Secondary allyltitanium(IV) reagents in aldehyde allylation I: Extension of the Hoppe reaction to γ-alkoxy secondary allyl carbamates

Article abstract of DOI:10.1055/s-2004-834912

An efficient access to optically active (R)- or (S)-γ-alkoxy allyltitanium(IV) intermediates, in aldehyde allylation reactions, is described. Enantiomeric γ-alkoxy secondary allyl carbamates (R)- and (S)-14 were first prepared. Determination of their enan

Full text of DOI:10.1055/s-2004-834912

102
PAPER
Secondary Allyltitanium(IV) Reagents in Aldehyde Allylation I: Extension of
the Hoppe Reaction to γ-Alkoxy Secondary Allyl Carbamates
Secondary
All
a
yltitanium
(
t
)
Re
r
i
A
ldeh
c
yde
A
llylat
k
ion Razon,a Sylvie Dhulut,a Sophie Bezzenine-Lafollée,a Jacques Courtieu,*a Ange Pancrazi,b Janick Ardisson*b
a
Laboratoire de Chimie Structurale Organique, ICMO, URA CNRS 1384, Université de Paris Sud, 91405 Orsay, France
Fax +33(1)69158105; E-mail: courtieu@icmo.u-psud.fr
b
Laboratoire de Synthèse Organique Sélective et Chimie Organométallique, CNRS-UCP-ESCOM, UMR 8123, ESCOM, Bat E,
13 Bd de l’Hautil, 95092 Cergy-Pontoise, France
Fax +33(1)307561; E-mail: janick.ardisson@chim.u-cergy.fr
Received 3 August 2004
O
R3O
Abstract: An efficient access to optically active (R)- or (S)-g-
alkoxy allyltitanium(IV) intermediates, in aldehyde allylation reac-
tions, is described. Enantiomeric g-alkoxy secondary allyl carbam-
ates (R)- and (S)-14 were first prepared. Determination of their
enantiomeric excess was realised on the corresponding deuterated
isotopic derivatives by NMR in chiral liquid media. Subsequent al-
dehyde allylation reaction with propanal performed under Hoppe
n-BuLi·(–)-sparteine/Ti(Oi-Pr)4 or n-BuLi·TMEDA/Ti(Oi-Pr)4 con-
ditions, led to both enantiomeric homoallylic alcohols 15 or ent-15
in 90% yield, 100% ed and 80% ee.
9
9
8
8
6
6
CHO
OR2
OH
CHO
OR2
OH
5
5
4
3
4
3
MeO
R1O
O
O
1
1
O
O
Tylosin I
R1 = D-mycinose
R2 = Mycaminose
Spiramycin II
3 = D-fucosamine
R
Key words: Hoppe allylation, allyltitanium reagent, 1H NMR
chiral nematic solvent, Sharpless resolution
O
9
8
6
OPG
In the past decades, several 14- and 16-membered mac-
rolide antibiotics have been isolated or synthesised, which
proved to be important therapeutic agents. In the same
time, aldehyde allylation and aldolisation reactions have
become the best tools for the diastereoselective and enan-
tioselective construction of 1,2- and 1,3-diol systems. As
a consequence, many efforts were devoted towards the to-
tal synthesis of several compounds in the important eryth-
romycin family,1 such as tylosin (I)2 or spiramycin (II),3
for either veterinary or clinical use (Scheme 1).
1
2
R= OMe
R= Me
5
4
3
R
OPG
1
PGO
OPG
Scheme 1
methyl group at C8 centre in a double stereodifferentia-
tion (Scheme 3).4
However, the installation of the side chain in C6 together
with introduction of the hydroxyl function at C5 in the
right configuration (5 → 6) was a real challenge. The op-
tically pure g-alkoxy allyltitanium(IV) derivative (R)-
We described earlier a synthetic approach to a C1-C9
eastern part 2 of tylosin (I),4 based on sequential Hoppe
aldehyde allylation5 reaction (Scheme 2). The original
Hoppe allylation involved the reaction of the crotyltitani-
um(IV) derivative (R)-‘Ti’-I on the Si face of aldehyde, to
give, with propanal for example, the homoallylic alcohol
(Z)-anti-4 in 90% yield, 100% de, and 92% ee (Scheme
2). This (R)-‘Ti’-I intermediate was formed in situ from
the achiral primary crotyl carbamate 3, after crystallisa-
tion of the (S)-‘Li’-I sparteine complex (second order
asymmetric induction) and transmetallation with Ti(Oi-
Pr)4.
Li⋅(–)-sparteine
n-BuLi/(–)-sparteine
OCb
OCb
3
(S)-"Li"-I
"Ti"
Ti(OiPr)4
OCb
(R)-"Ti"-I
In our previous preparation of the C1-C9 eastern part 8 of
tylosin (I), from optically active aldehyde 7 (7 → 8), the
Hoppe allylation invoked the reaction of the same crotyl-
titanium derivative (R)-‘Ti’-I for introduction of the
OH
OR
R
(Z)
EtCHO
Ti
si face
OR
O
Et
OCb
OCb
4
90% yield
100% de
92% ee
SYNTHESIS 2005, No. 1, pp 0102–0108
x
x
.
x
x
.2
0
0
4
Advanced online publication: 08.12.2004
DOI: 10.1055/s-2004-834912; Art ID: P09104SS
Scheme 25
© Georg Thieme Verlag Stuttgart · New York

PAPER
Secondary Allyltitanium(IV) Reagents in Aldehyde Allylation
103
H
1) n-BuLi/(–)-sparteine
CH3
OCb
"Ti"
5
4
3
toluene
"Ti"
OCb
H3C
THPO
OCb
O
( )-"Ti"-II
2) Ti(OiPr)4
HO
OTIPS
( )-10
(S)-"Ti"-III
1
5
HO
CHO
(Z)
11
OCb
6
36%, 75% ee
OCb
6
OHC
OPG
OTHP
5
1) n-BuLi/TMEDA
4
5
4
3
O
toluene
OH
ent-11
59%, 87% ee
(S)-10
(R)-"Ti"-III
O
3
2) Ti(OiPr)4
OTIPS
1
TBSO
Scheme 56
1
7
HO
6
"Ti"
OCb
These results indicate that transmetallation reaction Li →
Ti with Ti(Oi-Pr)4 occurred with inversion of configura-
tion when n-BuLi·(–)-sparteine/Ti(Oi-Pr)4 route was
used; retention was observed under application of n-Bu-
Li·(–)-TMEDA/Ti(Oi-Pr)4 conditions.
