Allyltitanates in stereospecific additions to chiral σ-lactol: Efficient enantioselective route to a potential precursor of the C1-C9 portion of Tylonolide

Article abstract of DOI:10.1021/jo9807722

The Hoppe reaction, which is an allylation reaction of aldehydes using an optically active titanated crotyl carbamate intermediate generated from the corresponding N,N-diisopropyl crotyl carbamate with n-BuLi/(-)-sparteine, was in most cases applied to achiral aldehydes. In this work an extension of this reaction is reported using a racemic γ-alkoxy allyltitanate (17) and an optically active aldehyde (16) to deliver in good yield the anti adduct 18 as the major isomer. When the corresponding σ-lactol 24 was used in place of aldehyde 16, the anti adduct 25 was obtained in 94% yield as the only product. Structural modifications effected on 25 delivered aldehyde 28 which was in turn submitted to a second allylation reaction in the presence of the optically active titanated crotyl carbamate 2, prepared as described by Hoppe from crotyl carbamate 1, to conduct to compound 29 in 80% yield. This derivative corresponds to a potential precursor of the C1-C9 portion of Tylonolide, aglycon of Tylosin (4).

Full text of DOI:10.1021/jo9807722

J . Org. Chem. 1999, 64, 373-381
373
Allyltita n a tes in Ster eosp ecific Ad d ition s to Ch ir a l δ-La ctol:
Efficien t En a n tioselective Rou te to a P oten tia l P r ecu r sor of th e
C1-C9 P or tion of Tylon olid e
Isabelle Berque,§ Patrick Le Me´nez,§ Patrick Razon,§ J acqueline Mahuteau,†
J ean-Pierre Fe´re´zou,‡ Ange Pancrazi,*,§ J anick Ardisson,*,§ and J ean-Daniel Brion§
Service de RMN, BIOCIS, Faculte´ de Pharmacie, 92296, Chaˆtenay-Malabry, France, Laboratoire de
Synthe`se Organique, DCSO, EÄ cole Polytechnique, 91128 Palaiseau, France, and Laboratoire de Chimie
The´rapeutique, BIOCIS, Faculte´ de Pharmacie, 92296, Chaˆtenay-Malabry, France
Received April 24, 1998
The Hoppe reaction, which is an allylation reaction of aldehydes using an optically active titanated
crotyl carbamate intermediate generated from the corresponding N,N-diisopropyl crotyl carbamate
with n-BuLi/(-)-sparteine, was in most cases applied to achiral aldehydes. In this work an extension
of this reaction is reported using a racemic γ-alkoxy allyltitanate (17) and an optically active
aldehyde (16) to deliver in good yield the anti adduct 18 as the major isomer. When the
corresponding δ-lactol 24 was used in place of aldehyde 16, the anti adduct 25 was obtained in
94% yield as the only product. Structural modifications effected on 25 delivered aldehyde 28 which
was in turn submitted to a second allylation reaction in the presence of the optically active titanated
crotyl carbamate 2, prepared as described by Hoppe from crotyl carbamate 1, to conduct to compound
29 in 80% yield. This derivative corresponds to a potential precursor of the C1-C9 portion of
Tylonolide, aglycon of Tylosin (4).
Sch em e 1
Allylation of aldehydes have been largely described in
the literature for many years.1 In most cases the dias-
tereoselectivities obtained were fair to excellent, in an
SE′ Lewis-acid-catalyzed reaction2,3 via an open transition
state or via a Zimmerman-Traxler transition state in
others cases.4 The enantioselectivity in these reactions
arise either from the allylmetal or the aldehyde, or from
both enantiopure partners.
The Hoppe reaction,5 which was reported as an ally-
lation of an achiral aldehyde with an optically active (E)-
crotyltitanate 2, proceeds with a high diastereo- and
enantioselectivities via a cyclic Zimmerman-Traxler
transition state to deliver the anti isomer 3 (Scheme 1).
† Service de RMN.
‡ EÄ cole Polytechnique.
§ Laboratoire de Chimie The´rapeutique.
(1) Pereyre, M.; Quintard, J .-P.; Rahm, A. Tin in Organic Synthesis;
Butterworths: London, 1987. For a recent review, see: Yamamoto,
Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
Reaction of (E)-crotylcarbamate 1 with n-BuLi/(-)-
sparteine gave both diastereomers of the (E)-crotyl-
lithium-(-)-sparteine complex; crystallization led to the
corresponding (S) complex6 in a second-order asymmetric
induction. After transmetalation with Ti(OiPr)4, the (R)-
(E)-allyltitanate 2 was formed and gave, by reaction with
aldehydes, the (Z)-anti homoallylic alcohol 3 with good
enantiomeric excess (92% ee for R ) Et).
In an approach to the C10-C15 western part of
Tylonolide, aglycon of the 16-membered Tylosin antibiotic
4,7 we employed the Hoppe reaction for a stereocontrolled
construction of C14 and C15 centers.8 In the present work
(2) Pereyre, M.; Quintard, J . P. Pure Appl. Chem. 1981, 53, 2401.
Quintard, J . P.; Elisondo, B.; Pereyre, M. J . Org. Chem. 1983, 48, 1559.
Quintard, J .-P.; Dumartin, G.; Elisondo, B.; Rahm, A.; Pereyre, M.
Tetrahedron 1989, 45, 1017.
(3) Marshall, J . A.; Gung, W. Y. Tetrahedron Lett. 1989, 30, 309.
Marshall, J . A.; Gung, W. Y. Tetrahedron 1989, 45, 1043 and references
therein. Denmark, S. E. Hosoi, S. J . Org. Chem. 1994, 59, 5133. Keck,
G. E.; Dougherty, S. M.; Savin, K. A. J . Am. Chem. Soc. 1995, 117,
6210. Nichigaichi, Y.; Ishida, N.; Nishida, M.; Takuwa, A. Tetrahedron
Lett. 1996, 37, 3701. For a review, see: Marshall, J . A. Chemtracts
1991, 298. Nichigaichi, Y.; Takuwa, A.; Naruta, Y.; Maruyama, K.
Tetrahedron 1993, 49, 7395. Thomas, E. J . Chemtracts-Org. Chem.,
1994, 2, 207. Marshall, J . A. Chem. Rev. 1996, 96, 1.
(4) (a) For allylation via boronates, see: Roush, W. R.; Palkowitz,
A. D.; Palmer, M. A. J . J . Org. Chem. 1987, 52, 316. Roush, W. R.;
Adam, M. A.; Walts, A. E.; Harris, D. J . J . Am. Chem. Soc. 1986, 108,
3422. Roush, W. R.; Banfi, L. J . Am. Chem. Soc. 1988, 110, 3979.
Roush, W. R.; Halterman, R. L. J . Am. Chem. Soc. 1986, 108, 294.
Coe, J . W. Roush, W. R. J . Org. Chem. 1989, 54, 915. (b) For allylation
via boranes, see: Brown, H. C.; Bhat, K. S. J . Am. Chem. Soc. 1986,
108, 5919. Brown, H. C.; Bhat, K. S.; Randad, R. S. J . Am. Chem. Soc.
1989, 54, 1570. Brown, H. C.; J adhav, P. K.; Bhat, K. S. J . Am. Chem.
Soc. 1988, 110, 1535.
(6) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1984, 23, 932. Hoppe,
D.; Zschage, O. Angew. Chem., Int. Ed. Engl. 1989, 28, 69. Paulsen,
H.; Hoppe, D. Tetrahedron 1992, 48, 5667. Zschage, O.; Hoppe, D.
Tetrahedron 1992, 48, 5657.
(7) Tatsuta, K.; Amemiya, Y.; Kanemura, Y.; Takahashi, H.; Ki-
noshita, M. Tetrahedron Lett. 1982, 23, 3375. Nicolaou, K. C.; Seitz,
S. P.; Pavia, M. R. J . Am. Chem. Soc. 1982, 104, 2030. Masamune, S.;
Lu, L. D.-L.; J ackson, W. P.; Kaiho, T.; Toyoda, T. J . Am. Chem. Soc.
1982, 104, 5523. Grieco, P. A.; Inanaga, J .; Lin, N.-H.; Yanami, T. J .
Am. Chem. Soc. 1982, 104, 5781. Tanaka, T.; Oikawa, Y.; Hamada,
T.; Yonemitsu, O. Chem. Pharm. Bull. 1987, 35, 2219. Omura, S., Ed.;
(5) For a recent review, see: Hoppe, D.; Hense, T. Angew. Chem.,
Int. Ed. Engl 1997, 36, 2282.
10.1021/jo9807722 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/29/1998

374 J . Org. Chem., Vol. 64, No. 2, 1999
Berque et al.
Sch em e 2
Sch em e 4
Sch em e 3
allylcarbamate in this reaction resulted in the lack of
crystallization of corresponding (R)- or (S)-allyllithium
and neither second-order asymmetric induction or enan-
tioselective deprotonation could be induced.11 Therefore,
reaction of aldehyde 6 was envisioned to be governed by
kinetic resolution using the intermediate allyltitanate
(()-7.12
Preparation of alcohol 13 was performed by reaction
of aldehyde 1113 with (Z)-(-)-(Ipc)2B-crotyl 124b [(Ipc)2 =
diisopinocampheyl] (82% yield, Scheme 4). The secondary
alcohol at C3 was protected as a triisopropylsilyl ether
(15, R ) TIPS, 90%), and ozonolysis of the double bond
led to aldehyde 16. Alcohol 13 was protected as the tert-
butyldimethylsilyl ether 14 (R ) TBS, 82%) which
appeared to be identical to the product described by
Boeckman [[R]D + 20.9 (c 1.0, CHCl3)].14
For allylation of aldehyde 16, several carbamates 7
were synthesized, starting with commercial 3-propyn-1-
ol, and after some experiments the tetrahydropyranyloxy
derivative 17 was retained for this approach.
In a first model study of reaction of 17 with propanal,
formation of the intermediate allyltitanate was not
observed when 1 equiv of n-BuLi/TMEDA was used.
However, deprotonation of 17 was effected in good yield
when 1.5-2 equiv of n-BuLi/TMEDA was employed.
Transmetalation with Ti(OiPr)4 then occurred at -78 °C,
and reaction with propanal was carried out at -78 °C
for 2 h to deliver the expected anti allylic alcohol in 90%
yield.15
we describe the results obtained in an application and
extension of the Hoppe reaction to a synthetic approach
to the C1-C9 eastern part 5 of Tylonolide (Scheme 2).
In our synthesis of the eastern part of Tylonolide, we
planned to prepare compound 10 (Scheme 3); for this
purpose, two allylations were designed as the key steps.
