Synthesis of spirolactonic C-sialosides induced by samarium diiodide

Article abstract of DOI:10.1055/s-0033-1340067

A method for the synthesis of spiro-δ-lactonic α-C-sialosides by samarium diiodide mediated cyclization reactions of glycosyl 2-pyridylsulfides or acetates with appropriate carbonyl side chains has been developed. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340067

LETTER
▌375
lSetyternthesis of Spirolactonic C-Sialosides Induced by Samarium Diiodide
Synthesis of Spirolactonic C-Sialosides
Justine Pezzotta,a Dominique Urban,a Régis Guillot,b Gilles Doisneau,*a Jean-Marie Beau*a,c
a
Laboratoire de Synthèse de Biomolécules, Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), Université Paris-Sud and
CNRS, 91405 Orsay, France
Fax +33(1)69853715; E-mail: gilles.doisneau@u-psud.fr; E-mail: jean-marie.beau@u-psud.fr
b
c
Service de Cristallographie, Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), Université Paris-Sud and CNRS,
91405 Orsay, France
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
E-mail: jean-marie.beau@cnrs.fr
Received: 18.09.2013; Accepted after revision: 01.10.2013
been prepared as useful intermediates in the synthesis of
analogues of C-gangliosides8 or CMP-Kdo synthetase in-
hibitors.14
Abstract: A method for the synthesis of spiro-δ-lactonic α-C-sialo-
sides by samarium diiodide mediated cyclization reactions of glyco-
syl 2-pyridylsulfides or acetates with appropriate carbonyl side
chains has been developed.
We report here an intramolecular Refortmatsky
Key words: carbohydrates, chemoselectivity, coupling, cycliza- reaction15,16 that provides spirolactonic α-C-sialosides
tion, samarium
with complete control of configuration at the quaternary
stereogenic center. Intramolecular C-glycosylations pro-
moted by SmI2 have previously been demonstrated on
hexoses glycosyl sulfones by trapping the initial anomeric
radical with temporary silicon-tethered alkenes/alkynes,
in a 5-exo cyclization fashion.17
N-Acetylneuraminic acid (Neu5Ac) is the most important
and widespread member of the sialic acid series, which is
part of the large ulosonic acid family. This nine-carbon
sugar is mainly found at the terminal position of oligosac-
charides and glycoconjugates. As a result of this external
position, Neu5Ac is involved in many biological phenom-
ena.1–3 The α-glycosidic linkage of naturally occurring
sialosides is, however, not stable to chemical and enzy-
matic hydrolytic conditions, making them poor tools for
biological research. As a consequence, their C-glycosidic
analogues,4 in which the interglycosidic oxygen is re-
placed by a carbon atom, are of particular interest as bio-
logical tools, and their α-selective preparations have been
extensively studied.4a,b,d,5 High-yielding α-selective nu-
cleophilic C-sialylations are achieved from enolate equiv-
alents, which are conveniently obtained by reductive
samariation of thioglycosides,6,7 or, in a less direct ap-
proach, by deprotonation.8 The simplest reductive proce-
dure in the sialic acid series relies on samarium-mediated
Reformatsky coupling reactions using anomeric acetates
or 2-thiopyridyl sulfides.9 Selective electrophilic α-C-si-
alylations of simple nucleophiles are also now available.10
O
O
O
X
O
O
O
O
OAc
OAc
n
AcO
AcO
SmI2
n
R
AcHN
AcO
AcHN
AcO
HO
R
OAc
OAc
A
B
X = functional group sensitive to reductive samariation
O
O
OAc
anionic trap
AcO
O
AcHN
AcO
M
OAc
C
Scheme 1 Target structures A and the proposed approach for the
SmI2-induced intramolecular coupling process
We believed that a chemoselective, one-electron reduc-
tive transfer from the reagent would operate, with the an-
omeric substituent X in B (OAc, SPy) being reduced first,
instead of the carbonyl group. It would eventually lead,
through a second electron transfer, to a samarium enolate
or its organometallic equivalent C, triggering an exo-
cyclization onto a suitably positioned carbonyl group. As
noted earlier,9 the reducing conditions used should not af-
fect the many other reducible functional groups (ester,
N- and O-Ac) present in the substrates.
While preparing potential ligands for the influenza sur-
face glycoprotein hemagglutinin, we became interested in
the preparation of α-C-glycosyl derivatives of Neu5Ac
with spiro structures engaging the carboxylic acid func-
tion of the sugar.11 Although the spirolactonic motif is
widespread in many natural products, the stereoselective
formation of the quaternary spirocenter remains a chal-
lenge.12 The synthesis of spirolactones derived from car-
bohydrates has not been extensively reported.13 They have
To study this methodology, a series of Neu5Ac deriva-
tives was prepared with a side chain equipped with an in-
ternal anionic trap. We took advantage of the anomeric
carboxylic moiety in 1 and 2 to attach several chains with
a carbonyl group by standard esterification reactions
(Scheme 2). Acetylated carboxylic acid 1 was provided
in quantitative yield as the β-anomer almost exclusively
SYNLETT 2014, 25, 0375–0380
Advanced online publication: 05.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340067; Art ID: ST-2013-D0889-L
© Georg Thieme Verlag Stuttgart · New York

