Direct selective and controlled protection of multiple hydroxyl groups in polyols via iterative regeneration of stannylene acetals

Article abstract of DOI:10.1016/j.tetlet.2009.03.114

A direct selective protection (O-benzylation) of two or more hydroxyl groups in polyols displaying diverse structural patterns was made possible by the establishment of conditions that enable an efficient turnover for the Bu₂Sn group, initially

Full text of DOI:10.1016/j.tetlet.2009.03.114

Tetrahedron Letters 50 (2009) 2744–2746
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct selective and controlled protection of multiple hydroxyl groups in polyols
via iterative regeneration of stannylene acetals
*
Alessandro B. C. Simas , Angelo A. T. da Silva, Tarcizio J. dos Santos Filho, Pedro T. W. Barroso
Universidade Federal do Rio de Janeiro, Núcleo de Pesquisas de Produtos Naturais (NPPN), Laboratório Roderick A. Barnes, Centro de Ciências da Saúde, bloco H,
Ilha do Fundão, Rio de Janeiro, RJ 21941-902, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct selective protection (O-benzylation) of two or more hydroxyl groups in polyols displaying
diverse structural patterns was made possible by the establishment of conditions that enable an efficient
turnover for the Bu2Sn group, initially at the corresponding stannylene acetals (only ꢀ1.0 mol equiv of
Bu2SnO was employed). It was also demonstrated that one might exert control over the number of pro-
tected groups, by means of appropriate tuning of reaction conditions. The feasibility of a substoichiomet-
ric (tin source) catalytic protocol was demonstrated as well.
Received 2 March 2009
Revised 13 March 2009
Accepted 16 March 2009
Available online 21 March 2009
Dedicated to professor Gilbert Stork for his
60-year professorship and his many seminal
contributions that helped to shape modern
Chemical Synthesis.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Polyol
Stannylene acetal
Catalysis
Benzylation
Protection of functional groups is a fundamental operation in
total syntheses. For various reasons, it is needed along the progres-
sive buildup of complexity in such processes.1 Protective transfor-
mations enabling direct selective incorporation of two or more
groups in multifunctional building blocks could diminish the cost
of such operations on synthetic efficiency. Despite the impressive
advances in Organic Synthesis, efficient and practical tools for con-
trol of regioselectivity in such contexts, particularly exploiting ef-
fects other than simple steric bias, are still needed.2 Polyols are
relevant molecular contexts for devising solutions to this problem.
Selective differentiation of the hydroxyl groups in carbohydrates,
for instance, is a fundamental issue in contemporary endeavors
such as syntheses of complex oligosaccharides (regiospecificity
regarding the free hydroxyl group for formation of a glycosidic
bond). This area of study continues to provide important tools for
probing intricate problems in Cell and Chemical Biology.3,4 The reg-
ioselectivity issue also arises in the use of these substances as
sources of chirality and/or functionalized carbon backbones5 in tar-
get-oriented synthesis.6 Herein, we report our results on the devel-
opment of a methodology which addresses this problem in a
conceptually different manner. We have found that selective
poly-protection of hydroxyl groups in polyols may be achieved
by means of a process wherein an activating group is reused con-
trollably. It is known that hydroxyl groups at 1,2- or 1,3-diol moi-
eties, by means of their stannylene acetal derivatives (1, Scheme
1),7,8 may be selectively modified (mono-O-alkylation, acylation,
sulfonylation, etc.) (such as in 1?2), even in the presence of other
similar diol moieties, in some cases.
Grindley’s group previously reported that, in the presence of
iPr2NEt (DIPEA), reactions of monostannylene derivatives of penta-
erythritol and two other similar polyols (also bearing primary hy-
droxyl groups), with BnBr could lead to complete mono-O-
Bu
HO HO
X
SnBu2Br
O
Bu Sn
O
OH
BnBr
BnO
O
OH
X
R
R´
R
R´
2
1
second
activation
base
SnBu2
O
OH
O
second
BnO
X
activation
R
R´
3
* Corresponding author. Tel.: +55 21 2652 6792; fax: +55 21 2562 6512.