We envisaged a reaction of allyltitanate 7 with optically
active aldehyde 6 in order to prepare homoallylic alcohol
8. After oxidative cleavage of the vinylic function into
aldehyde 9, the later could be reacted with (R)-(E)-
crotyltitanate 2 to furnish the expected key intermediate
10.9 Allylation with this intermediate 2 was well de-
scribed, but at this time only a few cases of double
asymmetric induction were reported for this reaction.10
The first allylation we wanted to develop, between
enantiopure aldehyde 6 and (()-(E)-allyltitanate 7 must
be considered as an extension of the Hoppe reaction; to
our knowledge the Hoppe reaction has always been
performed with (R)-(E)-crotyltitanate 2. Using a different
The allylation reaction of aldehyde 16 with allylcar-
bamate 17 was then carried out at -78 °C for 5 h using
(11) Second-order asymmetric induction was also described with the
1-(N,N-diisopropylcarbamoyloxy)-3-trimethylsilylallyl: Marsch, M.;
Harms, K.; Zschage, O.; Hoppe, D.; Boche, G. Angew. Chem., Int. Ed.
Engl 1991, 30, 321. When we tried to check this reaction with the
1-(N,N-diisopropylcarbamoyloxy)-4-dimethylphenylsilyl-2-butene (ref
8), no crystallization occurred and no enantioselective deprotonation
could be obtained.
(12) Hoffmann, R. W.; Lanz, J .; Metternich, R.; Tarara, G.; Hoppe,
D. Angew. Chem., Int. Ed. Engl. 1987, 26, 1145. Hoppe, D.; Tarara,
G.; Wilckens, M. Synthesis 1989, 83.
(13) Pirrung, M. C.; Webster, N. J . G.; Nicholas, J . G. J . Org. Chem
1987, 52, 3603.
(14) Boeckman, R. K.; Charette, A. B.; Asberom, T.; J ohnston, B.
H. J . Am. Chem. Soc. 1991, 113, 5337.
(15) Allylation of propanal with allylcarbamate 17 was performed
at -78 °C for 2 h using 2 equiv of BuLi/TMEDA for 1 equivalent of 17.
Macrolides Antibiotics; Academic Press: 1984. Kirst, H. A. J . Antimi-
crob. Chemother. 1991, 28, 787. Kirst, H. A. In Recent Progress in the
Chemical Synthesis of Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer-
Verlag: Berlin, 1990; p 39.
(8) Le Me´nez, P.; Fargeas, V.; Berque, I.; Poisson, J .; Ardisson, J .;
Lallemand, J .-Y.; Pancrazi, A. J . Org. Chem. 1995, 60, 3592.
(9) Our approch is slightly different from the synthesis of tylonolide
developed by Marshall et al. (Marshall, J . A.; Yashunsky, D. V. J . Org.
Chem. 1991, 56, 5493) which also involved a crucial step based on an
allylation reaction.
(10) Smith, N. D.; Kocienski, P. J .; Street, S. D. A. Synthesis 1996,
652. Fe´re´zou, J .-P.; J ulia, M.; Li, Y.; Liu, L. W.; Pancrazi, A. Bull. Soc.
Chim. Fr. 1995, 132, 428. Fe´re´zou, J .-P.; J ulia, M.; Khourzom, R.; Li,
Y.; Liu, L. W.; Pancrazi, A.; Robert, P. Synlett 1991, 611.

Allyltitanates in Stereospecific Additions
J . Org. Chem., Vol. 64, No. 2, 1999 375
Ta ble 1. Allyla tion of Ald eh yd e 16 a n d La ctol 24
temp
(°C)
reaction
time (h)
syn-anti 18
anti-anti 19
yield (%)
overall
yield (%)
entry
ratio 17/16
yield (%)a
selectivity
1
2
3
4
2:1
2:1
3:1
3:1
-78
0
0
20
5
4
4
5
55
58
65
66
36
19
22
9
91
77
87
75
60:40
75:25
75:25
88:12
temp
(°C)
reaction
time (h)
anti-anti 25
yield (%)
entry
ratio 17/24
solvent
selectivity
5
6
7
8
9
3:1
3:1
3:1
2:1
3:1
3:1
0
0
20
20
20
20
6
15
6
6
6
Et2O
Et2O
Et2O
Et2O
THFb
THFc
38
45
45
46
65
94
100:0
100:0
100:0
100:0
100:0
100:0
10
6
a
b
Isolated yields. Carbamate and BuLi/TMEDA were dissolved in diethyl ether and lactol in THF. c Lactol, carbamate, and BuLi/
TMEDA were dissolved in THF.
Sch em e 5
Sch em e 6
turn to the reaction of the allyltitanate 17 with lactol 24
in place of aldehyde 16.16 Starting from aldehyde 20,
allylic alcohol 21 was prepared in 82% yield using
allylborane 12 (Scheme 6).17 The secondary alcohol of 21
was protected as a TIPS ether (94% yield) and the
primary alcohol was revealed by acidic treatment with
Amberlyst 15 to furnish compound 23 in 86% yield.
Ozonolysis of the double bond then delivered δ-lactol 24
in 83% yield.
Treatment of 17 (3 equiv) with n-BuLi/TMEDA (6
equiv) at -78 °C followed by transmetalation with Ti-
(OiPr)4 (9 equiv, -78 °C) led to the corresponding racemic
allyltitanate which did not react with δ-lactol 24 at -78
°C for 6 h. When the temperature increased to 0 °C,
reaction took place to furnish only syn-anti isomer 25
(Scheme 7, Table 1, entries 5 and 6).
We then found that allylation of δ-lactol 24 took place
in 45% yield under the same conditions but when
temperature was maintained at 20 °C for 6 h (Table 1,
entry 7) to deliver the only 4,5-syn-5,6-anti adduct 25;
despite a high reaction temperature, this allylation
reaction was carried out without epimerization of lactol
24, and no 5,6-syn adduct was observed (Scheme 7).
Attempt to use only 2 equiv of the carbamate 17 in the
allylation reaction of lactol 24 (0 °C for 6 h) resulted in
formation of allylic alcohol 25 in the same yield (46%,
Table 1, entry 8).
2 equiv of 17 (Scheme 5). Deprotonation was effected at
-78 °C with 4 equiv of n-BuLi/TMEDA for 30 min, a
transmetalation occurred by addition of 6 equiv of Ti(Oi-
Pr)4 at -78 °C for 30 min, and aldehyde was then added
at -78 °C. This attempt resulted in formation of syn-
anti 18 (55% isolated yield) and anti-anti 19 (36% isolated
yield) isomers in 91% overall yield and a 60:40 ratio
(Table 1, entry 1). When this reaction was performed at
higher temperature (-78 f 0 °C) for 4 h compounds, 18
and 19 were obtained in 77% yield and a 75:25 ratio
(Table 1, entry 2). This increasing diastereoselectivity (60:
40 f 75:25) was in fact due to the lower yield obtained
for the anti-anti isomer 9 (19% instead of 36% yield),
while 18 was yielded as before (58% in place of 55% yield).
This loss of the minor isomer 19 was assigned and
tentatively proved to occur during the increase of tem-
perature from -78 to 0 °C; treatment of a 60:40 mixture
of 18 and 19 under the conditions led to 70:30 ratio after
2 h at 0 °C while allylic alcohols 18 and 19 were recovered
in 70% yield.
With three equivalents of carbamate 17, at 0 °C for 4
h, reaction led to isomers 18 and 19 in respectively 65%
and 22% yield (18/19 ) 75:25, 87% overall yield). When
this reaction was carried out at 20 °C for 5 h, the yield
decreased to 75% but the isomer ratio 18/19 increased
to 88:12.
(16) For examples using lactols in such a reaction, see: Smith, A.
L.; Pitsinos, E. N.; Hwang, C. K.; Mizuno, Y.; Saimoto, H.; Scarlato,
G. R.; Suzuki, T.; Nicolaou, K. C. J . Am. Chem. Soc. 1993, 115, 7612.
Hoffmann, R. W.; Rolle, U. Tetrahedron Lett. 1994, 35, 4751.
(17) For structural proof, compound 21 was converted into the bis-
silylated derivative 14.
During this study we decided to prepare δ-lactol 24
which could be considered as a masked aldehyde, and to

376 J . Org. Chem., Vol. 64, No. 2, 1999
Berque et al.
Sch em e 7
Sch em e 9
Sch em e 8
As an interesting assay, when the δ-lactol 24 was
dissolved in THF in place of Et2O, the carbamate 7 and
the n-BuLi/TMEDA base added in diethyl ether, the
allylation reaction led to the syn-anti adduct 25 in 65%
isolated yield (Table 1, entry 9). The beneficial effect of
THF was clearly shown when lactol, carbamate and BuLi/
TMEDA were dissolved in THF: the syn-anti adduct 25
was obtained as a pure isomer in high yield (Table 1,
entry 10, 94% isolated yield).
Sch em e 10
Realization of the strategy depicted in Scheme 3
involved at this stage to generate the aldehyde function
from vinylic carbamate 25 and to perform a second
allylation reaction using crotylcarbamate 1.
Homoallylic alcohol 25 was deprotected to triol 26 (Bu4-
NF, 80%), which was transformed into acetonide 27 after
selective protection of the primary alcohol (Scheme 8,
75% overall yield).
After ozonolysis of the vinylic ether of 27 to give
aldehyde 28 in 90% yield, the allylation reaction using a
double asymmetric induction was tested. Treatment of
crotylcarbamate 1 under Hoppe conditions [(1) n-BuLi/
(-)-sparteine, (2) Ti(OiPr)4, -78 °C] and reaction with
aldehyde 28 resulted in formation of compound 29 in 80%
yield (Scheme 9).
For structural elucidations of compound 18, 19, and
25, some chemical transformations were needed and
compound 25 was first transformed into 18 by silylation
with TPSCl/Im in 80% yield.
A 13C analysis of acetonide 27 (obtained from 25 or 18)
allowed us to determine the syn relationship between the
two oxygen atoms at C3 and C5 of the ketal by observa-
tion of the chemical shifts of the acetonide methyl groups
at 19.7 and 29.8 ppm.18 The methyl function at C4 was
observed at 4.8 ppm which corresponds to an axial
orientation; this configuration at C4 demonstrated that
no epimerization of lactol 24 occurred at 20 °C during
the allylation reaction.
between the two side chains at C5 and C6 (J H
Hz).
) 11.5
5-H6
The stereochemisty at C5 and C6 centers for compound
29 was proven by transformation into δ-lactol 32. Re-
moval of the acetonide and the THP group from 29 was
realized using Amberlyst 15/ MeOH, both primary alco-
hols of the resulting pentol were then selectively pro-
tected as tert-butyldiphenylsilyl ethers (TPS). Ozonolysis
of the vinyl carbamate then led to δ-lactol 32 as a mixture
1
of two epimeric derivatives (Scheme 10). H NMR study
and 2D experiments on the epimeric mixture determined
all configurations at the C5, C6, C7, and C8 centers.
