Primary and secondary allyltitanium(IV) reagents in aldehyde allylation II: Application to an enantioselective preparation of a C1-C7 fragment of spiramycin

Article abstract of DOI:10.1055/s-2004-834913

A synthetic approach to the eastern part of spiramycin, an important antibiotic compound, is described. Introduction of the side chain was first envisaged through a Hoppe aldehyde allylation. This reaction was carried out between an optically pure aldehyde 32 and a (±)-γ-alkoxy allyltitanium(IV) species derived from a primary γ-alkoxy allyl (diisopropyl)carbamate. Under kinetic resolution conditions, the anti-Cram compound 35 was obtained in an 80:20 mixture, with the Cram isomer 34, in 81% yield. Employing the optically pure (S)-γ-alkoxy allyl (diisopropyl)carbamate 36, the corresponding (R)-γ-alkoxy allyltitanium (R)-'Ti'-III was generated under n-BuLi·TMEDA/Ti(Oi-Pr)₄ conditions, that reacted with aldehyde 32 in double stereodifferentiation to deliver the expected Cram compound 40 in 80% yield (95% de). This latter corresponded to the C1-C7 fragment of spiramycin.

Full text of DOI:10.1055/s-2004-834913

PAPER
109
Primary and Secondary Allyltitanium(IV) Reagents in Aldehyde Allylation II:
Application to an Enantioselective Preparation of a C1-C7 Fragment of
Spiramycin
Primary and
S
a
e
condary A
t
llyltita
r
i
)
Reag
c
A
lde
k
hyde
A
llylation Razon, Marie-Ange N’Zoutani, Sylvie Dhulut, Sophie Bezzenine-Lafollée, Ange Pancrazi, Janick Ardisson*
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
Abstract: A synthetic approach to the eastern part of spiramycin,
an important antibiotic compound, is described. Introduction of the
side chain was first envisaged through a Hoppe aldehyde allylation.
This reaction was carried out between an optically pure aldehyde 32
and a ( )-g-alkoxy allyltitanium(IV) species derived from a primary
g-alkoxy allyl (diisopropyl)carbamate. Under kinetic resolution
conditions, the anti-Cram compound 35 was obtained in an 80:20
mixture, with the Cram isomer 34, in 81% yield. Employing the op-
tically pure (S)-g-alkoxy allyl (diisopropyl)carbamate 36, the corre-
sponding (R)-g-alkoxy allyltitanium (R)-‘Ti’-III was generated
under n-BuLi·TMEDA/Ti(Oi-Pr)4 conditions, that reacted with al-
dehyde 32 in double stereodifferentiation to deliver the expected
Cram compound 40 in 80% yield (95% de). This latter correspond-
ed to the C1-C7 fragment of spiramycin.
O
R3O
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 1
R1 = D-mycinose
R2 = Mycaminose
Spiramycin 2
R
3 = D-fucosamine
PGO
PGO
9
9
Key words: spiramycin, synthesis, Hoppe allylation, secondary al-
lyltitanium reagent, double stereodifferentiation
8
8
6
6
OPG
OPG
5
5
4
4
3
X
1
OH
OH
PGO
3
In the course of total synthesis of 14- and 16-membered
macrolide antibiotics we were interested in the prepara-
tion of tylosin (1) 1 and spiramycin (2),2 two components
of the important erythromycin family3 (Scheme 1).
OH
3a X = Me
3b X = OMe
1
4
PGO
Scheme 1
In a precedent study we described a synthetic approach to
the C1-C9 eastern part 3a of tylosin (1),4 based on sequen-
tial Hoppe aldehyde allylation reactions. We now focus
on spiramycin (2), for which only one total synthesis has
been reported.5 As the C1-C9 portions of tylosin (1) and
spiramycin (2) are quite similar, we first tried to develop
a common strategy for the construction of 3a and 3b.
OCb
8
9
6
OPG
OPG
HO
3
7
4
5
1
OH
In our retrosynthetic approaches of tylosin (1) and spira-
mycin (2), the key intermediate acetylenic compound 4
could be a hub for synthesis of eastern parts 3a and 3b as
well as analogues, and may arise from a Hoppe allylation6
of aldehyde ( )-6 with the optically active crotyltitane
(R)-‘Ti’-I (Scheme 2). A Barton deoxygenation at the C-
7 position7 was envisaged to transform 5 into 4 for the last
step of the sequence. On the other hand, precursor ( )-7 of
aldehyde ( )-6 could result from another allylation reac-
tion between aldehyde 8 and the g-alkoxy allyltitanium
‘Ti’-II in a Hoppe-like reaction.
4
PGO
PGO
5
"Ti"
O
OCb
R
6
7
(R)-"Ti"-I
1
OH
3
5
4
( )-6
OCb
6
"Ti"
5
CHO
PGO
OCb
OPG
7
( )-"Ti"-II
1
OH
3
5
4
1
PGO
PGO
SYNTHESIS 2005, No. 1, pp 0109–0121
x
x
.
x
x
.2
0
0
4
( )-7
8
Advanced online publication: 08.12.2004
DOI: 10.1055/s-2004-834913; Art ID: P09204SS
Scheme 2
© Georg Thieme Verlag Stuttgart · New York

110
P. Razon et al.
PAPER
OCb
We decided to employ racemic g-alkoxy allyltitanium ( )-
‘Ti’-II for the allylation of aldehyde 8, leading to racemic
vinyl carbamate ( )-7 in a large scale. An optically active
product will result from the second allylation of the race-
mic aldehyde ( )-6 with crotyltitane (R)-‘Ti’-I.
1) n-BuLi/TMEDA, Et2O, –78 °C, 1 h
2) Ti(OiPr)4, –78 °C, 45 min
3) 11, –78 °C, 3 h
8
OTIPS
17
4
1
OH
83%
( )-18
BnO
For this purpose, preparation of aldehyde 11 was effected
in 54% overall yield for three steps from but-3-ynol (9)
(Scheme 3): protection of the primary alcohol as a benzyl
ether was followed by an homologation into a pentynediol
derivative (10, 80% yield), and an oxidation step (67%
yield).
1) TESOTf, 2,6-lutidine
CH2Cl2, 20 °C, 2 h, 78%
OHC
4
OTIPS
2)
O3, Hexane/MeOH 99:1
DMS, –78 °C, > 98%
7
OTES
( )-19
BnO
Scheme 4
OH
CHO
a)
b)
HO
°C, 98%] gave the expected aldehyde ( )-19 in 76% yield
BnO
BnO
(Scheme 4).
9
10 (80%)
11 (67%)
This compound was then reacted with 2.5 equivalents of
the optically active crotyltitane (R)-‘Ti’-I at –78 °C for 30
minutes, and only one diastereomer 20 was isolated in
45% yield (Scheme 5). This Cram isomer could be con-
sidered as the ‘matched’ compound. Interestingly when
the reaction was kept at –78 °C for 2 hours, both the two
‘matched’ and ‘mismatched’ derivatives 20 and 21 were
produced in 45 and 30% yield, respectively.
c)
OH
d)
e)
RO
RO
12 R = TIPS (90%)
14 R = THP (98%)
13 R = TIPS (83%)
15 R = THP (90%)
f)
THPO
OCb
TIPSO
OCb
16 (80%)
17 (93%)
( )-19
Scheme 3 Reagents and conditions: a) i. NaH, BnBr, NaI cat.,
THF–Et2O (1:1), 20 °C, 8 h. ii. n-BuLi, THF, HCHO, –78 °C, then
20 °C, 5 h; b) IBX, DMSO, 20 °C, 4 h; c) TIPSOTf, 2,6-lutidine,
CH2Cl2, 20 °C, 2 h → 12, DHP, 10 N HCl, 20 °C, 2 h → 14; d) n-Bu-
Li, THF, HCHO, –78 °C, then 20 °C, 5 h, 12 → 13, 14 → 15; e) i. 15,
1 M LiAlH4, Et2O, reflux, 2.5 h. ii. NaH, THF, N(i-Pr)2C(O)Cl,
20 °C, 5 h; f) i. Amberlyst 15, MeOH, 20 °C, 4 h. ii. TIPSOTf, 2,6-
lutidine, CH2Cl2, 20 °C, 3 h.
(R)-"Ti"-I
(2.5 equiv)
OCb
OCb
10
9
7
4
OTIPS
BnO
OTIPS
HO
HO
3
5
For the synthesis of g-alkoxy carbamate 17, the alcohol
function of but-3-ynol was first protected as a triisopro-
pylsilyl ether to furnish 12 (TIPS, 90% yield). However,
after a homologation step of 12 (n-BuLi, THF, HCHO,
–78 °C, → 13, 88% yield), reduction of the propargyl al-
cohol 13 into the corresponding (E)-allylic alcohol did not
give satisfying results, and we were forced to use the tet-
rahydropyranyl ether 14. Thus, homologation of 14 (90%
yield) following by LiAlH4 reduction of the resulting pro-
pargylic alcohol 15 and carbamoylation led to the expect-
ed E-allyl carbamate 16 in 80% yield from 15. Because of
the unpractical use of the THP group in synthesis, two
supplementary steps were carried out to prepare allyl car-
bamate 17 from the THP analogue 16 (93% overall yield).
1
OTES
OTES
BnO
"Cram"
20
"anti-Cram"
21
–78 °C, 30 min
–78 °C, 2 h
45%
45%
0%
30%
Scheme 5
Structural proof of 20 and 21 was deduced from NMR
analysis of the corresponding lactols 22 and 23 obtained
after deprotection of the C5 TES ether and ozonolysis of
the C9–C10 double bond (Scheme 6).
Although the ‘mismatched’ derivative 21 was prepared in
good yield, the C1-C9 fragments 3a and 3b of tylosin (1)
and spiramycin (2) could not be synthesised by this route,
several difficulties arose linked to instability of compound
21 during triple bond transformation.
Having in our hands the required g-alkoxycarbamate 17,
we were able to realise the allylation of aldehyde 11.
Treatment of 17 under classical conditions, [n-BuLi/
TMEDA/Et2O, –78 °C, 1 h; Ti(Oi-Pr)4, –78 °C, 3 h; 11,
–78 °C, 3 h] furnished the racemic allylic alcohol ( )-18
in 83% as a single diastereomer (Scheme 4). This reaction
was carried out on a 50 g scale. Before the second allyla-
tion reaction, the secondary alcohol was protected as a tri-
ethylsilyl ether (TES, 78%), then ozonolysis under the
given conditions [O3, hexane–MeOH, 99:1, Me2S, –78
So we focused on a specific approach to the C1-C7 por-
tion 24 of spiramycin (2), and decided to investigate a ki-
netic resolution of racemic g-alkoxytitane ( )-‘Ti’-II by
optically active aldehyde 25, which is already functional-
ized at C3 and C4 (Scheme 7).
Synthesis 2005, No. 1, 109–121 © Thieme Stuttgart · New York

PAPER
Primary and Secondary Allyltitanium(IV) Reagents in Aldehyde Allylation
111
OH
"Cram"
"anti-Cram"
a)
20
21
OR
26 R = H (85%)
BnO
1) Amberlyst 15, MeOH, 20 °C, 15 min
2) O3, Hexane/MeOH 99:1, DMS, –78 °C
BnO
10
b)
27 R = TBS (93%)
28 R = TPS (95%)
BnO
BnO
HO
O
O
OH
O
OH
c)
OTBS
OTPS
OH
OH
27
BnO
BnO
BnO
OH
O
( )-30 (92%)
O
TIPSO
TIPSO
( )-29 (64%)
OH
OH
22 62%
23 60%
HO
d)
e)
c)
Scheme 6
28
30
BnO
BnO
OH
O
"Ti"
31 (83%, 90% ee)
30 (90%)
OCb
f)
PGO
OCb
5
4
3
O
1
CHO
O
O
7
4
( )-"Ti"-II
OPG
CHO
Cl
BnO
MeO
PGO
O
OPG
5
O
O
1
PGO
OH
3
33 (56%)
32 (86%)
24
25
Scheme 8 Reagents and conditions: a) i. 1 M LiAlH4, Et2O, reflux,
2.5 h, → 26. ii. 26, TBSCl, imidazole, CH2Cl2, 20 °C, 1 h, → 27; 26,
TPSCl, imidazole, CH2Cl2, 20 °C, 1 h, → 28; b) 27, cat. OsO4, NMO,
acetone–H2O (60:40); c) i. 2,2-DMP, PTSA, 2 h. ii. TBAF, THF,
20 °C, 1 h; d) 28 Sharpless AD-Mix-b; e) Py·SO3, DMSO, Et3N,
20 °C, 1 h; f) PPh3, CCl4, CH2Cl2, 20 °C, 8 h.
Scheme 7
Reduction of monoprotected pentynediol 10 with LiAlH4
in Et2O gave the (E)-allylic alcohol 26 in 85% yield
(Scheme 8). Both tert-butyldimethylsilyl (TBS) and tert-
butyldiphenylsilyl (TPS) ethers 27 and 28 were prepared
in 93 and 95% yields, respectively. At this stage, a dihy-
droxylation reaction was performed on the TBS derivative
27 using OsO4/NMO in acetone–water to give the racemic
diol ( )-29 in 64% yield. The corresponding ketal ( )-30
was then prepared in 92% yield.
17
OCb
TIPSO
1) n-BuLi/TMEDA, Et2O, –78 °C, 30 min
2) Ti(OiPr)4, –78 °C, 20 min
3) 32, –78 °C, 2 h
81%
OCb
OCb
Under Sharpless conditions, using AD-Mix-b,8 optically
active diol 31 was obtained in 83% yield and 90% ee from
the TIPS derivative 28. The enantiomeric excess was
measured by NMR analysis of the corresponding ketal 30
using Europium salt shifts. Absolute configuration of 30
was proved by comparison of the optical rotations of the
chloro derivative 33 prepared from 30, and from 26 as ear-
lier described in the literature.9
OTIPS
OTIPS
O
O
O
HO
HO
+
O
BnO
BnO
34
34/35 20:80
35
After oxidation of alcohol 30 (Py·SO3, DMSO, 20 °C, 1 h,
86%), the resulting aldehyde 32 was reacted with the ra-
cemic g-allyltitanium prepared from carbamate 17
(Scheme 9). The reaction was kept at –78 °C for 2 hours
and led, in 81% yield, to a 20:80 mixture of the two dia-
stereomers 34 and 35. This kinetic resolution led to a ma-
jor isomer 35 that presented the inverse expected
configurations at C5 and C6 centres.10
Scheme 9
In the course of our synthetic approaches of tylosin (1)
and spiramycin (2) we exploited the potentiality of opti-
cally pure g-alkoxy allyltitanium ‘Ti’-III derived from
secondary allyl carbamates (R)- and (S)-36.
At the outcome of the study,12 we were able to prepare ho-
moallylic alcohols 37 and ent-37 from either (R)-36 or
(S)-36 in 90% yield and 80% ee, depending of experimen-
tal conditions used. Employing n-BuLi/TMEDA, and
starting from the (R)- or (S)-36 allyl carbamate, the result-
ing stable lithio derivative then underwent a transmetalla-
tion with Ti(Oi-Pr)4 to deliver the (S)-‘Ti’-III or (R)-‘Ti’-
III titanium intermediate responsible for the formation of
ent-37 or 37. In contrast, when n-BuLi/(–)-sparteine con-
In order to improve and to reverse the diastereoselectivity
in this reaction, we turned our attention to the results pub-
lished by Hoppe about secondary crotylcarbamates.11 In
this work it was established that metallation of secondary
crotyl carbamates could be effected without racemisation.
Transmetallation with Ti(Oi-Pr)4 then delivered a reactive
optically pure crotyltitanium intermediate able to promote
aldehyde allylation in a good enantiomeric excess.
Synthesis 2005, No. 1, 109–121 © Thieme Stuttgart · New York

