Partial oxidation of alkenylsilanes with ozone: A novel stereoselective approach to the diol and triol derivatives

Article abstract of DOI:10.1055/s-2008-1032161

The reaction of alkenylsilanes with ozone provides synthetically versatile β-hydroxy or α-formyl silyl peroxides in good yield without normal fission of the C=C bond. The obtained α-formyl silyl peroxides serve as good precursors for the stereochemically

Full text of DOI:10.1055/s-2008-1032161

PRACTICAL SYNTHETIC PROCEDURES
1641
Partial Oxidation of Alkenylsilanes with Ozone: A Novel Stereoselective
Approach to the Diol and Triol Derivatives
Partial
Oxidation
o
a
f
A
lkenylsi
z
lanes
w
ith
uO
zone nobu Igawa,a Kyohei Sakita,b Masanori Murakami,b Katsuhiko Tomooka*a,b
a
Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga-koen 6-1, Kasuga-shi, Fukuoka 816-8580, Japan
Fax +81(92)5837810; E-mail: ktomooka@cm.kyushu-u.ac.jp
b
Department of Applied Chemistry, Tokyo Institute of Technology, Ookayama 2-12-1,
Meguro-ku, Tokyo 152-8552, Japan
Received 22 October 2007; revised 31 October 2007
Dedicated to Professor Paul A. Wender on the occasion of his 60th birthday
PSP
No124
Abstract: The reaction of alkenylsilanes with ozone provides synthetically versatile b-hydroxy or a-formyl silyl peroxides in good yield
without normal fission of the C=C bond. The obtained a-formyl silyl peroxides serve as good precursors for the stereochemically defined
diol or triol derivatives via nucleophilic addition to the formyl group and reduction of the peroxide moiety.
Key words: alkenes, oxidations, ozonolysis, peroxides, silicon
OH
R1
R2
O
OH
R2
OSiR3
OSiR3
R2–
R1
R1
O3
R1
H
SiR3
OH
O
O
OSiR3
R1
R2
O
Scheme 1 Oxidation of alkenylsilanes and transformation of resulting a-formyl silyl peroxides
cloaddition and subsequent rearrangement of the resultant
primary ozonide i. Generally, the second rearrangement
Introduction
Ozone is one of the most simple, economical, clean, and step proceeds much more rapidly than the first cycloaddi-
efficient oxidation agents, and is widely utilized in many tion and therefore, there has long been inherent difficulty
facets of industry. Also in the field of organic synthesis, in stopping this process at the intermediate stage.1,2 How-
ozone is quite an important reagent, especially for the ox- ever, we recently found that a number of organosilyl
idative cleavage of the C=C bond (i.e. ozonolysis), which groups directly bound to C=C bond successfully intercept
is well recognized as a ‘textbook reaction’.1 As illustrated the second rearrangement step by migrating from carbon
in Scheme 2 (path a), this ozone-mediated oxidative to oxygen in the primary ozonide.3,4 Furthermore, we have
cleavage reaction of the C=C bond consists of a [3+2] cy- successfully isolated the resultant silyl peroxides in which
O(H)
R2
O(H)
O
O
path a
workup
+
R1
R2
(X = R2:
alkyl, aryl)
R1
O
ii
O
O3
O
O
R1
X
R1
X
A
O(H)
O
i
workup
O
O
path b
R1
(X = SiR3)
R1
SiR3
O
OSiR3
B
Scheme 2 Oxidation of alkenes using ozone
SYNTHESIS 2008, No. 10, pp 1641–1645
x
x.
x
x
.