Although the reason for the excellent selectivity of the
allylation of lactol 24 is not clearly established, this
reaction runs in good yield; the strategy used here
provided an efficient access to the C1-C9 fragment 29
in 12 steps and 14.5% overall yield. The final steps
envisioned for the synthesis of Tylonolide, aglycon of
Tylosin 4, from 29 are now under study through a
Barton-Mc-Combie deoxygenation reaction19 at C7 after
oxidation of the vinylcarbamate function.
For the minor anti-anti 19 derivative, ozonolysis fol-
lowed by reduction of the intermediate aldehyde produced
diol 30 in 80% overall yield (Scheme 10). Formation of
1
the acetonide 31 was then carried out in 90% yield. H
NMR analysis of 31 clearly shown a trans relationship
(18) Rychnovsky, S. D.; Skalitzky, D. J . Tetrahedron Lett. 1990, 31,
945.
(19) Barton, D. H. R.; Mc-Combie, S. W. J . Chem. Soc., Perkin Trans.
1 1975, 1574.

Allyltitanates in Stereospecific Additions
J . Org. Chem., Vol. 64, No. 2, 1999 377
(3R,4R)-4-{[(ter t-Bu tyld im eth yl)silyl]oxy}-6-{[(ter t-bu -
tyld ip h en yl)silyl]oxy}-3-m eth ylh ex-1-en e (14). To a solu-
tion of alcohol 13 (250 mg, 0.7 mmol) in dried CH2Cl2 (15 mL)
at 0 °C was added triethylamine (0.2 mL, 1.4 mmol) and tert-
butyldimethylsilyltriflate (0.2 mL, 0.85 mmol). After 2 h of
stirring at 20 °C, the reaction mixture was partitioned between
diethyl ether and a saturated aqueous ammonium chloride
solution and extracted with diethyl ether. The organic layer
was then dried over sodium sulfate, and the solvent was
removed under reduced pressure. The residue was purified by
flash chromatography on silica gel (hexane/ethyl acetate, 97:
3) to give the title compound 14 as a colorless oil (272 mg,
82% yield): 1H NMR (200 MHz) δ 0.05 (s, 6H), 0.96 (d, J )
7.0 Hz, 3H), 1.08 (m, 30H), 1.71 (qd, J ) 6.0, 2.0 Hz, 2H), 2.38
(m 1H), 3.72 (t, J ) 6.0 Hz, 2H), 4.05 (q, J ) 6.0 Hz, 1H), 4.97
(dd, J ) 11.5, 1.2 Hz, 1H), 5.05 (dd, J ) 18.0, 1.2 Hz, 1H),
6.05 (ddd, J ) 18.0, 11.5, 6.5 Hz, 1H), 7.39 (m, 6H), 7.65 (m,
4H); IR (CCl4) ν 3060 cm-1; CIMS (NH3) m/z 483 (MH+); [R]D
+ 20.9 (c 1.01, CHCl3) [lit.14 +21 (c 1.0, CHCl3)]. Anal. Calcd
for C29H46O2Si2: C, 74.14; H, 9.60. Found: C, 72.20; H, 9.65.
(3R,4R)-6-{[(ter t-Bu tyld ip h en yl)silyl]oxy}-3-m eth yl-4-
{[(tr iisop r op yl)silyl]oxy}h ex-1-en e (15). To a solution of
alcohol 13 (1.74 g, 4.74 mmol) in dried CH2Cl2 (12 mL) at 0 °C
were added 2,6-lutidine (0.86 mL, 7.6 mmol) and TIPSOTf (1.4
mL, 5.2 mmol). After 2.5 h of stirring at 20 °C, the reaction
mixture was partitioned between diethyl ether and an aqueous
hydrochloric acid solution (1.5 N) and extracted with diethyl
ether. The organic layer was washed with brine, dried over
sulfate sodium, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel
(hexane/ethyl acetate, 98:02) to give compound 15 (2.24 g, 90%
yield): 1H NMR (200 MHz) δ 0.96 (d, J ) 7.0 Hz, 3H), 1.08 (s,
30H), 1.71 (qd, J ) 6.0, 2.0 Hz, 2H), 2.38 (m, 1H), 3.72 (t, J )
6.0 Hz, 2H), 4.05 (q, J ) 6.0 Hz, 1H), 4.97, 5.05 (2dd, J ) 18.0,
11.5, 1.5 Hz, 2H), 6.05 (ddd, J ) 18.0, 11.5, 6.5 Hz, 1H), 7.4
(m, 6H), 7.7 (m, 4H); 13C NMR (50.3 MHz) δ 12.9 (3C), 14.0,
18.0 (6C), 18.1, 26.8 (3C), 36.7, 42.4, 61.0, 73.3, 113.7, 127.6
(4C), 129.5 (4C), 133.4 (2C), 135.6 (2C), 141.3; IR (CCl4) ν 3060
cm-1; CIMS (NH3) m/z 525 (MH+); [R]D + 15.4 (c 1.37, hexane).
Anal. Calcd for C32H52O2Si2: C, 73.22; H, 9.98. Found: C,
73.28; H, 10.01.
Exp er im en ta l Section
Mass spectra were obtained via direct introduction by
chemical ionization with ammonia (CIMS, NH3). 1H NMR
spectra were recorded at 200 and 400 MHz, and 13C NMR were
at 50.3 and 100.6 MHz. The chemical shifts are expressed in
parts per million (ppm) downfield from tetramethylsilane
(TMS, δ ) 0) and referenced to residual chloroform (δ ) 7.27
ppm). Assignments were obtained using J -mod experiments
and, when necessary, COSY, HMBC, HMQC, and NOESY
experiments. Thin-layer chromatography (TLC) was performed
on precoated plate of silica gel 60F 254 or aluminum oxide
60F 254. Flash chromatography was performed on silica gel
60, 230-400 mesh.
3-{[(ter t-Bu tyldiph en yl)silyl]oxy}pr opion aldeh yde (11).
To a solution of 3-butenol (2.36 g, 32.8 mmol) in dried DMF
(40 mL) was added a solution of imidazole (5 g, 73.5 mmol)
and tert-butyldiphenylsilyl chloride (9.9 g, 36 mmol) in dried
DMF (10 mL). After 12 h of stirring at 20 °C, the reaction
mixture was partitioned between diethyl ether and an aqueous
hydrochloric acid solution (2 N) and extracted with diethyl
ether. The organic layer was then washed with brine, dried
over sodium sulfate, and filtered, and the solvent was removed
under reduced pressure. The residue was purified by flash
chromatography on silica gel (hexane/ethyl acetate, 98:02) to
give 4-{[(tert-butyldiphenyl)silyl]oxy}-1-butene as a colorless
oil (10.1 g, 99% yield): 1H NMR (200 MHz) δ 1.02 (s, 9H), 2.29
(q, J ) 7.0 Hz, 2H), 3.68 (t, J ) 7.0 Hz, 2H), 4.98 (dq, J )
19.0, 1.5 Hz, 1H), 5.05 (dq, J ) 10.0, 1.5 Hz, 1H), 5.88 (ddt, J
) 19.0, 10.0, 7.0 Hz, 1H), 7.37 (m, 6H), 7.65 (m, 4H); IR (CCl4)
ν 3080 cm-1; CIMS (NH3) m/z 311 (MH+). Anal. Calcd for
C
20H26OSi: C, 77.37; H, 8.44. Found: C, 77.41; H, 8.46.
Ozone was bubbled into a solution of 4-{[(tert-butyldiphe-
nyl)silyl]oxy}-1-butene (514 mg, 1.7 mmol) in CH2Cl2 (7 mL)
and methanol (3 mL) at -78 °C until the solution turned light
blue. Dimethyl sulfide (5 mL) was added at -78 °C, and the
mixture was allowed to warm to room temperature and stirred
for 8 h. The mixture was washed with water and a saturated
aqueous sodium chloride solution, dried over sodium sulfate,
and evaporated under reduced pressure to afford aldehyde 11
as a colorless liquid (0.513 mg, quantitative yield), pure enough
to be used in the next step.
For 11: 1H NMR (200 MHz) δ 1.02 (s, 9H), 2.58 (dt, J ) 6.0,
2.0 Hz, 2H), 4.00 (t, J ) 6.0 Hz, 2H), 7.39 (m, 6H), 7.64 (m,
(2S,3R)-5-{[(ter t-Bu tyld ip h en yl)silyl]oxy}-2-m eth yl-3-
{[(tr iisop r op yl)silyl]oxy}p en ta n a l (16). Ozone was bubbled
into a solution of compound 15 (1.5 g, 2.86 mmol) in CH2Cl2
(63 mL) and methanol (3 mL) at -78 °C until the solution
turned light blue. Dimethyl sulfide (15 mL) was added at -78
°C, and the mixture was allowed to warm to room temperature
and stirred for 8 h. The solvents were then removed under
reduced pressure, and the residue was purified by flash
chromatography on silica gel (hexane/ethyl acetate, 90:10) to
give aldehyde 16 as a colorless oil (1.13 g, 75% yield): 1H NMR
(200 MHz) δ 1.03 (d, J ) 7.0 Hz, 3H), 1.01 (s wide, 30H), 1.83
(m, 2H), 2.47 (qd, J ) 7.0, 3.0 Hz, 1H), 3.70 (m, 2H), 4.6 (td,
4H), 9.10 (t, J ) 2.0 Hz, 1H); IR (CCl4) ν 3060, 1720 cm-1
;
CIMS (NH3) m/z 313 (MH+). Anal. Calcd for C19H24O2Si: C,
73.01; H, 7.74. Found: C, 73.15; H, 7.83.
(3R,4R)-6-{[(ter t-Bu tyld ip h en yl)silyl]oxy}-4-h yd r oxy-
3-m eth ylh ex-1-en e (13). To a solution of freshly sublimed
potassium tert-butoxide (3 g, 26.7 mmol) in THF (40 mL) at
-78 °C was cannulated a solution of cis-2-butene (6 mL) in
THF (6 mL). n-BuLi (9.5 M in hexane, 3.3 mL, 31.3 mmol)
was then added dropwise, and the yellow mixture was stirred
at -78 °C for 5 min and at -45 °C for 40 min. The resulting
orange solution was cooled to -78 °C, and a solution of (-)-
B-diisopinocamphenylmethoxyborane (12 g, 38 mmol) in 30 mL
of diethyl ether was added dropwise over ca. 15 min. The
resulting white solution was stirred at -78 °C for 45 min.