112
P. Razon et al.
PAPER
ditions were used, transmetallation with Ti(Oi-Pr)4 oc- In another application of this strategy, optically active al-
curred with inversion of configuration and starting from dehyde 32, prepared earlier, was submitted to the reaction
the (S)-36 allyl carbamate, allylation led to the ent-37 de- of the optically active (R)-‘Ti’-III allyltitanium, derived
rivative (90% yield, 88% ee) (Scheme 10).
from (S)-36 under n-BuLi/TMEDA/Ti(Oi-Pr)4 conditions.
This expected aldehyde allylation, carried out under dou-
ble stereodifferentiation, gave access to compound 40 as
the only diastereomer in 80% chemical yield and 95% de
(Scheme 12).
9
HO
see ref.12
BnO
O
OCb
BnO
OCb
BnO
OCb
(S)-36
(S)-36
(R)-36
n-BuLi/TMEDA
toluene, –78 °C, 1 h
Ti(OiPr)4, –78 °C, 20 min
a)
"Ti"
OCb
b)
a)
CHO
BnO
O
32, –78 °C, 2 h
32
(S)-"Ti"-III
OCb
6
(R)-"Ti"-III
7
OBn
4
OH
OH
O
O
HO
5
3
OCb
OCb
1
BnO
BnO
BnO
40 80%> 95% de
37
ent-37
90% 80% ee
90% 80% ee
Scheme 12
Scheme 10 Reagents and conditions: a) n-BuLi/TMEDA, toluene,
–78 °C, 1 h, Ti(Oi-Pr)4, –78 °C, 20 min, propanal –78 °C, 2h; b) n-
BuLi/(–)-sparteine, toluene, –78 °C, 1 h, Ti(Oi-Pr)4, –78 °C, 20 min,
propanal –78 °C, 2 h.
In this work, an efficient synthesis of a C1-C7 fragment
40 of spiramycin (2) was achieved with total stereocontrol
of C5 and C6 centres using optically active secondary g-
oxygenated allyl carbamates. These compounds generate
optically active secondary g-alkoxy allyltitanium reagents
that react with aldehydes with a good enantiomeric excess
(80%) under simple asymmetric induction, but also with a
total diastereocontrol in the case of double stereodifferen-
tiation.
With optically active g-alkoxy carbamates (R)- and (S)-36
now available, we turned to our common synthetic ap-
proach to eastern parts 3a and 3b of tylosin (1) and spira-
mycin (2) from acetylenic aldehyde 38 and the (S)-36
carbamate (See Scheme 3). Conducted under n-BuLi/
TMEDA/Ti(Oi-Pr)4 conditions, this reaction led, via a
(R)-‘Ti’-III intermediate, to the allylic alcohol 39 as a sin-
gle diastereomer in 70% yield and 80% ee (Scheme 11).
For general introduction to the experimental part, see Ref.12
5-(Benzyloxy)pent-2-yn-1-ol (10)
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-
3-yn-1-ol (9; 20 g, 285 mmol) in Et2O (120 mL). The resulting so-
lution was stirred for 20 min at 20 °C and freshly distilled benzyl
bromide (37.3 g, 313.5 mmol, 1.1 equiv) in anhyd THF (60 mL)
was added along with NaI (500 mg). After stirring for 8 h at 20 °C,
the mixture was treated at 0 °C with 1 M aq HCl (75 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 distillation to give the 4-(ben-
zyloxy)butyne as a colourless oil (42.9 g, 94%); bp 83 °C/2 mbar.
BnO
OCb
(S)-36
CHO
n-BuLi/TMEDA
toluene, –78 °C, 1 h
Ti(OiPr)4, –78 °C, 20 min
38, –78 °C, 2 h
MnO2, CH2Cl2
13
63%
38
SPITO
OCb
OBn
3
4
39 70%, 80% ee
5
6
4-(Benzyloxy)butyne
IR (CCl4): 3329, 3040, 2216 cm–1.
HO
7
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).
13C NMR (67.8 MHz): d = 19.7 (CH2-3), 65.2 (CH2-4), 68.9 (≡CH-
8
OTIPS
Scheme 11
Synthesis 2005, No. 1, 109–121 © Thieme Stuttgart · New York

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Primary and Secondary Allyltitanium(IV) Reagents in Aldehyde Allylation
113
1), 73.2 (PhCH2), 81.1 (≡C-2), 127.4 (2 CH, C6H5), 128.2 (2 CH,
mixture was treated with 2 M aq HCl (70 mL) and extracted with
C6H5), 128.5 (CH, C6H5), 138.6 (C, C6H5).
Et2O. The organic layer was washed with aq 2 M HCl (70 mL),
brine, dried (Na2SO4), filtered and concentrated under reduced pres-
sure. The residue was purified by distillation to give the title com-
pound 12 as a colourless oil (14.5 g, 90%); bp 71 °C/0.1 mbar.
MS (CI, NH3): m/z = 161 (MH+).
To a solution of 4-(benzyloxy)butyne (17 g, 106 mmol) in anhyd
THF (120 mL) at –78 °C was slowly added n-BuLi (1.6 M in hex-
ane, 73 mL, 116 mmol, 1.1 equiv). After stirring for 15 min, the
temperature was then allowed to reach 0 °C and a stream of formal-
dehyde, obtained by depolymerisation of dried paraformaldehyde
(11.1 g, 119 mmol, 1.1 equiv) at 200 °C, was blown on the surface
of the anion solution. After stirring for 5 h at 20 °C, 1 M aq HCl
(50 mL) was added. After extraction with Et2O, drying (Na2SO4)
and filtration, the solvent was removed under reduced pressure. The
crude oil was purified by flash chromatography on silica gel (hex-
ane–EtOAc, 70:30) to give 10 as a colourless oil (17.0 g, 85%).
IR (CCl4): 2110 cm–1.
1H NMR (270 MHz): d = 1.07 {m, 21 H, 3 CH and 6 CH3,
Si[CH(CH3)2]3}, 1.97 (t, J = 2.6 Hz, 1 H, ≡CH-1), 2.45 (td, J = 7.3,
2.6 Hz, 2 H, CH2-3), 3.83 (t, J = 7.3 Hz, 2 H, CH2-4).
13C NMR (67.8 MHz): d = 12.2 {3 CH, Si[CH(CH3)2]3}, 18.2 {6
CH3, Si[CH(CH3)2]3}, 23.4 (CH2-3), 62.3 (CH2-4), 80.2 and 81.7
(C≡CH).
MS (CI, NH3): m/z = 227 (MH+).
Anal Calcd for C13H26OSi: C, 68.96; H, 11.57. Found: C, 69.05; H,
11.63.
10
IR (CCl4): 3650, 3470, 3040, 2280, 2220 cm–1.
1H NMR (200 MHz): d = 1.82 (t, J = 3.0 Hz, 1 H, OH), 2.55 (tt,
J = 7.0, 2.5 Hz, 2 H, CH2-4), 3.58 (dt, J = 3.0, 2.5 Hz, 2 H, CH2-1),
4.26 (t, J = 7.0 Hz, 2 H, CH2-5), 4.58 (s, 2 H, PhCH2), 7.2–7.4 (m,
5 H, C6H5).
13C NMR (50.3 MHz): d = 19.7 (CH2-4), 50.6 (CH2-1), 67.9 (CH2-
5), 72.5 (PhCH2), 79.4 and 82.3 (C≡C), 127.3 (3 CH, C6H5), 128.0
(2 CH, C6H5), 137.7 (C, C6H5).
5-[(Triisopropylsilyl)oxy]pent-2-yn-1-ol (13)
To a solution of 12 (8 g, 35.4 mmol) in anhyd THF (100 mL) at
–78 °C was slowly added n-BuLi (2.5M in hexane, 15.6 mL,
38.9 mmol, 1.1 equiv). After stirring for 15 min, the temperature
was then allowed to reach 0 °C and a stream of formaldehyde, ob-
tained by depolymerisation of dried paraformaldehyde (3.71 g,
38.9 mmol, 1.1 equiv) at 200 °C, was blown on the surface of the
anion solution. After stirring for 5 h at 20 °C, 1 M aq HCl (50 mL)
was added. After extraction with Et2O, drying (Na2SO4) and filtra-
tion, the solvent was removed under reduced pressure. The crude oil
was purified by flash chromatography on silica gel (hexane–EtOAc,
70:30) to give the alcohol 13 as a pale yellow oil (7.52 g, 83%).
MS (CI, NH3): m/z = 191 (MH+).
Anal Calcd for C12H14O2: C, 75.76; H, 7.42. Found: C, 75.83; H,
7.56.
5-(Benzyloxy)pent-2-yn-1-al (11)
IR (CCl4): 3333, 2227 cm–1.
Method A; Using Iodoxybenzoic Acid (IBX): To a solution of 10
(1.5 g, 7.9 mmol) in anhyd DMSO (15 mL) at 20 °C was slowly
added a solution of IBX (3.31 g, 12 mmol, 1.5 equiv) in anhyd
DMSO (20 mL). After stirring for 4 h, H2O (20 mL) was added and
the reaction mixture was filtered on a pad of Celite. After extraction
with Et2O, washing with NaHCO3, drying (Na2SO4) and filtration,
the solvent was removed under reduced pressure. The crude oil was
purified by flash chromatography on silica gel (hexane–EtOAc,
70:30) to give the aldehyde 11 as a colourless to pale yellow oil
(995 mg, 67%).
1H NMR (270 MHz): d = 1.07 {m, 21 H, 3 CH and 6 CH3,
Si[CH(CH3)2]3}, 1.62 (s, 1 H, OH), 2.36 (tt, J = 7.3, 2.2 Hz, 2 H,
CH2-4), 3.82 (t, J = 7.3 Hz, 2 H, CH2-5), 4.24 (t, J = 2.2 Hz, 2 H,
CH2-1).
13C NMR (67.8 MHz): d = 12.2 {3 CH, Si[CH(CH3)2]3}, 18.2 {6
CH3, Si[CH(CH3)2]3}, 23.4 (CH2-4), 51.5 (CH2-1), 60.8 (CH2-5),
79.8 and 83.5 (C≡C).
MS (CI, NH3): m/z = 274 (MH+ + 17), 257 (MH+).
Anal Calcd for C14H28O2Si: C, 65.57; H, 11.00. Found: C, 65.68; H,
11.13.
Method B, Using MnO2: To a solution of 10 (3 g, 15.8 mmol) in
CH2Cl2 (30 mL) was added portionwise MnO2 (6.9 g, 79 mmol,
5 equiv) until the starting material had completely disappeared. Af-
ter stirring for 4 h, the reaction mixture was filtered on a pad of
Celite and the solvent was removed under reduced pressure. The
crude oil was purified by flash chromatography on silica gel (hex-
ane–EtOAc, 70:30) to give 11 as a colourless to pale yellow oil
(1.9 g, 67%).
4-[(2-Tetrahydropyranyl)oxy]butyne (14)
To a solution of 3,4-dihydro-2H-pyran (25 g, 27 mL, 297 mmol,
1.1 equiv) in 10 N aq HCl (0.3 mL) was added but-3-yn-1-ol (9;
18.9 g, 20.4 mL, 270 mmol) keeping the temperature at 50 °C. Af-
ter completion of the addition, the solution was stirred for 2.5 h at
20 °C. The mixture was diluted with Et2O at r.t. and the Et2O layer
was washed with a sat. aq NaHCO3 (2 ×). The Et2O phase was dried
(Na2SO4), filtered, and the solvent was removed under reduced
pressure. The crude oil was purified by distillation to furnish the ti-
tle compound 14 as a colourless oil (40.74 g, 98%).; bp 70 °C/
2 mbar.
IR (CCl4): 2200, 1730 cm–1.
1H NMR (200 MHz): d = 2.74 (t, J = 7.0 Hz, 2 H, CH2-4), 3.62 (t,
J = 7.0 Hz, 2 H, CH2-5), 4.57 (s, 2 H, PhCH2), 7.2–7.4 (m, 5 H,
C6H5), 9.18 (s, 1 H, H-1).
13C NMR (50.3 MHz): d = 20.7 (CH2-4), 67.1 (CH2-5), 72.5
(PhCH2), 82.2 and 95.5 (C≡C), 127.7 (3 CH, C6H5), 128.4 (2 CH,
C6H5), 137.8 (C, C6H5), 175.8 (C-1).
IR (CCl4): 2110 cm–1.
1H NMR (200 MHz): d = 1.42–1.88 (m, 6 H, CH2-3¢ + CH2-4¢+ H2-
5¢), 1.94 (t, J = 2.5 Hz, 1 H, ≡CH-1), 2.45 (td, J = 7.0, 2.5 Hz, 2 H,
CH2-3), 3.45, 3.7 (2 m, 2 H, CH2-4), 3.45–3.77 (m, 1 H, Ha-6¢),
3.77–3.94 (m, 1 H, Hb-6¢), 4.6 (t, J = 3.5 Hz, 1 H, H-2¢).
13C NMR (50.3 MHz): d = 19.3 (CH2-5¢), 19.9 (CH2-3), 25.3 (CH2-
4¢), 30.4 (CH2-3¢), 62.1 (CH2-6¢), 65.4 (CH2-4), 69.1 (≡CH-1), 81.3
(≡C-2), 98.7 (CH-2¢).
MS (CI, NH3): m/z = 189 (MH+).
Anal Calcd for C12H12O2: C, 76.57; H, 6.43. Found: C, 76.63; H,
6.52.
4-[(Triisopropylsilyl)oxy]butyne (12)
To a solution of commercial but-3-yn-1-ol (9; 5 g, 5.4 mL,
71.3 mmol) in anhyd CH2Cl2 (60 mL) at 0 °C were added 2,6-luti-
dine (24.8 mL, 214 mmol, 3 equiv) and TIPSOTf (21.6 mL,
78.4 mmol, 1.1 equiv). After stirring for 2 h at 20 °C, the reaction
MS (CI, NH3): m/z = 172 (MH+ + 17), 155 (MH+).
Anal Calcd for C9H14O2: C, 70.10; H, 9.15. Found: C, 70.24; H,
9.21.
Synthesis 2005, No. 1, 109–121 © Thieme Stuttgart · New York