2
0
0
8
Advanced online publication: 08.02.2008
DOI: 10.1055/s-2008-1032161; Art ID: Z24207SS
© Georg Thieme Verlag Stuttgart · New York

1642
K. Igawa et al.
PRACTICAL SYNTHETIC PROCEDURES
the original carbon skeletons in the starting alkenylsilanes The present ozone oxidation is applicable to the g-silyl-
are perfectly retained (path b). The synthetic potential of allylic alcohol derivatives 1c–k, which are readily available
thus obtained silyl peroxides strongly suggested a new from the g-silylpropargylic alcohols 3 by hydroalumina-
possibility for ozone as a unique agent in organic synthe- tion with sodium bis(2-methoxyethoxy)aluminum hy-
sis. This paper deals with an overview of our recent dride (Red-Al) as shown in Scheme 4.8 As listed in Table
progress in this area (Scheme 1).
1, the ozone oxidation of 1c–k gives silyl peroxides 2c–k
in good yields.
OH
OX
R2
Scope and Limitations
Red-Al
R1
R1
SiR3
R2
toluene, 0 °C
80–98%
The typical procedure for the ozone oxidation of alkenyl-
silanes is illustrated in the case of the simple tert-butyl-
diphenylsilylethene (1a) and trans-1-triisopropylsilyl-
3,3-dimethylbut-1-ene (1b) (Scheme 3). At –78 °C, a
stream of ozone/oxygen gas is bubbled through the solu-
tion of 1a or 1b in EtOAc, which is essential for the selec-
tive formation of the corresponding silyl peroxides, until
the color of the solution turns from colorless to pale blue.5
After removal of the excess ozone remaining in the solu-
tion with argon, powdered NaBH4 is added portionwise
into the solution at the same temperature. The standard ex-
tractive workup of the resulting mixture affords b-hy-
droxy silyl peroxides 2a and 2b in moderate to good
yields. Although organic peroxides have been known as
potentially hazardous compounds, we have never experi-
enced any particular difficulties in handling new silyl per-
oxides including 2a or 2b.6,7
SiR3
3
1c–k
R33SiCl, base
84–99%
X = H
X = R33Si
Scheme 4 Preparation of 1c–k from g-silylpropargylic alcohol 3
Importantly, we have observed moderate to good diaste-
reoselectivities in the ozone oxidation of 1g–k bearing
stereogenic center at their allylic positions. The anti selec-
tivity becomes more pronounced as the R1 group becomes
more bulky, and the diastereoselectivity for 1j (R1 = t-Bu)
reaches >99% to give the anti-2j exclusively (entry 8). It
is worth noting that this oxidation was applicable to 1k
having an alkynyl substituent (entry 9). These results
clearly show that the present oxidation provides an effi-
cient approach to the multifunctionalized triol derivatives.
The intermediate a-formyl silyl peroxides can be success-
fully isolated by eliminating the reductive workup with
NaBH4 in the aforementioned protocol. As shown in Ta-
ble 2, a variety of a-formyl silyl peroxides 4 were ob-
tained in good yields by ozone oxidation of 1 followed by
a concentration of the crude mixture under reduced pres-
sure.
OH
R1
NaBH4
O3
R1
SiR3
EtOAc, –78 °C
O
OSiR3
1a: R1 = H, R3Si = TBDPS
1b: R1 = t-Bu, R3Si = TIPS
2a: 68%
2b: 53%
Scheme 3 Oxidation of alkenylsilanes 1a and 1b
Table 1 Synthesis of b-Hydroxy Silyl Peroxides 2
OX
R2
OX OH
O3, then NaBH4
EtOAc, –78 °C
R1
SiR3
R1
R2
O
OSiR3
1
2
Entry
1
R1
R2
X
R3Si
Yield (%)a
dr (anti/syn)b
1
2
3
4
5
6
7
8
9
1c
1d
1e
1f
Me
Me
H
TBDMS
TBDMS
TBDMS
TBDMS
TIPS
73
75
70
90
78
84
89
71
90
–
PhCH2CH2
PhCH2CH2
H
–
Me
Me
H
H
–
H
TBDMS
TMS
TMS
TMS
TMS
H
–
1g
1h
1i
Me
H
58:42
67:33
72:28
>99:<1
74:26c
Et
H
TIPS
c-C6H11
t-Bu
C≡C-TIPS
H
TIPS
1j
H
TIPS
1k
Me
TIPS
a Isolated yields after purification using silica gel column chromatography.
b Determined by 1H NMR analysis.
c Stereochemisrty of the major product has not been determined yet.