OCb
R
9
(R)-"Ti"-I
8
6
OPG
HO
5
4
3
O
Taking advantage of this work, we wanted to get an access
to optically active (R) or (S)-g-alkoxy allyltitanium (IV)
intermediates to realise aldehyde allylation reactions, un-
der simple asymmetric induction or double stereodiffer-
entiation. For this purpose, preparation of enantiomeric
allyl carbamates (R)- and (S)-14 was needed.
O
1
TBSO
8
Scheme 3
However, in these series, enantiomeric excess could not
be measured by classical NMR analysis, using derivatisa-
tion or Europium shifts. Consequently, we turned to an al-
ternative method based on NMR in chiral liquid crystal
media developed by Courtieu.7 For this study which in-
volved an observation of the deuterium element, we syn-
thesised the corresponding deuterated isotopic
derivatives.
‘Ti’-II cannot be prepared, via the corresponding lithio
derivative of carbamate 9, either by an enantioselective
deprotonation or a second-order asymmetric induction, as
for the (R)-‘Ti’-I reagent4,5 (Scheme 4).
1) n-BuLi/(–)-sparteine
2) Ti(OiPr)4
"Ti"
RO
OCb
OCb
(R)-"Ti"-II
First, racemic propargylic alcohol ( )-12 was obtained
from commercial butynol: after benzylation, an homolo-
gation was effected with acetaldehyde (83% yield); the
triple bond of ( )-12 was then reduced with LiAlH4 to
give the (E)-allylic alcohol ( )-13 in 84% yield (Scheme
6). For an access to the corresponding ( )-d2-13 com-
pound, the reduction was carried out using LiAlD4 and
quenching with D2O (74% yield). Carbamoylation of ( )-
13 or ( )-d2-13 was then carried out using KH/THF/N(i-
Pr)2COCl conditions to deliver carbamate ( )-14 or ( )-
d2-14 [Cb = CON(i-Pr)2] in 85% yield.
9
Scheme 4
To circumvent this difficulty, the side chain was intro-
duced using the racemic ( )-‘Ti’-II reagent under kinetic
resolution. Nevertheless, in order to develop a general al-
dehyde allylation reaction from g-alkoxy allyltitanium de-
rivatives, we turned our attention to the results published
by Hoppe about secondary crotylcarbamates, and to our
surprise, not used at this time in total synthesis.6
Optically active allylic alcohols (S)-13 or (S)-d2-13 and
(R)-13 or (R)-d2-13 were then synthesised by application
of the enantioselective Sharpless epoxidation reaction in a
kinetic resolution strategy.8 Starting from alcohol ( )-13,
and using (–)-diisopropyl D-tartrate, the (S)-13 allylic al-
cohol enantiomer was obtained in 38% yield (Scheme 7).
When (+)-diisopropyl L-tartrate was employed, kinetic
resolution furnished the enantiomer (R)-13 in 36% yield.
Allyl carbamates (R)- and (S)-14 were then prepared from
alcohols (R)-and (S)-13 under KH, THF, N(i-Pr)2COCl
conditions. Using the same sequence, alcohol ( )-d2-13
delivered respectively the (S)-d2-13 and (R)-d2-13 allylic
In this important work (Scheme 5), Hoppe6 has shown that
when the racemic secondary crotylcarbamate ( )-10 was
treated under classical conditions [n-BuLi·(–)-sparteine/
Ti(Oi-Pr)4], and reacted with an achiral aldehyde, such as
isobutyraldehyde, only the (Z)-anti homoallylic alcohol
11 was obtained in 36% yield and 75% ee by enantiomer-
differentiating deprotonation. Similarly, starting from the
(S)-10 enantiomer, Hoppe has demonstrated that using
BuLi·TMEDA/Ti(Oi-Pr)4 sequence, only the adduct ent-
11 was isolated, generated from the (R)-‘Ti’-III deriva-
tive (Scheme 5).
Synthesis 2005, No. 1, 102–108 © Thieme Stuttgart · New York

104
P. Razon et al.
PAPER
bamates ( )-14 and ( )-d2-14 treated under n-
BuLi·TMEDA/Ti(Oi-Pr)4 conditions led, after reaction
with propanal, to the expected (Z)-anti-homoallylic alco-
hols ( )-15 and ( )-d2-15 in 90% yield and a total diaste-
reoselectivity.
n-BuLi,THF, –78 °C
CH3CHO
OH
OH
HO
BnO
BnO
83%
( )-12
LiAlH4, Et2O
reflux, 2.5 h
When n-BuLi·(–)-sparteine/Ti(Oi-Pr)4 sequence was ap-
plied to the (S)-d2-14 allyl carbamate, in the reaction with
propanal under simple asymmetric induction, the expect-
ed d2-15 adduct was isolated in 90% yield (Scheme 8);
this compound d2-15 had a 80% enantiomeric excess
(measured by NMR in chiral liquid crystal media or by
classical NMR shift experiments with Europium salts
Eu(hfc)3). Reaction with carbamate (S)-14 under the same
method led to the homoallylic alcohol 15 in an equivalent
chemical yield (90%) and ee (80%).
( )-12
84%
( )-13
LiAlD4, Et2O
reflux, 2.5 h
D2O
D
BnO
BnO
OH
( )-12
74%
D
( )-d2-13
KH, THF, N(iPr)2C(O)Cl
20 °C, 30 min
[H]
A complementary experiment was also carried out from
(R)-14 or (R)-d2-14. Using n-BuLi·(–)-sparteine/Ti(Oi-
Pr)4 conditions, no deprotonation was observed and the
starting material was recovered. Finally, when carbamate
( )-14 was treated under the same route, only the homoal-
lylic alcohol 15 was isolated in 41% yield and 77% enan-
tiomeric excess under kinetic resolution by enantiomer-
differentiating deprotonation (Scheme 8).
( )-13
OCb
85%
( )-d2-13
[H]
( )-14 [H] = H
( )-d2-14 [H] = D
Scheme 6
alcohols and the corresponding allyl carbamates (S)-d2-14
and (R)-d2-14.
1) n-BuLi/(–)-sparteine
toluene, –78 °C, 4 h
2) Ti(OiPr)4, –78 °C, 20 min
3) propanal, –78 °C, 2 h
HO
5
D
Application of the NMR chiral liquid crystal media anal-
ysis led us to determine an enantiomeric excess of 95% for
(S)- and (R)-d2-13 and (S)- and (R)-d2-14 allylic deriva-
tives.