114
P. Razon et al.
PAPER
5-[(2-Tetrahydropyranyl)oxy]pent-2-yn-1-ol (15)
16
IR (CCl4): 1670 cm–1.
To a solution of 14 (22 g, 143 mmol) in anhyd THF (150 mL) at
–78 °C was slowly added n-BuLi (1.6 M in hexane, 96.5 mL,
154.5 mmol, 1.08 equiv). After stirring for 15 min, the temperature
was then allowed to reach 0 °C and a stream of formaldehyde, ob-
tained by depolymerisation of dried paraformaldehyde (1.6 g,
157 mmol, 1.1 equiv) at 200 °C, was blown on the surface of the an-
ion solution. After stirring for 5 h at 20 °C, 1 M aq HCl (50 mL) was
added. After extraction with Et2O, drying (Na2SO4) and filtration,
the solvent was removed under reduced pressure. The crude oil was
purified by flash chromatography on silica gel (hexane–EtOAc,
70:30) to give 15 as a colourless oil (23.6 g, 90%).
1H NMR (200 MHz): d = 1.20 {d, J = 7.0 Hz, 12 H, 4 CH3,
N[CH(CH3)2]2}, 1.44–1.95 (m, 6 H, 3 CH2, CH2-3¢ + CH2-4¢ + CH2-
5¢), 2.43 (q, J = 7.0 Hz, 2 H, CH2-4), 3.42, 3.60 (2 m, 2 H, Ha-5 +
Ha-6¢), 3.69–4.05 {m, 4 H, N[CH(CH3)2]2 + Hb-5 + Hb-6¢}, 4.56 (d,
J = 5.0 Hz, 2 H, H2-1), 4.62 (m, 1 H, H-2¢), 5.65 (dt, J = 16.0, 5.0
Hz, 1 H, =CH-2), 5.79 (dt, J = 16.0, 5.0 Hz, 1 H, =CH-3).
13C NMR (50.3 MHz): d = 19.3 (CH2-5¢), 20.8 {4 CH3,
N[CH(CH3)2]2}, 25.3 (CH2-4¢), 30.5 (CH2-3¢), 32.5 (CH2-4), 45.6
{2 CH, N[CH(CH3)2]2}, 62.0 (CH2-6¢), 64.9 (CH2-1), 66.5 (CH2-5),
98.5 (CH-2¢), 126.8 (=CH-2), 130.7 (=CH-3), 155.3 (C=O).
IR (CCl4): 3610, 3420, 2110 cm–1.
MS (CI, NH3): m/z = 331 (MH+ + 17), 314 (MH+).
1H NMR (200 MHz): d = 1.40–1.89 (m, 6 H, CH2-3¢ + CH2-4¢ +
CH2-5¢), 2.48 (m, 2 H, CH2-4), 2.49 (br s, 1 H, OH), 3.45, 3.74 (2
m, 2 H, CH2-5), 3.57–3.74 (m, 1 H, Ha-6¢), 3.75–3.90 (m, 1 H, Hb-
6¢), 4.17 (m, 2 H, CH2-1), 4.57 (t, J = 3.5 Hz, 1 H, CH-2¢).
Anal. Calcd for C17H31O4N: C, 65.14; H, 9.97; N, 4.47. Found: C,
65.17; H, 9.95; N, 4.52.
(2E)-1-{[(N,N-Diisopropyl)carbamoyl]oxy}-5-{[triisopropylsi-
lyl)]oxy}pent-2-ene (17)
13C NMR (50.3 MHz): d = 19.3 (CH2-5¢), 20.1 (CH2-4), 25.3 (CH2-
4¢), 30.4 (CH2-3¢), 51.0 CH2-1), 62.2 (CH2-6¢), 65.6 (CH2-5), 79.5
and 82.9 (C≡C), 98.7 (CH-2¢).
To a solution of 16 (12.4 g, 39 mmol) in MeOH (100 mL) was add-
ed Amberlyst 15. After stirring for 4 h at r.t., the reaction mixture
was filtered and the solvent was removed under reduced pressure.
The crude oily residue was purified by flash chromatography on sil-
ica gel (hexane–EtOAc, 60:40) to give (2E)-1-{[(N,N-diisopro-
pyl)carbamoyl]oxy}pent-2-en-5-ol as a colourless oil (8.6 g, 98%).
MS (CI, NH3): m/z = 185 (MH+).
Anal Calcd for C10H16O3: C, 65.19; H, 8.75. Found: C, 65.23; H,
8.77.
(2E)-1-{[(N,N-Diisopropyl)carbamoyl]oxy}-5-[2-(tetrahydro-
pyranyl)oxy]pent-2-ene (16)
(2E)-1-{[(N,N-Diisopropyl)carbamoyl]oxy}pent-2-en-5-ol
IR (CCl4): 3630, 1660 cm–1.
To a solution of alcohol 15 (15.2 g, 83 mmol) in anhyd Et2O
(85 mL) at 0 °C was slowly added a 1 M solution of LiAlH4 in THF
(108 mL, 108 mmol, 1.3 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 H2O
(28 mL), a 7.5 M aq solution of NaOH (14 mL), and H2O (28 mL).
The precipitate was filtered, washed with Et2O and the filtrate was
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (hexane–EtOAc, 50:50) to give
(2E)-5-[(2-tetrahydropyranyl)oxy]pent-2-en-1-ol as a colourless oil
(13.6 g, 88%).
1H NMR (200 MHz): d = 1.18 {d, J = 6.5 Hz, 12 H, 4 CH3,
N[CH(CH3)2]2}, 2.10 (br s, 1 H, OH), 2.17 (q, J = 6.0 Hz, 2 H, CH2-
4), 3.64, (t, J = 6.0 Hz, 2 H, CH2-5), 3.73, 3.98 {m, 2 H,
N[CH(CH3)2]2}, 4.51 (d, J = 5.0 Hz, 2 H, CH2-1), 5.68 (m, 2 H,
CH=CH).
13C NMR (50.3 MHz): d = 21.0 {4 CH3, N[CH(CH3)2]2}, 35.6
(CH2-4), 45.8 {2 CH, N[CH(CH3)2]2}, 61.6 (CH2-5), 64.9 (CH2-1),
128.4 and 130.4 (CH=CH), 155.4 (C=O).
MS (CI, NH3): m/z = 230 (MH+).
To a solution of (2E)-1-{[(N,N-diisopropyl)carbamoyl]oxy}pent-2-
en-5-ol (15 g, 65.5 mmol) in anhyd CH2Cl2 (100 mL) at 0 °C were
added 2,6 lutidine (22.8 mL, 196.5 mmol, 3 equiv) and TIPSOTf
(19.8 mL, 72 mmol, 1.1 equiv). After stirring for 3 h at 20 °C, the
reaction mixture was treated with 2 M aq HCl (60 mL) and extract-
ed with Et2O. The organic layer was washed with aq 2 M HCl (60
mL), brine, dried (Na2SO4), filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography on sil-
ica gel (hexane–EtOAc, 90:10) to give the title compound 17 as a
colourless oil (23.95 g, 95%).
(2E)-5-[(2-Tetrahydropyranyl)oxy]pent-2-en-1-ol
IR (CCl4): 3600, 3440 cm–1.
1H NMR (200 MHz): d = 1.40–1.97 (m, 6 H, CH2-3¢ + CH2-4¢ +
CH2-5¢), 2.35 (m, 2 H, CH2-4), 3.40, 3.71 (2 m, 2 H, CH2-5), 3.48
(m, 1 H, CHa-6¢), 3.76 (m, 1 H, CHb-6¢), 4.07 (m, 2 H, CH2-1), 4.54
(t, J = 3.5 Hz, 1 H, CH-2¢), 5.55–5.76 (m, 2 H, CH=CH).
13C NMR (50.3 MHz): d = 19.6 (CH2-5¢), 25.4 (CH2-4¢), 30.6 (CH2-
3¢), 32.5 (CH2-4), 62.3 (CH2-6¢), 63.5 (CH2-1), 66.8 (CH2-5), 98.8
(CH-2¢), 129.1 and 131.0 (CH=CH).
MS (CI, NH3): m/z = 187 (MH+).
17
IR (CCl4): 1670 cm–1.
To a suspension of NaH (60% in oil, 3.87 g, 96.8 mmol, 1.2 equiv)
in anhyd THF (40 mL) at 0 °C, was slowly added a solution of (2E)-
5-[(2-tetrahydropyranyl)oxy]pent-2-en-1-ol (15 g, 80.6 mmol) in
THF (40 mL). The resulting solution was stirred for 20 min at 20 °C
1H NMR (200 MHz): d = 1.04 {m, 21 H, 3 CH + 6 CH3,
Si[CH(CH3)2]3}, 1.19 {d, J = 6.5 Hz, 12 H, 4 CH3, N[CH(CH3)2]2},
2.29 (q, J = 6.0 Hz, 2 H, CH2-4), 3.73 (t, J = 6.0 Hz, 2 H, CH2-5),
3.90 {m, 2 H, N[CH(CH3)2]2}, 4.52 (d, J = 6.0 Hz, 2 H, CH2-1),
5.64 (dt, J = 16.0, 6.0 Hz, 1 H, CH=CH, H-2), 5.78 (dt, J = 16.0, 6.0
Hz, 1 H, CH=CH, H-3).
13C NMR (50.3 MHz): d = 12.3 {3 CH, Si[CH(CH3)3]3}, 17.7 {6
CH3, Si[CH(CH3)3]3}, 21.0 {4 CH3, N[CH(CH3)2]2}, 36.1 (CH2-4),
45.8 {2 CH, N[CH(CH3)2]2}, 63.0 (CH2-5), 65.3 (CH2-1), 126.9
(=CH-2), 131.3 (=CH-3), 155.5 (C=O).
and
a solution of diisopropylcarbamoyl chloride (15.84 g,
96.8 mmol, 1.2 equiv) in anhyd THF (60 mL) was added. After stir-
ring for 5 h at 20 °C, the mixture was treated at 0 °C with 1 M aq
HCl (50 mL) and extracted with Et2O. The combined organic phas-
es were then washed with brine, dried (Na2SO4), filtered and con-
centrated under reduced pressure. The oily residue was purified by
flash chromatography on silica gel (hexane–EtOAc, 80:20), or dis-
tillation, to give the title compound 16 as a colourless oil (22.7 g,
90%); bp 160 °C/2 mbar.
MS (CI, NH3): m/z = 386 (MH+).
Anal. Calcd for C21H43O3NSi: C, 65.40; H, 11.24; N, 3.63. Found:
C, 65.43; H, 11.28; N, 3.62.
Synthesis 2005, No. 1, 109–121 © Thieme Stuttgart · New York