Boron trifluoride etherate (5 mL, 39.2 mmol) was added
dropwise followed after 5 min by addition of a solution of
aldehyde 11 (3.61 g, 11.5 mmol) in THF (5 mL). The resulting
solution was stirred at -78 °C for 4 h. The reaction was then
quenched by addition of aqueous NaOH (24 mL, 2.5 N)
followed by aqueous H2O2 (8 mL, 30%). The mixture was
heated at 45 °C for 45 min. The cloudy solution was cooled to
room temperature, diluted with diethyl ether (50 mL), washed
with brine, dried over sodium sulfate, and filtered, and the
solvent was removed under reduced pressure to give, after
flash chromatography on silica gel (hexane/ethyl acetate, 90:
10), the title compound 13 as a colorless liquid (3.47 g, 82%
yield): 1H NMR (200 MHz) δ 1.03-1.05 (m, 12H), 1.66 (m,
2H), 2.26 (m, 1H), 3.18 (d, J ) 2.8 Hz, 1H, OH), 3.72 (m, 1H),
4.85 (m, 2H), 5.02 (m, 2H), 5.76 (m, 1H), 7.39 (m, 6H), 7.65
(m, 4H); IR (CCl4) ν 3500, 3060 cm-1; CIMS (NH3) m/z 369
(MH+); [R]D + 3.4 (c 1.1, CHCl3). Anal. Calcd for C23H32O2Si:
C, 74.95; H, 8.75. Found: C, 74.99; H, 8.79.
J ) 6.0, 3.0 Hz, 1H), 7.4 (m, 6H), 7.7 (m, 4H), 9.83 (s, 1H); 13
C
NMR (50.3 MHz) δ 7.1, 12.8 (3C), 18.2 (6C), 19.1, 26.8 (3C),
37.1, 50.9, 60.6, 69.7, 127.7 (4C), 129.7 (4C), 133.5 (2C), 135.5
(2C), 205.2; IR (CCl4) ν 3060, 1750 cm-1; CIMS (NH3) m/z 527
(MH+); [R]D + 18.5 (c 1.2, MeOH). Anal. Calcd for C31H50O3-
Si2: C, 70.67; H, 9.57. Found: C, 70.72; H, 9.61.
1-[(N,N-Diisop r op yl)ca r ba m a te]-5-[(2-tetr a h yd r op yr a -
n yl)oxy]p en t-2-en e (17). To a solution of 3,4-dihydro-2H-
pyran (14 mL, 154 mmol) in aqueous concentrated hydrochloric
acid solution (10 N, 0.05 mL), was added 3-butyn-1-ol (11 mL,
145 mmol), and the reaction was regulated to keep the
temperature at 50 °C. After the addition was complete, the
solution was stirred for 2.5 h at 20 °C. At room temperature,
the mixture was diluted with diethyl ether and washed 2 times
with a saturated aqueous sodium bicarbonate solution. The
etheral phase was then dried over sodium sulfate and filtered,
and the solvent was removed under reduced pressure. The
crude oil was purified by flash chromatography on silica gel
(hexane/ethyl acetate, 90:10) to furnish 4-[(2-tetrahydropyra-
nyl)oxy]butyne (22 g, 98% yield): bp: 70 °C/2 mmHg; 1H NMR
(200 MHz) δ 1.42-1.88 (m, 6H), 1.94 (t, J ) 2.5 Hz, 1H), 2.45
(td, J ) 7.0, 2.5 Hz, 2H), 3.45, 3,77 (2m, 2H), 3.45-3.77 (m,

378 J . Org. Chem., Vol. 64, No. 2, 1999
Berque et al.
1H), 3.77-3.94 (m, 1H), 4.6 (t, J ) 3.5 Hz, 1H); 13C NMR (50.3
MHz) δ 19.3, 25.3, 30.4, 19.9, 62.1, 65.4, 69.1, 81.3, 98.7; IR
(CCl4) ν 2110 cm- 1; CIMS (NH3) m/z 172 (MH+ + 17), 155
(MH+). Anal. Calcd for C9H14O2: C, 70.10; H, 9.15. Found: C,
70.13; H, 9.13.
N,N,N′,N′-tetramethylethylenediamine (TMEDA, 0.7 mL, 4.5
mmol) in dried diethyl ether (3 mL) at -78 °C, under argon
atmosphere, was added n-BuLi (1.6M in hexane, 2.8 mL, 4.5
mmol). After 30 min of stirring at -78 °C, a solution of the
allylcarbamate 17 (704 mg, 2.25 mmol), in dried diethyl ether
(2.5 mL), was slowly added. After 30 min of stirring at -78
°C, titanium tetraisopropoxide [Ti(OiPr)4, 2 mL, 6.75 mmol]
was slowly added, and the mixture became limpid and turned
orange. After 30 min at -78 °C, aldehyde 16 (395 mg, 0.75
mmol) in dried diethyl ether (2 mL) was slowly added, the
reaction mixture was stirred for 4 h at 0 °C, and the reaction
was quenched by addition of methanol (5 mL). The solution
was then poured into a mixture of diethyl ether/aqueous
hydrochloric acid solution (2 N). After extraction with diethyl
ether, the organic layer was washed with brine, dried over
sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel
(hexane/ethyl acetate, 80:20) to give the title compound 18 (409
mg, 65% yield) and its stereoisomer 19 (138 mg, 22% yield).
For 18: 1H NMR (400 MHz) {two diastereomers} δ 0.89, 0.91
(2d, J ) 6.5 Hz, 3H), 1.15 (m, 30H), 1.22 (m, 12H), 1.37-1.83
(m, 8H), 1.75 (m, 1H), 1.87 (m, 2H), 2.87 (m, 1H), 3.31 (m,
1H), 3.46 (m, 1H), 3.67 (m, 3H), 3.75 (m, 2H), 3.82 (m, 2H),
4.07 (m, 1H), 4.2 (m, 1H), 4.51, 4.53 (2t, J ) 3.5 Hz, 1H), 4.65,
4.67 (2dd, J ) 10.0, 6.5 Hz, 1H), 7.18 (d, J ) 6.5 Hz, 1H), 7.37,
7.40 (m, 6H), 7.64 (m, 4H); 13C NMR (100.6 MHz) {two
diastereomers} δ 6.5, 13.2 (3C), 18.0, 18.2 (3C), 18.3 (3C), 19.1
and 19.6 (1C), 20.1 (2C), 21.1 (2C), 25.4, 26.8 (3C), 30.7, 30.9,
37.2, 37.7, 38.6, 45.6, 46.3, 60.8, 62.2 and 62.3 (1C), 65.8, 75.3,
76.3, 98.6 and 99.0 (1C), 111.2 and 111.3 (1C), 127.4 (4C), 129.4
(4C), 133.6 (2C), 135.4 (2C), 137.3, 152.4; IR (CCl4) ν 3570,
To a solution of 4-[(2-tetrahydropyranyl)oxy]butyne (22 g,
143 mmol) in dried THF (150 mL) at -78 °C was slowly added
n-BuLi (1.6M in hexane, 96.5 mL, 154.5 mmol). After 15 min
of stirring, the temperature was then warmed to 0 °C and a
stream of formaldehyde, obtained by depolymerization of dried
paraformaldehyde (14.6 g, 157 mmol) at 180 °C, was blown
on the surface of the anion solution. After 12 h of stirring at
20 °C, the solution was poured into a cold saturated aqueous
ammonium chloride solution. After extraction with diethyl
ether, drying over sodium sulfate and filtration, the solvents
were removed under reduced pressure. The crude oil was
purified by flash chromatography on silica gel (hexane/ethyl
acetate, 70:30) to give the 5-[(2-tetrahydropyranyl)oxy]pent-
2-yn-1-ol as a colorless oil (23,6 g, 90% yield): 1H NMR (200
MHz) δ 1.40-1.89 (m, 6H), 2.48 (m 2H), 2.49 (s wide, 1H),
3.45, 3.74 (2 m, 2H), 3.57-3.74 (m, 1H), 3.75-3.90 (m, 1H),
4.17 (m, 2H), 4.57 (t, J ) 3.5 Hz, 1H); 13C NMR (50.3 MHz) δ
19.3, 20.1, 25.3, 30.4, 51.0, 62.2, 65.6, 79.5, 82.9, 98.7; IR (CCl4)
ν 3610, 3420, 2210 cm- 1; CIMS (NH3) m/z 185 (MH+). Anal.
Calcd for C10H16O3: C, 65.19; H, 8.75. Found: C, 65.22; H,
8.77.
To a solution of 5-[(2-tetrahydropyranyl)oxy]pent-2-yn-1-ol
(10.95 g, 59.5 mmol) in dried diethyl ether (70 mL) at 0 °C
was slowly added lithium aluminum hydride (LAH, 1 M in
THF, 65.5 mL, 65.5 mmol). 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
water (20 mL), an aqueous solution of sodium hydroxide (10
N, 5.2 mL), and water (10 mL). The precipitate was filtered
on Celite and washed with diethyl ether. The filtrate was dried
over sodium sulfate, filtered, concentrated in vacuo, and
purified by flash chromatography on silica gel (hexane/ethyl
acetate, 50:50) to give (2E)-5-[(2-tetrahydropyranyl)oxy]pent-
2-en-1-ol (9.7 g, 88% yield): 1H NMR (200 MHz) δ 1.40-1.97
(m, 7H), 2.35 (m, 2H), 3.40, 3.71 (2 m, 2H), 3.41-3.54 (m, 1H),
3.72-3.90 (m, 1H), 4.07 (m, 2H), 4.54 (t, J ) 3.5 Hz, 1H), 5.55-
5.76 (m, 2H); 13C NMR (50.3 MHz) δ 19.6, 25.4, 30.6, 32.5,
62.3, 63.5, 66.8, 98.8, 129.1, 131.0; IR (CCl4) ν 3600, 3440 cm-
1; CIMS (NH3) m/z 187 (MH+). Anal. Calcd for C10H18O3: C,
64.48; H, 9.74. Found: C, 64.51; H, 9.72.
3500, 3060, 1700 cm-1; CIMS (NH3) m/z 840 (MH+); [R]D
+
10.3 (c 1.27, MeOH). Anal. Calcd for C48H81O7NSi2: C, 68.60;
H, 9.72; N, 1.70. Found: C, 68.65; H, 9.77; N, 1.72.
For 19: 1H NMR (400 MHz) {two diastereomers} δ 0.71, 0.73
(2d, J ) 6.5 Hz, 3H), 1.03 (s wide, 30H), 1.26 (m, 12H), 1.45-
1.95 (m, 9H), 1.81 (m, 2H), 1.92 (m, 1H), 2.81 (m, 1H), 3.40
(m, 1H), 3.48 (m, 1H), 3.73 (m, 1H), 3.75 (t, J ) 6.0 Hz, 2H),
3.82 (m, 1H), 3.86 (m, 1H), 3.94 (m, 2H), 4.17 (m, 1H), 4.55,
4.57 (2t, J ) 3.5 Hz, 1H), 4.87, 4.89 (2dd, J ) 10.0, 6.5 Hz,
1H), 7.10, 7.18 (2d, J ) 6.5 Hz, 1H), 7.37 (m, 6H), 7.64 (m,
4H); 13C NMR (100.6 MHz) {two diastereomers} δ 12.4, 13.2
(3C), 17.9 (6C), 18.1, 19.3, 20.1 (2C), 21.1 (2C), 25.3, 26.6 (3C),
30.6, 32.1, 34.9, 35.2 and 35.3 (1C), 40.8, 45.2, 46.0, 60.7, 61.9
and 62.1 (1C), 65.3, 74.7, 75.0, 98.5, 109.3 and 109.5 (1C), 127.4
(4C), 129.4 (4C), 133.6 (2C), 135.4 (2C), 137.0, 152.4; CIMS
(NH3) m/z 840 (MH+); [R]D - 11 (c 3.8, MeOH). Anal. Calcd
for C48H81O7NSi2: C, 68.60; H, 9.72; N, 1.70. Found: C, 68.67;
H, 9.79; N, 1.73.