D
D
4
BnO
OCb
OCb
90%, 80% ee
D
BnO
Having in our hands all racemic and optically active g-
alkoxycarbamates 14, we investigated the aldehyde allyl-
ation reaction. First, it was shown that both racemic car-
(S)-d2-14
d2-15
same reagents
and conditions
as above
HO
5
4
BnO
OCb
OCb
90%, 80% ee
( )-13
( )-d2-13
BnO
(–)-DIPT, CH2Cl2
Ti(OiPr)4, TBHP
–35 °C, 24 h
38%
(+)-DIPT, CH2Cl2
Ti(OiPr)4,TBHP
–35 °C, 24 h
36%
(S)-14
15
same reagents
and conditions
as above
[H]
no
deprotonation
BnO
OCb
[H]
[H]
[H]
[H] = H
[H] = D
(R)-14
(R)-d2-14
BnO
OH
BnO
OH
same reagents
and conditions
as above
HO
[H]
[H]
5
4
(R)-13
(R)-d2-13
(S)-13
(S)-d2-13
BnO
OCb
OCb
41%, 77% ee
BnO
KH, THF, N(iPr)2C(O)Cl
20 °C, 30 min
85%
( )-14
Scheme 8
15
[H]
[H]
BnO
OCb
BnO
OCb
When n-BuLi·TMEDA/Ti(Oi-Pr)4 route was applied to
the (S)-d2-14 and (S)-14 allyl carbamates, homoallylic al-
cohols ent-d2-15 and ent-15 were isolated in 90% yield
(Scheme 9); as above a 80% enantiomeric excess was
measured.
[H]
[H]
(S)-14
(S)-d2-14
(R)-14
(R)-d2-14
Scheme 7
Synthesis 2005, No. 1, 102–108 © Thieme Stuttgart · New York

PAPER
Secondary Allyltitanium(IV) Reagents in Aldehyde Allylation
105
n-BuLi/TMEDA
Et2O, –78 °C, 1 h
Ti(OiPr)4, –78 °C, 20 min
propanal, –78 °C, 2 h
3-yn-1-ol (20 g, 285 mmol) in Et2O (120 mL) and the mixture was
stirred for 20 min at 20 °C. To this mixture were added a solution of
benzyl bromide (37.3 g, 313.5 mmol, 1.1 equiv) in anhyd THF
(60 mL) and NaI (0.5 g). After stirring for 8 h at 20 °C, the mixture
was treated at 0 °C with 1 M aq HCl (75 mL) and extracted with
Et2O. The combined organic phases were washed with brine, dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
oily residue was purified by distillation to give the 4-(benzyl-
oxy)butyne as a colourless oil (42.9 g, 94%); bp 83 °C/2 mbar.
HO [H]
[H]
[H]
5
4
BnO
OCb
OCb
[H]
90%, 80% ee
BnO
(S)-14
(S)-d2-14
ent-15 [H] = H
ent-d2-15 [H] = D
same reagents
and conditions
as above
HO [H]
[H]
4-(Benzyloxy)butyne
[H]
IR (CCl4): 3329, 3040, 2216 cm–1.
5
4
1H NMR (270 MHz): d = 2.01 (t, J = 2.5 Hz, 1 H, H-1), 2.55 (td,
J = 7.0, 2.5 Hz, 2 H, CH2-3), 3.62 (t, J = 7.0 Hz, 2 H, CH2-4), 4.56
(s, 2 H, PhCH2), 7.21–7.42 (m, 5 H, C6H5).
BnO
OCb
OCb
90%, 80% ee
[H]
BnO
13C NMR (67.8 MHz): d = 19.7 (CH2-3), 65.2 (CH2-4), 68.9 (CH-
1), 73.2 (PhCH2), 81.1 (C-2), 127.4 (2 CH, C6H5), 128.2 (2 CH,
C6H5), 128.5 (CH, C6H5), 138.6 (C, C6H5).
(R)-14
(R)-d2-14
15
d2-15
Scheme 9
MS (CI, NH3): m/z = 161 (MH+).
To a solution of 4-(benzyloxy)butyne (see above) (25 g, 155 mmol)
in anhyd THF (150 mL) at –78 °C was slowly added n-BuLi (1.6 M
in hexane, 106.7 mL, 171 mmol, 1.1 equiv). After stirring for
20 min, acetaldehyde (21.9 mL, 0.388 mmol, 2.5 equiv) was added.
The reaction mixture was then allowed to slowly warm to r.t. and
after stirring for 1 h, aqueous 1 M HCl (100 mL) was added. After
extraction with Et2O, drying (Na2SO4) and filtration, the solvents
were removed under reduced pressure. The crude oil was purified
by flash chromatography on silica gel (hexane–EtOAc, 80:20) to
give the alcohol ( )-12 as a colourless oil (26.2 g, 83%).
In conclusion, in this work, the Hoppe allylation was ex-
tended to the g-alkoxy secondary allyl carbamates (S)-
and (R)-14. We developed here an efficient route to pre-
pare (S)- or (R)-g-alkoxy secondary allyltitanium interme-
diates. With achiral aldehydes, in simple induction,
corresponding homoallylic alcohols are obtained in good
chemical yield, total diastereoselectivity and 80% ee.
Now, we expected that these titanium reagents exhibit a
high degree of reagent-control with chiral aldehydes;
therefore, we turned our efforts to an application in a syn-
thetic approach to the eastern part 1 of spiramycin (II).9
( )-12
IR (KBr): 3388, 2250 cm–1.
1H NMR (270 MHz): d = 1.42 (d, J = 6.6 Hz, 3 H, CHCH3), 2.52
(td, J = 6.9, 2.0 Hz, 2 H, CH2-5), 3.67 (t, J = 6.9 Hz, 2 H, CH2-6),
4.65 (s, 2 H, PhCH2), 4.24 (qt, J = 6.6, 2.0 Hz, 1 H, CHCH3), 7.44
(m, 5 H, C6H5).
13C NMR (67.8 MHz): d = 20.1 (CH2-5), 24.6 (CHCH3), 58.5
(CHCH3), 68.3 (CH2-6), 73.0 (PhCH2), 81.2 and 83.4 (C≡C), 127.8
and 128.5 (5 CH, C6H5), 138.0 (C, C6H5).
All air and/or H2O sensitive reactions were carried out under argon,
with freshly distilled anhyd solvents using standard syringe-cannu-
la/septa technique. All corresponding glassware was oven dried
(110 °C) and/or carefully dried in line with a flameless heat gun.
THF, Et2O, toluene were distilled from sodium-benzophenone;
CH2Cl2, pentane, cyclohexane were distilled from CaH2; TMEDA,
(–)-sparteine, Ti(Oi-Pr)4 were distilled prior to use. All reactions
were monitored by TLC carried out on precoated plates of silica gel
60F 254 (Merck, Art. 7735). Visualisation was accomplished with
UV light then 10% ethanolic phosphomolybdic acid solution fol-
lowed by heating. Flash chromatography was performed on silica
gel Merck, 60, 230–400 mesh (Art. 9385). NMR spectra were re-
corded in CDCl3.
