.3 (C-7), 27.8
(C-4), 38.0, 40.5 (C-3Ј), 39.7 (C-3), 40.7 (C-5), 42.7 (C-6), 46.2 (CH-
4
4.04 (2 m, 2 H, CH-Cb), 4.13 (d, JH,H = 2.13 Hz, 1 H, 1Ј-H), 5.20
(m, 1 H, 3-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.3, 20.5,
20.6, 20.8 (CH3-Cb), 21.2 (C-8), 25.2 (C-3Ј), 26.4 (C-9), 31.0 (C-4),
31.5 (C-7), 37.9 (C-6), 40.9 (C-1/5), 43.6 (C-1/5), 46.8 (CH-Cb),
48.2 (CH-Cb), 80.0 (C-1Ј, C-2Ј), 112.0 (C-3), 146.5 (C-2), 162.4
Cb), 47.7 (C-1), 86.2 (C-2Ј), 125.5 (C-2), 131.7 (C-1Ј), 152.4 (CCO
-
(CCO-Cb) ppm. IR (ATR): ν = 2971, 2916 (C–H), 1614 (NC=O),
˜
Cb) ppm. IR (KBr): ν = 3509 (OH), 2973, 2909, 2861 (C–H), 1696
˜
1499 (B–C), 1449, 1366 (B–O), 1195, 1154, 1112, 1033 cm–1. MS
(ESI): m/z = 428.29 [M + Na+]. C23H40BNO4 (405.38): calcd. C
68.15, H 9.95, N 3.46; found C 68.08, H 10.04, N 3.42.
(C=O) cm–1. MS (ESI): m/z = 386.2673 [M + Na+]. C22H37NO3
(362.53): calcd. C 72.69, H 10.26, N 3.85; found C 72.53, H 10.24,
N 3.73.
17: For analytical data, see below.
(2R)-2-{(1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl}-2-hy-
Reaction with Pivaloyl Chloride: {(1R,2Z,3S,5R)-3-(2,2-Dimeth-
ylpropanoyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ylidene]methyl N,N-
Diisopropylcarbamate (9f): According to the General Procedure, 6
(85 mg, 0.30 mmol, 1.0 equiv.) was deprotonated with nBuLi
(0.25 mL, 0.40 mmol, 1.3 equiv.) and 14 (129 mg, 0.44 mmol,
1.4 equiv.) for 4 h and treated with pivaloyl chloride (105 mg,
0.96 mmol, 2.9 equiv.) for 3 h to furnish after column chromatog-
raphy (Et2O/PE, 1:15 Ǟ 1:10) 9f (72 mg, 0.20 mmol, 67%) as a
colorless solid (dr = 95:5).
droxy-N,N-diisopropylacetamide (17): tR = 15.3 min (HP5). RF
=
0.48 (TBME/PE, 1:6). M.p. 68 °C (TBME/PE). [α]2D0 = –17.1 (c =
1.01, CHCl3, dr = 97:3). 1H NMR (400 MHz, CDCl3): δ = 0.83,
2
1.29 (2 s, 6 H, 8-H, 9-H), 1.13 (br. d, JH,H = 8.8 Hz, 1 H, 7-HA),
3
1.15, 1.18 (2 d, JH,H = 6.6 Hz, 6 H, 4Ј-H), 1.43, 1.45 (2 d, 6 H,
3
4Ј-H), 2.10 (m, 1 H, 5-H), 2.26–2.30 (m, 2 H, 4-H), 2.34 (dt, JH,H
2
3
= 5.6, J = 1.4 Hz, 1 H, 1-H), 2.40 (dt, JH,H = 8.8, JH,H = 5.6 Hz,
1 H, 7-HB), 3.44, 3.89 (2 sept, 2 H, 3Ј-H), 3.66 (br. s 1 H, OH),
4.48 (s, 1 H, 2Ј-H), 5.41 (s, 1 H, 3-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.4, 20.3, 20.5, 21.0 (C-4Ј), 21.5, 26.0 (C-8, C-9), 31.3
(C-4), 31.8 (C-7), 37.9 (C-6), 40.6 (C-5), 43.8 (C-1), 46.2, 47.8 (C-
3Ј), 71.5 (C-2Ј), 120.3 (C-3), 146.7 (C-2), 170.5 (C-1Ј) ppm. IR
9f: tR = 21.7 min (HP5). RF = 0.34 (Et2O/PE, 1:4). M.p. 80 °C
(Et2O). [α]2D0 = +63.8 (c = 0.86, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 0.79 (s, 3 H, 8-H), 1.21 (m, 12 H, CH3-Cb), 1.23 (s, 3
2
H, 9-H), 1.26 (s, 9 H, 4Ј-H), 1.52 (d, JH,H = 5.5 Hz, 1 H, 7-HA),
(ATR): ν = 3391 (OH), 2987, 2968, 2934, 2912, 2877 (C–H), 1635
˜
2
3
(C=O) cm–1. MS (ESI): m/z = 302.2093 [M + Na+]. C17H29NO2
(279.42): calcd. C 73.07, H 10.46, N 5.01; found C 73.07, H 10.50,
N 4.85.