To a suspension of NaH (60% in oil, 768 mg, 19.2 mmol) in
dried diethyl ether (10 mL) at 0 °C, was slowly added a solution
of (2E)-5-[(2-tetrahydropyranyl)oxy]pent-2-en-1-ol (3 g, 16
mmol) in dried diethyl ether (10 mL). The resulting solution
was stirred for 20 min at 20 °C, and a solution of diisopropy-
lcarbamyl chloride (5.22 g, 32 mmol) in dried diethyl ether (10
mL) was added. After 12 h of stirring at 20 °C, the mixture
was diluted at 0 °C with diethyl ether, treated with an aqueous
hydrochloric acid solution (1 N, 10 mL), and extracted with
diethyl ether. The combined organic phases were then washed
with brine, dried over sodium sulfate, filtered and concentrated
in vacuo. The oily residue was purified by flash chromatog-
raphy on silica gel (hexane/ethyl acetate, 80:20) to give the
title compound 17 as a colorless oil (4.55 g, 90% yield).
P r ep a r a tion of 18 fr om 25. To a solution of compound 25
(390 mg, 0.65 mmol) in dried DMF (3 mL), was added a
solution of imidazole (66 mg, 0.85 mmol) and tert-butyldiphe-
nylsilyl chloride (0.2 mL, 0.71 mmol). After 12 h of stirring at
20 °C, the reaction mixture was partitioned between diethyl
ether and an aqueous hydrochloric acid solution (2 N) and
extracted with diethyl ether. The organic layer was then
washed with brine, dried over sodium sulfate, and filtered, and
the solvent was removed under reduced pressure. The residue
was purified by flash chromatography on silica gel (hexane/
ethyl acetate, 80:20) to give compound 18 as a colorless oil (436
mg, 80% yield).
3-{[(ter t-Bu tyldim eth yl)silyl]oxy}pr opion aldeh yde (20).
To a solution of 1,3-propanediol (50 mL, 0.69 mol) in dried CH2-
Cl2 (400 mL) was added a solution of imidazole (17 g, 0.25 mol)
and tert-butyldimethylsilyl chloride (30 g, 0.2 mol) in dried
CH2Cl2 (100 mL). After 12 h of stirring at 20 °C, the reaction
mixture was partitioned between CH2Cl2 and an aqueous
hydrochloric acid solution (2 N) and extracted with CH2Cl2.
The diol excess was removed into the aqueous layer. The
organic layer was then washed with brine, dried over sodium
sulfate, and filtered, and the solvent was removed under
reduced pressure. The residue was purified by flash chroma-
tography on silica gel (hexane/ethyl acetate, 80:20) to give 3-{-
[(tert-butyldimethyl)silyl]oxy}propanol as a colorless oil (31.16
g, 82% yield): 1H NMR (200 MHz) δ 0.09 (s, 6H), 0.90 (s, 9H),
1
For 17: bp 160 °C/ 2 mmHg; H NMR (200 MHz) δ 1.20 (d,
J ) 7.0 Hz, 12H), 1.44-1.95 (m, 6H), 2.43 (q, J ) 7.0 Hz, 2H),
3.42-3.6 (m, 2H), 3.69-4.05 (m, 4H), 4.56 (d, J ) 5.0 Hz, 2H),
4.62 (m, 1H), 5.65 (dt, J ) 16.0, 5.0 Hz, 1H), 5.79 (dt, J )
16.0, 7.0 Hz, 1H); 13C NMR (50.3 MHz) δ 19.3, 20.8 (4C), 25.3,
30.5, 32.5, 45.6 (2C), 62.0, 64.9, 66.5, 98.5, 126.8, 130.7, 155.3;
IR (CCl4) ν 1670 cm- 1; CIMS (NH3) m/z 331 (MH+ + 17), 314
(MH+). Anal. Calcd for C17H31O4N: C, 65.14; H, 9.97; N, 4.57.
Found: C, 65.17; H, 9.95; N, 4.48.
{3R,4S,5S,6S[2R/S-(2-tetr ah ydr opyr an yl)oxy]}-[1-{[(ter t-
Bu tyldiph en yl)silyl]oxy}-8-[(N,N-diisopr opyl)car bam ate]-
5-h yd r oxy-4-m eth yl-6-{(2-[(2-tetr a h yd r op yr a n yl)oxy]eth -
yl}-3-{[(tr iisopr opyl)silyl]oxy}oct-7-en e (18)an d {3R,4S,5R,-
6R-[2R/S-(2-tetrahydropyranyl)oxy]}-1-{[(tert-Butyldiphenyl)-
silyl]oxy}-8-[(N,N-d iisop r op yl)ca r ba m a te]-5-h yd r oxy-4-
m e t h y l-6-{(2-[(2-t e t r a h y d r o p y r a n y l)o x y ]e t h y l-}-3-
{[(t r iisop r op yl)silyl]oxy}oct -7-en e (19). To a solution of

Allyltitanates in Stereospecific Additions
J . Org. Chem., Vol. 64, No. 2, 1999 379
1.78 (quint, J ) 6.0 Hz, 2H), 3.67 (t, J ) 5.0 Hz, 1H, OH),
3.76 and 3.80 (2m, 4H); 13C NMR (50.3 MHz) δ -5.6 (2C), 18.0,
25.7 (3C), 34.2, 61.7, 62.4; IR (CCl4) ν 3560 cm-1; CIMS (NH3)
m/z 191 (MH+). Anal. Calcd for C9H22O2Si: C, 56.86; H, 11.65.
Found: C, 56.91; H, 11.67.
(3R,4R)-3-Meth yl-4-{[(tr iisop r op yl)silyl]oxy}h ex-1-en -
6-ol (23). To a solution of compound 21 (696 mg, 1.75 mmol)
in methanol (5 mL) and CH2Cl2 (1 mL) was added Amberlyst
H
+ 15 (500 mg). After 4 h of stirring at room temperature, the
reaction mixture was filtered through Celite, and the solvent
was removed under reduced pressure. The crude oily residue
was purified by flash chromatography on silica gel (hexane/
ethyl acetate, 90:10) to give alcohol 23 as a colorless oil (430
mg, 86% yield): 1H NMR (200 MHz) δ 1.01 (d, J ) 6.0 Hz,
3H), 1.1 (s, 22H), 1.75 (m, 2H), 2.50 (sext, J ) 6.0 Hz, 1H),
3.72 (t, J ) 6.0 Hz, 2H), 4.05 (q, J ) 6.0 Hz, 1H), 5.03 (dq, J
) 19.0, 1.5 Hz, 1H), 5.05 (dq, J ) 10.0, 1.5 Hz, 1H), 6.05 (ddd,
J ) 19.0, 10.0, 6.0 Hz, 1H); 13C NMR (50.3 MHz) δ 12.9 (3C),
15.0, 18.2 (6C), 35.3, 42.6, 60.2, 74.9, 114.3, 140.2; IR (CCl4) ν
To a solution of the 3-{[(tert-butyldimethyl)silyl]oxy}-
propanol (7.85 g, 41 mmol) and dried triethylamine (38 mL)
in dried DMSO was added, at room temperature, a solution
of pyridine‚sulfur trioxide complex (19.65 g, 124 mmol) in dried
DMSO (55 mL). After 10 min of stirring, the mixture was
dropped in ice and diluted hydrochloric acid was added to
adjust the pH to about 7. The solution was extracted with
diethyl ether, and the organic layer was washed with brine,
dried over sodium sulfate, and filtered. The solvent was then
removed under reduced pressure, and the residue was purified
by flash chromatography on silica gel (hexane/ethyl acetate,
90:10) to give compound 20 as a colorless oil (5.95 g, 77% yield).
For 20: 1H NMR (200 MHz) δ 0.06 (s, 6H), 0.85 (s, 9H), 2.55
(td, J ) 6.0, 2.0 Hz, 2H), 4.95 (t, J ) 6.0 Hz, 2H), 9.78 (t, J )
2.0 Hz, 1H); 13C NMR (50.3 MHz) δ -5.5 (2C), 18.1, 25.7 (3C),
46.5, 57.3, 176.4; IR (CCl4) ν 1730 cm-1; CIMS (NH3) m/z 189
(MH+). Anal. Calcd for C9H20O2Si: C, 57.40; H, 10.70. Found:
C, 57.72; H, 10.73.
(3R,4R)-6-{[(ter t-Bu tyld im eth yl)silyl]oxy}-4-h yd r oxy-
3-m eth ylh ex-1-en e (21). To a solution of freshly sublimed
potassium tert-butoxide (8 g, 71.3 mmol) in THF (110 mL) at
-78 °C was cannulated a solution of cis-2-butene (13.5 mL)
in THF (13 mL); n-BuLi (1.5 M in hexane, 49 mL, 73.5 mmol)
was then added dropwise, and the yellow mixture was stirred
at -78 °C for 5 min and at -45 °C for 20 min. The resulting
orange solution was cooled to -78 °C, and a solution of (-)-
B-diisopinocamphenylmethoxyborane (27 g, 85 mmol) in 50 mL
of diethyl ether was added dropwise over ca. 15 min. The
resulting white solution was stirred at -78 °C for 40 min.