Enantiomeric excess were measured in CDCl3 by 1H NMR chemi-
cal shift at 400 MHz with Eu(hfc)3: a solution of Eu(hfc)3 10 mg/
mL in CDCl3 was added to a sample of 2 to 5 mg of title compound
in CDCl3 up to significant splitting of signals. Alternatively, enan-
tiomeric excess were measured by 2D NMR chemical shift at
400 MHz in polybenzyl-L-glutamate with CH2Cl2 as solvent: 80 to
100 mg of polybenzyl-L-glutamate and 25 to 50 mg of deuterated ti-
tle compound in a NMR tube were dissolved in 0.5 mL of CH2Cl2.
The sample was centrifuged until forming a solid crystal liquid
phase. 2D NMR spectra were then recorded.
MS (CI, NH3): m/z = 222 (MH+ + 17).
Anal. Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.52; H,
7.98.
(3E,R/S)-6-(Benzyloxy)hex-3-en-2-ol [( )-13]
To a solution of the alcohol ( )-12 (26.2 g, 128 mmol) in anhyd
Et2O (140 mL) at 0 °C was slowly added a 1 M solution of LiAlH4
in THF (141 mL, 141 mmol, 1.1 equiv). The reaction mixture was
placed in a preheated bath and refluxed for 2.5 h. The solution was
then cooled at 0 °C, and carefully and successively treated with H2O
(50 mL), aq 10 M solution of NaOH (12.5 mL), and H2O (25 mL).
The precipitate was filtered and washed with Et2O. The filtrate was
concentrated under reduced pressure and purified by flash chroma-
tography on silica gel (hexane–EtOAc, 50:50) to give the title com-
pound ( )-13 as a colourless oil (22.5 g, 84%); bp 130 °C/0.03
mbar.
IR (CCl4): 3387 cm–1.
Optical rotations were determined at 20 °C in MeOH, 589 nm, on a
Perkin-Elmer 241 instrument or a JASCO DIP 370 instrument.
Bulbs to bulbs distillations were performed using a Büchi GKR 51
Kugelrohr apparatus.
1H NMR (250 MHz): d = 1.26 (d, J = 6.4 Hz, 3 H, CH3-1), 2.36 (td,
J = 6.6, 5.8 Hz, 2 H, CH2-5), 3.52 (t, J = 6.6 Hz, 2 H, CH2-6), 4.28
(qd, J = 6.4, 5.2 Hz, 1 H, CH-2), 4.52 (s, 2 H, PhCH2), 5.56 (dd,
J = 15.5, 5.2 Hz, 1 H, =CH-3), 5.74 (dt, J = 15.5, 5.8 Hz, 1 H, =CH-
4), 7.32 (m, 5 H, C6H5).
13C NMR (67.8 MHz): d = 23.4 (CH3-1), 32.6 (CH2-5), 68.8
(CHCH3), 69.7 (CH2-6), 72.9 (PhCH2), 127.1 (=CH, C-4), 127.6
(2R/S)-6-(Benzyloxy)hex-3-yn-2-ol [( )-12]
To a suspension of NaH (60% in oil, 13.7 g, 342 mmol, 1.2 equiv)
in anhyd THF (120 mL) at 0 °C, was slowly added a solution of but-
Synthesis 2005, No. 1, 102–108 © Thieme Stuttgart · New York

106
P. Razon et al.
PAPER
(CH, C6H5), 127.8 (2 CH, C6H5), 128.4 (2 CH, C6H5), 136.3 (=CH,
C-3), 138.4 (C, C6H5).
Anal. Calcd for C20H31NO3: C, 72.04; H, 9.37; N, 4.20. Found: C,
72.18; H, 9.48; N, 4.22.
MS (CI, NH3): m/z = 207 (MH+).
(R)-14
Anal. Calcd for C13H18O2: C, 75.69; H, 8.80. Found: C, 75.74; H,
8.98.
[a]D –6.5 (c = 2.00, MeOH).
(S)-14
(2R,3E)-6-(Benzyloxy)hex-3-en-2-ol [(R)-13]; Typical Proce-
dure
[a]D +6.8 (c = 2.05, MeOH).
To a solution of diisopropyl L-(+)-tartrate (10.13 g, 43.2 mmol,
1 equiv) in freshly distilled anhyd CH2Cl2 (220 mL) was added
freshly distilled Ti(Oi-Pr)4 (10.7 mL, 36 mmol, 0.83 equiv). After
stirring for 20 min at r.t., the reaction mixture was cooled at –35 °C
(bath temperature) and a solution of the alcohol ( )-13 (8.9 g) in an-
hyd CH2Cl2 (220 mL) was added via canula. After stirring for 1 h,
a 5.5 M solution of tert-butyl hydroperoxide in decane (4.17 mL,
23 mmol, 0.53 equiv) was slowly added. The stirring was main-
tained for 24 h at –35 °C, and the mixture was then quenched at r.t.
by addition of 10% aq solution of citric acid (200 mL). After 3 h,
the solution was filtered through a pad of Celite, the Celite pad was
washed with Et2O and the aqueous phase was extracted with Et2O.
The combined Et2O layers were concentrated under reduced pres-
sure and the residue was diluted in Et2O (120 mL) and a 7.5 M so-
lution of NaOH in H2O (120 mL) was added. After 6 h, the organic
phase was separated, washed with brine, dried (Na2SO4), filtered
and concentrated under reduced pressure. The oily residue was flash
chromatographed on silica gel (cyclohexane–EtOAc, 60:40) and
purified further by bulb to bulb distillation to give the title com-
pound (R)-13 as a colourless oil (3.2 g, 36%); [a]D +20 (c = 1.03,
MeOH).
(3E,3d,4d)-6-(Benzyloxy)hex-3-en-2-ol [( )-d2-13]
To a solution of alcohol ( )-12 (11.04 g, 69 mmol) in anhyd Et2O
(80 mL) at 0 °C was slowly added a 1 M solution of LiAlD4 in THF
(83 mL, 83 mmol, 1.2 equiv). The reaction mixture was placed in a
preheated bath and refluxed for 2.5 h. The solution was then cooled
to 0 °C, and carefully and successively treated with D2O (98%-d,
27.5 mL, 1.37 mol, 20 equiv), 10 M aq solution of NaOH (7 mL),
and H2O (15 mL). The precipitate was filtered and washed with
Et2O. The filtrate was concentrated under reduced pressure and the
residue was purified by flash chromatography on silica gel (hexane–
EtOAc, 50:50) to give the title compound ( )-d2-13 as a colourless
oil (10.6 g, 74%).
IR (CCl4): 3387 cm–1.
