An unexpected migration of O-silyl group under Mitsunobu reaction conditions

Article abstract of DOI:10.1016/j.tetlet.2011.04.015

A 1,4 O→O silyl migration followed by nucleophilic substitution with phthalimide was observed under Mitsunobu reaction conditions. This one step secondary alcohol protection and primary alcohol substitution with N-nucleophiles was extended to a variety of

Full text of DOI:10.1016/j.tetlet.2011.04.015

Tetrahedron Letters 52 (2011) 3045–3047
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Tetrahedron Letters
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An unexpected migration of O-silyl group under Mitsunobu reaction conditions
Ramu Sridhar Perali a, , Suresh Mandava b, Venkata Rao Chunduri b
⇑
a School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
b Department of Chemistry, Sri Venkateswara University, Tirupati, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A 1,4 O?O silyl migration followed by nucleophilic substitution with phthalimide was observed under
Mitsunobu reaction conditions. This one step secondary alcohol protection and primary alcohol substitu-
tion with N-nucleophiles was extended to a variety of 2-hydroxyethyl trialkylsilylether derivatives. A
possible mechanism has been postulated based on the pKa values of the alcohol and nucleophile. The
present one-pot silyl migration and substitution reaction might find application in the stereoselective
synthesis of novel iminosugar derived anti diabetic agents.
Received 7 February 2011
Revised 30 March 2011
Accepted 1 April 2011
Available online 19 April 2011
Keywords:
N-Nucleophiles
Ó 2011 Elsevier Ltd. All rights reserved.
1,4 O?O Silyl migration
Amino alcohols
Nucleophilic substitution
Carbohydrates
Mitsunobu reaction has been widely used in organic synthesis
for the stereochemical inversion of a hydroxyl carbon with several
nucleophiles.1 A number of protective groups are found to be stable
under this reaction conditions. Eventhough several reports were
published for the hydroxyl group inversion with different carbox-
ylic acids,2 comparatively, fewer methods were discussed with
nitrogen based nucleophiles.1d Trialkylsilyl group (R3Si-) serves as
an excellent protective group for alcohol function in total synthesis
of natural products.3 It is well documented that silyl protective
groups are stable under a variety of reaction conditions.4 However,
a few unexpected deprotection of trialkylsilyl groups were ob-
served in rare cases.5 It has been shown that these silyl protective
groups migrate to different nucleophilic centers in a molecule un-
der anionic conditions.6 These migrations are assumed to involve
nucleophilic attack at Si generating a pentaco-ordinate Si interme-
diate or transition state.7 Migrations involving 1,2-diol-1-trialkylsi-
lyl ether?1,2-diol-2-trialkylsilyl ether (1,4 O?O migration) are
very common under strong basic conditions8 with retention of con-
figuration at both the alcoholic carbon centers. However, in this
Letter we report an unexpected 1,4 O?O silyl migration, for the first
time under Mitsunobu reaction conditions.
HO
OH
O
1
O
O
6
5
OH
O
Ref. 11
39%
2
3
HO
OH
4
O
O
OH
1
-Fructose
2
D
I2, Ph3P,
imidazole
95%
O
I
O
O
O
i. Zn, THF:H2O
OR
ii. TBSCl/TBDPSCl,
imidazole, CH2Cl2
85%
O
4a
O
O
O
R = TBS
3
4b R = TBDPS
Scheme 1. Preparation of key intermediates 4a or 4b.
with iodine using I2/Ph3P/imidazole under reflux in toluene pro-
6-deoxy-6-iodo-1,2:3,4-di-O-isopropylidene-D-psicofura-
nose 3 in 95% yield. Zinc mediated fragmentation of 3 gave
vided
a-
hydroxy ketone in which the hydroxyl function was protected with
TBS (tert-butyldimethylsilyl) or TBDPS (tert-butyldiphenylsilyl)
without isolation to produce compound 4a or 4b, respectively, in
good yield (85% after two steps) (Scheme 1).