E-mail addresses: abcsimas@nppn.ufrj.br, abcsimas@yahoo.com (A.B.C. Simas).
Scheme 1. Double activation of polyols via organotin species.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.114

A.B.C. Simas et al. / Tetrahedron Letters 50 (2009) 2744–2746
2745
Table 1
i. Bu2SnO
Direct di- and poly-O-protection of hydroxyl groupsa
O
O
(1.05 mol eq.),
MeOH, PhMe, Δ
O
O
OBn
OH
Entry
Substrate
Productb
Yield (%)
95
OH
OH
BnO
HO
ii. BnBr, DIPEA,
OH
5, 71 %
OH
(0.3M)
TBAB, PhMe, Δ
4
OH
OH
HO
OH
BnO
OBn
1
Scheme 2. Selective di-O-benzylation of 4 using equimolar Bu2SnO.
7
6
OH
OBn
benzylation of the 1,3-diol moieties.9,10 Our investigations have
established that halostannyl ether species (2) (Scheme 1) formed
in the medium can engage in further activations (protections) of
hydroxyl groups, either directly (from 2) or as a reformed stannyl-
ene derivative (involving step 2?3) in a controlled and tunable
fashion. Besides, in both cases, activations may occur in very good
selectivities in most of involved steps. In fact, we have found that
this reactivity mode may be exploited in reactions wherein regi-
oselectivity issues arise. O-Benzylations were chosen in our study
because of their importance in complex carbohydrate synthesis.
Moreover, the benzyl group is a model for a set of groups (display-
ing different aryl substituents) which allows the exploitation of
protecting strategies relying on principles of orthogonal lability.1
Thus, monostannylene derivative of 4 reacted with BnBr at 100,
120 °C leading to diether 5 in a single step (Scheme 2). No other di-
O-benzylated compound was detected. As occurred in other exper-
iments (See Table 1), the only significant component detected in
the reaction mixture, besides the desired product, was a mixture
of mono-O-benzyl ethers (C-3; C-6) in ꢀ20% yield. This transforma-
tion (synthesis of 5) could also be effected in absence of base (iPr2-
NEt: DIPEA) (56% yield). This additive nonetheless accelerated it,
allowing it to be performed at lower temperature. This strongly
indicates that, in the presence of base, formation of stannylene ace-
tals, from the halostannyl ether precursors, occurred.9 It is recog-
nized that halostannyl ethers are much less reactive than
stannylene acetals. Such difference in reactivity explains why
mono-O-protections of polyols via monostannylenes can be real-
ized, as commonly shown in the literature.
O
O
HO
HO
HO
2
3
4
5
89
HO
OH
BnO
O
O
9
8
OH
OBn
OH
O
OH
O
HO
HO
HO
55c
BnO
O
O
11
10
OH OBn OH
OH OBn OBn
88
OH
OBn
OBn OH
12
OBn OH
13a
OH
OH
OBn
OBn
1
OR
OR´
BnO
OH
OH
47d,e
HO
4
OBn
OBn
R= Bn(H);R´= H(Bn)
rac-14
15a(rac-15b)
O
O
O
O
OBn
6
78f
OH
BnO
OR´
HO
OH
OR
OH
R= Bn(H);R´= H(Bn)
rac-4
rac-16a(rac-16b)
We found that the direct multiple protections strongly depended
on the concentration of substrates in the medium. The reactions only
operated efficiently in concentrated media (polyol usually at
ꢀ0.3 M). Indeed, the reaction of 4, in the presence of DIPEA, when
runat0.1 M, instead, at100–130 °C(18 h)afforded53%of5. Through
this concentration window, even halostannyl ethers, such as 2
(Scheme 1), proved themselves (absence of base) nucleophilic en-
ough to successfully provide a second round of activation and hence,
O-alkylation (Note the result with 6, below). The interaction of the
tin atom with a neighboring (1,2- or 1,3-diol moiety) hydroxyl group
(as in 2, Scheme 1) appears to significantly enhance the reactivity of
halostannylethers formed after the first O-alkylation. If this interac-
tion is not possible, the reaction stops and one hydroxyl group is re-
tained. It is also noteworthy that these reactions (either entirely via
stannylene acetals, or partially via halostannyl ethers) led to the
same product (O-protections at C-3 and C-6) that was obtained via
the bis-stannylene derivative of acetonide 4.11
Glycerol (6) underwent the intended transformation at 100 °C
efficiently to afford product 7 (81% without base) (Table 1, entry
1). Building on these preliminary results, this methodology was ap-
plied to glucoside 8 and mannoside 10 (100 °C) to afford selectively
di-O-protected derivatives 9 and 11, respectively (Table 1, entries 2
and 3). The formation of substances 9 and 5 (from 4, Scheme 2) in
good yields, leaving one last 1,2-diol moiety untouched, clearly
indicates that, under this protocol, one can arrest the process at a
certain point. Some of the following data will show that one can
otherwise choose the reaction to proceed to further hydroxyl group
activations.