1.79 (dt, JH,H = 13.6, JH,H = 3.6 Hz, 1 H, 4-HA), 1.97 (m, 1 H,
3
5-H), 2.25 (ddt, JH,H = 11.5 Hz, 1 H, 4-HB), 2.31 (m, 1 H, 7-HB),
2.43 (t, 3JH,H = 5.5 Hz, 1 H, 1-H), 3.63, 3.95 (2 br. s, 2 H, CH-Cb),
4.03 (ddd, 4JH,H = 1.8 Hz, 1 H, 3-H), 6.68 (d, 1 H, 1Ј-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 20.7 (CH3-Cb), 21.7 (C-8), 25.6 (C-
9), 26.9 (C-7), 28.1 (C-4), 28.2 (C-4Ј), 38.6 (C-3), 40.6 (C-6), 40.7
(C-5), 44.1 (C-3Ј), 46.5 (C-1, CH-Cb), 123.2 (C-2), 130.5 (C-1Ј),
Reaction with Acetone: {(1R,2Z,3S,5R)-3-(1-Hydroxy-1-methyl-
ethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ylidene}methyl N,N-Diiso-
propylcarbamate (16b): According to the General Procedure, 6
(837 mg, 3.00 mmol, 1.0 equiv.) was deprotonated with nBuLi
(2.4 mL, 3.90 mmol, 1.3 equiv.) and TMEDA (468 mg, 3.90 mmol,
1.3 equiv.) for 2 h and treated with acetone (522 mg, 9.0 mmol,
3.0 equiv.) to yield after column chromatography (TBME/PE, 1:4)
products 16b and 17 (144 mg, 16b/17 = 57:43, dr = 95:5; 465 mg,
16b/17 = 93:7). Calculated yield: 16b: 514 mg, 1.5 mmol, 52%; 17:
82 mg, 0.33 mmol, 10%. tR = 17.5 min (HP5). RF = 0.12 (Et2O/
PE, 1:4). M.p. 104 °C (Et2O/PE). [α]2D0 = –23.9 (c = 0.99, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.72, 1.24 (2 s, 6 H, 8-H, 9-H),
1.25, 1.26 (2 br. s, 12 H, CH3-Cb), 1.29, 1.30 (2 s, 6 H, 3Ј-H), 1.69
151.7 (CCO-Cb), 215.8 (C-2Ј) ppm. IR (ATR): ν = 2970, 2930 (C–
˜
H), 1700 (NC=O), 1436, 1333, 1309, 1140, 1105, 1043, 964,
758 cm–1. MS (ESI): m/z = 386.27 [M + Na+]. C22H37NO3 (363.53):
calcd. C 72.69, H 10.26, N 3.85; found C 72.33, H 10.21, N 3.73.
Lithium-Mediated Homoaldol Reaction of 6
General Procedure: 6 (1.0 equiv.) and TMEDA (1.3 equiv.) were dis-
solved in Et2O (3.0 mLmmol–1). At –78 °C nBuLi (1.3 equiv.) was
added, and stirring was continued at –78 °C for 2 h. The ketone
(3.0 equiv.) was added dropwise, and the solution was stirred at
–78 °C for 10 h. The reaction solution was then warmed up to 0 °C
over a period of 9 h and quenched at 0 °C by addition of a satd.
aq. NH4Cl solution (5 mLmmol–1). The layers were separated, and
the aqueous phase was extracted with TBME three times
(5 mLmmol–1). The combined organic layers were dried with
MgSO4, and the solvent was removed under vacuum. Purification
of the crude product was accomplished by column chromatography.
2
3
2
(br. d, JH,H = 10.0 Hz, 1 H, 7-HA), 1.83 (dt, JH,H = 3.5, JH,H
=
3
13.8, JH,H = 3.5 Hz, 1 H, 4-HA), 1.90–2.06 (m, 2 H, 4-HB, 7-HB),
2.18–2.30 (m, 2 H, 5-H, OH), 2.34 (t, JH,H = 5.6 Hz, 1 H, 1-H),
3
3
2.89 (ddd, JH,H = 10.4, J = 1.9 Hz, 1 H, 3-H), 3.94 (br. s, 2 H,
CH-Cb), 6.79 (d, J = 1.8 Hz, 1 H, 1Ј-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 20.7 (CH3-Cb), 21.7, 25.7 (C-8, C-9), 26.3 (C-7), 27.6
(C-4), 28.6, 29.5 (C-3Ј), 40.7 (C-5), 41.8 (C-3), 42.6 (C-6), 46.3 (CH-
Reaction with Cyclopentanone: {(1R,2Z,3S,5R)-3-(1-Hydroxycy-
clopentyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ylidene}methyl N,N-Di-
isopropylcarbamate (16a): According to the General Procedure, 6
(837 mg, 3.00 mmol, 1.0 equiv.) was deprotonated with nBuLi
(2.4 mL, 3.90 mmol, 1.3 equiv.) and TMEDA (468 mg, 3.90 mmol,
Cb), 47.9 (C-1), 74.4 (C-2Ј), 124.7 (C-2), 131.8 (C-1Ј), 152.2 (CCO-
Cb) ppm. IR (KBr): ν = 3504 (OH), 2978, 2969, 2926, 2909, 2865
˜
(C–H), 1996 (C=O) cm–1. MS (ESI): m/z = 360.2523 [M + Na+].