Synthesis 2008, No. 10, 1641–1645 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Partial Oxidation of Alkenylsilanes with Ozone
1643
Table 2 Synthesis of a-Formyl Silyl Peroxides 4
A combination of these transformations and the ozone ox-
idation of chiral g-silylallylic alcohol enable the stereose-
lective construction of three continuous chiral centers in
triol derivatives. As shown in Scheme 7, the aforemen-
tioned diastereoselective ozone oxidation of 1j followed
by nucleophilic addition of MeLi provides (1,2-anti, 2,3-
syn)-8 with 94% dr. Again, reduction of TMS-ether of 8
using Me3P proceeds in a stereospecific manner to obtain
silyl ether of triol (1,2-anti, 2,3-syn)-9.
OX
O
OX
O3
R1
H
R1
SiR3
R1
EtOAc, –78 °C
R1
O
OSiR3
1
4
Entry
1
R1
H
X
R3Si
Yield (%)a
1
2
3
4
5
6
7
8
1l
TBDMS
TBDMS
TBDMS
H
TBDMS
TBDMS
TIPS
82
89
80
73
80
82
67
75
1f
H
TMSO
t-Bu
TMSO
t-Bu
O
1m
1c
1n
1o
1p
1q
H
O3
MeLi
TIPS
H
EtOAc, –78 °C
76%
toluene, –78 °C
87%
Me
Me
Me
Me
Me
TBDMS
TIPS
O
1j
OTIPS
anti-4r (>99% dr)
H
TBDMS
TMS
TMS
TBDMS
TBDMS
TIPS
TMSO
OH
OTMS
TMSO
TMSCl
Et3N, DMAP
2
2
3
Me3P
1
3
1
t-Bu
t-Bu
CH2Cl2, r.t.
98%
toluene, r.t.
O
OY
OTIPS
a Isolated yields after purification using silica gel column chromatog-
raphy.
(1,2-anti, 2,3-syn)-9
Y = TIPS: 30%
Y = H: 54%
(1,2-anti, 2,3-syn)-8
(94% dr)
Scheme 7 Construction of three continuous chiral centers by diaste-
reoselective ozone oxidation/nucleophilic addition
The a-formyl silyl peroxides 4 thus obtained are valuable
building blocks for polyol derivatives. Thus, the reaction
of 4q with alkyllithiums in toluene gave syn-5 with pre-
servation of peroxide moiety in good to excellent diaste-
reoselectivity (Scheme 5). This stereochemical outcome
is explainable on the basis of chelation-controlled mecha-
nism, in which the lithium cation coordinates to carbonyl
oxygen and peroxide oxygen.
Furthermore, at the expense of the loss of stereogenic cen-
ter at the middle carbon, silyl peroxide 8 was also convert-
ible to the a,a¢-dihydroxyketone derivative anti-10 upon
base treatment (Scheme 8). These results clearly show
that the silyl peroxide functionality acts as not only a syn-
thetic equivalent of silyl ether, but also as masked carbo-
nyl.10
TMSO
O
TMSO
OH
RLi
H
R
TMSO
t-Bu
OH
toluene, –78 °C
O
O
Et3N, DMAP
OTIPS
OTIPS
(1,2-anti, 2,3-syn)-8
(94% dr)
THF, r.t.