In our investigations for the synthesis of phytosphingosines9
from commercially inexpensive carbohydrate raw materials, we
planned to synthesize
1. Towards this, 1 was converted to the known 1,2:3,4-di-O-isopro-
D D-fructose
-ribo-phytosphingosine10 from
Reduction of ketone 4a with NaBH4 at À78 °C in ethanol12 pro-
vided 2,3-syn alcohol 5a13 and 2,3-anti alcohol 6a14 in a ratio of
1:24, respectively. When LAH was used as a reducing agent the ra-
tio of 5a and 6a was found to be 1:1. Interestingly, when LiAlH(O-t-
pylidene-D-psicofuranose 2 in an overall yield of 39% after four
steps.11 Substitution of the resulting primary hydroxyl group in 2
12
Bu)3 was employed for the reduction the ratio of 5a and 6a was
7:3, respectively, with 78% combined yield. Both the diastereomers
⇑
Corresponding author.
E-mail address: prssc@uohyd.ernet.in (R.S. Perali).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.015

3046
R. S. Perali et al. / Tetrahedron Letters 52 (2011) 3045–3047
can be isolated in pure form by conventional silica–gel column
chromatography. No major difference in diastereomeric ratio was
observed when the reduction was performed on TBDPS protected
ketone 4b to produce the corresponding 2,3-syn alcohol 5b and
2,3-anti alcohol15 6b (Scheme 2).
O
O
O
Ph3P, DIAD
phthalimide
OTBS
OTBS
NPhth
NPhth
OTBS
O
OH
O
O
THF, 0-25 o
C
5a
7
8
expected
observed
Having good amount of alcohol 5a in hand we planned to intro-
duce a protected amino group at C-2 position with inversion of
Scheme 3. Mitsunobu reaction on alcohol 5a.
configuration, to resemble the stereochemisry present in D-ribo-
phytosphingosine, using Mitsunobu reaction. For the convenience
we chose to use phthalimide as nucleophile. Accordingly, treat-
ment of alcohol 5a with Ph3P/DIAD/phthalimide in dry THF at
0 °C followed by allowing it to 25 °C, surprisingly, we obtained ole-
fin 8 as the sole product, instead of expected Mitsunobu substi-
tuted product 7. The formation of compound 8 can be envisaged
through a 1,4 O?O silyl migration followed by substitution at C-
1 with phthalimide. (Scheme 3).
The structure of compound 8 was confirmed by an upfield shift
of C-1 carbon and a down field shift of C-2 carbon in 13C NMR spec-
tra. It was also observed that the migration was occurred with
retention of configuration at C-2 position. The structure of com-
pound 8 was also confirmed by single crystal X-ray diffraction
(Fig. 1).16
Figure 1. ORTEP diagram of compound 8.17
The probable reason for the formation of 8 could be explained
based on the initial formation of ionpair (9 and 10) due to the low-
er pKa value of the alcohol 5 compared to the nucleophile, phthal-
imide. As illustrated in the proposed mechanism (Scheme 4)
oxyanion 10 could form the oxyphosphonium ion 1118 that could
undergo an SN2 substitution at C-2 to give the expected Mitsunobu
product 7. On the otherhand 10 may undergo a 1,4 O?O silyl
migration giving oxyanion 1219 which will produce oxyphosphoni-
um ion 13 followed by nucleophilic substitution at C-1 to produce
the observed product 8. As can be seen in the mechanism, the ap-
proach of the oxyanion 10 towards the phosphonium ion 9 to form
the oxyphosphonium ion 11 is inhibited by more steric hindrance
owing to the adjacent acetonide. Due to this reason, the facile for-
mation of oxyphosphonium ion 13 leads to the formation of prod-
uct 8.
A similar kind of reaction was observed even with alcohol 6a
producing compound 14 and in both cases no trace amount of
the expected Mitsunobu product was observed (Table 1, entry 1).