PAPER
Primary and Secondary Allyltitanium(IV) Reagents in Aldehyde Allylation
115
(7Z,5S*,6S*)-1-Benzyloxy-8-{[(N,N-diisopropyl)carbam-
oyl]oxy}-5-hydroxy-6-{2-[(triisopropylsilyl)oxy]ethyl}oct-7-
ene-3-yne [( )-18]
13C NMR (100.6 MHz): d = 4.7 [3 CH2, Si(CH2CH3)3], 6.7 [3 CH3,
Si(CH2CH3)3], 11.9 {3 CH, Si[CH(CH3)2]3}, 17.9 {6 CH3,
Si[CH(CH3)2]3}, 20.2 (CH2-2), 20.3 and 21.4 {4 CH3,
N[CH(CH3)2]2}, 33.2 (CH2-1¢), 39.6 (CH-6), 45.8 and 46.4 {2 CH,
N[CH(CH3)2]2}, 61.9 (CH2-2¢), 65.5 (CH-5), 68.5 (CH2-1), 72.9
(PhCH2), 81.1 and 81.7 (C≡C), 110.6 (=CH-7), 127.6 (3 CH, C6H5),
128.3 (2 CH, C6H5), 136.2 (=CH-8), 138.0 (C, C6H5), 152.5 (C=O).
To a solution of N,N,N¢,N¢-tetramethylethylenediamine (TMEDA,
34.5 mL, 229 mmol, 2.2 equiv) in anhyd Et2O (150 mL) at –78 °C,
under argon, was added n-BuLi (1.6 M in hexane, 143 mL,
229 mmol, 2.2 equiv). After stirring for 1 h at –78 °C, a solution of
the allyl carbamate 17 (40 g, 104 mmol, 1.1 equiv) in anhyd Et2O
(100 mL), was slowly added. After stirring for 1 h at –78 °C, Ti(Oi-
Pr)4 (74 mL, 260 mmol, 2.5 equiv) was rapidly added and the reac-
tion mixture was stirred for 45 min at –78 °C (transmetallation
time). Then, the acetylenic aldehyde 11 (17.8 g, 94.5 mmol) diluted
in anhyd Et2O (50 mL) was added. The reaction mixture was stirred
for 3 h at –78 °C and quenched by transferring to a vigorously stir-
ring mixture of aq 3 M HCl (150 mL) and Et2O (100 mL) at –20 °C.
The temperature was allowed to reach 20 °C and the resulting solu-
tion 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, 80:20), to give the title compound ( )-18 as a yellow oil
(45.0 g, 83%).
MS (CI, NH3): m/z = 688 (MH+).
Ozone was bubbled into a solution of the above prepared carbamate
(5.28 g, 7.7 mmol) in hexane–MeOH (99:1, 200 mL) at –78 °C un-
til the solution turned light blue. Me2S (20 mL) was added at
–78 °C, and the mixture was allowed to warm to r.t. and stirred for
4 h. The solvent was partially removed under reduced pressure and
the solution was washed with H2O. The organic layer was dried
(Na2SO4), filtered and evaporated to give the aldehyde ( )-19 as a
pale yellow oil (4.18 g, quant.).
19
IR (CCl4): 2962, 2870, 1728 cm–1.
1H NMR (400 MHz): d = 0.55–0.63 [m, 6 H, 3 CH2, Si(CH2CH3)3],
0.88–1.02 [m, 9 H, 3 CH3, Si(CH2CH3)3], 1.04 {m, 21 H, 3 CH + 6
CH3, Si[CH(CH3)2]3}, 1.81–1.85 (m, 1 H, Ha-1¢), 1.93–2.08 (m, 1
H, Hb-1¢), 2.53 (td, J = 7.0, 2.0 Hz, 2 H, CH2-6), 2.63–2.72 (m, 1 H,
H-2), 3.57 (t, J = 7.0 Hz, 2 H, CH2-7), 3.81–3.88 (m, 2 H, CH2-2¢),
4.50 (s, 2 H, PhCH2), 4.70 (dt, J = 6.0, 2.0 Hz, 1 H, H-3), 7.3–7.4
(m, 5 H, C6H5), 9.01 (d, J = 2.0 Hz, 1 H, H-1).
13C NMR (100.6 MHz): d = 4.8 [3 CH2, Si(CH2CH3)3], 6.8 [3 CH3,
Si(CH2CH3)3], 11.9 {3 CH, Si[CH(CH3)2]3}, 18.0 {6 CH3,
Si[CH(CH3)2]3}, 20.2 (CH2-6), 29.6 (CH2-1¢), 55.8 (CH-2), 61.2
(CH2-2¢), 62.8 (CH-3), 68.3 (CH2-7), 73.0 (PhCH2), 80.5 and 83.7
(C≡C), 127.7 (3 CH, C6H5), 128.4 (2 CH, C6H5), 138.0 (C, C6H5),
203.6 (C=O).
IR (CCl4): 3646, 3396, 2948, 1710 cm–1.
1H NMR (400 MHz): d = 1.06 {m, 21 H, 3 CH + 6 CH3,
Si[CH(CH3)2]3}, 1.15 {d, J = 6.5 Hz, 12 H, 4 CH3, N[(CH(CH3)2]2},
1.50–1.70 (m, 1 H, Ha-1¢), 1.97–2.15 (m, 1 H, Hb-1¢), 2.51 (td,
J = 7.0, 3.0 Hz, 2 H, CH2-2), 2.78–2.93 (m, 1 H, H-6), 3.58 (t,
J = 7.0 Hz, 2 H, CH2-1), 3.62–3.88 (m, 2 H, OH, Ha-2¢), 3.70–3.88
[m, 2 H, Hb-2¢ + NCH(CH3)2], 4.0–4.10 [m, 1 H, NCH(CH3)2],
4.31–4.40 (m, 1 H, H-5), 4.51 (s, 2 H, PhH2O), 4.67 (dd, J = 6.0, 9.0
Hz, 1 H, CH=CH, H-7), 7.06 (d, J = 6.0 Hz, 1 H, CH=CHOCb, H-
8), 7.2–7.4 (m, 5 H, C6H5).
13C NMR (100.6 MHz): d = 11.7 {3 CH, Si[CH(CH3)2]3}, 17.7 {6
CH3, Si[CH(CH3)2]3}, 20.0 (CH2-2), 20.1 and 21.2 {4 CH3,
N[CH(CH3)2]2}, 34.1 (CH2-1¢), 40.7 (CH-6), 45.8 and 45.9 {2 CH,
N[CH(CH3)2]2}, 62.0 (CH2-2¢), 65.1 (CH-5), 68.3 (CH2-1), 72.7
(PhCH2), 82.8 and 84.6 (C≡C), 110.3 (=CH-7), 127.4 (3 CH, C6H5),
128.2 (2 CH, C6H5), 131.3 (=CH-8), 136.0 (C, C6H5), 152.1 (C-1).
MS (CI, NH3): m/z = 547 (MH+).
Anal Calcd for C31H54O4Si2: C, 68.08; H, 9.95. Found: C, 68.21; H,
10.11.
(9Z,5R,6R,7S,8S)-1-Benzyloxy-10-[(N,N-diisopropylcarbam-
oyl)oxy]-7-hydroxy-8-methyl-5- [(triethylsilyl)oxy]-6-{-2-[(tri-
isopropylsilyl)oxy]ethyl}dec-9-ene-3-yne (Cram-20) and
(9Z,5S,6S,7S,8S)-1-Benzyloxy-10-[(N,N-diisopropylcarbam-
oyl)oxy]-7-hydroxy-8-methyl-5- [(triethylsilyl)oxy]-6-{-2-[(tri-
isopropylsilyl)oxy]ethyl}dec-9-ene-3-yne (anti-Cram-21)
To a rapidly stirred solution of the crotyl carbamate (900 mg,
4.52 mmol, 2.5 equiv) and (–)-sparteine (1.10 g, 4.7 mmol,
2.6 equiv) in pentane (6.4 mL) and cyclohexane (0.75 mL) at
–78 °C was added a solution of n-BuLi (1.6 M in hexane, 2.93 mL,
4.7 mmol, 2.6 equiv). White crystals appeared after 10 min. After
allowing 3 h for crystallisation at –78 °C, a precooled (–78 °C,
30 min) solution of Ti(Oi-Pr)4 (4.05 mL, 13.5 mmol, 6.5 equiv) in
pentane (10 mL) was quickly added via cannula to the reaction mix-
ture of lithio carbamate which became limpid and turned red. After
20 min at –78 °C, aldehyde ( )-19 (990 mg, 1.81 mmol) in pentane
(4 mL) was added to the red solution. The mixture was stirred for
2 h at –78 °C and quenched by transferring to a vigorously stirred
mixture of 1 M aq HCl (25 mL) and Et2O at 0 °C. The temperature
was allowed to reach 20 °C, eventually filtered 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 two successive flash chromatography on sil-
ica gel (hexane–EtOAc, 80:20), to give the title compounds Cram-
20 (606 mg, 45%) and anti-Cram-21 (404 mg, 30%) as colourless
oils.
MS (CI, NH3): m/z = 574 (MH+).
Anal Calcd for C33H55NO5Si: C, 69.07; H, 9.66; N, 2.44. Found: C,
69.14; H, 9.72; N, 2.48
(2R,3S)-7-Benzyloxy-3-[(triethylsilyl)oxy]-2-{-2-[(triisopropyl-
silyl)oxy]ethyl}hept-4-ynal [( )-19]
To a solution of alcohol ( )-18 (8.7 g, 15.2 mmol) in anhyd CH2Cl2
(80 mL) at 0 °C were added 2,6-lutidine (5.3 mL, 45.6 mmol,
3 equiv) and TESOTf (3.8 mL, 16.7 mmol, 1.1 equiv). After stir-
ring for 2 h at 20 °C, the reaction mixture was treated with 1 M aq
HCl (60 mL) and extracted with Et2O. The organic layer was
washed with brine, dried (Na2SO4), filtered and concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy on silica gel (hexane–EtOAc, 90:10) to give the corresponding
triethylsilyloxy derivative (8.14 g, 78%).
Triethylsilyloxy Derivative of 18
IR (CCl4): 2963, 1711 cm–1.
1H NMR (400 MHz): d = 0.55–0.63 [m, 6 H, 3 CH2, Si(CH2CH3)3],
0.89–1.02 [m, 9 H, 3 CH3, Si(CH2CH3)3], 1.04 {m, 21 H, 3 CH + 6
CH3, Si[CH(CH3)2]3}, 1.23 {d, J = 6.5 Hz, 12 H, 4 CH3,
N[CH(CH3)2]2}, 1.50–1.68 (m, 1 H, Ha-1¢), 1.91–2.10 (m, 1 H, Hb-
1¢), 2.50 (td, J = 7.0, 3.0 Hz, 2 H, CH2-2), 2.78–2.85 (m, 1 H, H-6),
3.58 (t, J = 7.0 Hz, 2 H, CH2-1), 3.62–3.88 [m, 2 H, NCH(CH3)2 +
Ha-2¢), 3.75–4.05 [m, 2 H, Hb-2¢ + NCH(CH3)2], 4.30–4.35 (m, 1
H, H-5), 4.52 (s, 2 H, PhCH2), 4.62 (dd, J = 6.0, 9.0 Hz, 1 H, =CH-
7), 7.08 (d, J = 6.0 Hz, 1 H, =CH-8), 7.2–7.4 (m, 5 H, C6H5).
Cram-20
[a]D +10.8 (c = 1.6, MeOH).
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116
P. Razon et al.
PAPER
IR (CCl4): 3607, 2965, 2870, 1700 cm–1.
CH3, N[CH(CH3)2]2}, 1.60–2.1 (m, 3 H, CH2-1¢ + H-6), 2.55 (td,
J = 7.0, 3.0 Hz, 2 H, CH2-2), 2.85 (m, 1 H, H-8), 3.57 (t, J = 7.0 Hz,
2 H, CH2-1), 3.70–4.2 {m, 5 H, CH2-2¢ + N[CH(CH3)2]2 + H-7},
4.52 (s, 2 H, PhCH2), 4.60 (m, 1 H, H-5), 4.65 (dd, J = 6.0, 9.0 Hz,
1 H, H-9), 7.10 (d, J = 6.0 Hz, 1 H, H-10), 7.30–7.40 (m, 5 H, C6H5).
13C NMR (100.6 MHz): d = 11.9 {3 CH, Si[CH(CH3)2]3}, 17.1
(CH3-3¢), 17.9 {6 CH3, Si[CH(CH3)2]3}, 20.2 (CH2-2), 20.4 and
21.2 {4 CH3, N[CH(CH3)2]2}, 26.9 (CH2-1¢), 34.1 (CH-8), 43.7
(CH-6), 46.8 and 47.8 {2 CH, N[CH(CH3)2]2}, 61.7 (CH2-2¢), 64.2
(CH-5), 68.5 (CH2-1), 72.9 (PhCH2), 76.1 (CH-7), 78.5 and 81.8
(C≡C), 113.2 (CH-9), 127.7 (3 CH, C6H5), 128.4 (2 CH, C6H5),
138.3 (CH-10). C, C6H5 and C=O were not observed.
1H NMR (400 MHz): d = 0.55–0.63 [m, 6 H, 3 CH2, Si(CH2CH3)3],
0.88–1.02 [m, 9 H, 3 CH3, Si(CH2CH3)3], 1.03 (d, J = 7.0 Hz, 3 H,
CH3-8), 1.04 {m, 21 H, 3 CH + 6 CH3, Si[CH(CH3)2]3}, 1.25 {d,
J = 6.5 Hz, 12 H, 4 CH3, N[CH(CH3)2]2}, 1.81–1.85 (m, 3 H, CH2-
1¢ + H-6), 2.51 (td, J = 7.0, 3.0 Hz, 2 H, CH2-2), 2.86 (m, 1 H, H-8),
3.56 (t, J = 7.0 Hz, 2 H, CH2-1), 3.70 [m, 2 H, Ha-2¢ + NCH(CH3)2],
3.85 (m, 2 H, Hb-2¢ + H-7), 4.10 [m, 1 H, NCH(CH3)2], 4.5 (s, 2 H,
PhCH2), 4.58 (m, 1 H, H-5), 4.84 (dd, J = 6.5, 9.5 Hz, 1 H, =CH-9),
7.12 (d, J = 6.5 Hz, 1 H, =CH-10), 7.3–7.4 (m, 5 H, C6H5).
13C NMR (100.6 MHz): d = 4.6 [3 CH2, Si(CH2CH3)3], 6.8 [3 CH3,
Si(CH2CH3)3], 11.9 {3 CH, Si[CH(CH3)2]3}, 18.0 (CH3-8), 18.1 {6
CH3, Si[CH(CH3)2]3}, 20.1 (CH2-2), 20.4 and 21.2 {4 CH3,
N[CH(CH3)2]2}, 28.2 (CH2-1¢), 33.4 (CH-8), 44.3 (CH-6), 45.3 and
46.4 {2 CH, N[CH(CH3)2]2}, 62.3 (CH2-2¢), 64.7 (CH-5), 68.5
(CH2-1), 73.0 (PhCH2), 75.4 (CH-7), 81.3 and 82.4 (C≡C), 113.4
(=CH-9), 127.7 (3 CH, C6H5), 128.4 (2 CH, C6H5), 135.2 (=CH-10),
138.0 (C, C6H5), 152.9 (C=O).
MS (CI, NH3): m/z = 632 (MH+).
(9Z,5S,6S,7S,8S)-anti-Cram Diol Isomer
[a]D –5.3 (c = 1.7, MeOH).
IR (CCl4): 3607, 3403, 2948, 2870, 1711 cm–1.
1H NMR (400 MHz): d = 1.03 (d, J = 7.0 Hz, 3 H, CH3-8), 1.04 {m,
21 H, 3 CH + 6 CH3, Si[CH(CH3)2]3}, 1.25 {d, J = 6.5 Hz, 12 H, 4
CH3, N[CH(CH3)2]2}, 1.68 (m, 1 H, Ha-1¢), 1.92 (m, 1 H, Hb-1¢),
2.01 (m, 1 H, H-6), 2.36 (s, 1 H, OH), 2.52 (td, J = 7.0, 3.0 Hz, 2 H,
CH2-2), 3.04 (m, 1 H, H-8), 3.50 (m, 1 H, H-7), 3.57 (t, J = 7.0 Hz,
2 H, CH2-1), 3.69 (m, 1 H, CHa-2¢), 3.80 and 4.08 {2 m, 2 H,
N[CH(CH3)2]2}, 3.83 (m, 1 H, Hb-2¢), 4.55 (s, 2 H, PhCH2), 4.71 (m,
1 H, H-5), 4.81 (dd, J = 9.0, 6.0 Hz, 1 H, H-9), 7.09 (d, J = 6.0 Hz,
1 H, H-10), 7.30–7.40 (m, 5 H, C6H5).
13C NMR (100.6 MHz): d = 11.8 {3 CH, Si[CH(CH3)2]3}, 17.9 {6
CH3, Si[CH(CH3)2]3}, 18.2 (CH3-3¢), 20.2 (CH2-2), 20.4 and 21.2
{4 CH3, N[CH(CH3)2]2}, 31.5 (CH2-1¢), 33.6 (CH-8), 45.3 and 46.4
{2 CH, N[CH(CH3)2]2}, 46.0 (CH-6), 62.4 (CH2-2¢), 62.9 (CH-5),
68.4 (CH2-1), 73.0 (PhCH2), 76.9 (CH-7), 81.9 and 83.1 (C≡C),
111.6 (CH-9), 127.7 (3 CH, C6H5), 128.3 (2 CH, C6H5), 138.3 (CH-
10). C, C6H5 and C=O were not observed.
MS (CI, NH3): m/z = 747 (MH+).
Anal Calcd for C42H75NO6Si2: C, 67.60; H, 10.13; N, 1.88. Found:
C, 67.75; H, 10.31; N, 1.75
anti-Cram-21
[a]D –15.1 (c = 1.6, MeOH).
IR (CCl4): 3607, 2965, 2870, 1700 cm–1.
1H NMR (400 MHz): d = 0.55–0.63 [m, 6 H, 3 CH2, Si(CH2CH3)3],
0.88–1.02 [m, 9 H, 3 CH3, Si(CH2CH3)3], 1.03 (d, J = 7.0 Hz, 3 H,
CH3-8), 1.04 {m, 21 H, 3 CH + 6 CH3, Si[CH(CH3)2]3}, 1.25 {d,
J = 6.5 Hz, 12 H, 4 CH3, N[CH(CH3)2]2}, 1.60–1.90 (m, 3 H, CH2-
1¢ + H-6), 2.45 (td, J = 7.0, 3.0 Hz, 2 H, CH2-2), 2.95 (m, 1 H, H-8),
3.50 (t, J = 7.0 Hz, 2 H, CH2-1), 3.60–4.1 [m, 5 H, H2-2¢ +
N[CH(CH3)2]2 + H-7), 4.48 (s, 2 H, PhCH2), 4.72 (m, 1 H, H-5),
4.85 (dd, J = 6.0, 9.0 Hz, 1 H, =CH-9), 7.08 (d, J = 6.0 Hz, 1 H,
=CH-10), 7.3–7.4 (m, 5 H, C6H5).
MS (CI, NH3): m/z = 632 (MH+).
13C NMR (100.6 MHz): d = 5.0 [3 CH2, Si(CH2CH3)3], 6.9 [3 CH3,
Si(CH2CH3)3], 12.2 {3 CH, Si[CH(CH3)2]3}, 18.2 (CH3-8), 18.8 {6
CH3, Si[CH(CH3)2]3}, 20.4 (CH2-2), 20.5 and 21.2 {4 CH3,
N[CH(CH3)2]2}, 31.4 (CH2-1¢), 33.9 (CH-8), 45.2 (CH-6), 45.3 and
46.4 {2 CH, N[CH(CH3)2]2}, 61.9 (CH2-2¢), 64.5 (CH-5), 68.6
(CH2-1), 73.1 (PhCH2), 76.3 (CH-7), 82.2 and 83.5 (C≡C), 112.3
(=CH-9), 127.8 (3 CH, C6H5), 128.5 (2 CH, C6H5), 138.3 (=CH-10),
139.5 (C, C6H5), 153.0 (C=O).
Ozone was bubbled into a solution of the above Cram diol (2 g,
3.17 mmol) or anti-Cram diol (500 mg, 0.79 mmol) in hexane–
MeOH (99:1, 50 mL) at –78 °C until the solution turned light blue.
Me2S (10 mL) was added at –78 °C, and the mixture was allowed to
warm to r.t. and stirred for 6 h. The solvents were partially removed
under reduced pressure and the organic solution was washed with
H2O. The organic layer was dried (Na2SO4), filtered, and evaporat-
ed to give the title compound 22 (274 mg, 71%) or 23 (1.29 g, 84%).
MS (CI, NH3): m/z = 747 (MH+).
Lactol 22, Major Epimer (Cram Isomer)
[a]D –1.5 (c = 1.6, MeOH).
IR (CCl4): 3632, 3421, 2949, 2871 cm–1.
Anal Calcd for C42H75NO6Si2: C, 67.60; H, 10.13; N, 1.88. Found:
C, 67.73; H, 10.34; N, 1.82
(6S,5S,2R,3R,5RS)- and (6R,5R,2R,3R,5RS)-6-[4-(Benzyl-
oxy)but-1-ynyl]-3-methyl-5-{2-[triisopropylsilyl)oxy]ethyl}tet-
rahydropyran-2,5-diol (22 and 23)
The numbers given to lactols correspond to the respective precursor
aldehydes.
1H NMR (400 MHz): d = 1.04 {m, 21 H, 3 CH + 6 CH3,
Si[CH(CH3)2]3}, 1.10 (d, J = 7.0 Hz, 3 H, CH3-8), 1.55 (m, 1 H, Ha-
1¢), 1.75 (m, 1 H, H-6), 1.95 (m, 1 H, Hb-1¢), 2.18 (m, 1 H, H-8), 2.53
(td, J = 7.0, 3.0 Hz, 2 H, CH2-2), 3.55 (t, J = 7.0 Hz, 2 H, CH2-1),
3.70 and 3.87 (2 m, 4 H, CH2-2¢, H-7, OH), 4.40 (d, J = 11.0 Hz, 1
H, H-5), 4.50 (s, 2 H, PhCH2), 4.55 (s, 1 H, OH), 5.15 (s, 1 H, H-9),
7.43 (s, 5 H, C6H5).
13C NMR (100.6 MHz): d = 10.5 (CH3-8), 11.8 {3 CH,
Si[CH(CH3)3]}, 17.8 {Si[CH(CH3)2]3}, 20.2 (CH2-2), 33.1 (CH2-
1¢), 38.0 (CH-8), 43.3 (CH-6), 62.8 (CH2-1), 64.0 (CH-5), 68.2
(CH2-2¢), 68.8 (CH-7), 72.9 (PhCH2), 79.4 and 82.2 (C≡C), 97.4
(CH-9), 127.5, 127.6, 128.3 (5 CH, C6H5), 137.9 (C, C6H5).
To a solution of Cram-20 or anti-Cram-21 (500 mg, 0.67 mmol) in
MeOH (10 mL) was added Amberlyst 15. After 15 min, the solution
was filtered and concentrated under reduced pressure. The crude oil
was chromatographed on silica gel (hexane–EtOAc, 70:30) to give
the corresponding diol in 71% (300 mg) or in 87% yield (368 mg),
respectively, as colourless oils.
(9Z,5R,6R,7S,8S)-Cram Diol Isomer
[a]D –15.2 (c = 1.2, MeOH).
IR (CCl4): 3607, 3523, 2947, 2871, 1710 cm–1.
1H NMR (400 MHz): d = 0.95 (d, J = 7.0 Hz, 3 H, CH3-8), 1.04 {m,
21 H, 3 CH + 6 CH3, Si[CH(CH3)2]3}, 1.25 {d, J = 6.5 Hz, 12 H, 4
MS (CI, NH3): m/z = 491 (MH+).
Anal Calcd for C28H46O5Si: C, 68.53; H, 9.45. Found: C, 68.61; H,
9.53.
Synthesis 2005, No. 1, 109–121 © Thieme Stuttgart · New York