OR´
OBn OBn
OH OBn
OH
7
8
66g
OBn
OR OH
OH OH OH
R= Bn(H);R´= H(Bn)
17
13a(13b)
OH
OH OBn
OH OBn OBn
49
OH OH OH
OBn OH OH
18
17
OH
OH
OH
OBn
OH
9
42, 34e
OH
OH
BnO
OH
HO
OBn
OH
rac-20, 15
19
a
General conditions (See Supplementary data): (i) Bu2SnO (1.05–1.10 mol e-
quiv), MeOH/toluene, 100 °C, 3 h; (ii) BnBr, DIPEA, Bu4NBr (TBAB) (0.6 mol equiv),
toluene (0.3 M), 100–130 °C.
b
Pure compounds: only the specific regioisomers presented here were detected.
16% of mono-O-benzylated (C-3) product was also formed.
c
d
21% of rac-20 was formed as well.
15a/15b ratio = 1.5–2.0:1.0, respectively.
16a/16b ratio = 1.5–2.0:1.0, respectively.
13a/13b ratio = 3–4:1, respectively.
e
f
g
accordingly. Compound 14, a hard case,8c offered a particularly dif-
ferent challenge as the reaction centers are secluded in separate
Mannitol derivative 12 and myo-inositol derivative 14 (Table 1,
entries 4 and 5), which bear separate 1,2-diol moieties, also reacted

2746
A.B.C. Simas et al. / Tetrahedron Letters 50 (2009) 2744–2746
Bu2Sn(OMe)2
(0.16 mol eq.)
BnBr, DIPEA
derivatives (synthetic blocks, etc.). We believe that these results
motivate further developments in this important area.
OH OBn
OBn OH
OH OBn
HO
BnO
OBn
OH
TBAB, PhMe,
100-110oC
OBn OH
13a, 89%
Acknowledgments
12
We thank CNPq, CAPES, and UFRJ for funding and fellowships;
Central Analítica/NPPN, CNRMN/IBM-UFRJ, Depto. Química Inorgâ-
nica, Lab. Síntese Orgânica Ambiental/IQ-UFRJ and professor
Luzineide W. Tinoco for analytical data.
Scheme 3. Catalyzed di-O-benzylation of 12.
parts of a more rigid molecule. Notwithstanding the formation of
regioisomers (15a,b), resulting from low selectivity in the mono-
protection of the C4,C5-diol moiety, high chemoselectivity is main-
tained: only mono-O-benzylation at this moiety is observed.12 We
have not attempted to improve the yield of 15a,b.
Supplementary data
Supplementary data (experimental details and physical data for
products) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2009.03.114.