Boron trifluoride etherate (13 mL, 102 mmol) was added
dropwise followed after 5 min by addition of a solution of the
aldehyde 20 (11.2 g, 59.5 mmol) in THF (26 mL). The resulting
solution was stirred at -78 °C for 4 h. The reaction was then
quenched by addition of aqueous NaOH (70 mL, 2.5 N)
followed by aqueous H2O2 (21 mL, 30%). The acetone-dry ice
bath was then removed, and the mixture was heated at 45 °C
for 45 min. The cloudy solution was cooled to room tempera-
ture, diluted with diethyl ether (150 mL), washed with brine,
dried over sodium sulfate, and filtered, and the solvent was
removed under reduced pressure to give, after a flash chro-
matography on silica gel (hexane/ethyl acetate, 90:10), com-
pound 21 as a colorless liquid (11.9 g, 82% yield): 1H NMR
(200 MHz) δ 0.07 (s, 6H), 0.88 (s, 9H), 1.03 (d, J ) 7.0 Hz,
3H), 1.63 (m, 2H), 2.23 (sext, J ) 7.0 Hz, 1H), 3.36 (d, J ) 2.5
Hz, 1H, OH), 3.63 (dtd, J ) 7.0, 6.0, 2.5 Hz, 1H), 4.12 (m, 2H),
4.99, 5.00 (2d, J ) 17.5, 10.5 Hz, 2H), 5.75 (ddd, J ) 17.5,
10.5, 7.0 Hz, 1H); 13C NMR (50.3 MHz) δ -5.6 (2C), 15.2, 18.1,
25.8 (3C), 35.5, 43.9, 62.9, 75.2, 114.6, 141.1; IR (CCl4) ν 3510,
3050 cm-1; CIMS (NH3) m/z 245 (MH+). Anal. Calcd for
3620, 3530, 3060 cm-1; CIMS (NH3) m/z 287 (MH+); [R]D
+
44.2 (c 0.97, hexane). Anal. Calcd for C16H34O2Si: C, 67.07;
H, 11.96. Found: C, 67.10; H, 11.99.
(2RS,3S,4R)-2-Hydr oxy-3-m eth yl-4-{[(tr iisopr opyl)silyl]-
oxy}tetr a h yd r op yr a n e (24). Ozone was bubbled into a
solution of compound 23 (1.85 g, 6.50 mmol) in CH2Cl2 (145
mL) and methanol (5 mL) at -78 °C until the solution turned
light blue. Dimethyl sulfide (30 mL) was added at -78 °C, and
the mixture was allowed to warm to room temperature and
stirred for 6 h. The solvents were then removed under reduced
pressure, and the residue was purified by flash chromatogra-
phy on silica gel (hexane/ethyl acetate, 80:20) to give lactol
24 as a colorless oil (1.55 g, 83% yield): 1H NMR (400 MHz)
{two epimers at C-2} δ 1.10 (m, 24H), 1.55 (m, 1H), 1.98 (m,
1H), 2.05 (m, 1H), 3.56 (m, 1H), 3.99 (m, 1H), 4.23 (td, J )
12.0, 4.0 Hz, 1H), 4.76 (s wide, 1H), 5.29 (s wide, 1H, OH);
{epimer} δ 1.79 (m, 1H), 1.89 (m, 1H), 3.70 (m, 1H), 3.90 (m,
1H), 5.13 (m, J ) 3.0 Hz, 1H); 13C NMR (100.6 MHz) {two
epimers at C-2} δ 12.1 (3C), 14.5, 17.9 (3C), 18.0 (3C), 29.3,
40.7, 55.3, 71.7, 96.9; {epimer} δ 33.0, 42.7, 59.7, 70.2, 95.6;
IR (CCl4) ν 3600, 3360, 3460 cm-1; CIMS (NH3) m/z 289 (MH+);
[R]D - 38.1 (c 2.07, MeOH). Anal. Calcd for C15H32O3Si: C,
62.45; H, 11.18. Found: C, 62.49; H, 11.21.
{3R,4S,5S,6S[2R/S-(2-Tetr a h yd r op yr a n yl)oxy]}-1,5-d i-
h yd r oxy-8-[(N,N-d iisop r op yl)ca r ba m a te]-4-m eth yl-6-{(2-
[(2-tetr a h yd r op yr a n yl)oxy]eth yl}-3-{[(tr iisop r op yl)silyl]-
oxy}oct-7-en e (25). To a solution of N,N,N′,N′-tetramethyl-
ethylenediamine (TMEDA, 0.9 mL, 6.0 mmol) in dried THF
(4 mL) at -78 °C, under argon atmosphere, was added n-BuLi
(1.6M in hexane, 3.7 mL, 6.0 mmol). After 30 min of stirring
at -78 °C, a solution of the allylcarbamate 17 (940 mg, 3.0
mmol), in dried THF (3 mL), was slowly added. After 45 min
of stirring at -78 °C, titanium tetraisopropoxide (Ti(OiPr)4,
2.7 mL, 9.0 mmol) was slowly added, and the mixture became
limpid and turned orange. After 35 min at -78 °C, lactol 24
(288 mg, 1.0 mmol) in dried THF (3 mL), was slowly added.
The cooled bath was removed after 5 min, and the reaction
mixture was cooled at -5°-0 °C for 5-10 min before it was
stirred for 6 h at 20 °C. The solution was then poured into a
cooled mixture (0 °C) of diethyl ether/aqueous hydrochloric acid
solution (2 N). After extraction with diethyl ether, the organic
layer was washed with brine, dried over sodium sulfate,
filtered, and concentrated in vacuo. The residue was purified
by flash chromatography on silica gel (hexane/ethyl acetate,
80:20) to give compound 25 (565 mg, 94% yield): 1H NMR (400
MHz) {correlations COSY, HMBC, HMQC, two diastereomers}-
δ 0.97, 0.98 (2d, J ) 6.5 Hz, 3H), 1.06 (m, 21H), 1.5-1.8 (m,
12H), 1.20 (m, 12H), 1.80 (m, 1H), 2.95 (m, 1H), 3.30 (m, 1H),
3.50 (m, 1H), 3.70 (m, 1H), 3.70 (m, 2H), 3.80 (m, 1H), 3.80
(m, 1H), 3.84 (m, 1H), 4.10 (m, 1H), 4.12 (m, 1H), 4.55 (2t, J
) 3.5 Hz, 1H), 4.75, 4.76 (2dd, J ) 10.5, 6.5 Hz, 1H), 7.10,
7.12 (2d, J ) 6.5 Hz, 1H); 13C NMR (100.6 MHz) {two
diastereomers} δ 8.1, 13.2 (3C), 18.2 (3C), 18.3 (3C), 19.6, 20.1
(2C), 21.3 (2C), 25.4, 30.7, 32.0 and 32.1 (1C), 36.8, 37.6, 39.6,
46.3, 46.5, 59.7, 62.4 and 62.5 (1C), 65.6 and 65.7 (1C), 74.2,
74.4, 98.2 and 98.8 (1C), 111.1 and 111.4 (1C), 134.5, 152.6;
IR (CCl4) ν 3630, 3400-3500, 1690 cm-1; CIMS (NH3) m/z 602
(MH+); [R]D + 11.4 (c 0.97, MeOH). Anal. Calcd for C32H63O7-
NSi: C, 63.85; H, 10.55; N, 2.33. Found: C, 63.88; H, 10.59;
N, 2.35.
C
13H28O2Si: C, 63.88; H, 11.55. Found: C, 63.92; H, 11.58.
(3R,4R)-6-{[(ter t-Bu tyld im eth yl)silyl]oxy}-3-m eth yl-4-
{[(tr iisop r op yl)silyl]oxy}h ex-1-en e (22). To a solution of
alcohol 21 (10.5 g, 43 mmol) in dried CH2Cl2 (86 mL) at 0 °C
were added 2,6-lutidine (8.2 mL, 70 mmol) and TIPSOTf (12.8
mL, 47.6 mmol). After 1.5 h of stirring at 20 °C, the reaction
mixture was partitioned between diethyl ether and an aqueous
hydrochloric acid solution (1.5 N) and extracted with diethyl
ether. The organic layer was washed with brine, dried over
sulfate sodium, filtered and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel (hexane/
ethyl acetate, 98:02) to give the title compound 22 (16.2 g, 94%
yield): 1H NMR (200 MHz) δ 0.04 (s, 6H), 0.88 (s, 9H), 0.94
(d, J ) 6.0 Hz, 3H), 1.1 (s, 21H), 1.63 (q, J ) 6.0 Hz, 2H), 2.41
(m, 1H), 3.70 (t, J ) 6.0 Hz, 2H), 3.95 (q, J ) 6.0 Hz, 1H),
4.96, 5.04 (2dd, J ) 17.0, 10.0, 1.0 Hz, 2H), 6.15 (ddd, J )
17.0, 10.0, 6.0 Hz, 1H); 13C NMR (50.3 MHz) δ -5.3 (2C), 8.0,
12.9 (3C), 18.0, 18.3 (6C), 25.9 (3C), 36.8, 42.5, 60.1, 73.3, 113.7,
141.2; IR (CCl4) ν 3050 cm-1; CIMS (NH3) m/z 401 (MH+); [R]D
+ 29 (c 2.83, hexane). Anal. Calcd for C22H48O2Si2: C, 65.93;
H, 12.07. Found: C, 65.95; H, 12.11.

380 J . Org. Chem., Vol. 64, No. 2, 1999
Berque et al.
{3R,4S,5S,6S[2R/S-(2-Tetr ah ydr opyr an yl)oxy]}-8-[(N,N-
d iisop r op yl)ca r ba m a te]-4-m eth yl-6-{(2-[(2-tetr a h yd r op y-
r a n yl) oxy]eth yl}-1,3,5-tr ih yd r oxyoct-7-en e (26). To a
solution of compound 25 (2 g, 2.4 mmol) in dried THF (8 mL)
at 20 °C was added tetrabutylammonium fluoride (Bu4NF,
1.1M in THF, 4.4 mL, 4.8 mmol). After 4 h of stirring, the
mixture was poured into a saturated aqueous ammonium
chloride solution (5 mL) and extracted with ethyl acetate (six
times). The organic layer was dried over sodium sulfate,
filtered, and concentrated under reduced pressure. A flash
chromatography on silica gel of the crude oil (ethyl acetate,
80:20) gave the triol 26 (855 mg, 80% yield): 1H NMR (400
MHz) {two diastereomers} δ 0.97, 0.98 (2d, J ) 6.5 Hz, 3H),
1.20 (m, 12H), 1.5-1.8 (m, 13H), 1.90 (m, 1H), 2.90 (m, 1H),
3.40 (m, 1H), 3.55 (m, 1H), 3.60 (dd, J ) 10.0, 2.0 Hz, 1H),
3.70 (m, 2H), 3.85 (m, 1H), 3.90 (m, 1H), 3.91 (m, 1H), 4.10
(m, 1H), 4.12 (m, 1H), 4.51, 4.55 (2t, J ) 3.5 Hz, 1H), 4.58,
-5.4 (2C), 4.8, 18.2, 19.7, 20.3 and 20.5 (1C), 20.3 (2C), 21.6
(2C), 25.4, 25.9 (3C), 29.5 and 29.8 (1C), 29.8, 30.7, 33.4, 34.8,
36.2, 45.5, 46.7, 59.3, 62.2 and 62.4 (1C), 65.4 and 65.5 (1C),
69.6, 75.7 and 75.8 (1C), 98.6 and 99.2 (1C), 98.8, 111.7 and
111.8 (1C), 136.6 and 136.7 (1C), 152.1; IR (CCl4) ν 1700 cm-1
;
CIMS (NH3) m/z 600 (MH+); [R]D + 63.4 (c 1.47, MeOH). Anal.