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Primary and Secondary Allyltitanium(IV) Reagents in Aldehyde Allylation
117
Lactol 23, Major Epimer (anti-Cram Isomer)
[a]D +9.0 (c = 1.5, MeOH).
IR (CCl4): 3607, 3488, 2949, 2871 cm–1.
(2E)-5-(Benzyloxy)-1-[(tert-butyldiphenylsilyl)oxy]pent-2-ene
(28)
To a solution of alcohol 26 (22 g, 114 mmol) in anhyd CH2Cl2
(200 mL) was added imidazole (11.64 g, 171 mmol, 1.5 equiv) and
TPSCl (29.64 mL, 114 mmol, 1 equiv). The mixture was stirred for
1 h at r.t. and then quenched at 0 °C with 1 M aq HCl (75 mL). The
resulting mixture was extracted with Et2O. The combined organic
layers were washed with brine and concentrated under reduced
pressure. The crude oil was purified by flash chromatography on sil-
ica gel (cyclohexane–EtOAc, 95:5) to give the title compound 28 as
a colourless oil (46.5 g, 95%).
1H NMR (200 MHz): d = 0.85 [s, 9 H, 3 CH3, SiC(CH3)3], 2.34 (q,
J = 7.0 Hz, 2 H, CH2-4), 3.50 (t, J = 7.0 Hz, 2 H, CH2-5), 4.21 (m,
2 H, CH2-1), 4.52 (s, 2 H, PhCH2O), 5.52–5.69 (m, 2 H, CH=CH),
7.32 (m, 4 H, C6H5), 7.43 (m, 11 H, C6H5).
1H NMR (400 MHz): d = 1.07 {m, 21 H, 3 CH + 6 CH3,
Si[CH(CH3)2]3}, 1.15 (d, J = 6.0 Hz, 3 H, CH3-8), 1.50–2.00 (m, 4
H, CH2-1¢ + H-6 + H-8), 2.51 (td, J = 7.0, 3.0 Hz, 2 H, CH2-2), 3.60
(t, J = 7.0 Hz, 2 H, CH2-1), 3.75 (m, 1 H, Ha-2¢), 3.87 (m, 1 H, Hb-
2¢), 4.00 (s, 1 H, OH), 4.25 (s, 1 H, H-7), 4.52 (s, 2 H, PhCH2), 4.65
(d, J = 11.0 Hz, 1 H, H-5), 4.97 (s, 1 H, H-9), 7.33 (s, 5 H, C6H5).
13C NMR (100.6 MHz): d = 11.8 (CH3-8), 13.7 {3 CH,
Si[CH(CH3)2]3}, 17.9 {Si[CH(CH3)2]3}, 20.2 (CH2-2), 31.4 (CH2-
1¢), 38.5 (CH-8), 45.3 (CH-6), 58.9 (CH-5), 62.0 (CH2-2¢), 68.2
(CH2-1), 70.5 (CH-7), 72.9 (PhCH2), 79.4 and 82.2 (C≡C), 97.4
(CH-9), 127.5, 127.6, 128.3 (5 CH, C6H5), 137.9 (C, C6H5).
MS (CI, NH3): m/z = 491 (MH+).
13C NMR (50.8 MHz): d = 19.2 [SiC(CH3)3], 25.8 [3 CH3,
SiC(CH3)3], 30.9 (CH2-4), 64.4 (CH2-1), 70.3 (CH2-5), 73.0
(PhCH2O), 127.4, 127.7, 128.5, 128.1, 129.3 129.7 (16 CH, C6H5 +
=CH-2), 132.4 (=CH-3), 137.2 (C, C6H5). C, C6H5–Si was not ob-
served.
Anal Calcd for C28H46O5Si: C, 68.53; H, 9.45. Found: C, 68.67; H,
9.49.
(2E)-5-(Benzyloxy)pent-2-en-1-ol (26)
MS (CI, NH3): m/z = 431 (MH+).
To a solution of alcohol 10 (26 g, 136 mmol) in anhyd Et2O
(150 mL) at 0 °C was slowly added a 1 M solution of LiAlH4 in
THF (150 mL, 150 mmol, 1.1 equiv). The 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 H2O (52 mL),
10 M aq NaOH (12.4 mL), and H2O (24.8 mL). The precipitate was
filtered and washed with Et2O. The filtrate was concentrated under
reduced pressure and purified by flash chromatography on silica gel
(cyclohexane–EtOAc, 50:50) to give the title compound 26 as a co-
lourless oil (22.3 g, 85%).
Anal Calcd for C28H34O2Si: C, 78.09; H, 7.96. Found: C, 78.18; H,
8.12.
(2R*,3R*)-5-(Benzyloxy)-1-[(tert-butyldimethylsilyl)oxy]pen-
tane-2,3-diol (29)
Racemic ( )-29
To a solution of NMO (1.53 g, 13 mmol, 2 equiv) in a mixture of ac-
etone and H2O (60 mL, 60:40) was added a catalytic amount of
OsO4 (165 mg, 0.65 mmol, 0.1 equiv) and compound 27 (2 g,
6.52 mmol). The resulting solution was stirred until all the starting
material was consumed, and quenched by the addition of aq 1 M
HCl (30 mL). The mixture was extracted with EtOAc. The organic
layers were washed with brine, filtered and concentrated under re-
duced pressure. The crude oil was purified by flash chromatography
to give the title compound ( )-29 (1.42 g, 64%).
IR (CCl4): 3385, 2857, 1495, 1361, 1092, 735, 696 cm–1.
1H NMR (200 MHz): d = 1.40 (s, 1 H, OH), 2.30 (q, J = 6.5 Hz, 2
H, CH2-4), 3.45 (t, J = 6.5 Hz, 2 H, CH2-5), 4.03 (m, 2 H, CH2-1),
4.45 (s, 2 H, PhCH2), 5.58–5.73 (m, 2 H, CH=CH), 7.36 (m, 5 H,
C6H5).
13C NMR (50.8 MHz): d = 32.5 (CH2-4), 62.7 (CH2-1), 69.5 (CH2-
5), 72.6 (PhCH2), 127.5, 127.6, 128.1, 128.2 (6 CH, 5 C6H5 + =CH-
2), 131.2 (=CH-3), 138.1 (C, C6H5).
Optically Active 29
A 100 mL round-bottomed flask equipped with a magnetic stirrer
was charged with tert-butyl alcohol (32 mL, 5 mL/mmol), H2O (32
mL, 5 mL/mmol), AD-Mix-b (9.13 g, 1.4 g/mmol) and methane-
sulfonamide (620 mg, 95 mg/mmol). The mixture was stirred at r.t.
until both phases were clear, and then cooled to 0 °C, whereupon
the inorganic salts partially precipitated. Compound 27 was added
(2 g, 6.5 mmol) and the heterogeneous slurry was stirred vigorously
at 0 °C until the starting material was consumed. The reaction was
quenched at 0 °C by addition of Na2SO3 (9.75 g, 1.5 g/mmol) and
then warmed to r.t. and stirred for 1 h. The mixture was extracted
several times with EtOAc. The combined organic layers were
washed with aq 2 M KOH, dried (MgSO4) and concentrated under
reduced pressure. The crude diol was purified by flash chromatog-
raphy on silica gel (cyclohexane–EtOAc, 60:40) to give the title
compound 29 (1.78 g, 80% yield, 60% ee).
MS (CI, NH3): m/z = 193 (MH+).
(2E)-5-(Benzyloxy)-1-[(tert-butyldimethylsilyl)oxy]pent-2-ene
(27)
To a solution of alcohol 26 (3 g, 15.5 mmol) in anhyd CH2Cl2
(25 mL) at 0 °C were added imidazole (1.6 g, 23.3 mmol,
1.5 equiv) and TBSCl (2.6 g, 17.1 mmol, 1.1 equiv). After stirring
for 1 h at 20 °C, the reaction mixture was treated with 1 M aq HCl
(25 mL) and extracted with Et2O. The organic layer was washed
with brine, dried (Na2SO4), filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography (hex-
ane–EtOAc, 95:5) to give the title compound 27 as a colourless oil
(4.43 g, 93%).
1H NMR (200 MHz): d = 0.00 [s, 6 H, 2 CH3, Si(CH3)2], 0.80–0.9
[s, 9 H, 3 CH3, SiC(CH3)3] 1.8 (q, J = 6.5 Hz, 2 H, CH2-4), 3.50–
3.70 (m, 4 H, CH2-1 + CH2-5), 4.50 (s, 2 H, PhCH2), 5.73 (m, 2 H,
CH=CH), 7.37 (m, 5 H, C6H5).
IR (CCl4): 3438, 2928, 2856, 1251, 1095, 834, 776, 696 cm–1.
1H NMR (200 MHz): d = 0.05 [s, 6 H, 2 CH3, Si(CH3)2], 0.85 [s, 9
H, 3 CH3, SiC(CH3)3], 1.55–1.84 (m, 2 H, CH2-4), 2.72 (d, J = 5.7
Hz, 1 H, OH), 3.04 (d, J = 5.7 Hz, 1 H, OH), 3.38 (m, 1 H, CH-2),
3.50–3.60 (m, 4 H, CH2-1 + CH2-5), 3.64 (m, 1 H, H-3), 4.40 (s, 2
H, PhCH2), 7.30 (m, 5 H, C6H5).
13C NMR (50.3 MHz): d = – 4.90 [2 CH3, Si(CH3)2], 18.2 [3 CH3,
SiC(CH3)3], 25.9 [3 CH3, SiC(CH3)3], 33.5 (CH2-4), 65.3 (CH2-1),
67.9 (CH, C-2 or C-3), 70.4 (CH2-5), 73.2 (PhCH2), 73.4 (CH, C-3
or C-2), 127.7, 128.4 (5 CH, C6H5), 138.1 (C, C6H5).
13C NMR (50.3 MHz): d = 4.7 [Si(CH3)2], 18.2 [SiC(CH3)3], 25.9
[SiC(CH3)3], 33.5 (CH2-4), 67.8 (CH2-1), 70.4 (CH2-5), 73.2
(PhCH2), 127.7 and 128.4 (6 CH, 5 C6H5 + =CH-2), 129.5 (=CH-3),
138.1 (C, C6H5).
MS (CI, NH3): m/z = 307 (MH+).
Anal Calcd for C18H30O2Si: C, 70.53; H, 9.87. Found: C, 70.67; H,
9.94.
MS (CI, NH3): m/z = 341 (MH+).
Synthesis 2005, No. 1, 109–121 © Thieme Stuttgart · New York