73%
syn-5a: R = Me (91%, 93% dr)
syn-5b: R = Ph (66%, >99% dr)
syn-5c: R = C C-TIPS (52%, 87% dr)
4q
O
anti-10 (94% dr)
Scheme 5 Nucleophilic addition reaction of RLi to 4q
Scheme 8 Transformation of silyl peroxide 8 to ketone 10
The obtained chiral racemic silyl peroxides 5 are stereo-
specifically deoxygenated by Me3P to give the silyl ethers
7. For example, the reduction of syn-6 using Me3P at room
temperature yielded syn-7 without loss of diastereopurity
(Scheme 6). This result indicates that the a-silyl oxygen of
the peroxide moiety is selectively removed in this pro-
cess.9
In summary, we have described an oxidation of alkenylsi-
lanes using ozone, which provides an access to syntheti-
cally versatile silyl peroxides with retention of s-bond of
alkene moiety. Furthermore, concise and stereoselective
synthesis of triol derivatives from g-silylpropargylic alco-
hols has been accomplished by the combination of hy-
droalumination, ozone oxidation, and nucleophilic
alkylation.
TMSO
TMSO
OTMS
OTMS
TMSCl
Et3N, DMAP
Me3P
syn-5a
toluene, r.t.
CH2Cl2, r.t.
96%
O
OY
Procedures
OTIPS
Herein we describe typical procedures for the preparation of alke-
nylsilanes 1 (depicted in Scheme 4), its ozone oxidation (depicted
in Tables 1 and 2), and the reaction of a-formyl silyl peroxides with
alkyllithium (depicted in Scheme 5).
syn-7 (93% dr)
syn-6 (93% dr)
Y = TIPS: 61%
Y = H: 35%
Scheme 6 Transformation of silyl peroxide syn-5a to syn-7
All reactions were carried out in dried glassware under argon unless
otherwise noted. 1H NMR spectra were recorded on a Varian Mer-
cury (300 MHz) spectrometer using CDCl3 as solvent; CHCl3 (1H,
Synthesis 2008, No. 10, 1641–1645 © Thieme Stuttgart · New York

1644
K. Igawa et al.
PRACTICAL SYNTHETIC PROCEDURES
d = 7.26) was used as an internal reference. 13C NMR spectra were
recorded on a Varian Mercury (75 MHz) spectrometer using CDCl3
as solvent; CDCl3 (13C, d = 77.1) was used as an internal reference.
Infrared spectra were recorded on a Perkin Elmer SpectrumOne as
neat liquid samples on NaCl plates. MS spectra were recorded on a
JEOL JMS-T100CS.
ane–Et2O, 100:1) to afford the silyl peroxide 4q (644 mg, 75%) as
a colorless oil.
IR (neat): 2947, 2869, 1740, 1465, 1367, 1252, 1172, 1044, 842
cm–1.
1H NMR (300 MHz, CDCl3): d = 9.70 (d, J = 3.9 Hz, 1 H), 3.88 (d,
J = 3.9 Hz, 1 H), 1.30 (s, 3 H), 1.29 (s, 3 H), 1.21 (qq, J = 6.6, 6.6
Hz, 3 H), 1.15–1.05 (m, 18 H), 0.10 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 203.34, 94.10, 75.36, 28.31, 26.83,
18.06, 11.67, 2.49.
Procedure 1
(E)-4-(tert-Butyldimethylsilyl)-2-methylbut-3-en-2-ol (1c); Typ-
ical Procedure for Hydroalumination
To a solution of 4-tert-butyldimethylsilyl-2-methylbut-3-yn-2-ol
(3c; 497 mg, 2.50 mmol) in toluene (10 mL) at r.t. was added Red-
Al (2.32 mL of 1.62 M solution in toluene, 3.75 mmol) and the mix-
ture was stirred at that temperature for 1.5 h. Then, the reaction was
quenched with powdered Na2SO4·10H2O (1.0 g), diluted with hex-
ane (20 mL), and Na2SO4 (10.0 g) was added for absorption of alu-
minum hydroxide. After the organic layer had changed to a clear
solution, the mixture was filtered through a pad of Celite and the
solvent was removed in vacuo. The crude product was purified by
silica gel chromatography (hexane–EtOAc, 8:1) to afford 451 mg of
1c (90%) as a colorless oil.