C20H35NO3 (337.49): calcd. C 71.18, H 10.45, N 4.15; found C
71.07, H 10.61, N 4.09.
Eur. J. Org. Chem. 2010, 3711–3720
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3717

T. Hémery, J. Becker, R. Fröhlich, D. Hoppe
FULL PAPER
Titanium-Mediated Homoaldol Reaction of 6
H, 1Ј-H), 7.27–7.41 (m, 5 H, HAr) ppm. 13C NMR (125 MHz,
CDCl3): δ = 20.6, 21.2 (CH3-Cb), 21.7 (C-8,C-9), 25.6 (C-4) 26.3
(C-7), 38.0 (C-3), 40.5 (C-5), 42.0 (C-6), 46.3 (CH-Cb), 47.0 (C-1),
78.4 (C-2Ј), 124.5 (C-2), 127.6 (CHAr), 127.7 (CHAr), 128.8 (CHAr),
General Procedure: 6 (1.0 equiv.) and (–)-sparteine (13) (1.3 equiv.)
were dissolved in Et2O (3.0 mL mmol–1). At –78 °C nBuLi
(1.3 equiv.) was added, and stirring was continued at –78 °C for
2 h. A solution of ClTi(NEt2)3 (2.0 equiv.) in Et2O (0.5 mLmmol–1)
was added in a dropwise fashion, and the solution was stirred at
–78 °C for additional 3 h. The carbonyl compound (3.0 equiv.) was
added dropwise, and the solution was stirred at –78 °C for 3 or 4 h.
The reaction was quenched at –78 °C by addition of a satd. aq.
NH4Cl solution (3 mLmmol–1) and warmed up to room temp.; a
2  HCl solution was added until the titanium salts were fully dis-
solved. The layers were separated, and the aqueous phase was ex-
132.1 (C-1Ј), 142.7 (CAr), 152.5 (CCO-Cb) ppm. IR (KBr): ν = 3491
˜
(OH), 3091, 3061, 3030 (C–HAr), 2970, 2922, 2861 (C–H), 1700
(C=O) cm–1. MS (ESI): m/z = 408.2521 [M + Na+]. C24H35NO3
(385.54): calcd. C 74.77, H 9.15, N 3.63; found C 74.73, H 9.01, N
3.47.
epi-16c: tR = 21.3 min (HP5). RF = 0.32 (Et2O/PE, 2:5). M.p. 96 °C.
[α]2D0 = –72.2 (c = 1.03, CHCl3). H NMR (300 MHz, CDCl3): δ =
1
0.75, 1.23 (2 s, 2 H, 8-H, 9-H), 0.89 (m, 1 H, 7-HA), 1.28, 1.31 (2
tracted with TBME three times (5 mLmmol–1). The combined or- br. s, 12 H, CH3-Cb), 1.51 (m, 1 H, 4-HA), 1.66–1.78 (m, 2 H, 4-
ganic layers were dried with MgSO4, and the solvent was removed
under vacuum. Purification of the crude product was accomplished
by column chromatography.
HB, 7-HB), 1.87 (m, 1 H, 5-H), 2.21 (s, 1 H, OH), 2.36 (m, 1 H, 1-
H), 3.29 (m, 1 H, 3-H), 3.80, 4.18 (2 br. s, 2 H, CH-Cb), 5.53 (s, 1
H, 2Ј-H), 6.84 (d, JH,H = 2.3 Hz, 1 H, 1Ј-H), 7.22–7.44 (m, 5 H,
CHAr) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.9 (CH3-Cb), 21.7
(C-8, C-9), 24.8 (C-4), 25.9 (C-7), 37.8 (C-3), 40.3 (C-5), 41.2 (C-
6), 46.4 (CH-Cb), 47.3 (C-1), 72.4 (C-2Ј), 125.6 (C-2), 125.5 (CHAr),
Reaction with Cyclopentanone: {(1R,2Z,3S,5R)-3-(1-Hydroxycy-
clopentyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ylidene}methyl N,N-Di-
isopropylcarbamate (16a): According to the General Procedure, 6
(837 mg, 3.0 mmol, 1.0 equiv.) was deprotonated with nBuLi
(2.43 mL, 3.90 mmol, 1.3 equiv.) and 13 (912 mg, 3.90 mmol,
1.3 equiv.), transmetalleted with ClTi(NEt2)3 (1.8 g, 6.0 mmol,
2.0 equiv.) and treated with cyclopentanone (756 mg, 9.0 mmol,
3.0 equiv.) for 3 h to yield after purification by column chromatog-
raphy (Et2O/PE, 1:2) 16a (607 mg, 1.67 mmol, 56%) as a colorless
solid. For analytical data see above.
126.5 (CHAr), 128. 0 (CHAr), 130.4 (C-1Ј), 143.2 (CAr), 152.2 (CCO
,
Cb) ppm. IR (KBr): ν = 3439 (OH), 3096, 3061, 3000 (C–HAr),
˜
2974, 2930, 2896, 2861 (C–H), 1683 (C=O) cm–1. MS (ESI): m/z =
408.2499 [M + Na+]. C22H37NO3 (362.53): calcd. C 74.77, H 9.15,
N 3.63; found C 74.65, H 9.25, N 3.41.
