Unexpected cyclization during the mitsunobu reaction of d -talose derivatives

Article abstract of DOI:10.1055/s-0032-1318196

A d-talose derivative underwent unexpected cyclization during a Mitsunobu reaction. A plausible pathway for the reaction involves an attack of the nucleophilic azide on the benzyl ring by intramolecular cyclization with loss of the benzyl group. These newly formed, unexpected compounds may be used in the synthesis of derivatives of C-nucleosides. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318196

522▌
LETTER
lUettner expected Cyclization During the Mitsunobu Reaction of D-Talose
Derivatives
Mitsunobu Reaction of D-Talose Derivatives
Huei-Lin Chuang,1 R. C. Sawant,1 Shun-Yuan Luo*
Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan
Fax +886(4)22862547; E-mail: syluo@dragon.nchu.edu.tw
Received: 26.12.2012; Accepted after revision: 18.01.2013
to achieve inversion of stereochemistry in product 7 by
generating side products 8 and 9.
Abstract: A D-talose derivative underwent unexpected cyclization
during a Mitsunobu reaction. A plausible pathway for the reaction
involves an attack of the nucleophilic azide on the benzyl ring by in-
tramolecular cyclization with loss of the benzyl group. These newly
formed, unexpected compounds may be used in the synthesis of
derivatives of C-nucleosides.
Albeck et al. reported an unexpected rearrangement of
sugar derivatives during Mitsunobu epimerization.4a Sev-
eral protective groups are stable under Mitsunobu reaction
conditions; the benzyl group is relatively more susceptible
to the Mitsunobu conditions.4b However, a number of un-
expected rearrangements and migrations have been docu-
mented in the literature.5a–e Recently, Kulkarni et al.5f
examined debenzylative cyclization. In addition to these
studies, the rearrangements and cyclizations have been
documented extensively in related literature.6 We focused
on the development of simple methodologies for the syn-
thesis of tetrahydroxy-LCB (long-chain base) 11, which is
a component of natural cerebroside (10, Figure 1) and has
considerable biological activity.7 A few studies have ad-
dressed the synthesis of tetrahydroxy-LCB.8 However,
these studies examined the tetrahydroxy-LCB synthesis
using acetonide-protected D-galactose. Albeck et al.
reported4a the formation of unexpected products from D-
glucose, D-mannose, and D-galactose. To the best of our
knowledge, the unexpected products from D-talose have
not been reported in previous studies. Therefore, this is
the first study to address unexpected cyclization of D-
talose derivatives under Mitsunobu conditions.
Key words: Mitsunobu reaction, tetrahydroxy-LCB, D-talose,
nucleosides, cyclization
In the past few decades, the Mitsunobu reaction2 has at-
tracted considerable attention because of its broad appli-
cation in C–O, C–S, C–N, and C–C bond formation with
excellent stereochemical inversion.3 The mild reaction
conditions offer inversion of primary and secondary alco-
hols to various functional groups. Azido or phthalimido
nucleophiles can be installed on the alcohol starting mate-
rial followed by reduction to form the desired amines. For
clarity the general mechanistic pathway4a for the Mitsuno-