118
P. Razon et al.
PAPER
Anal Calcd for C18H32O4Si: C, 63.49; H, 9.47. Found: C, 63.54; H,
9.52.
was quenched at 0 °C by addition of Na2SO3 (73.2 g, 1.5 g/mmol)
and then warmed to r.t. and stirred for 1 h. The mixture was extract-
ed several times with EtOAc. The combined organic layers were
washed with aq 2 M KOH, dried (MgSO4) and concentrated under
reduced pressure. The crude diol was purified by flash chromatog-
raphy on silica gel (cyclohexane–EtOAc, 60:40) to give the title
compound 31 (18.8 g, 83% yield, 90% ee); [a]D +21.3 (c = 0.61,
MeOH).
(2R*,3R*)-5-(Benzyloxy)-2,3-[(isopropylidene)dioxy]pentan-1-
ol [( )-30]
To a solution of diol ( )-29 (1.5 g, 4.4 mmol) in CH2Cl2 (15 mL)
was added 2,2-dimethoxypropane (6.55 mL, 53 mmol, 12 equiv)
and a catalytic amount of PPTS (10% w/w, 150 mg). The solution
was stirred for 2 h and quenched with H2O (15 mL). The reaction
mixture was extracted with Et2O. The combined organic layers
were washed with aq sat. NaHCO3 and brine, dried (MgSO4) and
concentrated under reduced pressure. The crude oil was then puri-
fied by flash chromatography on silica gel (hexane–EtOAc, 90:10)
to give (2R,3R)-5-(benzyloxy)-2,3-[(isopropylidene)dioxy]-1-
[(tert-butyldimethylsilyl)oxy]pentane (1.54 g, 92%).
IR (CCl4): 3436, 2929, 2856, 1427, 1108, 698 cm–1.
1H NMR (400 MHz): d = 1.10 [s, 9 H, 3 CH3, SiC(CH3)3], 1.82 (m,
1 H, Ha-4), 1.92 (m, 1 H, Hb-4), 3.61 (dt, J = 8.9, 6.0 Hz, 1 H, H-2),
3.69 (m, 2 H, CH2-5), 3.81 (2dd, J = 10.3, 6.0 Hz and J = 10.3 Hz,
6.0 Hz, 2 H, CH2-1), 3.96 (dt, J = 8.9, 3.6 Hz, 1 H, H-3), 4.53 (s, 2
H, PhCH2), 7.30–7.45 (m, 11 H, C6H5), 7.9 (m, 4 H, C6H5).
13C NMR (100.6 MHz): d = 19.1 [SiC(CH3)3], 26.8 [3 CH3,
SiC(CH3)3], 33.4 (CH2-4), 65.8 (CH2-1), 67.8 (CH2-5), 70.1 (CH-
2), 73.2 (PhCH2), 73.8 (CH-3), 132.8, 132.9, 137.9 (3 C, C6H5),
127.5, 127.6, 127.7, 128.4, 129.8, 135.4 (15 CH, C6H5).
(2R,3R)-5-(Benzyloxy)-2,3-[(isopropylidene)dioxy]-1-[(tert-bu-
tyldimethylsilyl)oxy]pentane
IR (CCl4): 2929, 2857, 1367, 1251, 1087, 834, 776, 696 cm–1.
1H NMR (200 MHz): d = 0.05 [s, 6 H, 2 CH3, Si(CH3)2], 0.84 {s, 9
H, 3 CH3, Si[C(CH3)3]}, 1.30 [s, 3 H, CH3, OC(CH3)2O], 1.32 [s, 3
H, CH3, OC(CH3)2O], 1.60–2.00 (m, 2 H,CH2-4), 3.61 (t, J = 7.6
Hz, 2 H, CH2-5), 3.64 (dd, J = 13.5, 3.5 Hz, 1 H, Ha-1), 3.70–3.80
(m, 2 H, H-2 + Hb-1), 4.03 (dt, J = 8.5, 5.0 Hz, 1 H, H-3), 4.42 (s, 2
H, PhCH2), 7.28 (m, 5 H, C6H5).
13C NMR (50.8 MHz): d = –5.5 [2 CH3, Si(CH3)2], 18.2 [SiC(CH3)3]
25.8 [3 CH3, SiC(CH3)3], 26.9 and 27.3 [OC(CH3)2O], 33.6 (CH2-
4), 63.4 (CH2-1), 67.1 (CH2-5), 72.8 (PhCH2), 75.7 (CH-3), 81.2
(CH-2), 108.4 [OC(CH3)2O], 127.4, 128.2 (5 CH, C6H5), 138.4 (C,
C6H5).
MS (CI, NH3): m/z = 465 (MH+).
Anal Calcd for C28H36O4Si: C, 72.37; H, 7.81. Found: C, 72.42; H,
7.92.
(2R,3R)-5-(Benzyloxy)-2,3-[(isopropylidene)dioxy]pentan-1-ol
(30)
To a solution of diol 31 (8 g, 17.2 mmol) in CH2Cl2 (80 mL) was
added 2,2-dimethoxypropane (25.5 mL, 206 mmol, 12 equiv) and a
catalytic amount of PPTS (5% w/w, 400 mg). The mixture was
stirred for 2 h and then quenched with H2O (80 mL). The mixture
was extracted with Et2O. The combined organic layers were washed
with aq sat. NaHCO3 and brine, dried (MgSO4) and concentrated
under reduced pressure. The crude oil was then purified by flash
chromatography on silica gel (hexane–EtOAc, 95:5) to give
(2R,3R)-5-(benzyloxy)-2,3-[(isopropylidene)dioxy]-1-[(tert-butyl-
diphenylsilyl)oxy]pentane (7.8 g, 90%).
MS (CI, NH3): m/z = 381 (MH+).
( )-30
To a solution of the ( )-(2R,3R)-5-(benzyloxy)-2,3-[(isopropyl-
idene)dioxy]-1-[(tert-butyldimethylsilyl)oxy]pentane (1 g, 2.63
mmol) in THF (10 mL) was added an 1 M solution of TBAF in THF
(5.26 mL, 5.26 mmol, 2 equiv). The resulting solution was stirred
for 1 h at 20 °C, quenched with H2O (10 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 flash chromatography on silica gel
(hexane–EtOAc, 70:30) to give the title compound ( )-30 as a co-
lourless oil (695 mg, quant.).
(2R,3R)-5-(Benzyloxy)-2,3-[(isopropylidene)dioxy]-1-[(tert-bu-
tyldiphenylsilyl)oxy]pentane
[a]D +19.2 (c = 1.25, MeOH).
1H NMR (200 MHz): d = 0.84 [s, 9 H, 3 CH3, SiC(CH3)3], 1.30 [s,
3 H, CH3, OC(CH3)2O], 1.32 [s, 3 H, CH3, OC(CH3)2O], 1.60–2.00
(m, 2 H, CH2-4), 3.61 (t, J = 7.6 Hz, 2 H, CH2-5), 3.64 (dd, J = 15.0,
3.5 Hz, 1 H, Ha-1), 3.71–3.80 (m, 2 H, H-2 + Hb-1), 4.04 (dt, J = 8.5,
5.0 Hz, 1 H, H-3), 4.42 (s, 2 H, PhCH2), 7.28 (m, 4 H, C6H5), 7.41
(m, 11 H, C6H5).
13C NMR (50.8 MHz): d = 19.3 [SiC(CH3)3], 25.8 [3 CH3,
SiC(CH3)3], 26.9 and 27.3 [OC(CH3)2O], 33.4 (CH2-4), 63.5 (CH2-
5), 67.1 (CH2-1), 72.8 (PhCH2), 75.7 (CH-3), 81.2 (CH-2), 108.4
[OC(CH3)2O], 127.5, 127.6, 128.1, 128.2 (15 CH, C6H5), 138.4 (C,
C6H5). C, C6H5–Si not observed.
IR (CCl4): 3448, 2985, 2869, 1369, 1087, 736, 697 cm–1.
1H NMR (400 MHz): d = 1.43 and 1.42 [2 s, 6 H, 2 CH3,
OC(CH3)2O], 1.94 (q, J = 6.6 Hz, 2 H, CH2-4), 3.60–3.70 (m, 3 H,
CH2-5 + Ha-1), 3.70 (m, 1 H, H-2), 3.79 (dd, J = 15.3, 3.6 Hz, 1 H,
Hb-1), 3.84 (m, 1 H, H-2), 4.04 (dt, J = 8.1, 6.6 Hz, 1 H, H-3), 4.53
(s, 2 H, PhCH2O), 7.30 (m, 5 H, C6H5).
13C NMR (100.6 MHz): d = 26.9, 27.2 [2 CH3, OC(CH3)2O], 33.2
(CH2-4), 61.9 (CH2-1), 66.9 (CH2-5), 73.0 (PhCH2), 74.7 (CH-3),
81.3 (CH-2), 108.5 [OC(CH3)2O], 126.6, 127.4, 127.6, (5 CH,
C6H5), 138.6 (C, C6H5).
MS (CI, NH3): m/z = 505 (MH+).
To a solution of the (2R,3R)-5-(benzyloxy)-2,3-[(isopropylid-
ene)dioxy]-1-[(tert-butyldiphenylsilyl)oxy]pentane (7 g, 13.9 mmol)
in THF (50 mL) was added an 1 M solution of TBAF in THF
(27.8 mL, 27.8 mmol, 2 equiv). The resulting solution was stirred
for 1 h at 20 °C, quenched with H2O (20 mL) and extracted with
Et2O. The combined organic phases were then washed with brine,
dried (Na2SO4), filtered and concentrated under reduced pressure.
The oily residue was purified by flash chromatography on silica gel
(hexane–EtOAc, 70:30) to give the title compound 30 as a colour-
less oil (3.69 g, quant.).
MS (CI, NH3): m/z = 267 (MH+).
(2R,3R)-5-(Benzyloxy)-1-[(tert-butyldiphenylsilyl)oxy]pentane-
2,3-diol (31)
A 1 L round-bottomed flask equipped with a magnetic stirrer was
charged with tert-butyl alcohol (244 mL, 5 mL/mmol), H2O
(244 mL, 5 mL/mmol), AD-Mix-b (68.32 g, 1.4 g/mmol) and meth-
anesulfonamide (4.64 g, 95 mg/mmol). The mixture was stirred at
r.t. until both phases were clear, and then cooled to 0 °C, whereupon
the inorganic salts partially precipitated. Compound 28 was added
(21 g, 48.8 mmol) and the heterogeneous slurry was stirred vigor-
ously at 0 °C until the starting material was consumed. The reaction
30
[a]D +17.4 (c = 0.75, MeOH).
Synthesis 2005, No. 1, 109–121 © Thieme Stuttgart · New York