We further investigated the migratory aptitude of more stable
and bulky O-protective group TBDPS. Towards this, reaction of 5b
and 6b with phthalimide under Mitsunobu reaction conditions
again produced 15 and 16, respectively, similar to what we ob-
served for TBS derivatives (Table 1, entries 2 and 3). Similarly, reac-
tion of sugar derived alcohol 1720 with phthalimide under
Mitsunobu reaction conditions produced compound 18 as a single
product (entry 4).
O
O
-Ph3PO
OTBS
OTBS
O-PPh3
+
Nu
SN
2
O
O
Nu
7
substitution
11
O
H
N
O
N
H
O
Ph3P
DIAD
+
O
NuH
O
O
O
O
H
N
O
N
O
5a
+
N
N
OTBS
O
Ph3P
O
Ph3P
O
O
O
10
9
1,4(O O)
migration
O
NuH = HN
O
O
NuH
O
O
OTBS
H
N
O
N
H
O
O
O
12
O
O
O
-Ph3PO
SN2
+
Nu
O-PPh3
Nu
OTBS
OTBS
O
substitution
13
8
Scheme 4. Proposed mechanism for the formation of 7 and 8.
However, Mitsunobu reaction on simple TBS protected hydrox-
yacetonide 1921 gave a mixture of products 20 and 21 in a ratio of
4:6 which are derived from a 1,4 O?O silyl migration with reten-
tion of configuration and usual Mitsunobu inversion product,
respectively (entry 5). The formation of 21 may be due to the pres-
ence of less hindered terminal acetonide in 19. Finally, 1-(tert-
butyldimethylsilyloxy)propan-2-ol 22,22 in which no steric hin-
drance is present adjacent to the secondary alcohol, upon reaction
with Ph3P/DIAD/phthalimide in dry THF at 0–25 °C produced a
completely substituted product 23 without any migration of TBS
(entry 6).
O
O
O
i
+
OR
OR
OR
O
O
O
OH
O
OH
5a
5b
4a
4b
6a
6b
In conclusion, an interesting one-pot 1,4 O?O silyl migration
followed by nucleophilic substitution with phthalimide was dis-
cussed. The probability of the reaction has been evaluated by
applying the methodology to a number of substituted 2-hydroxy-
ethyl trialkylsilyl ethers. A tentative mechanism is proposed. The
application of this methodology towards the synthesis of 6-mem-
bered iminosugars23 as anti diabetic agents is under progress.
The present observation needs to be taken into account during
the planning of any synthesis involving Mitsunobu reaction24 at a
R = TBS (5a, 6a)
R = TBDPS (5b, 6b)
If (i) = NaBH4, -78 oC, EtOH, yield 85%. 5a:6a (1:24), 5b:6b (0:100)
(i) = LiAlH4, -78 oC, THF, yield 75%. 5a:6a (1:1)
(i) = LiAlH(O-tBu)3, -78 oC, EtOH, yield 78%. 5a or 5b: 6a or 6b (7:3)
Scheme 2. Reduction of ketones 4a and 4b.

R. S. Perali et al. / Tetrahedron Letters 52 (2011) 3045–3047
3047
Table 1
3. (a) Pierce, A. E. Silylation of Organic Compounds; Pierce Chemical: Rockford,
1968; (b) Sommer, L. H. In Stereochemistry, Mechanism and Silicon; McGraw-
Hill: New York, 1965; (c) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972,
94, 6190; (d) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4462; (e) Ogilvie,
K. K.; Sadana, K. L.; Thompson, E. A.; Quilliam, M. A.; Westmore, J. B.
Tetrahedron Lett. 1974, 15, 2861.
4. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis;
John Wiley Sons: New Jersey, 2007.
5. (a) Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2001, 57, 2109; (b) Kim, S.;
Jacobo, S. M.; Chang, C. –T.; Bellone, S.; Powellb, W. S.; Rokacha, J. Tetrahedron
Lett. 2004, 45, 1973.