1H NMR (270 MHz): d = 1.26 (d, J = 6.4 Hz, 3 H, CH3-1), 1.74 (s,
1 H, OH), 2.36 (t, J = 6.6 Hz, 2 H, CH2-5), 3.52 (t, J = 6.6 Hz, 2 H,
CH2-6), 4.27 (q, J = 6.4 Hz, 1 H, CH-2), 4.52 (s, 2 H, PhCH2), 7.35
(m, 5 H, C6H5).
13C NMR (67.8 MHz): d = 23.2 (CH3-1), 32.3 (CH2-5), 68.5 (CH-
2), 69.6 (CH2-6), 72.8 (PhCH2), 126.4 (3 signals, CD, J = 23.2 Hz,
C-4), 127.6 (CH, C6H5), 127.7 (2 CH, C6H5), 128.4 (2 CH, C6H5),
135.8 (3 signals, CD, J = 23.2 Hz, C-3), 138.4 (C, C6H5).
(2S,3E)-6-(Benzyloxy)hex-3-en-2-ol [(S)-13]
The enantiomeric compound (S)-13 was obtained by the same pro-
cedure using diisopropyl D-(–)-tartrate in 38% yield; [a]D –22 (c =
1.35, MeOH).
Anal. Calcd for C13H16D2O2: C, 77.96; H, 9.68. Found: C, 78.04; H,
9.74.
(2R,3E,3d,4d)-6-(Benzyloxy)hex-3-en-2-ol [(R)-d2-13] and
(2S,3E,3d,4d)-6-(Benzyloxy)hex-3-en-2-ol [(S)-d2-13]
Starting from ( )-d2-13, compounds (S)-d2-13 and (R)-d2-13 were
obtained by Sharpless kinetic resolution method using the same typ-
ical procedure described above for the preparation of (R)-13. Enan-
tiomeric excess were measured by 2D NMR in PBLG and found to
be superior to 95%. See above for spectroscopic data.
(2R/S,3E)-6-(Benzyloxy)-2-{[(N,N-diisopropyl)carbam-
oyl]oxy}hexene [( )-14], (2R,3E)-6-(Benzyloxy)-2-{[(N,N-diiso-
propyl)carbamoyl]oxy}hexene [(R)-14], and (2S,3E)-6-
(Benzyloxy)-2-{[(N,N-diisopropyl)carbamoyl]oxy}hex-3-ene
[(S)-14]; Typical Procedure
To a suspension of KH (30% in oil, 5.88 g, 44 mmol, 1.4 equiv) in
anhyd THF (40 mL) at 0 °C, was slowly added a solution of alcohol
( )-13, or (R)-13, or (S)-13 (6.5 g, 31.4 mmol) in THF (35 mL). The
resulting solution was stirred for 20 min at 20 °C and a solution of
diisopropylcarbamoyl chloride (5.63 g, 34.5 mmol, 1.1 equiv) in
anhyd THF (25 mL) was added. After stirring for 30 min at 20 °C,
the mixture was treated at 0 °C with 1 M aq HCl (40 mL) and ex-
tracted with Et2O. The combined organic phases were washed with
brine, dried (Na2SO4), filtered and concentrated under reduced pres-
sure. The oily residue was purified by flash chromatography on sil-
ica gel (hexane–EtOAc, 80:20) or distillation to give the title
compound ( )-14 or (R)-14 or (S)-14 as a colourless oil (8.92 g,
85%); bp 140 °C/0.04 mbar.
(R)-d2-13
[a]D +4.5 (c = 2.05, MeOH).
(S)-d2-13
[a]D –4.3 (c = 2.00, MeOH).
(2R,3E,3d,4d)-6-(Benzyloxy)-2-{[(N,N-diisopropyl)carbam-
oyl]oxy}hex-3-ene [(R)-d2-14], (2S,3E,3d,4d)-6-(Benzyloxy)-2-
{[(N,N-diisopropyl)carbamoyl]oxy}hex-3-ene [(S)-d2-14]
Compounds (R)-d2-14 and (S)-d2-14 were obtained from (R)-d2-13
and (S)-d2-13 in 85% yield, each by the same carbamoylation pro-
cedure used before to prepare (R)-14 and (S)-14.
IR (CCl4): 1688 cm–1.
IR (CCl4): 1688 cm–1.
1H NMR (250 MHz): d = 1.18 {d, J = 6.8 Hz, 12 H, 4 CH3,
N[CH(CH3)2]2}, 1.30 (d, J = 6.4 Hz, 3 H, CH3-1), 2.35 (q, J = 6.8
Hz, 2 H, CH2-5), 3.49 (t, J = 6.8 Hz, 2 H, CH2-6), 3.60–4.2 {wide
m, 2 H, N[CH(CH3)2]2}, 4.52 (s, 2 H, PhCH2O), 5.27 (quint, J = 6.4
Hz, 1 H, H-2), 5.63 (dt, J = 15.9, 6.8 Hz, 1 H, =CH-4), 5.64 (dd,
J = 15.9, 6.4 Hz, 1 H, =CH-3), 7.32 (m, 5 H, C6H5).
13C NMR (62.5 MHz): d = 20.7 and 21.1 {4 CH3, N[CH(CH3)2]2},
26.8 (CH3-1), 32.7 (CH2-5), 45.6 {2 CH, N[CH(CH3)2]2}, 69.6
(CH2-6), 70.8 (CH-2), 72.8 (PhCH2), 127.5 (=CH-4), 127.6 and
128.3 (5 CH, C6H5), 132.6 (=CH-3), 138.5 (C, C6H5), 155.2 (C=O).
1H NMR (270 MHz): d = 1.20 {d, J = 6.9 Hz, 12 H, 4 CH3,
N[CH(CH3)2]2}, 1.31 (d, J = 6.6 Hz, 3 H, CH3-1), 2.37 (t, J = 6.9
Hz, 2 H, CH2-5), 3.51 (t, J = 6.9 Hz, 2 H, CH2-6), 3.60–4.20 {wide
m, 2 H, N[CH(CH3)2]2}, 4.52 (s, 2 H, PhCH2), 5.29 (q, J = 6.6 Hz,
1 H, H-2), 7.33 (m, 5 H, C6H5).
13C NMR (67.8 MHz): d = 20.7 and 21.1 {4 CH3, N[CH(CH3)2]2},
26.9 (CH3-1), 32.7 (CH2-5), 45.6 {2 CH, N[CH(CH3)2]2}, 69.7
(CH2-6), 70.8 (CH-2), 72.9 (PhCH2), 127.6 and 128.4 (5 CH, C6H5),
132.2 (3 signals, CD, J = 23.2 Hz, C-3), 138.5 (C, C6H5), 155.2
(C=O). C-4 was not observed.