Furthermore, the feasibility of selective activation of multiple
hydroxyl groups was proven through reactions of tetrol 4 and pen-
tol 17 (Table 1, entries 6 and 7), which led to products of tri-O-ben-
zylation 16a and 13a as major regioisomers, respectively, in good
overall yields. In the case of reaction of compound 4, reaction chan-
neling to the formation of tri-O-protected product relied on the
reaction temperature (130 °C instead of 100 °C, 120 °C). As it oc-
curred in transformation 4?5 (Scheme 2), BnBr and DIPEA were
not used in large excesses. Thus, temperature plays a key role in
reaction tuning. We were also able to convert 17 into product of
di-O-alkylation 18 by simply using less BnBr (3.0 mol equiv) and
monitoring the reaction progress closely (Table 1, entry 8). In an at-
tempt to suppress formation of products of tribenzylation 13, low-
er reaction temperature (80–85 °C, 11 h) was tried, but it led to
lower yield of 18 (41%). This result suggests that, in cases of diffi-
culty in controlling the number of O-protections, it might be more
rewarding to maintain the reaction fast (higher temperature) and
to adjust the stoichiometry (BnBr).
References and notes
1. Schelhass, M.; Waldmann, H. Angew. Chem., Int. Ed. 1996, 35, 2056. and
references cited therein.
2. Menger, F. M.; Lu, H. Chem. Commun. 2006, 3235.
3. (a) Wang, C.-C.; Lee, J.-C.; Luo, S.-Y.; Kulkarni, S. S.; Huang, Y.-W.; Lee, C.-C.;
´
Chang, K.-L.; Hung, S.-C. Nature 2007, 446, 896; (b) Galonic, D. P.; Gin, D. Y.
Nature 2007, 446, 1000; (c) Fraser-Reid, B.; Madsen, R.; Campbell, A. S.; Roberts,
C. S.; Merrit, J. R. In Bioorganic Chemistry Carbohydrates; Hecht, S. M., Ed.; Oxford
University Press: Oxford, 1999; p 89.
4. Seeberger, P. H.; Werz, D. B. Nature 2007, 446, 1046.
5. (a) Bols, M. In Carbohydrate Building Blocks; WILEY-Interscience: New York,
1995; (b) Hanessian, S. Total Synthesis of Natural Products: The Chiron Approach;
Pergamon Press: Oxford, 1983.
6. Corey, E. J. The Logic of Chemical Synthesis; Wiley-Interscience: New York, 1989.
7. Selected reviews: (a) Grindley, T. B. Adv. Carbohydr. Chem. Biochem. 1998, 53,
17; (b) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643.
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Augé, C.; David, S.; Veyrières, A. J. J. Chem. Soc., Chem. Commun. 1976, 375; (c)
Simas, A. B. C.; Pais, K. C.; da Silva, A. A. T. J. Org. Chem. 2003, 68, 5426.
9. (a) Al-Mughaid, H.; Grindley, T. B. Carbohydr. Res. 2004, 339, 2607; Ohno and coll.,
had disclosed that the reaction of the monostannylene of glycerol, under the
effect of CsF (2.1 mol equiv was required), afforded 7 (71%). However, this
significant finding does not appear to be applicable to higher turnovers and more
complicate cases: (b) Nagashima, N.; Ohno, M. Chem. Pharm. Bull. 1991, 39, 1972.
10. Our first observations of successful multiple activations partially mediated by
halostannylethers (reactions of monostannylenes of glycerol and 4) occurred in
the course of a previous study (Ref. 8c).
An even more challenging substrate would be myo-inositol itself,
19. Gratifyingly, in an exploratory experiment, mono-stannylene of
19, despite its low solubility at the outset, reacted at 120–130 °C giv-
ing triether 20,13 as major product, in a single step (Table 1, entry
9).14 Ongoing investigation suggests that the yields of products like
20 (directly from 19) may be significantly increased by minimizing
formation of tetra-O-protected derivatives.
With the realization that a turnover process for the Bu2Sn group
was taking place in these transformations, we envisaged that a
substoichiometric catalytic procedure could be put forward.15,16
The successful reaction of tetrol 12 catalyzed by preformed Bu2S-
n(OMe)2 shows its feasibility (Scheme 3). In this experiment, start-
ing material (and intermediate triether, likely) remained mostly in
a second liquid phase before their consumption.
The underlying turnover of the activating group (Bu2Sn) relies,
most likely, on different dynamical processes allowing its mobility,
which include (intramolecular) migrations and intermolecular
transfers of this group.17 The latter processes are favored in more
concentrated mixtures.