Deprotonation of Silanes 8a, epi-8a, epi-8b and 23 Followed by Sub-
stitution with Pivaloyl Chloride
Reaction with Acetone: {(1R,2Z,3S,5R)-3-(1-Hydroxy-1-metyhl-
ethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ylidene}methyl N,N-Di-
isopropylcarbamate (16b): According to the General Procedure, 6
(837 mg, 3.0 mmol, 1.0 equiv.) was deprotonated with nBuLi
(2.43 mL, 3.90 mmol, 1.3 equiv.) and 13 (912 mg, 3.90 mmol,
1.3 equiv.), transmetalleted with ClTi(NEt2)3 (1.8 g, 6.0 mmol,
2.0 equiv.) and treated with acetone (522 mg, 9.0 mmol, 3.0 equiv.)
for 3 h to yield after purification by column chromatography (Et2O/
PE, 1:2) 16b (665 mg 1.97 mmol, 66%) as a colorless solid. For
analytical data see above.
General Procedure: A solution of the carbamate (0.3 mmol,
1.0 equiv.) and TMEDA (1.2 equiv.) in Et2O (2 mL) was cooled
down to –78 C, sBuLi (1.28 , 1.2 equiv.) was added slowly. After
2 h of deprotonation, pivaloyl chloride (3.0 equiv.) was added in a
dropwise fashion within 5 min. After additional 3 h of stirring, the
reaction was stopped by addition of a satd. aq. NH4Cl solution
(5 mL), and the mixture was warmed up to room temp. After ad-
dition of Et2O or TBME (5 mL) and separation of the organic
phase, the aqueous layer was extracted three times with Et2O or
TBME (10 mL of each). The combined organic phases were dried
with MgSO4, and the solvent was evaporated under reduced pres-
sure. The crude product was purified by column chromatography.
Reaction with Benzaldehyde: {(1R,2Z,3S,5R)-3-[(S)- and (R)-Hy-
droxy(phenyl)methyl]-6,6-dimethylbicyclo[3.1.1]hept-2-ylidene}-
methyl N,N-Diisopropylcarbamate (16c and epi-16c): According to
the General Procedure, 6 (1.40 g, 5.0 mmol, 1.0 equiv.) was depro-
tonated with nBuLi (4.1 mL, 6.5 mmol, 1.3 equiv.) and 13 (1.52 g,
6.5 mmol, 1.3 equiv.), transmetalleted with ClTi(NEt2)3 (3.0 g,
10.0 mmol, 2.0 equiv.) and treated with benzaldehyde (1.6 g,
15.0 mmol, 3.0 equiv.) for 4 h to yield after purification by column
chromatography (Et2O/PE, 1:2) epi-16c (84 mg, 0.22 mmol, 4%) as
a colorless solid and 16c/epi-16c = 92:8 (1.307 g, 3.39 mmol, 68%)
as a colorless crystalline solid. Total yield: 1.391 g (3.61 mmol,
72%). A single crystal of 16c suitable for X-ray structure analysis
was obtained by slow evaporation of the solvent from a saturated
solution of 16c/epi-16c (92:8) in Et2O. After measuring, the crystal
was dissolved in Et2O and the retention time (HP5) compared to
those of the diastereoisomers. The comparison clearly revealed that
the crystal was the major diastereoisomer 16c.
Reaction of 8a: {(1R,2E,3S,5R)- and (1R,2Z,3S,5R)-3-(2,2-Dimeth-
ylpropanoyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ylidene}(trimethyl-
silyl)methyl N,N-Diisopropylcarbamate [(E)- and (Z)-21]: According
to the General Procedure, 8a (dr = 87:13) (108 mg, 0.31 mmol,
1.0 equiv.) was deprotonated with sBuLi (0.30 mL, 0.38 mmol,
1.2 equiv.) and TMEDA (42 mg, 0.36 mmol, 1.2 equiv.) and treated
with pivaloyl chloride (109 mg, 0.90 mmol, 2.9 equiv.) to yield after
purification by column chromatography (Et2O/PE, 1:15) (E)-21
(106 mg, 0.24 mmol, 77%) as a colorless solid and (Z)-21 (10 mg,
0.02 mmol, 6%) as a yellowish oil (dr = 92:8).