MS (CI, NH3): m/z = 334 (MH+).
MS (CI, NH3): m/z = 336 (MH+).
Synthesis 2005, No. 1, 102–108 © Thieme Stuttgart · New York

PAPER
Secondary Allyltitanium(IV) Reagents in Aldehyde Allylation
107
Anal. Calcd for C20H29D2NO3: C, 71.60; H, 9.91; N, 4.18. Found:
C, 71.72; H, 10.12; N, 4.15.
(5.0 mL) was rapidly added via cannula and the reaction mixture
was stirred for 20 min at –78 °C (transmetallation time). Then,
freshly distilled propionaldehyde (0.65 mL, 9 mmol, 6 equiv) was
added. The mixture was stirred for 2 h at –78 °C and quenched by
transferring to a vigorously stirred mixture of aq 3 M HCl (20 mL)
and Et2O (20 mL) at 0 °C. The temperature was allowed to reach to
20 °C and the resulting solution was eventually filtered on a pad of
Celite to removed titanium salts and extracted with Et2O. The or-
ganic layer was washed with brine, dried (Na2SO4) and concentrat-
ed under reduced pressure. The residue was purified by flash
chromatography on silica gel (hexane–EtOAc, 70:30) to give the ti-
tle compound 15 as a pale yellow oil (236 mg, 41% yield, 77% ee).
(R)-d2-14
[a]D –2.0 (c = 2.10, MeOH).
(S)-d2-14
[a]D +1.8 (c = 2.00, MeOH).
(2Z,4R*,5S*)-4-[2-(Benzyloxy)ethyl]-2-{[(N,N-diisopropyl)car-
bamoyl]oxy}-5-hydroxy-hept-2-ene [( )-15], (2Z,4R,5S)-4-[2-
(Benzyloxy)ethyl]-2-{[(N,N-diisopropyl)carbamoyl]oxy}-5-hy-
droxyhept-2-ene (15) and (2Z,4S,5R)-4-[2-(Benzyloxy)ethyl]-2-
{[(N,N-diisopropyl)carbamoyl]oxy}-5-hydroxyhept-2-ene [ent-
15]; Typical Procedures
Optically Active Compound ent-15 from Optically Active Car-
bamate (S)-14
Racemic Homoallylic Alcohol ( )-15 from Racemic Carbamate
( )-14
To a solution of TMEDA (0.45 mL, 3 mmol, 2.0 equiv) in anhyd
Et2O–cyclohexane (10 mL/1.0 mL) at –78 °C, under argon, was
added n-BuLi (1.6 M in hexane, 1.9 mL, 3 mmol, 2.0 equiv). After
stirring for 20 min at –78 °C, a solution of the optically active allyl
carbamate (S)-14 (500 mg, 1.5 mmol) in anhyd pentane (3.0 mL),
was slowly added. The solution turned pale yellow. After stirring
for 1 h at –78 °C, precooled Ti(Oi-Pr)4 (1.33 mL, 4.5 mmol,
3 equiv) in pentane (5.0 mL) at –78 °C was rapidly added via can-
nula and the reaction mixture was stirred for 20 min at –78 °C
(transmetallation time). Then, freshly distilled propionaldehyde
(0.65 mL, 9 mmol, 6 equiv) was added. The mixture was stirred for
2 h at –78 °C and quenched by transferring to a vigorously stirring
mixture of aq 3 M HCl (20 mL) and Et2O (20 mL) at 0 °C. The tem-
perature was allowed to reach 20 °C and the resulting solution was
eventually filtered on a pad of Celite to removed titanium salts and
extracted with Et2O. The organic layer was washed with brine, dried
(Na2SO4) and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (hexane–EtOAc,
70:30), to give the title compound ent-15 as a pale yellow oil
(520 mg, 90% yield, 80% ee).
To a solution of N,N,N¢,N¢-tetramethylethylenediamine (TMEDA,
0.45 mL, 3 mmol, 2.0 equiv) in anhyd Et2O (10 mL) at –78 °C, un-
der argon, was added n-BuLi (1.6 M in hexane, 1.9 mL, 3 mmol,
2.0 equiv). After stirring for 20 min at –78 °C, a solution of the ra-
cemic allyl carbamate ( )-14 (500 mg, 1.5 mmol) in anhyd Et2O
(3 mL), was slowly added. The solution turned pale yellow. After
stirring for 1 h at –78 °C, Ti(Oi-Pr)4 (1.33 mL, 4.5 mmol, 3 equiv)
was rapidly added and the reaction mixture was stirred for 20 min
at –78 °C (transmetallation time). Then, freshly distilled propional-
dehyde (0.65 mL, 9 mmol, 6 equiv) was added. The mixture was
stirred for 2 h at –78 °C and quenched by transferring to a vigorous-
ly stirred mixture of 3 M aq HCl (20 mL) and Et2O (20 mL) at 0 °C.
The temperature was allowed to reach to 20 °C and the resulting so-
lution was eventually filtered on a pad of Celite to remove titanium
salts and extracted with Et2O. The organic layer was washed with
brine, dried (Na2SO4) and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (hexane–
EtOAc, 70:30) to give the title compound ( )-15 as a pale yellow oil
(520 mg, 90%).
Enantiomeric Homoallylic Alcohol 15
Optically Active Homoallylic Alcohol 15 from Carbamate (S)-
14
The same procedure was used for the (R)-14 enantiomer, which
gave the enantiomeric homoallylic alcohol 15 with the same enan-
tiomeric excess. Enantiomeric excess values were determined by
NMR shift experiment with europium salts Eu(hfc)3.
To a solution of (–)-sparteine (705 mg, 3 mmol, 2.0 equiv) in anhyd
pentane (10 mL) at –78 °C under argon , was added a solution of the
optically active allyl carbamate (S)-14 (500 mg, 1.5 mmol) in anhyd
pentane (3.0 mL). After stirring for 20 min at –78 °C, n-BuLi (1.6
M in hexane, 1.9 mL, 3 mmol, 2.0 equiv) was slowly added. The so-
lution turned pale yellow. After stirring for 4 h at –78 °C, precooled
Ti(Oi-Pr)4 (1.33 mL, 4.5 mmol, 3 equiv) in pentane (5.0 mL) was
rapidly added via cannula and the reaction mixture was stirred for
20 min at –78 °C (transmetallation time). Then, freshly distilled
propionaldehyde (0.65 mL, 9 mmol, 6 equiv) was added. The mix-
ture was stirred for 2 h at –78 °C and quenched by transferring to a
vigorously stirred mixture of aq 3 M HCl (20 mL) and Et2O
(20 mL) at 0 °C. The temperature was allowed to reach to 20 °C and
the resulting solution was eventually filtered on a pad of Celite to
remove titanium salts and extracted with Et2O. The organic layer
was washed with brine, dried (Na2SO4) and concentrated under re-
duced pressure. The residue was purified by flash chromatography
on silica gel (hexane–EtOAc, 70:30) to give the title compound 15
as a pale yellow oil (520 mg, 90% yield, 80% ee).