MS (ESI, +): m/z = 385 [M + Na]+.
Procedure 4
syn-3-Triisopropylsilylperoxy-4-methyl-4-trimethylsilyloxy-
pentan-2-ol (syn-5a)
To a solution of 4q (153 mg, 0.423 mmol) in toluene (12 mL) was
slowly added MeLi (0.619 mL of 1.03 M solution in Et2O, 0.634
mmol) at –78 °C. After 20 min, the reaction was quenched by phos-
phate buffer (pH 7, 5 mL), the aqueous layer was extracted with
hexane (3 × 10 mL), dried (Na2SO4), filtered, and the solvent was
removed in vacuo. The crude product was purified by silica gel
chromatography (hexane–EtOAc, 20:1) to afford 5a (147 mg, 91%,
93% dr) as a colorless oil.
IR (neat): 3365, 2953, 2857, 1616, 1471, 1361, 1248, 1147, 991,
831 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.16 (d, J = 18.9 Hz, 1 H), 5.80 (d,
J = 18.9 Hz, 1 H), 1.50 (s, 1 H), 1.31 (s, 6 H), 0.87 (s, 9 H), 0.04 (s,
6 H).
13C NMR (75 MHz, CDCl3): d = 154.65, 121.54, 72.22, 29.61,
26.57, 16.71, –5.91.
Major Isomer
IR (neat): 3582, 2947, 2868, 1465, 1384, 1367, 1251, 1170, 1040,
869, 841 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.21 (ddq, J = 6.6, 2.4, 2.4 Hz, 1
H), 3.61 (d, J = 2.4 Hz, 1 H), 3.38 (d, J = 6.6 Hz, 1 H), 1.39 (d,
J = 2.4 Hz, 3 H), 1.35 (s, 3 H), 1.29 (s, 3 H), 1.22 (qq, J = 6.3, 6.3
Hz, 3 H), 1.12–1.08 (m, 18 H), 0.14 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 92.91, 76.39, 66.86, 29.69, 26.00,
23.33, 18.06, 11.55, 2.54.
Procedure 2
2-(tert-Butyldimethylsilylperoxy)-3-methylbutane-1,3-diol(2c);
Typical Procedure for the Ozone Oxidation of Alkenylsilanes
with NaBH4 Workup
A stream of O3 (ca. 1.2 v/v% in O2, ca. 150 mL/min) was bubbled
through a solution of allylic alcohol 1c (127 mg, 0.636 mmol) in
EtOAc (7 mL) at –78 °C. After 30 min, the solution turned pale Acknowledgment
blue, indicating the completion of oxidation. Dissolved O3 was re-
This research was supported in part by a Grant-in-Aid for Scientific
moved by bubbling argon through the solution for 10 min. To the
solution was added NaBH4 (100 mg, 2.64 mmol) and stirred at that
temperature for 1.5 h. After quenching the reaction with sat. aq
NH4Cl (5 mL), the aqueous layer was extracted with EtOAc (3 × 5
mL), dried (Na2SO4), filtered, and the solvent was removed in vac-
uo. The crude product was purified by silica gel chromatography
(hexane–EtOAc, 3:1) to afford the silyl peroxide 2c (116 mg, 73%)
as a colorless oil.
Research on Priority Areas (A) ‘Creation of Biologically Functional
Molecules’, Basic Areas (B) No. 19350019 and Young Scientists
(B) No. 18750081 from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
References
(1) For leading reviews on ozonolysis and other ozone
oxidations, see: (a) Bailey, P. S. Ozonation in Organic
Chemistry, Olefinic Compounds, Vol. 1; Academic Press:
London, 1978. (b) Bailey, P. S. Ozonation in Organic
Chemistry, Nonolefinic Compounds, Vol. 2; Academic
Press: London, 1982.