(E)-21: tR = 20.1 min (HP5). RF = 0.51 (Et2O/PE, 1:4). M.p. 121–
1
122 (Et2O). [α]2D0 = +75.7 (c = 1.05, CHCl3). H NMR (400 MHz,
CDCl3): δ = 0.13 (d, 9 H, 2Ј-H), 0.86 (s, 3 H, 8-H), 1.12 (dd, 6 H,
CH3-Cb), 1.22 (s, 9 H, 5Ј-H), 1.27 (s, 3 H, 9-H), 1.33 (d, 6 H, CH3-
3
3
Cb), 1.61 (d, JH,H = 5.4 Hz, 1 H, 7-HA), 1.74 (dt, JH,H = 3.0,
3
16c: tR = 21.2 min (HP5). RF = 0.32 (Et2O/PE, 2:5). M.p. 115–
2JH,H = 13.6 Hz, 1 H, 4-HA), 1.94 (m, 1 H, 5-H), 2.19 (dd, JH,H
116 °C (PE, 16/epi-16c = 92:8). [α]2D0 = –54.9 (c = 1.02, CHCl3, 16/
= 11.8 Hz, 1 H, 4-HB), 2.28 (m, 1 H, 7-HB), 2.77 (t, 1 H, 1-H),
1
3
4
epi-16c = 92:8). H NMR (500 MHz, CDCl3): δ = 0.72, 1.20 (2 s, 3.40 (dt, JH,H = 6.7, JH,H = 3.0 Hz, 1 H, CH-Cb), 4.02 (dd, 1 H,
6 H, 8-H, 9-H), 0.84 (br. d, 2JH,H = 10.2 Hz, 1 H, 7-HA), 1.29, 1.30 3-H), 4.30 (dt, 1 H, CH-Cb) ppm. 13C NMR (100 MHz, CDCl3):
(2 br. s, 12 H, CH3-Cb), 1.69 (m, 1 H, 4-HA), 1.77 (m, 1 H, 4-HB),
δ = 0.4 (C-2Ј), 20.5, 20.6, 21.0, 21.2 (CH3-Cb), 21.8 (C-8), 25.6 (C-
9), 25.9 (C-7), 27.8 (C-4), 28.4 (C-5Ј), 39.4 (C-3), 40.5 (C-5), 40.7
(C-6), 44.1 (C-4Ј), 44.7 (CH-Cb), 45.6 (C-1), 47.3 (CH-Cb), 143.4
3
2
1.84 (m, 1 H, 5-H), 2.15 (dt, JH,H = 5.5, JH,H = 10.2 Hz, 1 H, 7-
HB), 2.35 (t, 3JH,H = 5.5 Hz, 1 H, 1-H), 2.63 (s, 1 H, OH), 3.30 (dt,
3
3JH,H = 1.6, JH,H = 8.6, JH,H = 1.9 Hz, 1 H, 3-H), 3.88, 4.18 (2 (C-2), 147.5 (C-1Ј), 152.7 (CCO-Cb), 216.2 (C-3Ј) ppm. IR (ATR):
3
br. s, 2 H, CH-Cb), 4.89 (d, JH,H = 8.6 Hz, 1 H, 2Ј-H), 6.95 (s, 1
ν = 2961 (C–H), 2938, 2872, 1703 (C=O), 1686 (NC=O), 1478,
˜
3718
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3711–3720

(–)-Myrtenyl N,N-Diisopropylcarbamate
1425, 1369, 1314 (Si–CH3), 1246, 1138, 1074, 1062, 1043, 988, 855,
839 (Si–CH3), 761 cm–1. MS (ESI): m/z = 458.31 [M + Na+].
C25H45NO3Si (458.72): calcd. C 68.91, H 10.41, N 3.21; found C
68.70, H 10.31, N 3.16.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB424) and the Fonds der Chemischen Industrie.
(Z)-21: tR = 20.6 min (HP5). RF = 0.34 (Et2O/PE, 1:4). [α]2D0
=
+10.2 (c = 0.84, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 0.13
(s, 9 H, 2Ј-H), 0.79 (s, 3 H, 8-H), 1.21 (m, 9 H, 9-H, CH3-Cb), 1.24
[1] a) D. Hoppe, Angew. Chem. 1984, 96, 930–946; Angew. Chem.
Int. Ed. Engl. 1984, 23, 932–948; b) D. Hoppe, in Methoden
Org. Chem. (Houben-Weyl) (“Allytitanium and Allylzirconium
Reagents”) (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E.
Schaumann), 4th ed., Thieme-Verlag, Stuttgart, 1995, vol.
E21b, pp. 1551–1583; c) D. Hoppe, T. Hense, Angew. Chem.
1997, 109, 2376–2410; Angew. Chem. Int. Ed. Engl. 1997, 36,
2282–2316; d) H. Ahlbrecht, U. Beyer, Synthesis 1999, 365–
390; e) D. Hoppe, F. Marr, M. Brüggemann in Topics in Orga-
nometallic Chemistry (“Organolithiums in Enantioselctive Syn-
thesis”) (Ed.: D. M. Hodgson), Springer, Berlin, 2003, vol. 5,
pp. 61–138; f) G. Christoph, D. Hoppe, in The Chemistry of
Organolithium Compounds (Eds.: Z. Rappoport, I. Marek),
Whiley, Chichester, 2004, pp. 1055–1164; g) D. Hoppe, in
Asymmetric Synthesis – The Essentials (Eds.: M. Christmann,
S. Bräse), Wiley-VCH, Weinheim, 2006, pp. 100–104; h) D.
Hoppe, Synthesis 2009, 43–55.
3
(br. d, JH,H = 6.8 Hz, 6 H, CH3-Cb), 1.32 (m, 10 H, 7-HA, 5Ј-H),
1.96 (m, 1 H, 5-H), 2.17 (m, 2 H, 7-HB, 4-HA), 2.33 (m, 1 H, 4-
3
HB), 3.06 (t, JH,H = 5.6 Hz, 1 H, 1-H), 3.83 (br. s, 1 H, CH-Cb),
3
3
3.86 (dd, JH,H = 11.2, JH,H = 1.9 Hz, 1 H, 3-H), 4.04 (br. s, 1 H,
CH-Cb) ppm. 13C NMR (100 MHz, CDCl3): δ = 0.2 (C-2Ј), 20.6,
20.6, 21.5, 21.5 (CH3-Cb), 21.5 (C-8), 24.7 (C-4), 26.0 (C-9), 27.3
(C-7), 29.1 (C-5Ј), 41.2 (C-5), 41.4 (C-6/4Ј), 43.4 (C-3), 44.1 (C-6/
4Ј), 44.3 (C-1), 45.6, 46.1 (CH-Cb),143.5 (C-2), 149.1 (C-1Ј), 154.1
(CCO-Cb), 217.1 (C-3Ј) ppm. IR (ATR): ν = 2968 (C–H), 1696
˜
(NC=O, C=O), 1429, 1367, 1321 (Si–CH3), 1298, 1287, 1246, 1145,
1069, 1040, 839 (Si–CH3) cm–1. MS (ESI): m/z = 458.31 [M + Na+].