Calcd for C32H61O7NSi: C, 64.06; H, 10.25; N, 2.33. Found:
C, 64.11; H, 10.30; N, 2.35.
{2R(4R,5S,6R)[2R/S-(2-Tetr a h yd r op yr a n yl)oxy]}-2-{4-
[2-{[(ter t-bu tyld im eth yl)silyl]oxy}eh yl]]-2,2,5-tr im eth yl-
[1,3]d ioxola n -6-yl}-4-{[(2-t e t r a h yd r op yr a n yl)-oxy]}-
bu tyr a ld eh yd e (28). Ozone was bubbled into a solution of
compound 27 (1.2 g, 2 mmol) in CH2Cl2 (37 mL) and methanol
(3 mL) at -78 °C until the solution turned light blue. Dimethyl
sulfide (6 mL) was added at -78 °C, and the mixture was
allowed to warm to room temperature and stirred for 12 h.
The mixture was washed with water and saturated aqueous
sodium chloride solution, dried over sodium sulfate, and
evaporated under reduce pressure to afford, after flash chro-
matography on silica gel (hexane/ethyl acetate 90:10), the
desired aldehyde 28 as a colorless liquid (825 g, 90% yield):
1H NMR (400 MHz) {correlations COSY, HMBC, HMQC, two
diastereomers} δ 0.03, 0.04 (s, 6H), 0.83 (s, 9H), 0.9 (d, J )
7.0 Hz, 3H), 1.14-1.81 (m, 8H), 1.30 (m, 3H), 1.35 (m, 3H),
1.70 (m, 1H), 2.70 (m, 1H), 3.35 (m, 1H), 3.50 (m, 1H), 3.70
(m, 2H), 3.70 (m, 3H), 3.80 (m, 1H), 4.10 (2m, 1H), 4.20 (2dd,
J ) 10.5, 2.0 Hz, 1H), 4.52, 4.53 (2t, J ) 3.5 Hz, 1H), 9.65 (2d,
J ) 2.5 Hz, 1H); 13C NMR (100.6 MHz) {two diastereomers} δ
-5.4 (2C), 4.9, 18.2, 19.3, 19.5, 25.3, 25.5, 25.9 (3C), 29.7, 30.5,
32.7, 36.1, 50.5 and 50.6 (1C), 59.1, 62.2, 65.4 and 65.5(1C),
69.5, 73.4 and 73.5 (1C), 98.8 and 99.0 (1C), 98.6 and 99.2 (1C),
204.4 and 204.5 (1C); IR (CCl4) ν 1710 cm-1; CIMS (NH3) m/z
459 (MH+); [R]D - 7.5 (c 0.8, hexane). Anal. Calcd for C24H46O6-
Si: C, 62.84; H, 10.11. Found: C, 62.89; H, 10.16.
4.61 (2dd, J ) 10.5, 6.5 Hz, 1H), 7.24 (2d, J ) 6.5 Hz, 1H); 13
C
NMR (100.6 MHz) {two diastereomers} δ 4.9, 19.7, 20.3 (2C),
21.4 (2C), 24.0, 25.3, 30.6, 36.5, 37.0 and 37.2 (1C), 38.8, 45.7,
47.0, 61.8, 62.3 and 62.5 (1C), 65.4, 78.3, 78.5, 98.6 and 99.3
(1C), 111.1 and 111.2 (1C), 138.9, 152.7; IR (CCl4) ν 3400-
3500, 1690 cm-1; CIMS (NH3) m/z 446 (MH+); [R]D + 19.3 (c
0.47, MeOH). Anal. Calcd for C23H43O7N: C, 62.00; H, 9.73;
N, 3.14. Found: C, 62.05; H, 9.79; N, 3.16.
{4R,5S,6S(3S)[2R/S-(2-Tetr a h yd r op yr a n yl)oxy]}-4-({2-
[(ter t-b u t yld im et h yl)silyl]oxy}et h yl)-6-[(5-[(N,N-d iiso-
p r op yl)ca r ba m a te]-1-{[(2-tetr a h yd r op yr a n yl)oxy]}-p en t-
4-en )-3-yl]-2,2,5-tr im eth yl[1,3]d ioxola n (27). To a solution
of triol 26 (805 mg, 1.8 mmol) in dried CH2Cl2 (3.5 mL) and
dried DMF (0.7 mL) were added imidazole (157 mg, 2.3 mmol)
and tert-butyldimethylsilyl chloride (301 mg, 2 mmol) in
solution of dried CH2Cl2 (1.5 mL). After 12 h of stirring at 20
°C, the reaction mixture was partitioned between CH2Cl2 and
a saturated aqueous ammonium chloride solution and ex-
tracted with CH2Cl2. The organic layer was then dried over
sodium sulfate, and the solvent was removed under reduced
pressure. The residue was purified by flash chromatography
on silica gel (hexane/ethyl acetate, 70:30) to give [3R,4S,5S,6S]-
3,5-dihydroxy-8-[(N,N-diisopropyl)carbamate]-4-methyl-6-{(2-
[(2-tetrahydropyranyl)oxy]ethyl}-1-{[(tert-butyldimethyl)silyl]-
oxy}oct-7-ene as a colorless oil (885 mg, 88% yield): 1H NMR
(400 MHz) {two diastereomers} δ 0.05 (s, 6H), 0.86 (s, 9H),
0.97, 0.98 (2d, J ) 6.5 Hz, 3H), 1.5-1.8 (m, 12H), 1.22 (m,
12H), 1.70 (m, 1H), 2.90 (m, 1H), 3.30 (m, 1H), 3.50 (m, 1H),
3.50 (m, 1H), 3.62 (m, 1H), 3.80 (m, 1H), 3.80 (m, 1H), 3.80
(m, 1H), 3.84 (m, 1H), 3.99 (m, 1H), 4.12 (m, 1H), 4.52, 4.54
(2t, J ) 3.5 Hz, 1H), 4.50, 4.60 (2dd, J ) 10.0, 6.5 Hz, 1H), 7.2
(2d, J ) 6.5 Hz, 1H); 13C NMR (100.6 MHz) {two diastereo-
mers} δ -5.0 (2C), 5.5, 18.1, 19.7, 20.1 (2C), 21.3 (2C), 25.4,
25.6 (3C), 30.7, 31.4, 37.1, 37.2, 39.3, 45.9, 46.3, 62.2, 62.3 and
62.5 (1C), 65.5 and 65.6 (1C), 75.0 and 75.1 (1C), 77.8 and 77.9
(1C), 98.7, 111.3, 128.8, 152.8; IR (CCl4) ν 3570, 3500, 1700
cm-1; CIMS (NH3) m/z 560 (MH+); [R]D + 10.1 (c 1.48, MeOH).
Anal. Calcd for C29H57O7NSi: C, 62.23; H, 10.26; N, 2.50.
Found: C, 62.27; H, 10.31; N, 2.53.
{4R,5S,6R(3S,4S,5S)[2R/S-(2-Tetr a h yd r op yr a n yl)oxy]}-
4-({2-[(ter t-b u t yld im et h yl)silyl]oxy}et h yl)-6-[(7-[(N,N-
d iis o p r o p y l)c a r b a m a t e ]-4-h y d r o x y -5-m e t h y l-1-{[(2-
tetrahydropyranyl)oxy]}-hept-6-en)-3-yl]-2,2,5-trimethyl[1,3]-
d ioxola n (29). To a rapidly stirred solution of crotylcarbamate
1 (900 mg, 4.5 mmol) and (-)-sparteine (1.1 g, 4.63 mmol) in
pentane (6 mL) and cyclohexane (0.9 mL) at -78 °C, was added
a solution of n-BuLi (1.6 M in hexane, 3 mL, 4.8 mmol), and
after 10 min white crystals appeared. After 3 h of crystalliza-
tion at - 78 °C, a precooled (-50 °C, 30 min) solution of
titanium tetraisopropoxide (Ti(OiPr)4 (4 mL, 13.5 mmol) in
pentane (10 mL) was quickly added via cannula to the reaction
mixture of lithio carbamate which became limpid and turned
orange. After 1 h at -78 °C, aldehyde 28 (1.03 g, 2.25 mmol)
in pentane (3 mL) was slowly added to the orange solution.
The reaction mixture was stirred for 2 h at - 78 °C, and the
reaction was quenched by addition of an aqueous hydochloric
acid solution (2 N). After extraction with diethyl ether, the
organic layer was washed with brine, dried over sodium
sulfate, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (hexane/ethyl
acetate, 80:20) to give compound 29 as a colorless oil (1.18 g,
80% yield): 1H NMR (400 MHz) {correlations COSY, HMBC,
HMQC, two diastereomers} δ 0.2 (s, 6H), 0.87 (s, 9H), 0.9 (d,
J ) 6.5 Hz, 3H), 1.12 (d, J ) 6.5 Hz, 3H), 1.14-1.81 (m, 24H),
1.39 (m, 3H), 1.47 (m, 3H), 2.95 (m, 1H), 3.27 (m, 1H), 3.50
(m, 1H), 3.65 (m, 2H), 3.74 (m, 1H), 3.76 (m, 1H), 3.81 (m,
1H), 3.83 (m, 1H), 4.09 (m, 1H), 4.15 (m, 1H), 4.25 (dd, J )
10.0, 1.5 Hz, 1H), 4.4 (d, J ) 11.0 Hz, 1H, OH), 5.02 (2dd, J )
10.0, 6.5 Hz, 1H), 4.53 (2t, J ) 3.5 Hz, 1H), 7.10 (d, J ) 6.5
Hz, 1H); 13C NMR (100.6 MHz) {two diastereomers} δ -5.0
(2C), 5.1, 18.2, 18.6, 19.8, 19.3 and 19.5 (1C), 20.3 (2C), 21.4
(2C), 25.4 and 25.5 (1C), 25.9 (3C), 29.9, 30.6, 30.7, 33.2 and
33.3 (1C), 36.1 and 36.2 (1C), 40.0, 40.2, 46.4 and 46.5 (1C),
59.1 and 59.2 (1C), 62.1 and 62.2 (1C), 64.2 and 64.3 (1C), 69.8
and 70.1 (1C), 77.2, 77.5, 98.8 and 99.0 (1C), 99.1, 111.5 and
111.6 (1C), 138.5, 152.9; IR (CCl4) ν 3590, 1710 cm-1; CIMS
(NH3) m/z 658 (MH+); [R]D + 16.4 (c 3.36, MeOH). Anal. Calcd
for C34H67O8NSi: C, 63.87; H, 10.26; N, 2.13. Found: C, 63.91;
H, 10.29; N, 2.15.