(2) Theoretical studies suggest that the formation of primary
ozonide is a rate-determining step for the ozonolysis of
alkenes. For a representative example, see: Anglada, M. J.;
Crehuet, R.; Bofill, J. M. Chem. Eur. J. 1999, 5, 1809.
(3) Murakami, M.; Sakita, K.; Igawa, K.; Tomooka, K. Org.
Lett. 2006, 8, 4023.
(4) Büchi and Wüest reported the ozonization of trimethylsilyl-
substituted alkenes in the 1970s, in which they proposed a
similar silyl peroxide as an intermediate, see: Büchi, G.;
Wüest, H. J. Am. Chem. Soc. 1978, 100, 294.
(5) Normal oxidative cleavage products were obtained in the
ozonation of alkenylsilanes 1 in MeOH, CH2Cl2 or hexane in
10–30% yields.
IR (neat): 3391, 2931, 2859, 1472, 1410, 1363, 1252, 1182, 1038,
838 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.98–3.92 (m, 2 H), 3.88 (dd,
J = 4.5, 4.5 Hz, 1 H), 2.96 (br s, 1 H), 2.56 (br s, 1 H), 1.26 (s, 6 H),
0.95 (s, 9 H), 0.22 (s, 3 H), 0.20 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 91.18, 73.05, 61.68, 27.27, 26.76,
26.49, 18.51, –5.38, –5.30.
MS (ESI, +): m/z = 273 [M + Na]+.
Procedure 3
2-Triisopropylsilylperoxy-3-trimethylsilyloxy-3-methylbutyr-
aldehyde (4q); Typical Procedure for the Ozone Oxidation of
Alkenylsilanes without Reductive Workup
A stream of O3 (ca. 1.2 v/v% in O2, 150 mL/min) was bubbled
through a solution of the ether 1q (747 mg, 2.38 mmol) in EtOAc
(30 mL) at –78 °C. After 1 h, the solution turned pale blue, indicat-
ing the completion of oxidation. Dissolved O3 was removed by bub-
bling argon through the solution for 10 min, followed by allowing
the temperature to rise to r.t. After removal of the solvent by evap-
oration, the residue was purified by silica gel chromatography (hex-
(6) (a) Castrantas, H. M.; Banerjee, D. K.; Noller, D. C. Fire and
Explosion Hazards of Peroxy Compounds, ASTM STP 394;
Synthesis 2008, No. 10, 1641–1645 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Partial Oxidation of Alkenylsilanes with Ozone
1645
American Society for Testing and Materials: Philadelphia
PA, 1965. (b) Castrantas, H. M.; Banerjee, D. K. Laboratory
Handling and Storage of Peroxy Compounds, ASTM STP
471; American Society for Testing and Materials:
Philadelphia PA, 1970.
>80 °C in thermogravimetric analysis (TGA) of 2c and 4q;
see ref. 3.
(8) (a) Denmark, S. E.; Jones, T. K. J. Org. Chem. 1982, 47,
4595. (b) Igawa, K.; Tomooka, K. Angew. Chem. Int. Ed.
2006, 45, 232.
(9) A related reduction of silyl peroxide in a norcamphor
derivative has been reported, see: Jefford, C. W.; Rimbault,
C. G. J. Am. Chem. Soc. 1978, 100, 6437.
(7) Although Büchi’s trimethylsilyl peroxide is too reactive to
be handled with ease (see ref. 4), our silyl peroxides are
tolerant not only to the reductive workup process using
NaBH4 but also to purification on silica gel, most probably
due to the bulky silyl group on the peroxide moiety.
Furthermore, slow thermal degradation was observed at
(10) Cyclic peroxide has been utilized as a synthetic equivalent of
ketone, see: Singh, C.; Malik, H. Org. Lett. 2005, 7, 5673.
Synthesis 2008, No. 10, 1641–1645 © Thieme Stuttgart · New York