C25H45NO3Si (435.72): calcd. C 68.91, H 10.41, N 3.21; found C
68.76, H 10.41, N 3.15.
Reaction of epi-8a: According to the General Procedure, epi-8a (dr
= 91:9) (107 mg, 0.30 mmol, 1.0 equiv.) was deprotonated with
sBuLi (0.30 mL, 0.38 mmol, 1.2 equiv.) and TMEDA (42 mg,
0.36 mmol, 1.2 equiv.) and treated with pivaloyl chloride (109 mg,
0.90 mmol, 3.0 equiv.) to yield after purification by column
chromatography (Et2O/PE, 1:10) (Z)-21 (98 mg, 0.22 mmol, 73%)
as a yellowish oil and (E)-21 (19 mg, 0.04 mmol, 13%) as a yellow-
ish solid (dr = 82:18). For analytical data see above.
Some selected chiral d3-reagents and applications: a) H. Roder,
G. Helmchen, E.-M. Peters, K. Peters, H.-G. von Schnering,
Angew. Chem. 1984, 96, 895–896; Angew. Chem. Int. Ed. Engl.
1984, 23, 898–899; b) D. Hoppe, O. Zschage, Angew. Chem.
1989, 101, 67–69; Angew. Chem. Int. Ed. Engl. 1989, 28, 69–71;
c) O. Zschage, D. Hoppe, Tetrahedron 1992, 48, 5657–5666; d)
H. Paulsen, D. Hoppe, Tetrahedron 1992, 48, 5667–5670; e) O.
Zschage, J.-R. Schwark, D. Hoppe, Tetrahedron 1992, 48, 8377–
8388; f) J. P. Férézou, M. Julia, R. Khourzom, Y. Li, A.
Pancrazi, P. Robert, Synlett 1991, 611–614; g) H. Paulsen, C.
Graeve, D. Hoppe, Synthesis 1996, 141–144; h) P. Le Ménez,
V. Fargeas, I. Berque, J. Poisson, J. Ardisson, J.-Y. Lallemand,
A. Pancrazi, J. Org. Chem. 1995, 60, 3592–3599; i) M. C.
Whisler, P. Beak, J. Org. Chem. 2003, 68, 1207–1215.
a) T. Krämer, J.-R. Schwark, D. Hoppe, Tetrahedron Lett. 1989,
30, 7037–7040; b) I. Berque, P. Le Ménez, P. Razon, A.
Pancrazi, J. Ardisson, A. Neuman, T. Prangé, J.-D. Brion, Syn-
lett 1998, 1132–1134; c) J. Becker, R. Fröhlich, K. Salorinne,
D. Hoppe, Eur. J. Org. Chem. 2007, 3337–3348; d) J. Becker,
R. Fröhlich, O. Kataeva, D. Hoppe, Eur. J. Org. Chem. 2007,
3349–3364; e) J. Becker, K. Bergander, R. Fröhlich, D. Hoppe,
Angew. Chem. 2008, 120, 1678–1681; Angew. Chem. Int. Ed.
2008, 47, 1654–1657.
[2]
Reaction of 23: According to the General Procedure, 23 (104 mg,
0.30 mmol, 1.0 equiv.) was deprotonated with sBuLi (0.30 mL,
0.38 mmol, 1.3 equiv.) and TMEDA (45 mg, 0.38 mmol, 1.3 equiv.)
and treated with pivaloyl chloride (108 mg, 0.90 mmol, 3.0 equiv.)
to furnish after column chromatography (Et2O/PE, 1:15) (E)-21
(113 mg, 0.26 mmol, 87%) as a colorless solid (dr Ͼ 97:3). For
analytical data, see above.
[3]
[4]
Reaction of epi-8b: {(1R,2Z,3S,5R)-3-(2,2-Dimethylpropanoyl)-6,6-
dimethylbicyclo[3.1.1]hept-2-ylidene}(triethylsilyl)methyl N,N-Diiso-
propylcarbamate [(Z)-24]: According to the General Procedure, epi-
8b (dr Ͼ 97:3) (83 mg, 0.21 mmol, 1.0 equiv.) was deprotonated
with sBuLi (0.21 mL, 0.27 mmol, 1.3 equiv.) and TMEDA (31 mg,
0.27 mmol, 1.32 equiv.) and treated with pivaloyl chloride (75 mg,
0.62 mmol, 2.9 equiv.) to yield after purification by column
chromatography (Et2O/PE, 1:20) (Z)-24 (76 mg, 0.16 mmol, 76%)
as a colorless solid (dr = 95:5).