6. For O?O migrations: (a) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout,
T. J. J. Am. Chem. Soc. 1990, 112, 7001; (b) Evans, D. A.; Gauchet-Prunet, J. A.;
Carreira, E. M.; Charette, A. B. J. Org. Chem. 1991, 56, 741; (c) Tirado, R.; Prieto, J.
A. J. Org. Chem. 1993, 58, 5666; For O?C migrations: (a) Marumoto, S.;
Kuwajima, I. J. Am. Chem. Soc. 1993, 115, 902; (b) Corey, E. J.; Rücker, Ch.
Tetrahedron Lett. 1984, 25, 4345; (c) Beese, G.; Keay, B. A. Synlett 1991, 33; (d)
Rücker, Ch. Tetrahedron Lett. 1984, 25, 4349; (e) Lautens, M.; Delanghe, P. H. M.;
Goh, J. B.; Zhang, C. H. J. Org. Chem. 1992, 57, 3270; (f) Kim, K. D.; Magriotis, P. A.
Tetrahedron Lett. 1990, 31, 613; (g) Hoffmann, R.; Briickner, R. Chem. Ber. 1992,
125, 1471; (h) Linderman, R. J.; Ghannam, A. J. Am. Chem. Soc. 1990, 112, 2392.
7. Muller, J.; Schöllhorn, B. Angew. Chem., Int. Ed. 1990, 29, 431.
Mitsunobu reaction products of differentially protected 2-hydroxyethyl trialkylsilyl
ether derivatives
Entry Alcohola
Product after Mitsunobu reactionb (%)
O
O
OTBS
NPhth
1
2
3
O
O
O
OH
6a
O
O
OTBS
14 (75)
O
O
O
OTBDPS
OTBDPS
NPhth
OTBDPS
OH
5b
15 (85)
O
NPhth
OH
6b
O
OTBDPS
16 (80)
TBSO
HO
PhthN
8. (a) Boger, D. L.; Ichikawa, S.; Zhong, W. J. Am. Chem. Soc. 2001, 123, 4161; (b)
Lassaletta, R. M.; Schmidt, R. R. Synlett 1995, 925; (c) Masaguer, C. F.; Bleriot, Y.;
Charlwood, J.; Winchester, B. G.; Fleet, G. W. J. Tetrahedron 1997, 53, 15147; (d)
Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3, 1049.
9. For a review see: Howell, A. R.; Ndakala, A. J. Curr. Org. Chem. 2002, 6, 365.
10. Zellner, J. Monatsh. Chem. 1911, 36, 133.
11. Mio, S.; Kumagawa, Y.; Sugai, S. Tetrahedron 1991, 47, 2133.
12. Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J. Org. Chem. 2002, 67, 1045.
13. Chang, C.-W.; Chen, Y.-N.; Adak, A. K.; Lin, K.-H.; Tzou, D.-L. M.; Lin, C.-C.
Tetrahedron 2007, 63, 4310.
14. Shiozaki, M.; Tashiro, T.; Koshino, H.; Nakagawa, R.; Inoue, S.; Shigeura, T.;
Watarai, H.; Taniguchi, M.; Mori, K. Carbohydr. Res. 2010, 345, 1663.
15. The numbers were assigned based on the starting material fructose.
16. Crystal data for compound 8 (C23H33NO5Si): Mr = 431.59, orthorhombic, space
group P212121 a = 7.5487 Å, b = 15.382 Å, c = 21.659 Å, V = 2514.8(10) Å3,
O
O
O
O
O
O
TBSO
4
BnO
17
BnO
18 (75)
O
O
O
O
O
+
O
OTBS
NPhth
OTBS
NPhth
21 (46)
5
6
OH
19
OH
TBSO
20 (31)
TBSO NPhth
TBSO
Z = 4, Mo
wR2 = 0.1556 (I >2
K
a
radiation (k = 0.71073 Å), T = 100(2) K; R1 = 0.0626,
(I)); R1 = 0.0667, wR2 = 0.1589 (all data). The CIF file for
22
23 (82)
r
the crystal data of compound 8 and 16 is available from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif under
CCDC ref no. 801190 and 801191, respectively.
a
No silyl-tropism was observed by stirring the alcohols in dry THF for 72 h at
25 °C.
b
Yield represents to pure and isolated products.