To a solution of {3R,4S,5S,6S[2R/ S-(2-tetrahydropyranyl)-
oxy]}-3,5-dihydroxy-8-[(N,N-diisopropyl)carbamate]-4-methyl-
6-{(2-[(2-tetrahydropyranyl)oxy]ethyl}-1-{[(tert-butyldimethyl)-
silyl]oxy}oct-7-ene (870 mg, 1.55 mmol) in CH2Cl2 (4 mL) were
added 2,2-dimethoxypropane (4 mL, 42 mmol) and p-toluene-
sulfonic pyridinium (10%). The reaction mixture was stirred
for 2 h at 20 °C. Triethylamine (2 mL) was then added, and
the reaction mixture was concentrated under reduced pressure.
The crude residue was purified by flash chromatography on
silica gel (hexane/ethyl acetate, 85:15) to give acetonide 27 as
a colorless oil (836 mg, 90% yield).
1
For 27: H NMR (400 MHz) {correlations, COSY, HMBC,
HMQC, two diastereomers} δ 0.03, 0.04 (s, 6H), 0.87 (m, 12H),
1.14-1.81 (m, 25H), 1.33 (m, 3H), 1.70 (m, 1H), 2.88 (m, 1H),
3.31 (m, 1H), 3.44 (m, 1H), 3.57 (m, 1H), 3.62 (m, 2H), 3.71
(m, 1H), 3.81 (m, 2H), 4.02 (m, 1H), 4.15 (m, 1H), 4.43 (2dd, J
) 10.0, 6.5 Hz, 1H), 4.49, 4.53 (2t, J ) 3.5 Hz, 1H), 7.09 (d, J
) 6.5 Hz, 1H); 13C NMR (100.6 MHz) {two diastereomers} δ

Allyltitanates in Stereospecific Additions
J . Org. Chem., Vol. 64, No. 2, 1999 381
{3R,4S,5R,6R[2R/S-(2-Tetr ah ydr opyr an yl)oxy]}-1-[(ter t-
bu tyld ip h en ylsilyl)oxy]-5,7-d ih yd r oxy-4-m eth yl-6-[2-{(2-
t et r a h yd r op yr a n yl) oxy]et h yl}-1-yl]-3-{[(t r iisop r op yl)-
silyl]oxy}octa n e (30). Ozone was bubbled into a solution of
compound 19 (50 mg, 0.06 mmol) in CH2Cl2 (5 mL) and
methanol (2.5 mL) at -78 °C until the solution turned light
blue. Sodium borohydride (14 mg, 0.36 mmol) was added at
-78 °C, and the mixture was allowed to warm to room
temperature and stirred for 5 h. The reaction mixture was then
cooled, treated with an aqueous hydrochloric acid solution (0.5
N, 2 mL), and extracted with diethyl ether. The organic layers
were washed with brine, dried over sodium sulfate, filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (hexane/ethyl acetate, 80:20) to
give diol 30 as a colorless oil (34 mg, 80% yield): 1H NMR
(400 MHz) {two diastereomers} δ 0.78 (2d, J ) 7.0 Hz, 3H),
0.87 (s wide, 9H), 1.10 (s wide, 21H), 1.37-1.83 (m, 10H), 1.71
(m, 1H), 2.17 (m, 1H), 3.52 (m, 1H), 3.84 (m, 1H), 3.90 (m,
1H), 3.41 (m, 1H), 3.53 (m, 1H), 3.75 (m, 2H), 3.87 (m, 1H),
3.92 (m, 1H), 4.25 (m, 1H), 4.60 (2t, J ) 3.5 Hz, 1H), 3.52 (m,
1H), 3.90 (m, 1H), 7.38 (m, 6H), 7.64 (t, J ) 7.8 Hz, 4H); 13C
NMR (100.6 MHz) {two diastereomers} δ 12.7 (3C), 13.3, 18.1,
18.2 (6C), 19.7, 25.4, 26.8 (3C), 29.4, 30.7, 30.7, 35.5, 38.4, 60.8,
62.0, 62.3 and 63.4, (1C), 65.7, 74.7, 78.0, 99.0, 127.6 (4C),
129.7 (4C), 133.6 (2C), 135.6 (2C); CIMS (NH3) m/z 701 (MH+).
[2R/S,3R,4R,5R,6R(1S,2R)]-5-{2-[(ter t-Bu t yld ip h en yl-
silyl)oxy]eth yl}-6-{5-[(ter t-bu tyld ip h en ylsilyl)oxy]-3-h y-
d r oxyp en t-2-yl}-3-m eth yl-tetr a h yd r op yr a n -2,4-d iol (32).
To a solution of compound 29 (360 mg, 0.53 mmol) in methanol
(3 mL) was added Amberlyst H+ 15. After 48 h of stirring at
room temperature, the reaction mixture was filtered through
Celite, and the solvent was removed under reduced pressure.
To a solution of the crude oily residue obtained above in
dried DMF (0.7 mL) was added a solution of imidazole (94 mg,
1.38 mmol) and tert-butyldiphenylsilyl chloride (0.3 mL, 1.16
mmol) in dried DMF (0.7 mL). After 24 h of stirring at 20 °C,
the reaction mixture was partitioned between diethyl ether
and an aqueous hydrochloric acid solution (2 N) and extracted
with diethyl ether. The organic layer was then washed with
brine, dried over sodium sulfate, and filtered, and the solvent
was removed under reduced pressure. The residue was purified
by flash chromatography on silica gel (hexane/ethyl acetate,
80:20) to give [3R,4S,5R,6S,7S,8S]-1-{[(tert-butyldiphenyl)-
silyl]oxy}-6-{(2-{[(tert-butyldiphenyl)silyl]oxy}-ethyl}-10-[(N,N-
diisopropyl)carbamate]-4,8-dimethyl-3,5,7-trihydroxydeca-9-
ene as a colorless oil (332 mg, 70% yield).
Ozone was bubbled into a solution of [3R,4S,5R,6S,7S,8S]-
1-{[(tert-butyldiphenyl)silyl]oxy}-6-{(2-{[(tert-butyldiphenyl)-
silyl]oxy}-ethyl}-10-[(N,N-diisopropyl)carbamate]-4,8-dimethyl-
3,5,7-trihydroxydeca-9-ene (302 mg, 0.33 mmol) in CH2Cl2 (7
mL) and methanol (1 mL) at -78 °C until the solution turned
light blue. Dimethyl sulfide (2 mL) was added at -78 °C, and
the mixture was allowed to warm to room temperature and
stirred for 12 h. The mixture was washed with water and a
saturated aqueous sodium chloride solution, dried over sodium
sulfate, and evaporated under reduce pressure to afford, after
flash chromatography on silica gel (hexane/ethyl acetate 80:
20), the desired lactol 32 as a colorless liquid (174 mg, 70%
yield).
{5R,6R(2S,3R)[2R/S-(2-Tetr a h yd r op yr a n yl)oxy]}-6-(5-
[(ter t-bu tyldiph en ylsilyl)oxy]-3-{[(tr iisopr opyl)silyl]oxy}-
p en t a n e-4-ol-2-yl)-2,2-t r im et h yl-5-[2-{(2-t et r a h yd r op yr -
a n yl)oxy]eth yl}-1-yl][1,3] d ioxa n e (31). To a solution of
compound 30 (27 mg, 0.04 mmol) in CH2Cl2 (1 mL) were added
2,2-dimethoxypropane (1 mL, 8.2 mmol) and p-toluenesulfonic
pyridinium (10%). The reaction mixture was stirred for 1.5 h.
Triethylamine (0.5 mL) was then added, and the reaction
mixture was concentrated under reduced pressure. The crude
residue was purified by flash chromatography on silica gel
(hexane/ethyl acetate, 90:10) to give acetonide 31 as a colorless
oil (26 mg, 90% yield): 1H NMR (400 MHz) {correlations
COSY, HETCOR, HMQC two diastereomers} δ 0.87 (2d, J )
7.0 Hz, 3H), 0.89 (m, 9H), 1.06 (m, 21H), 1.29 (s, 3H), 1.35 (s,
3H), 1.5-1.8 (m, 8H), 1.52 (m, 1H), 1.66, 1.84 (m, 2H), 1.74
(m, 1H), 3.35 (m, 1H), 3.47 (dd, J ) 11.5, 3.0 Hz, 1H), 3.47 (m,
1H), 3.52 (m, 1H), 3.63 (m, 2H), 3.77 (m, 1H), 3.77 (m, 1H),
3.88 (dd, J ) 11.5, 3.9 Hz, 1H), 4.46 (m, 1H), 4.55 (2t, J ) 3.5
Hz, 1H), 7.4 (m, 4H), 7.65 (m, 6H); 13C NMR (100.6 MHz) {two
diastereomers} δ 8.8 and 8.9 (1C), 13.1 (3C), 18.1, 18.5 (6C),
19.4, 19.5, 25.5, 26.7 (3C), 28.2, 29.5, 30.6, 37.1 and 37.3 (1C),
38.1, 42.5, 60.8, 61.5 and 61.7 (1C), 62.0 and 62.1 (1C), 65.1
and 65.3 (1C), 68.7, 73.5, 98.0, 99.0, 127.6 (4C), 129.5 (4C),
135.6 (2C), 135.7 (2C); CIMS (NH3) m/z 741 (MH+); [R]D - 11.4
(c 0.7, MeOH). Anal. Calcd for C43H72O6Si2: C: 69.68, H: 9.79.
Found: C: 69.73, H: 9.82.
For 32: 1H NMR (400 MHz) {correlations COSY, HMBC,
HMQC, two epimers, the minor is in italics} δ 0.89, 0.91 (2d,
J ) 6.9 Hz, 3H), 1.06 (s wide, 18H), 1.10.(d, J ) 6.0 Hz, 3H),
1.55 (m, 2H), 1.65 (m, 1H), 1.78, 1.82 (m, 2H), 1.79 (m, 2H),
3.67 (dd, J ) 10.0, 5.0 Hz, 1H), 3.72 (dd, J ) 10.0, 5.0 Hz,
1H), 3.81 (t, J ) 6.2 Hz, 2H), 3.95 (m, 1H), 3.98, 4.01 (2dd, J
) 4.7, 2.8 Hz, 1H), 4.15 (dd, J ) 10.7, 1.8 Hz, 1H), 4.81 (d, J
) 9.0 Hz, 0.5H), 4.96 (d, J ) 6.2 Hz, 0.5H), 7.40 (m, 12H),
7.65 (t, J ) 7.8 Hz, 8H); 13C NMR (100.6 MHz) {two epimers}
δ 5.7, 13.7, 18.1 (2C), 26.8 (3C), 26.9 (3C), 29.4, 36.7, 37.0, 37.9,
40.6, 61.5, 62.3, 70.2, 70.9, 74.0, 96.0, 127.6 (4C), 127.8 (4C),
129.6 (4C), 129.8 (4C), 132.8 (2C), 133.7 (2C), 135.6 (4C); CIMS
(NH3) m/z 755 (MH+).
Ack n ow led gm en t. Many thanks are due to Dr. J .
Prunet for helpful discussions.
J O9807722