bu reaction is shown in Scheme 1. Initially, the nucleo-
philic attack of triphenylphosphine (1) on 2 forms a
betaine intermediate 3a and 3b deprotonates the alcohol
4a to form alkoxide 4b. This alkoxide 4b attacks the elec-
tron-deficient Ph3P to obtain intermediate 5. Finally, nu-
cleophile 6 attacks from the conflicting side of the alcohol
O
O
O
O
H
H+
N
OR
N
OR
RO
N
N
OR
RO
N
RO
N
Ph3P
O
2
Ph3P
3a
O
3b
R1
R2
R1
R2
– H+
Ph3P
OH
O
1
4a
4b
O
O
PPh3
O
H
N
R2
R1
8
OR
H+
RO
N
Ph3P
O
Nu
O
H
N
R2
7
OR
RO
N
H
R1
5
O
Nu–
9
6
Scheme 1 The Mitsunobu reaction mechanism
SYNLETT 2013, 24, 0522–0526
Advanced online publication: 29.01.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318196; Art ID: ST-2012-W1103-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Mitsunobu Reaction of D-Talose Derivatives
523
O
HN
OH
OH
OH
O
HO
HO
O
HO
OH OH
natural cerebroside (10)
NH2 OH
HO
OH OH
tetrahydroxy-LCB (11)
Figure 1 Structures of natural cerebroside (10) and (2S,3S,4R,5R,6Z)-2-amino-1,3,4,5-tetrahydroxyoctadecene (tetrahydroxy-LCB, 11)
We prepared acetonide-protected D-galactose9 as the able to obtain the expected product. Moreover, epimeriz-
starting material from the literature procedure. The syn- ing compound 13 using PCC11c oxidation and NaBH4
thesis began with a simple TBDPS-group10 protection of reduction resulted in the formation of a trace amount of
primary alcohol 12, which provided compound 13 in good the product. Conversely, Swern oxidation11c of compound
yield (Scheme 2). The epimerization of compound 13 ex- 13 followed by NaBH4 reduction also produced a trace
posed a number of failures; for example, a triflation11a re- amount of the product. Finally, the Dess–Martin periodin-
action in the presence of pyridine produced an ane reaction11d using 1.22 equivalents of Dess–Martin re-
intermediate triflation compound, whereas the SN2 reac- agent followed by NaBH4 reduction generated 20% of the
tion with H2O formed another compound that showed a product. The stepwise increase in the amount of the Dess–
higher polarity spot on the TLC plate than the starting ma- Martin reagent from 1.22 to 2.42 equivalents increased the
terial.
A similar triflation reaction followed by yield of product 14 considerably to 89%. The use of the
epimerization11b with NaNO2 in the presence of HMPA relatively costly Dess–Martin reagent provides an
resulted in several spots by TLC; therefore, we were un- excellent yield.
O
OTBDPS
OH
OH
O
O
OTBDPS
O
O
a
b
O
O
STol
O
STol
O
STol
HO
HO
14
13
12
OTBDPS
OBn
OTBDPS
OBn
O
O
O
c
e
d
O
O
STol
O
OH
15
16
O
O
O
C11H23
RO
BnO
HO
observed
+
19 R = TBDPS
20 R = Tr
g
RO
C11H23
O
BnO
N3
O
RO
C11H23
17 R = TBDPS
18 R = Tr
f
O
O
expected
21 R = TBDPS
22 R = Tr
Scheme 2 Preparation of compounds 19 and 20. Reagents and conditions: (a) TBDPSCl, imidazole, CH2Cl2, r.t., 84%; (b) (1) Dess–Martin
periodinane, CH2Cl2, r.t.; (2) NaBH4, MeOH, r.t., 89% in 2 steps; (c) BnBr, NaH, DMF, r.t., 90%; (d) NBS, acetone–H2O, 0 °C, 95%; (e)
LHMDS, C12H25PPh3Br, THF, –30 °C to 0 °C, 89% (cis/trans = 3.5:1); (f) (1) TBAF, THF, r.t., 93%; (2) TrCl, Et3N, DMAP, r.t., 76%; (g)
Ph3P, DIAD, DPPA, THF, 0 °C to r.t., 19: 64%; 20: 66%.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 522–526

524
H.-L. Chuang et al.