In summary, a methodology for direct selective activation
(and protection) of multiple hydroxyl groups in polyols, exempli-
fied by reactions of O-benzylation, has been established as a
consistent synthetic tool. This establishes the selective protec-
tions of polyols via stannylene acetals as a more atom-econom-
ical methodology.18 Medium dilution and careful tuning of
appropriate reaction conditions (temperature, more importantly)
were identified as fundamental requisites for the needed turn-
over of the Bu2Sn group to operate efficiently. This work also
demonstrated that one can exert significant control over the
number of hydroxyl group activations, which greatly enhances
the flexibility of the methodology. Such control is a corollary
of the efficiency (adequate rates) and flexibility (tuning ability)
of this reactivity mode for stannylene acetals.
11. Desai, T.; Gigg, J.; Gigg, R.; Martín-Zamora, F.; Schnetz, N. Carbohydr. Res. 1994,
258, 135.
12. Partial loss of regioselectivity is also observed in the reactions leading to 16
and 13 (Table 1, entries 6 and 7). Our results show that this is a main issue in
reactions of direct tri-O-benzylation, whose last stage of diol monoalkylation,
only, occurs with low regioselectivity. In spite of this fact, syntheses like these
may be competitive due to the simplicity of the processes and the obtained
good yields. The alternative procedures usually employ larger amounts of tin
reagents or increased number of steps or both; for 15, see Refs. 8c,14; for 16:
(a) Desai, T.; Gigg, J.; Gigg, R.; Martín-Zamora, E. Carbohydr. Res. 1996, 296, 97;
(b) Ref. 8c.
13. For alternative syntheses of 20 involving increased number of steps or lower
yields, see: (a) Vacca, J. P.; deSolms, S. J.; Huff, J. R.; Billington, D. C.; Baker, R.;
Kulagowski, J. J.; Mawer, I. M. Tetrahedron 1989, 45, 5679; (b) Zapata, A.; de la
Padrilla, R. F.; Martin-Lomas, M.; Penadés, S. J. Org. Chem. 1991, 56, 444.
14. Interestingly, despite the use of a tight stoichiometry (4.0 mol equiv of BnBr),
good overall yield was obtained. A non-optimized experiment yielded 48% of
15 from myo-inositol, 19, in a single step. For a multistep alternative toward
this substance: Offer, J. L.; Voorheis, H. P.; Metcalfe, J. C.; Smith, G. A. J. Chem.
Soc. Perkin Trans 1 1992, 953. and references cited therein.
15. For seminal papers on the use of catalytic quantities of tin oxides in selective
O-sulfonylations and O-acylations: (a) Martinelli, M. J.; Vaidyanathan, R.;
Pawlak, J. M.; Nayyar, N. K.; Dhokte, U. P.; Doecke, C. W.; Zollars, L. M. H.;
Moher, E. D.; Khau, V. V.; Košmrlj, B. J. Am. Chem. Soc. 2002, 124, 3678. and
references cited therein; (b) Iwasaki, F.; Maki, T.; Nakashima, W.; Onomura, O.;
Matsumura, Y. Org. Lett. 1999, 1, 969. and references cited therein; (c)
Herradón, B.; Morcuende, A.; Valverde, S. Synlett 1995, 455.
16. Onomura and coworkers recently reported on selective acylations and related
transformations of polyols employing catalytic quatities of
a dialkyl tin
reagent: Demizu, Y.; Kubo, Y.; Miyoshi, H.; Maki, T.; Matsumura, Y.;
Moriyama, N.; Onomura, O. Org. Lett. 2008, 10, 5075.
17. For considerations on the dynamics of acylations mediated by stannylene
acetals advanced in previous studies: (a) David, S. Carbohydr. Res. 2001, 331,
327; (b) David, S.; Malleron, A. Carbohydr. Res. 2000, 329, 215; (c) Kong, X.;
Grindley, T. B. Can. J. Chem. 1994, 72, 2396.
Due to its broad scope, this methodology may be regarded as a
valuable alternative for fast access to selectively protected polyol
18. Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.