IR (CCl4): 3395, 1715 cm–1.
1H NMR (400 MHz): d = 0.94 (t, J = 7.4 Hz, 3 H, CH3-7), 1.23 {d,
J = 7.2 Hz, 12 H, 4 CH3, N[CH(CH3)2]2}, 1.43 (m, 1 H, Ha-6), 1.55
(m, 1 H, Ha-1¢), 1.57 (m, 1 H, Hb-6), 1.83 (dq, J = 14, 5.5 Hz, 1 H,
Hb-1¢), 1.93 (s, 3 H, CH3-1), 2.51 (tt, J = 10.5, 5.5 Hz, 1 H, H-4),
3.40 (td, J = 6.5, 5.5 Hz, 1 H, H-5), 3.45 (dt, J = 9.3, 5.5 Hz, 1 H,
Ha-2¢), 3.55 (dt, J = 9.3, 5.5 Hz, 1 H, Hb-2¢), 3.82 [br m, 1 H,
NCH(CH3)2], 4.03 [br m, 1 H, NCH(CH3)2], 4.51 (s, 2 H, PhCH2),
4.91 (d, J = 10.5 Hz, 1 H, =CH-3), 7.32 (m, 5 H, C6H5).
13C NMR (100.6 MHz):
d = 9.6 (CH3-7), 20.3 {4 CH3,
N[CH(CH3)2]2}, 26.9 (CH3-1), 27.8 (CH2-6), 32.2 (CH2-1¢), 39.0
(CH-4), 45.9 and 46.7 {2 CH, N[CH(CH3)2]2}, 68.7 (CH2-2¢), 73.1
(PhCH2), 75.1 (CH-5), 116.9 (=CH-3), 127.5 (2 CH, C6H5), 127.7
(2 CH, C6H5), 128.3 (CH, C6H5), 138.4 (C, C6H5), 147.3 (C-2),
153.6 (C=O).
MS (CI, NH3): m/z = 392 (MH+).
Anal. Calcd for C23H37NO4: C, 70.55; H, 9.52; N, 3.58. Found: C,
70.67; H, 9.69; N, 3.54.
Optically Active Homoallylic Alcohol 15 from Racemic ( )-14
To a solution of (–)-sparteine (705 mg, 3 mmol, 2.0 equiv) in anhyd
pentane (10 mL) at –78 °C under argon, was added a solution of the
racemic allyl carbamate ( )-14 (500 mg, 1.5 mmol) in anhyd pen-
tane (3.0 mL). After stirring for 20 min at –78 °C, n-BuLi (1.6 M in
hexane, 1.9 mL, 3 mmol, 2.0 equiv), was slowly added. The solu-
tion turned pale yellow. After stirring for 4 h at –78 °C, a solution
of precooled Ti(Oi-Pr)4 (1.33 mL, 4.5 mmol, 3 equiv) in pentane
15
From (–)-sparteine and (S)-allyl carbamate [(S)-14]; [a]D –20.0 (c =
1.20, MeOH).
From (R)-allyl carbamate [(R)-14]/TMEDA; [a]D –20.0 (c = 1.20,
MeOH).
Synthesis 2005, No. 1, 102–108 © Thieme Stuttgart · New York

108
P. Razon et al.
PAPER
ent-15
References
From (S)-allyl carbamate [(S)-14]/TMEDA; [a]D +20.0 (c = 1.20,
MeOH).
(1) (a) Kirst, H. A. In Recent Progress in the Chemical Synthesis
of Antibiotics; Lucas, G.; Ohno, M., Eds.; Springer Verlag:
Berlin, 1990, 39. (b) In Macrolide Antibiotics; Omura, S.,
Ed.; Academic Press: New York, 1984. (c) Kirst, H. A. J.
Antimicrob. Chemother. 1991, 28, 787.
(2Z,4S,5R,3d,4d)-4-[2-(Benzyloxy)ethyl]-2{[(N,N-diisopro-
pyl)carbamoyl]oxy}-5-hydroxyhept-2-ene (ent-d2-15) and
(2Z,4S,5R,3d,4d)-4-[2-(Benzyloxy)ethyl]-2{[(N,N-diisopro-
pyl)carbamoyl]oxy}-5-hydroxyhept-2-ene (d2-15); Optically
Active ent-d2-15 from Optically Active Carbamate (S)-d2-14;
Typical Procedure
(2) (a) Tatsuta, K.; Amemiya, Y.; Kanemura, Y.; Takahashi, H.;
Kinoshita, M. Tetrahedron Lett. 1982, 23, 3375.
(b) Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R. J. Am Chem.
Soc. 1982, 104, 2031. (c) Masamune, S.; Lu, L. D.-L.;
Jackson, W. P.; Kaiho, T.; Toyoda, T. J. Am. Chem. Soc.
1982, 104, 5523. (d) Grieco, P. A.; Inanaga, J.; Lin, N. H.;
Yanami, T. J. Am. Chem. Soc. 1982, 104, 578. (e) Tanaka,
T.; Oikawa, Y.; Hamada, T.; Yonemitsu, O. Chem. Pharm.
Bull. 1987, 35, 2219.
To a solution of TMEDA (0.45 mL, 3 mmol, 2.0 equiv) in anhyd
Et2O–cyclohexane (10 mL/1.0 mL) at –78 °C, under argon, was
added n-BuLi (1.6 M in hexane, 1.9 mL, 3 mmol, 2.0 equiv). After
stirring for 20 min at –78 °C, a solution of the optically active allyl
carbamate (S)-d2-14 (500 mg, 1.5 mmol) in anhyd pentane
(3.0 mL), was slowly added. The solution turned pale yellow. After
stirring for 1 h at –78 °C, precooled Ti(Oi-Pr)4 (1.33 mL, 4.5 mmol,
3 equiv) in pentane (5.0 mL) at –78 °C was rapidly added via can-
nula and the reaction mixture was stirred for 20 min at –78 °C
(transmetallation time). Then, freshly distilled propionaldehyde
(0.65 mL, 9 mmol, 6 equiv) was added. The mixture was stirred for
2 h at –78 °C and quenched by transferring to a vigorously stirred
mixture of aq 3 M HCl (20 mL) and Et2O (20 mL) at 0 °C. The tem-
perature was allowed to reach 20 °C and the resulting solution was
eventually filtered on a pad of Celite to remove titanium salts and
extracted with Et2O. The organic layer was washed with brine, dried
(Na2SO4) and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (hexane–EtOAc,
70:30), to give the title compound ent-d2-15 as a pale yellow oil
(520 mg, 90% yield, 80% ee).