LETTER
The benzylation of compound 14 in the presence of sodi-
um hydride in DMF produced fully protected compound
15. The thiocresol at the anomeric carbon was hydrolyzed
using NBS in acetone–water at 0 °C which resulted in an
excellent yield of compound 16. Wittig reaction of 16 in
the presence of NaH12a and n-BuLi12b did not proceed,
whereas, in the presence of KOt-Bu a trace amount of the
product was formed. Furthermore, the use of LiHMDS12c
in anhydrous tetrahydrofuran at 0 °C formed an expected
product in a 43% cis/trans mixture of compounds. There-
fore, the reaction flask was stirred at –30 °C to 0 °C and
generated the expected compound 17 in 89% yield in a
3.5:1 ratio (cis/trans). This mixture of compounds was
separated using column chromatography to obtain the ma-
jor cis compound 17 in 70% yield.
H
H
H
O
H
O
H
O
C11H23
TrO
H
20
Figure 2 NOESY data for cyclic olefin 20
TBAF in THF, followed by tritylation in the presence of
trityl chloride in pyridine at room temperature. Subse-
quently, compound 18 was subjected to the Mitsunobu
conditions.13 The debenzylative cyclized product 20 evi-
dently indicated no effect of the bulky group at the prima-
ry carbon. A detailed analysis of the newly formed
compounds revealed the formation of the debenzylative
cyclized product (β-L-ribofuranose). These cyclized com-
pounds 19 and 20 can serve as valuable intermediates in
the synthesis of C-nucleosides and related analogues.15
The overall yield of compounds 19 and 20 were 28% and
29%, respectively.
To resemble the expected stereochemistry in tetra-
hydroxy-LCB at the C2 position, we tried to introduce an
azido group at the C2 position with inversion of configu-
ration using the Mitsunobu reaction. However, when alco-
hol 17 was subjected to the Mitsunobu conditions,13 and
the reaction was stirred at room temperature overnight, a
colorless liquid as the crude product was obtained, which
was purified using silica gel chromatography to produce
colorless oil 19. The 1H NMR analysis of the product in-
dicated that the benzyl protons have disappeared. Further-
more, olefinic protons moved upfield, indicating that the
group adjacent to the olefin may have changed. The MS
data showed an m/z peak at 615 corresponding to the [M
+ Na+] peak of the debenzylated compound. The 1H NMR
and 13C NMR spectra did not show benzylic aromatic pro-
tons and carbons. Furthermore, the IR spectra showed no
azido stretching vibration.
1
The H–1H COSY analysis permitted the assignment of
the H1–H5 and side-chain protons. A NOESY spectrum
of 20 (Figure 2) confirmed the correlation between the H2
proton and the olefin proton, and the correlation between
the H1 and H4 weak-proton interaction confirmed the
structure of compound 20.
This study led to the proposal of a suitable mechanism
based on previously reported mechanisms.4a When olefin
17 or 18 was subjected to the Mitsunobu reagents,14 we
expected the formation of the common, cyclic oxonium
intermediate 24 through intramolecular attack of the C14
benzylic oxygen on the C17 carbon bearing the activated
alcohol, through intermediate 23.
The TBDPS bulky group at the primary carbon may drive
the reaction to debenzylative cyclization. However, we
performed a similar reaction with another bulky trityl
group on the primary alcohol in adduct 17. Compound 18
was prepared by hydrolysis of the TBDPS group using
Nu
A
OR
B
BnO
HO
O
OBn
O
Bn
O+
C
O
PPh3
RO
C11H23
O
O
14
O
O
H23C11
RO
23
17 R = TBDPS
18 R = Tr
H23C11
24
starting material
path B
cyclization
path A
rearrangement
path C
OR
O
OR
OBn
OH
O
O
O
O
Nu
OBn
O
O
C11H23
RO
H23C11
19 R = TBDPS
20 R = Tr
H23C11
25
26
Scheme 3 Plausible mechanisms for the formation of the rearrangement products 19 and 20 during the Mitsunobu reaction on 17 and 18
Synlett 2013, 24, 522–526
© Georg Thieme Verlag Stuttgart · New York

LETTER
Mitsunobu Reaction of D-Talose Derivatives
525
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the common intermediate 24 in three manners. First, nu-
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yield the cyclized products 19 and 20 (path A, Scheme 3).