Chiral diamine (–)-sparteine (14) is a commercially available
natural alkaloid: Review: M. Breuning, M. Steiner, Synthesis
2008, 2841–2867.
[5]
[6]
M. J. Dearden, C. R. Firkin, J.-P. R. Nermet, P. O’Brien, J. Am.
Chem. Soc. 2002, 124, 11870–11871.
a) D. Hoppe, T. Krämer, Angew. Chem. 1986, 98, 171–173; An-
gew. Chem. Int. Ed. Engl. 1986, 25, 160–162; b) O. Zschage, J.-
R. Schwark, D. Hoppe, Angew. Chem. 1990, 102, 336–337; An-
gew. Chem. Int. Ed. Engl. 1990, 29, 296–298; c) O. Zschage, D.
Hoppe, Tetrahedron 1992, 48, 8389–8392.
(Z)-24: tR = 22.4 min (HP5). RF = 0.50 (Et2O/PE, 1:4). M.p. 82–
1
84 °C (Et2O). [α]2D0 = –2.0 (c = 1.16, CHCl3). H NMR (400 MHz,
3
CDCl3): δ = 0.61 (m, 6 H, 2Ј-H), 0.82 (s, 3 H, 8-H), 0.96 (t, JH,H
3
= 7.9 Hz, 9 H, 3Ј-H), 1.19 (m, 9 H, 9-H, CH3-Cb), 1.26 (dd, JH,H
4
= 6.8, JH,H = 0.8 Hz, 6 H, CH3-Cb), 1.31 (s, 9 H, 6Ј-H), 1.33 (d,
2JH,H = 10.5 Hz, 1 H, 7-HA), 1.96 (m, 1 H, 5), 2.15 (m, 2 H, 7-HB,
4-HA), 2.33 (m, 1 H, 4-HB), 3.02 (t, 3JH,H = 5.6 Hz, 1 H, 1-H), 3.71
[7]
[8]
H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957, 79,
1920–1923.
3
3
(m, 1 H, CH-Cb), 3.83 (dd, JH,H = 11.1, JH,H = 2.0 Hz, 1 H, 3-
H), 4.12 (m, 1 H, CH-Cb) ppm. 13C NMR (100 MHz, CDCl3): δ
= 3.6 (C-2Ј), 7.4 (C-3Ј), 20.6, 20.6, 21.3, 21.5 (CH3-Cb), 21.7 (C-
8), 24.8 (C-7), 26.0 (C-9), 27.2 (C-4), 29.0 (C-6Ј), 41.2 (C-5), 41.4
(C-6), 43.4 (C-3), 44.1 (C-5Ј), 44.5 (C-1), 45.3 (CH-Cb), 46.3 (CH-
Cb), 144.8 (C-2), 148.1 (C-1Ј), 153.7 (CCO-Cb), 216.9 (C-4Ј) ppm.
a) M. T. Reetz, in Organometallics in Synthesis (Ed.: M.
Schlosser), 2nd ed., Wiley-VCH, Chichester, 2002, pp. 817–923;
b) B. Weidmann, D. Seebach, Angew. Chem. 1983, 95, 12–26;
Angew. Chem. Int. Ed. Engl. 1983, 22, 31–45.
J. Becker, S. Grimme, R. Fröhlich, D. Hoppe, Angew. Chem.
2007, 119,1672–1676; Angew. Chem. Int. Ed. 2007, 46, 1645–
1649.
Y. S. Park, E. K. Yum, A. Basu, P. Beak, Org. Lett. 2006, 8,
2667–2670, and references therein.
a) D. Hoppe, R. Hanko, A. Brönneke, F. Lichtenberg, Angew.
Chem. 1981, 93, 1106–1107; Angew. Chem. Int. Ed. Engl. 1981,
[9]
IR (ATR): ν = 2952 (C–H), 2906, 2873, 1698 (C=O), 1673
˜
(NC=O), 1477, 1439, 1367, 1296, 1286, 1220, 1129, 1069, 1040,
1003, 960, 951, 764, 717 cm–1. MS (ESI): m/z = 500.35 [M + Na+].
C28H51NO3Si (477.79): calcd. C 70.39, H 10.76, N 2.93; found C
70.06, H 10.50, N 2.91.
[10]
[11]
Eur. J. Org. Chem. 2010, 3711–3720
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3719

T. Hémery, J. Becker, R. Fröhlich, D. Hoppe
FULL PAPER
20, 1024–1026; b) T. Hémery, B. Wibbeling, R. Fröhlich, D.
Hoppe, Synthesis 2010, 329–342.
[12] A. Brönneke, Dissertation, University of Göttingen, 1983.
[13] K. Behrens, R. Fröhlich, O. Meyer, D. Hoppe, Eur. J. Org.
Chem. 1998, 2397–2403.
[14] a) E. Beckmann, V. Desai, D. Hoppe, Synlett 2004, 2275–2280;
b) J. L. Stymiest, G. Dutheuil, A. Mahmood, V. K. Aggarwal,
Angew. Chem. 2007, 119, 7635–7638; Angew. Chem. Int. Ed.
2007, 46, 7491–7494.
[15] J. L. Stymiest, V. Bagutski, R. M. French, V. K. Aggarwal, Na-
ture 2008, 456, 778–782.