(3) (a) Omura, S.; Sano, H.; Sunazuka, T. J. Antimicrob.
Chemother. 1985, 16 Suppl. A, 1. (b) Omura, S.; Sano, H.;
Inoue, M.; Yamashita, K.; Okachi, R. J. Antibiot. 1983, 36,
1336. (c) Tsuchiya, M.; Hamada, H.; Takeuchi, T.;
Umewaza, H.; Yamamoto, K.; Tanaka, H.; Kiyoshima, K.;
Mori, S.; Okamoto, R. J. Antibiot. 1982, 35, 661.
(4) (a) Berque, I.; Razon, P.; Le Ménez, P.; Aniès, C.; Pancrazi,
A.; Ardisson, J. Synlett 1998, 1129. (b) Berque, I.; Razon,
P.; Le Ménez, P.; Pancrazi, A.; Ardisson, J. Synlett 1998,
1135. (c) Berque, I.; Razon, P.; Le Ménez, P.; Mahuteau, J.;
Férézou, J. P.; Pancrazi, A.; Ardisson, J. J. Org. Chem. 1999,
64, 373.
(5) (a) Hoppe, D.; Zschage, O. Angew. Chem., Int. Ed. Engl.
1989, 28, 69. (b) Zschage, O.; Hoppe, D. Tetrahedron 1992,
48, 5657. (c) Zschage, O.; Hoppe, D. Tetrahedron 1992, 48,
8389. (d) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 2282. (e) Hoppe, D.; Paulsen, H. Tetrahedron
1992, 48, 5667. (f) Férézou, J.-P.; Julia, M.; Li, Y.; Liu, L.
W.; Pancrazi, A. Bull. Soc. Chim. Fr. 1995, 132, 428.
(g) Smith, N. D.; Kocienski, P. J.; Street, S. D. A. Synthesis
1996, 652.
(6) (a) From racemic secondary crotyl carbamate, see: Zschage,
O.; Schwark, J.-A.; Hoppe, D. Angew. Chem., Int. Ed. Engl.
1990, 29, 296. (b) See also: Zschage, O.; Schwark, J.-A.;
Krämer, T.; Hoppe, D. Tetrahedron 1992, 48, 8377.
(c) From optically active secondary crotyl carbamates, see:
Hoppe, D.; Krämer, T. Angew. Chem., Int. Ed. Engl. 1986,
25, 160. (d) Hoppe, D.; Krämer, T. Tetrahedron Lett. 1987,
28, 5149. (e) Hoppe, D.; Schwark, J.-R. Synthesis 1990,
291. (f) See also: Zschage, O.; Hoppe, D. Tetrahedron 1992,
48, 8389.
The same procedure was used with (R)-d2-14 to give the enantio-
meric homoallylic alcohol d2-15 with the same enantiomeric excess.
The enantiomeric homoallylic alcohol ent-d2-15 was also obtained
with the same enantiomeric excess from the (S)-d2-14 carbamate us-
ing the n-BuLi/(–)-sparteine conditions.
Enantiomeric excess were determined by NMR shift experiment
with europium salts Eu(hfc)3.
IR (CCl4): 3395, 1715 cm–1.
1H NMR (400 MHz): d = 0.94 (t, J = 7.4 Hz, 3 H, CH3-7), 1.24 {d,
J = 7.2 Hz, 12 H, 4 CH3, N[CH(CH3)2]2}, 1.43 (m, 1 H, Ha-6), 1.55
(m, 1 H, Ha-1¢), 1.57 (m, 1 H, Hb-6), 1.83 (dt, J = 14, 7 Hz, 1 H, Hb-
1¢), 1.93 (s, 3 H, CH3-1), 3.40 (dd, J = 7.2, 4.3 Hz, 1 H, H-5), 3.45
(m, 1 H, Ha-2¢), 3.55 (dt, 1 H, Hb-2¢), 3.82 [br m, 1 H, NCH(CH3)2],
4.03 [br m, 1 H, NCH(CH3)2], 4.51 (s, 2 H, PhCH2), 7.32 (m, 5 H,
C6H5).
13C NMR (100.6 MHz): d = 9.6 (CH3-7), 20.3 {4 CH3,
N[CH(CH3)2]2}, 26.9 (CH3-1), 27.8 (CH2-1¢), 32.2 (CH2-6), 45.9
and 46.7 {2 CH, N[CH(CH3)2]2}, 68.7 (CH2-2¢), 73.1 (PhCH2), 75.1
(CH-5), 127.5 (2 CH, C6H5), 127.7 (2 CH, C6H5), 128.3 (CH, C6H5),
138.4 (C, C6H5), 147.3 (C-2), 153.6 (C=O). C-3 and C-4 were not
observed.
(7) (a) Meddour, A.; Canet, I.; Loewenstein, A.; Péchiné, J. M.;
Courtieu, J. J. Am. Chem. Soc. 1994, 116, 9652. (b) Canet,
I.; Courtieu, J.; Loewenstein, A.; Meddour, A.; Péchiné, J.
M. J. Am. Chem. Soc. 1995, 117, 6520. (c) Meddour, A.;
Berdagué, P.; Hedli, A.; Courtieu, J.; Lesot, P. J. Am. Chem.
Soc. 1997, 119, 4502. (d) Merlet, D.; Ancian, B.; Courtieu,
J.; Lesot, P. J. Am. Chem. Soc. 1999, 121, 5249.
(8) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980,
102, 5974. (b) Finn, M. G.; Sharpless, K. B. Asymmetric
Synthesis; Morrison, J. D., Ed.; Academic Press: New York,
1985. (c) Katsuki, T.; Martin, V. S. Organic Reactions, Vol.
48; Paquette, L. A., Ed.; Wiley: New York, 1996.
(9) Razon, P.; N’Zoutani, M.-A.; Dhulut, S.; Bezzenine-
Lafollée, S.; Pancrazi, A.; Ardisson, J. Synthesis 2004,
following paper.
MS (CI, NH3): m/z = 394 (MH+).
Anal. Calcd for C23H35D2NO2: C, 70.19; H, 9.99; N, 3.56. Found:
C, 70.26; H, 10.17; N, 358.
d2-15
[a]D –4.6 (c = 2.00, MeOH).
ent-d2-15
[a]D +4.2 (c = 1.80, MeOH).
Synthesis 2005, No. 1, 102–108 © Thieme Stuttgart · New York