Second, a nucleophilic attack on the C17 carbon forms the
corresponding ester and after solvolysis the starting mate-
rial is obtained (path B, Scheme 3). Finally, a similar at-
tack occurs on the C14 carbon to obtain the rearranged
product 26 with inversion of configuration (path C,
Scheme 3). In addition, the approach in path A (Scheme
3) is more favorable for talose derivative 17 because only
a cyclized product without the formation of other rear-
ranged products was obtained, which may be attributed to
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Besides, the nucleophilicity of the C14 benzyloxy group
is susceptible enough to promote the cyclization reaction
rather than the rearrangement. Moreover, the steric hin-
drance of the neighboring acetonide inhibited the intermo-
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of the intermediate 23; therefore the reaction favored the
intramolecular attack of the C14 benzyloxy group to form
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blocked the azide nucleophile from favoring pathway B
and C.
In conclusion, D-talose derivatives exhibit unexpected ac-
tivity during Mitsunobu reaction. Bulky groups on the pri-
mary alcohol do not affect the driving force of the
Mitsunobu reaction and promote cyclization. However,
Albeck et al. indicated that D-glucose, D-mannose, and D-
galactose sugars undergo rearrangement. Further studies
will extend D-talose derivatives to these sugars for unex-
pected cyclization without the formation of other rear-
ranged products. These debenzylative cyclized products
may serve as intermediate compounds for the synthesis of
derivatives of C-nucleosides with potential applications in
the synthesis of natural products.
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Acknowledgment
(11) (a) Xiao, H.; Wang, G.; Wang, P.; Li, Y. Chin. J. Chem.
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The author thanks the National Science Council in Taiwan (NSC99-
2113-M-005-013-MY2 and NSC101-2113-M-005-006-MY2) and
National Chung Hsing University for financial support. R.C.S. ack-
nowledges the receipt of a doctoral fellowship from National Chung
Hsing University.
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(13) Procedure for the Synthesis of Compound 19
To a solution of olefin 17 (104 mg, 0.15 mmol) and Ph3P
(116 mg, 0.47 mmol) in anhyd THF (1 mL) was stirred at 0
°C. Diisopropyl azodicarboxylate (87 μL, 0.44 mmol) and
diphenyl phosphoryl azide (102 μL, 0.44 mmol) were slowly
added to the reaction mixture at 0 °C. The reaction mixture
was stirred at r.t. overnight. The solvent was evaporated and
the colorless oil 19 (57 mg, 0.096 mmol, 64%) was obtained
by column chromatography.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
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ti
References and Notes
(1) Huei-Lin Chuang and R. C. Sawant contributed equally to
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 522–526

526
H.-L. Chuang et al.
LETTER
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1H NMR (400 MHz, CDCl3): δ = 7.71–7.67 (m, 4 H, ArH),
7.45–7.26 (m, 6 H, ArH), 5.63–5.60 (m, 1 H, CH=CH),
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4.10 (td, J = 7.2, 4.0 Hz, 1 H, H-4), 3.77 (d, J = 3.6 Hz, 1 H,
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(m, 2 H, CH2), 1.35 (s, 3 H, CH3), 1.31–1.26 (m, 16 H, CH2),
1.06 (m, 9 H, CH3), 0.90–0.86 (m, 3 H, CH3). 13C NMR (150
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(CH), 133.3 (C), 133.1 (C), 129.71 (CH), 129.66 (CH),
127.72 (CH), 127.69 (2 × CH), 127.65 (2 × CH), 113.8 (C),
85.9 (CH), 84.0 (CH), 82.3 (CH), 80.5 (CH), 64.2 (CH2),
31.9 (CH2), 29.69 (CH2), 29.66 (CH2), 29.64 (CH2), 29.61
(CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 28.0 (CH2), 27.6
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Synlett 2013, 24, 522–526
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