17. Hydrogen atoms were removed for clarity of the structure.
18. A similar kind of intermediate has been found in the azidation of 1,2 and 1,3-
diols by azidotrimethylsilane via a Mitsunobu reaction to give C-2 and C-3
azides, respectively. It is also noticed that the selectivity depends on the
surrounding sterichindrance of the C-2 or C-3 alcohol. (a) He, L.; Wanunu, M.;
Byun, H.-S.; Bittmann, R. J. Org. Chem. 1999, 64, 6049; (b) Mathieu-Pelta, I.;
Evans, S. A., Jr. J. Org. Chem. 1992, 57, 3409.
sterically hindered secondary alcohol that is spatially oriented to a
nearby silylether.
19. One of the intermediate similar to 12 has been isolated as an alcohol by
quenching a stirred mixture of DIAD, Ph3P and 6a in THF with water. This
intermediate was further confirmed by observing a downfield shift of C1
Acknowledgments
protons in the corresponding C1-O-acetylated derivative. Where as
downfield shift of C2 proton was observed in C2-O-acetylated derivative of
compound 6a.
a
This work was supported by the Department of Science and
Technology (DST) FAST track project grant No. SR/FTP/SC-64/
2007. M.S. and C.V.R. thank UGC Networking Facility to do research
work at University of Hyderabad.
20. Ashim, R.; Basudeb, A.; Sukhendu, B. M. Synthesis 2006, 1035.
21. Marco, J. L. J. Chem. Res. (S) 1988, 276.
22. Koppisch, A. T.; Blagg, B. S. J.; Poulter, C. D. Org. Lett. 2000, 2, 215.
23. (a) Martin, O. R.; Saavedra, O. M.; Xie, F.; Liu, L.; Picasso, S.; Vogel, P.; Kizu, H.;
Asano, N. Bioorg. Med. Chem. 2001, 9, 1269; (b) Goujon, J. –Y.; Gueyrard, D.;
Compain, P.; Martin, O. R.; Ikeda, K.; Kato, A.; Asano, N. Bioorg. Med. Chem.
2005, 13, 2313; (c) Bernotas, R. C.; Ganem, B. Tetrahedron Lett. 1985, 26, 1123;
(d) Bernotas, R. C.; Ganem, B. Tetrahedron Lett. 1985, 26, 4981; (e) Bernotas, R.
C.; Pezzone, M. A.; Ganem, B. Carbohydr. Res. 1987, 167, 305.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.015.
24. General procedure for Mitsunobu reaction: To a stirred solution of alcohol 5a
(300 mg, 0.99 mmol), Ph3P (781.6 mg, 2.98 mmol) and phthalimide (175.3 mg,
1.19 mmol) in dry THF (8 mL) at 0 °C was injected DIAD (602 mg, 2.98 mmol)
dropwise. The reaction mixture was allowed to stir at 25 °C for 6 h. After
completion of reaction (by TLC) the mixture was concentrated and the product
was purified by column chromatography using ethyl acetate: hexane (1:9) to
give compound 8 (322 mg, 75%) as a colorless liquid.
References and notes
1. For reviews see: (a) Mitsunobu, O. Synthesis 1981, l; (b) Castro, B. R. Org. React.
1983, 29, 1; (c) Hughes, D. L. Org. React. 1992, 42, 336; (d) Swamy, K. C. K.;
Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551.
2. Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994, 59, 234.