PAPER
Primary and Secondary Allyltitanium(IV) Reagents in Aldehyde Allylation
119
IR (CCl4): 3448, 2985, 2869, 1369, 1087, 736, 697 cm–1.
A 1 L round-bottomed flask equipped with a magnetic stirrer was
charged with tert-butyl alcohol (50 mL, 5 mL/mmol), H2O (50 mL,
5 mL/mmol), AD-Mix-b (13.4 g, 1.4 g/mmol) and methanesulfon-
amide (910 mg, 95 mg/mmol). The mixture was stirred at r.t. until
both phases were clear, and then cooled to 0 °C, whereupon the in-
organic salts partially precipitated. The (2E)-5-(benzyloxy)-1-chlo-
ropent-2-ene was added (2 g, 9.6 mmol) and the heterogeneous
slurry was stirred vigorously at 0 °C until all the starting material
was consumed. The reaction was quenched at 0 °C by addition of
Na2SO3 (14.4 g, 1.5 g/mmol) and then warmed to r.t., and stirred for
1 h. The mixture was extracted several times with EtOAc. The com-
bined organic layers were washed with aq 2 M KOH, dried
(MgSO4) and concentrated under reduced pressure. The crude diol
which was purified by flash chromatography on silica gel (cyclo-
hexane–EtOAc, 60:40) to give (2R,3R)-5-(benzyloxy)-1-chloro-
pentane-2,3-diol (2.06 g, 89%).
1H NMR (400 MHz): d = 1.43 and 1.42 [2 s, 6 H, 2 CH3,
OC(CH3)2O], 1.94 (q, J = 6.6 Hz, 2 H, CH2-4), 3.60–3.70 (m, 3 H,
CH2-5 + Ha-1), 3.70 (m, 1 H, H-2), 3.79 (dd, J = 15.3, 3.6 Hz, 1 H,
Hb-1), 3.84 (m, 1 H, H-2), 4.04 (dt, J = 8.1, 6.6 Hz, 1 H, H-3), 4.53
(s, 2 H, PhCH2), 7.30 (m, 5 H, C6H5).
13C NMR (100.6 MHz): d = 26.9, 27.2 [2 CH3, OC(CH3)2O], 33.2
(CH2-4), 61.9 (CH2-1), 66.9 (CH2-5), 73.0 (PhCH2O), 74.7 (CH-3),
81.3 (CH-2), 108.5 [OC(CH3)2O], 126.6, 127.4, 127.6, (5 CH,
C6H5), 138.6 (C, C6H5).
MS (CI, NH3): m/z = 267 (MH+).
Anal Calcd for C15H22O4: C, 67.64; H, 8.33. Found: C, 67.68; H,
8.41.
(2R,3R)-5-(Benzyloxy)-2,3-[(isopropylidene)dioxy]pentanal
(32)
(2R,3R)-5-(Benzyloxy)-1-chloropentane-2,3-diol
[a]D –12.3 (c = 2.0, MeOH) {Lit.9 [a]D –13 (c = 2.0, CH2Cl2)
(ee = 96%)}.
IR (CCl4): 3430, 1455, 1100, 850 cm–1.
1H NMR (400 MHz): d = 1.73–1.82 (m, 1 H, Ha-4), 1.92–2.07 (m,
1 H, Hb-4), 3.02 (s, 1 H, OH), 3.27 (s, 1 H, OH), 3.56–3.76 (m, 5 H,
CH2-1, CH2-5, H-3), 3.97–4.02 (m, 1 H, H-2), 4.53 (s, 2 H,
PhCH2O), 7.27–7.38 (m, 5 H, C6H5).
13C NMR (67.8 MHz): d = 33.2 (CH2-4), 45.9 (CH2-1), 68.5 (CH2-
5), 70.7 (CH-3), 73.5 (PhCH2O), 74.0 (CH-2), 127.7 and 128.6 (5
CH, C6H5), 137.6 (C, C6H5).
To a solution of alcohol 30 (2.67 g, 10.1 mmol) in anhyd DMSO
(40 mL) was added Et3N (9.9 mL, 71 mmol, 7 equiv). The resulting
mixture was cooled to 0 °C and a solution of pyridine sulfur trioxide
complex (4.84 g, 30.4 mmol, 3 equiv) in DMSO (25 mL) was slow-
ly added. The solution was allowed to warm to r.t. and after 1 h
quenched with ice. The resulting solution was extracted with Et2O
and the combined organic phases were washed with brine, dried
(Na2SO4), filtered and concentrated under reduced pressure. The
oily residue was purified by flash chromatography on silica gel
(hexane–EtOAc, 70:30) to give the title compound 32 as a pale yel-
low oil (2.30 g, 86%).
IR (CCl4): 2985, 2926, 1735, 1086, 735, 697 cm–1.
MS (CI, NH3): m/z = 245 (MH+).
1H NMR (200 MHz): d = 1.38 [s, 3 H, CH3, OC(CH3)2O], 1.48 [s, 3
H, CH3, OC(CH3)2O], 2.03 (q, J = 6.0 Hz, 2 H, CH2-4), 3.50 (t,
J = 6.0 Hz, 2 H, CH2-5), 4.11 (dd, J = 9.0, 1.0 Hz, 1 H, H-2), 4.23
(dt, J = 9.0, 6.0 Hz, 1 H, H-3), 4.52 (s, 2 H, PhCH2), 7.31 (m, 5 H,
C6H5), 9.64 (d, J = 1.0 Hz, 1 H, H-1).
To a solution of (2R,3R)-5-(benzyloxy)-1-chloropentane-2,3-diol
(0.20 g, 0.82 mmol) in CH2Cl2 (10 mL) was added 2,2-dimethoxy-
propane (1.21 mL, 9.8 mmol, 12 equiv) and a catalytic amount of
PPTS (20 mg). The solution was stirred for 2 h and was quenched
with H2O (10 mL). The reaction mixture was extracted with Et2O,
the organic layers were washed with aq sat. NaHCO3 and brine,
dried (MgSO4) and concentrated under reduced pressure. The crude
oil was purified by flash chromatography on silica gel (cyclohex-
ane–EtOAc, 95:5) to give the title compound 33 (150 mg, 65%).
MS (CI, NH3): m/z = 265 (MH+).
Anal Calcd for C15H20O4: C, 68.16; H, 7.63. Found: C, 68.22; H,
7.71.
(2R,3R)-5-(Benzyloxy)-1-chloro-2,3-[(isopropylidene)di-
oxy]pentane (33) from Allylic Alcohol 26
33
[a]D +31.4 (c = 0.93, MeOH).
To a solution of N-chlorosuccinimide (3.9 g, 29 mmol, 2 equiv) in
anhyd CH2Cl2 (75 mL) was added Me2S (2.15 mL, 2 equiv) at 0 °C.
After stirring for 1 h at 0 °C, the mixture was cooled to –20 °C and
a solution of the allylic alcohol 26 (2.8 g, 14.5 mmol, 1 equiv) in
CH2Cl2 (25 mL) was added dropwise over a period of 15 min. After
stirring for 30 min a 0 °C, the mixture was allowed to warm slowly
to r.t. and stirred at this temperature for 1 h. Then, H2O (35 mL) was
added and the organic layers were washed with brine, dried
(Na2SO4), filtered and concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography on silica gel (cyclo-
hexane–EtOAc, 90:10) led to (2E)-5-(benzyloxy)-1-chloropent-2-
ene as a colourless oil (2.68 g, 88%).
1H NMR (200 MHz): d = 1.0 [m, 6 H, 2 CH3, OC(CH3)2O], 1.90 (m,
2 H, CH2-4), 3.50 (m, 4 H, CH2-1, CH2-5), 3.95 (m, 2 H, CH-2, H-
3), 4.45 (s, 2 H, PhCH2), 7.25 (m, 5 H, C6H5).
13C NMR (50.3 MHz): d = 27.0, 27.4 [2 CH3, OC(CH3)2O], 33.7
(CH2-4), 44.2 (CH2-1), 66.9 (CH2-5), 73.1 (PhCH2), 76.8 (CH-3),
80.4 (C-2), 109.2 [OC(CH3)2O], 127.5 (2 CH, C6H5), 127.7 (2 CH,
C-Ar), 128.3 (CH, C6H5), 138.4 (C, C6H5).
MS (CI, NH3): m/z = 285 (MH+).
Anal Calcd for C15H21ClO3: C, 63.26; H, 7.43. Found: C, 63.31; H,
7.55.
(2E)-5-(Benzyloxy)-1-chloropent-2-ene
(2R,3R)-5-(Benzyloxy)-1-chloro-2,3-[(isopropylidene)di-
oxy]pentane (33) from Acetonide 30
IR (CCl4): 1453, 1363, 1251 cm–1.
1H NMR (270 MHz): d = 2.39 (dt, J = 6.6, 6.5 Hz, 2 H, CH2-4), 3.51
(t, J = 6.6 Hz, 2 H, CH2-5), 4.04 (d, J = 6.7 Hz, 2 H, CH2-1), 4.51
(s, 2 H, PhCH2O), 5.60–5.90 (m, 2 H, CH=CH), 7.26–7.35 (m, 5 H,
C6H5).
13C NMR (67.8 MHz): d = 32.6 (CH2-4), 45.2 (CH2-1), 69.3 (CH2-
5), 72.9 (PhCH2O), 127.7 and 128.4 (6 CH, 5 C6H5 + =CH-3), 132.3
(=CH-2), 138.0 (C, C6H5).
To a solution of acetonide 30 (0.20 g, 0.75 mmol) in CH2Cl2 (10
mL) was added Ph3P (245 mg, 9.0 mmol, 1.2 equiv) and CCl4 (140
mg, 9.0 mmol, 1.2 equiv). The mixture was stirred for 8 h, quenched
with pentane (10 mL) and H2O (10 mL). The resulting mixture was
filtered and extracted with Et2O. The combined organic layers were
washed with brine, dried (MgSO4) and concentrated under reduced
pressure. The crude oil was purified by flash chromatography on sil-
ica gel (cyclohexane–EtOAc, 95:5) to give the title compound 33
(120 mg, 56%); [a]D +30.1 (c = 0.83, MeOH). For spectral data, see
above.
MS (CI, NH3): m/z = 210 (MH+).
Synthesis 2005, No. 1, 109–121 © Thieme Stuttgart · New York