[16] For examples of applications of BOX ligands as chelating
agents in the organolithium field, see: a) S. E. Dennmark, N.
Nakajima, O. J.-C. Nicaise, J. Am. Chem. Soc. 1996, 116, 8797–
8798; b) N. Komine, L.-F. Wang, K. Tomooka, T. Nakai, Tetra-
hedron Lett. 1999, 40, 6809–6812; c) K. Tomooka, L.-F. Wang,
N. Komine, T. Nakai, Tetrahedron Lett. 1999, 40, 6813–6816;
d) S. Nakamura, R. Nakagawa, Y. Watanabe, T. Toru, Angew.
Chem. 2000, 112, 361–363; Angew. Chem. Int. Ed. 2000, 39,
353–355; e) S. Nakamura, R. Nakagawa, Y. Watanabe, T. Toru,
J. Am. Chem. Soc. 2000, 122, 11340–11347; f) R. P. Sonawane,
R. Fröhlich, D. Hoppe, Adv. Synth. Catal. 2006, 348, 1847–
1854; g) H. Lange, R. Huenerbein, B. Wibbeling, R. Föhlich,
S. Grimme, D. Hoppe, Synthesis 2008, 2905–2918; h) H. Lange,
R. Huenerbein, R. Fröhlich, S. Grimme, D. Hoppe, Chem.
Asian J. 2008, 3, 78–87.
770166 (for 9f) and -770167 (for 16c) contain the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[19] X-ray crystal structure analysis for 9f: Formula C22H37NO3, M
= 363.53, colorless crystal 0.30ϫ0.25ϫ0.20 mm, a =
6.1844(3), b = 34.3049(14), c = 10.4690(4) Å, β = 91.941(2)°, V
= 2219.8(2) Å3, ρcalcd. = 1.088 gcm–3, µ = 0.556 mm–1, empiri-
cal absorption correction (0.851ՅTՅ0.897), Z = 4, mono-
clinic, space group P21 (No. 4), λ = 1.54178 Å, T = 223 K, ω
and φ scans, 18723 reflections collected (Ϯh, Ϯk, Ϯl), (sinθ)/λ
= 0.60 Å–1, 5594 independent (Rint = 0.051) and 5020 observed
reflections [IՆ2σ(I)], 487 refined parameters, R = 0.044, wR2
= 0.117, Flack parameter 0.2(2), two almost identical mole-
cules in the asymmetric unit, max. residual electron density
0.12 (–0.14) eÅ–3, hydrogen atoms calculated and refined as
riding atoms.
[20] X-ray crystal structure analysis for 16c: Formula C24H35NO3,
M = 385.53, colorless crystal 0.60ϫ0.20ϫ0.20 mm, a =
6.986(1), b = 10.867(1), c = 15.321(1) Å, β = 101.93(1)°, V =
1138.0(2) Å3, ρcalcd. = 1.125 gcm–3, µ = 0.574 mm–1, empirical
absorption correction (0.725ՅTՅ0.894), Z = 2, monoclinic,
space group P21 (No. 4), λ = 1.54178 Å, T = 223 K, ω and φ
scans, 12418 reflections collected (Ϯh, Ϯk, Ϯl), (sinθ)/λ =
0.60 Å–1, 2808 independent (Rint = 0.025) and 2794 observed
reflections [IՆ2σ(I)], 260 refined parameters, R = 0.037, wR2
= 0.101, Flack parameter 0.0(2), max. residual electron density
0.11 (–0.09) eÅ–3, hydrogen atoms calculated and refined as
riding atoms.
[21] J. Reuber, R. Fröhlich, D. Hoppe, Org. Lett. 2004, 6, 783–786.
[22] For the determination of acidities of silyl compounds in solu-
tion, see: a) A. Streitwieser, L. Xie, P. Wang, S. M. Bachrach,
J. Org. Chem. 1993, 58, 1778–1784; b) S. McN. Sieburth, J. J.
Somers, Tetrahedron 1996, 52, 5683–5690.
[17] K. Tomooka, H. Shimizu, T. Inoue, H. Shibata, T. Nakai,
Chem. Lett. 1999, 759–760.
[18] Data sets were collected with a Nonius KappaCCD dif-
fractometer. Programs used: data collection COLLECT (Non-
ius B. V., 1998), data reduction Denzo-SMN (Z. Otwinowski,
W. Minor, Methods Enzymol. 1997, 276, 307–326), absorption
correction Denzo (Z. Otwinowski, D. Borek, W. Majewski, W.
Minor, Acta Crystallogr., Sect. A 2003, 59, 228–234), structure
solution SHELXS-97 (G. M. Sheldrick, Acta Crystallogr., Sect.
A 1990, 46, 467–473), structure refinement SHELXL-97 (G. M.
Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112–122), graph-
ics Diamond (G. Bergerhoff, M. Berndz, K. Brandenburg, J.
Res. Natl. Inst. Stand. Technol. 1996, 101, 221–225). CCDC-
[23] T. Hémery, Dissertation, University of Münster, 2009.
[24] W. G. Wofron, L. M. Baclawski, J. Org. Chem. 1976, 41, 1879–
1880.
Received: March 22, 2010
Published Online: May 19, 2010
3720
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Eur. J. Org. Chem. 2010, 3711–3720