120
P. Razon et al.
PAPER
(7Z,3R,4S,5S,6S)- and (7Z,3R,4S,5R,6R)-1-(Benzyloxy)-5-hy-
droxy-3,4-[(isopropylidene)dioxy]-6-{[(triisopropylsi-
lyl)oxy]ethyl}oct-7-ene (34 and 35)
J = 6.8 Hz, 2 H, CH2-5), 9.18 (d, J = 1.0 Hz, 1 H, H-1).
13C NMR (67.8 MHz): d = 12.0 {3 CH, Si[CH(CH3)2]3}, 18.0 {6
CH3, Si[CH(CH3)2]3}, 23.7 (CH2-4), 61.0 (CH2-5), 82.4 and 96.3
(C≡C), 177.1 (C-1).
To a solution of TMEDA (6.21 mL, 41.1 mmol, 5.1 equiv) in anhyd
Et2O (50 mL) at –78 °C, under argon, was added n-BuLi (1.6 M in
hexane, 25.7 mL, 41.1 mmol, 5.1 equiv). After stirring for 30 min at
–78 °C, a solution of the allyl carbamate 17 (7.2 g, 20 mmol,
2.5 equiv) in anhyd Et2O (50 mL), was slowly added. After stirring
for 40 min at –78 °C, Ti(Oi-Pr)4 (18 mL, 60 mmol, 7.5 equiv) was
rapidly added and the reaction mixture was stirred for 20 min at
–78 °C (transmetallation time). Then, the aldehyde 32 (2.13 g,
8.07 mmol) diluted in anhyd Et2O (10 mL) was added. The mixture
was stirred for 2 h at –78 °C and quenched by transferring to a vig-
orously stirred mixture of aq 3 M HCl (100 mL) and Et2O (100 mL)
at 0 °C. The temperature was allowed to reach 20 °C and the result-
ing 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 sil-
ica gel (cyclohexane–EtOAc, 80:20) to give a 20:80 mixture of
compounds 34 and 35 as a pale yellow oil (4.3 g, 81%).
MS (CI, NH3): m/z = 272 (MH+ + NH3), 255 (MH+).
Anal Calcd for C14H26O2Si: C, 66.09; H, 10.30. Found: C, 66.13; H,
10.38.
(2Z,4S*,5R*)- and (2Z,4S,5R)-4-[2-(Benzyloxy)ethyl]-2-{[(N,N-
diisopropyl)carbamoyl]oxy}-5-hydroxy-9-[(triisopropylsi-
lyl)oxy]non-2-ene-6-yne [( )-39] and [(2Z,4S,5R)-39]
Racemic Compound ( )-39
To a solution of ( )-36 (2.48 g, 7.5 mmol) at –78 °C in anhyd Et2O
(30 mL) and TMEDA (2.25 mL, 15.0 mmol, 2.0 equiv) was slowly
added n-BuLi (1.6M in hexane, 9.3 mL, 15 mmol, 2.0 equiv). After
stirring for 1 h at –78 °C, Ti(Oi-Pr)4 (6.7 mL, 22 mmol, 3 equiv)
was rapidly added and the reaction mixture was stirred for 20 min
at –78 °C (transmetallation time). Then, a solution of 38 (1.9 g,
7.5 mmol, 1 equiv) in Et2O (10 mL) was added. The mixture was
stirred for 2 h at –78 °C and quenched by transferring to a vigorous-
ly stirred mixture of aq 3 M HCl (30 mL) and Et2O (30 mL) at 0 °C.
The temperature was allowed to reach 20 °C and the resulting solu-
tion 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 ( )-39 as a pale yellow
oil (3.2 g, 72%).
IR (CCl4): 3490, 2929, 2865, 1704, 1061, 732 cm–1.
1H NMR (400 MHz, CDCl3): d (two diastereomers, minor isomer
underlined) = 1.10 {m, 21 H, 3 CH + 6 CH3, Si[CH(CH3)2]3}, 1.20
{m, 12 H, 4 CH3, N[(CH(CH3)2]2}, 1.25, 1.30 and 1.32, 1.40 [2 s, 6
H, 2 CH3, OC(CH3)2O], 1.50–2.0 (m, 4 H, CH2-2 + CH2-1¢), 2.10
and 2.60 (m, 1 H, H-6), 3.50–4.10 {2 m, 9 H, CH2-1 + CH2-2¢ + H-
3 + H-4 + H-5 + N[(CH(CH3)2]2}, 4.59 and 4.60 (s, 2 H, PhCH2),
4.70 (dd, J = 10.0, 7.0 Hz, 1 H, =CH-7), 7.1 (d, J = 7.0 Hz, 1 H,
=CH-8), 7.30 (m, 5 H, C6H5).
Optically Active Compound 39
1H NMR (400 MHz, DMSO-d6): d (two diastereomers, minor iso-
mer underlined) = 1.10 {m, 21 H, 3 CH + 6 CH3, Si[CH(CH3)2]3},
1.20 {m, 12 H, 4 CH3, N[(CH(CH3)2]2}, 1.25, 1.26 and 1.34, 1.36 [2
s, 6 H, 2 CH3, OC(CH3)2O], 1.64 (m, 2 H, CH2-2), 1.74 (m, 2 H,
CH2-1¢), 2.05 (m, 1 H, H-6), 3.32–3.68 (2 m, 6 H, CH2-1 + CH2-2¢
+ H-3 + H-4), 4.00 (m, 1 H, H-5), 3.75–4.00 {m, 2 H,
N[(CH(CH3)2]2}, 4.46 and 4.47 (s, 2 H, PhCH2O), 4.70 and 4.82
(dd, J = 8.9, 6.5 Hz, 1 H, =CH-7), 4.97 (d, J = 6.6 Hz, 1 H, OH),
6.86 and 6.95 (d, J = 6.5 Hz, 1 H, =CH-8), 7.30 (m, 5 H, C6H5).
13C NMR (100.6 MHz, DMSO-d6): d (two diastereomers, minor
isomer underlined) = 11.9 {3 CH, Si[CH(CH3)2]3}, 17.9 {6 CH3,
Si[CH(CH3)2]3}, 21.0 {4 CH3, N[(CH(CH3)2]2}, 27.0 and 27.2 [2
CH3, OC(CH3)2O], 36.6 (2 CH2, C-2 + C-1¢), 36.0 and 36.5 (CH-6),
45.7 {2 CH, N[(CH(CH3)2]2}, 61.6 (CH2-2¢), 67.2 (CH2-1), 73.3
(PhCH2), 75.2 and 75.7 (CH-3), 78.4 and 71.7 (CH-5), 80.6 and
81.4 (CH-4), 81.6 (CH-4), 109.9 [OC(CH3)2O], 110.5 (=CH-7),
128.3, 128.7 (5 CH, C6H5), 138.3 (C, C6H5), 138.6 (=CH-8), 155.2
(C=O).
To a solution of the optically active allyl carbamate (S)-36 (1.0 g,
3.02 mmol) in anhyd pentane–cyclohexane (20 mL/2 mL) and
TMEDA (1.0 mL, 6.05 mmol, 2.0 equiv) at –78 °C was slowly add-
ed n-BuLi (1.6 M in hexane, 3.8 mL, 6.05 mmol, 2.0 equiv). After
stirring for 1 h 15 min to 1 h 30 min at –78 °C, precooled Ti(Oi-Pr)4
(5.5 mL, 18.1 mmol, 3 equiv) at –78 °C in anhyd pentane (15 mL)
was rapidly added via cannula and the reaction mixture was stirred
for 30 min at –78 °C (transmetallation time). Then, a solution of 38
(880 mg, 3.0 mmol, 1 equiv) in pentane (5.0 mL) 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 (30 mL) and Et2O
(30 mL) at 0 °C. The temperature 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 re-
duced pressure. The residue was purified by flash chromatography
on silica gel (hexane–EtOAc, 70:30), to give 39 as a pale yellow oil
(1.26 g, 70% yield, ee = 80%).
1H NMR (400 MHz): d = 1.05 {m, 21 H, 3 CH and 6 CH3,
Si[CH(CH3)2]3}, 1.21 {d, J = 7.2 Hz, 12 H, 4 CH3, N[CH(CH3)2]2},
1.53 (m, 1 H, Ha-1¢), 1.89 (s, 3 H, CH3-1), 2.11 (m, 1 H, Hb-1¢), 2.46
(2 td, J = 7.4, 1.9 Hz, 2 H, CH2-8), 2.62 (m, 1 H, H-4), 3.45 (m, 1
H, Ha-2¢), 3.52 (m, 1 H, Hb-2¢), 3.75 {br m, 1 H, N[CH(CH3)2]2},
3.78 (t, J = 7.4 Hz, 2 H, CH2-9), 4.03 {br m, 1 H, N[(CH(CH3)2]2},
4.15 (dt, J = 5.9, 1.9 Hz, 1 H, H-5), 4.47 (d, J = 11.8 Hz, 1 H,
PhCH2), 4.52 (d, J = 11.8 Hz, 1 H, PhCH2), 4.85 (d, J = 10.3 Hz, 1
H, =CH-3), 7.37 (m, 5 H, C6H5 ).
13C NMR (100.6 MHz): d = 11.8 {3 CH, Si[CH(CH3)2]3}, 18.1 {3
CH3, Si[CH(CH3)2]3}, 20.1 (CH3-1), 20.4 and 22.1 {4 CH3,
N[CH(CH3)2]2}, 23.2 (CH2-8), 31.2 (CH2-1¢), 41.3 (CH-4), 45.9 and
47.0 {2 CH, N[CH(CH3)2]2}, 62.3 (CH2-9), 65.7 (CH-5), 68.7
(CH2-2¢), 72.9 (PhCH2), 81.4 (≡C-7), 82.4 (≡C-6), 117.1 (=CH-3),
127.5 (2 CH, C6H5), 127.7 (2 CH, C6H5), 128.3 (CH-7¢), 138.4 (C,
C6H5), 147.5 (C-2), 153.7 (C=O).
MS (CI, NH3): m/z = 650 (MH+).
Anal Calcd for C36H63NO7Si: C, 66.52; H, 9.77; N, 2.15. Found: C,
66.63; H, 9.83; N, 2.12.
5-[(Triisopropyl)oxy]pent-2-yn-1-al (38)
To a solution of 13 (3 g, 12 mmol) in CH2Cl2 (15 mL) was added
portionwise MnO2 (5.1 g, 58.5 mmol, 5 equiv) until all the starting
material was completely consumed. After stirring for 2 h, the reac-
tion mixture was filtered on a pad of Celite and the solvent was re-
1
moved under reduced pressure. The crude oil (81% yield by H
NMR, before chromatography) was purified by flash chromatogra-
phy on silica gel (hexane–EtOAc, 70:30) to give 38 as a colourless
to pale yellow oil (1.9 g, 63%).
IR (KBr): 2204, 1670 cm–1.
1H NMR (270 MHz): d = 1.08 {m, 21 H, 3 CH and 6 CH3,
Si[CH(CH3)2]3}, 2.64 (td, J = 6.8, 1.0 Hz, 2 H, CH2-4), 3.90 (t,
Synthesis 2005, No. 1, 109–121 © Thieme Stuttgart · New York

PAPER
Primary and Secondary Allyltitanium(IV) Reagents in Aldehyde Allylation
121
Anal Calcd for C34H57NO5Si: C, 69.46; H, 9.77; N, 2.38. Found: C,
69.51; H, 9.89; N, 2.42.
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.
(3) (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.
(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) Oddon, G.; Uguen, D. Tetrahedron 1997, 38, 4407.
(b) Oddon, G.; Uguen, D. Tetrahedron Lett. 1997, 38, 4411.
(c) Breuilles, P.; Oddon, G.; Uguen, D. Tetrahedron Lett.
1997, 38, 6607. (d) Oddon, G.; Uguen, D.; De Cain, A.;
Fischer, J. Tetrahedron Lett. 1998, 39, 1149. (e) Oddon,
G.; Uguen, D. Tetrahedron Lett. 1998, 39, 1153. (f)Oddon,
G.; Uguen, D. Tetrahedron Lett. 1998, 39, 1157. (g) For
the synthesis of the eastern part of spiramycin, see:
Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. Tetrahedron Lett.
1979, 25, 2327. (h) See also: Nicolaou, K. C.; Seitz, S. P.;
Pavia, M. R. J. Am. Chem. Soc. 1981, 103, 1222. (i) See
also: Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. J. Am. Chem.
Soc. 1981, 103, 1224. (j) See also: Tatsuta, K.; Amemiya,
Y.; Maniwa, S.; Kinoshita, M. Tetrahedron Lett. 1980, 21,
2837. (k) See also: Wuts, P. M. G.; Bigelow, S. S. J. Org.
Chem. 1988, 53, 5023.
(6) (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.
(2Z,3R,4S,5S,6S)-1-(Benzyloxy)-3,4-[(isopropylidene)dioxy]-5-
hydroxy-6-[2-(benzyloxy)ethyl]-8-{[(N,N-diisopropyl)carbam-
oyl]oxy}non-7-ene (40)
To a solution of (S)-allyl carbamate (S)-36 (1.0 g, 3.0 mmol) in an-
hyd pentane–cyclohexane (10 mL/1.0 mL), was added TMEDA
(0.90 mL, 6.0 mmol, 2.0 equiv). The solution was cooled at –78 °C,
and after 15 min, n-BuLi (1.6M in hexane, 3.8 mL, 6.0 mmol,
2.0 equiv) was slowly added. After stirring for 1 h at –78 °C, a pre-
cooled solution of Ti(Oi-Pr)4 (2.7 mL, 9.0 mmol, 3 equiv) in pen-
tane (10 mL) at –78 °C was rapidly added via cannula and the
reaction mixture was stirred for 20 min at –78 °C (transmetallation
time). Then, aldehyde 32 (800 mg, 3.0 mmol, 1 equiv) diluted in
pentane–Et2O (8.0 mL/2.5 mL) 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 (3 M, 20 mL) and Et2O (20 mL) at
0 °C. The temperature was allowed to reach 20 °C and the resulting
solution was eventually filtered on a pad of Celite to remove titani-
um salts and extracted with Et2O. The organic layer was washed
with brine, dried (Na2SO4) and concentrated under reduced pres-
sure. The residue was purified by flash chromatography on silica gel
(hexane–EtOAc, 70:30) to give 40 as a single diastereomer; pale
yellow oil; yield: 1.4 g (80%).
1H NMR (400 MHz): d = 1.22 {m, 12 H, 4 CH3, N[CH(CH3)2]2},
1.36 [s, 6 H, 2 CH3, OC(CH3)2O], 1.47 and 1.90 (2 m, 4 H, CH2-1¢
and CH2-2), 1.90 (s, 3 H, CH3-9), 2.65 (m, 1 H, H-6), 3.33 (dd,
J = 7.6, 2.0 Hz, 1 H, H-5), 3.46 (m, 2 H, CH2-1), 3.58 (m, 2 H, CH2-
2¢), 3.74 (dd, J = 8.0, 2.0 Hz, 1 H, H-4), 3.80 [m, 1 H, NCH(CH3)2],
4.05 [m, 1 H, NCH(CH3)2], 4.22 (m, 1 H, H-3), 4.50 and 4.47 (2 s,
4 H, 2 PhCH2), 4.92 (d, J = 11.1 Hz, 1 H, =CH-7), 7.30–7.37 (2 s,
10 H, C6H5).
13C NMR (100.6 MHz): d = 20.1 (CH3-9), 20.5 and 21.4 {4 CH3
N[CH(CH3)2]2}, 26.7 and 26.8 [2 CH3,OC(CH3)2O], 31.2 (CH2-1¢),
33.0 (CH2-2), 37.0 (CH-6), 46.3 and 46.6 {2 CH, N[CH(CH3)2]2},
68.6 (CH2-1), 67.4 (CH2-2¢), 71.4 (CH-5), 72.8 and 72.9 (2 CH2, 2
PhCH2), 74.5 (CH-3), 80.9 (CH-4), 108.3 [OC(CH3)2O], 117.5
(=CH-7), 127.3, 127.6, 128.2 (10 CH, C6H5), 138.4 and 138.6 (2 C,
C6H5), 146.8 (C-8), 153.5 (C=O).
(7) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1754.
(8) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
(9) Maier, M. E.; Hermann, C. Tetrahedron 2000, 56, 557.
(10) The structure of 36 was established by comparison of its 1H
and 13C NMR spectra with those of compound 46. Analysis
of 1H and 13C NMR spectra was supported by 2D
experiments.
MS (CI, NH3): m/z = 598 (MH+).
Anal Calcd for C35H51NO7: C, 70.32; H, 8.60; N, 2.34. Found: C,
70.48; H, 8.79; N, 2.46.
References
(1) (a) Tatsuta, K.; Amemiya, Y.; Kanemura, Y.; Takahashi, H.;
Kinoshita, M. Tetrahedron Lett. 1982, 23, 3375.
(11) (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) See also: Hoppe, D.; Krämer, T. Tetrahedron
Lett. 1987, 28, 5149. (e) See also: Hoppe, D.; Schwark, J.-
R. Synthesis 1990, 291. (f) See also: Zschage, O.; Hoppe,
D. Tetrahedron 1992, 48, 8389.
(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.
(2) (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,
(12) Razon, P.; Dhulut, S.; Bezzenine-Lafollée, S.; Courtieu, J.;
Pancrazi, A.; Ardisson, J. Synthesis 2004, preceding paper.
Synthesis 2005, No. 1, 109–121 © Thieme Stuttgart · New York