376
J. Pezzotta et al.
LETTER
(β/α > 20:1) from commercially available Neu5Ac by us- with peracetylated acid 1 was not effective, leading to the
ing standard acetic anhydride/pyridine conditions.18 Be- anomeric acylazido derivative as the unique product. The
cause we were unable to introduce directly the 2- mono-ester obtained with 1,3-propanediol (Table 1, entry
thiopyridyl group at the anomeric position of carboxylic 6) was directly oxidized, using two equivalents of Dess
acid 1, carboxylic acid 219 was prepared by a four-step Martin’s periodinane reagent in dichloromethane,26 to
protection/deprotection sequence (Scheme 2). Thus, allyl aldehyde 20 in 76% yield.
ester formation by treatment of 1 with cesium carbonate
The reductive samariation of the sialyl esters was con-
ducted at room temperature by using 3.0 equivalents of
and allylbromide in DMF furnished 3,20 and anomeric
chlorination (AcCl in MeOH–CH2Cl2)21 followed by a nu-
SmI2 as a freshly prepared 0.1 M THF solution. We start-
cleophilic substitution with 2-mercaptopyridine22 provid-
ed our study with 2-thiopyridyl glycosides 18 and 19,
which were the most promising substrates for the desired
regioselective reductive samariation of the anomeric sub-
ed thioglycoside 4 (66% yield from 3). Palladium-
catalyzed deallylation conducted at room temperature in
THF gave the corresponding carboxylic acid 2 in a 90%
stituent. Thioglycoside 1819 was very reactive and fur-
isolated yield.23
nished the six-membered ring lactone 2119 in an excellent
90% yield (Table 2, entry 1). Lactone 21 was isolated as a
OAc
OAc
OAc
OAc
CO2H
1:1 mixture of isomers, which were difficult to separate by
AcO
b
AcO
using silica gel column chromatography.27 The cycliza-
O
O
O
AcHN
AcO
AcHN
AcO
tion products showed a standard C2-chair conformation,
5
O
OAc
OAc
1 (β/α > 20:1)
a
1
as determined by H NMR analysis [JH3ax–H4, JH4–H5, and
3
Neu5Ac
JH5–H6 values of 10.7, 10.0, and 10.0 Hz for one isomer
(21R; first eluted isomer) and 11.4, 10.8 and 10.8 for the
other (21S; second eluted isomer)]. The equatorial orien-
tation of the newly formed carbon–carbon bond at the an-
omeric center in both products was determined by the
large values of 3JC1–H3ax of 9.5 Hz in 21R and 10.5 Hz in
21S.6b,9a,b Confirmation of the configuration at the quater-
nary center in 21S was provided by a single-crystal X-ray
analysis (Figure 1).28 This also unambiguously estab-
lished the stereochemistry at C1′ relative to the other
asymmetric centers, showing an S configuration at this
center in 21S.
c, d
O
O
O
OAc
OAc
CO2H
S
AcO
AcO
e
S
O
AcHN
AcO
AcHN
AcO
OAc
OAc
N
N
2
4
Scheme 2 Synthesis of carboxylic acids 1 and 2. Reagents and con-
ditions: (a) Ac2O in pyridine, quantitative; (b) allylbromide (1.5
equiv), Cs2CO3 (1.5 equiv) in DMF, r.t., 5 h, 85%; (c) AcCl, MeOH–
CH2Cl2 (1:1), r.t., 16 h; (d) 2-PyrSH (3 equiv), NBu4HSO3 (1 equiv),
EtOAc–NaHCO3 (aq) (1 M), r.t., 4 h, 66%, two steps; (e) morpholine
(30 equiv), Pd(PPh3)4 (0.1 equiv), THF, r.t., 1 h; Dowex H+, CH2Cl2,
0.5 h, 90%.
Esterification of the two sialic acid derivatives 1 and 2
with the appropriate keto-alcohols and 1,3-propanediol
was best achieved under two different reaction conditions
depending on the substrate. The application of either
Yamaguchi’s conditions24 (trichlorobenzoylchloride, Et3N
and DMAP in CH2Cl2) starting from acid 1, or conditions
involving phosphorylazide activation [diphenylphosphor-
ylazide (DPPA), Et3N in DMF]25 for acid 2, were applied
with 3–6 equivalents of alcohols 5–11 (Table 1). All alco-
hols were commercially available, except for keto-
alcohols 8–10, which were prepared by following a standard
synthetic sequence from 1,3-propanediol (monosilylation
and PCC oxidation gave the 3-O-silylated propanal,
which was treated with the appropriate Grignard reagent).
The secondary alcohol thus obtained was oxidized with
TEMPO and NaOCl and finally fluoride-mediated depro-
tection easily furnished the desired functionalized prima-
ry alcohols.
Anomeric esters 12–19 were provided in moderate to
good yields (50–78%) under either Yamagushi’s condi-
tions (conditions A; Table 1, entries 1–4) or DPPA (con-
ditions B; Table 1, entries 5 and 6). The DPPA procedure
Figure 1 Single-crystal X-ray structure of the peracetylated spiro
C-sialoside 21S (ORTEP drawing); ellipsoids are drawn at the 30%
probability level
Synlett 2014, 25, 375–380
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Spirolactonic C-Sialosides
377
Surprisingly, thiopyridyl glycoside 19, with an additional duced from which no cyclized product could be identified.
methylene group, only provided a complex reaction mix- The reductive cyclization of aldehyde 20, equipped with
ture from which the seven-membered-ring lactone could the easily reduced thio-pyridyl group, was inefficient for
not be identified. Although the reduction rate (first elec- cyclization.29 In this case, the chemoselectivity of the re-
tron transfer) of an anomeric axial β-acetate was slow duction was lost. Pinacol derivatives were obtained as the
compared to that of the 2- thiopyridyl group (2 h versus only identified products from the crude reaction mixture,
less than 1 min),9a,b regioselective reduction of the β-ace- arising from electron transfer in the aldehyde first.
tate anomeric substituent 13 also occurred, giving the
same spirolactones 21 in 70% yield, also as a 1:1 mixture
of isomers (Table 2, entry 3). Treatment of β-acetate 12 or
14 under identical SmI2 in THF conditions did not give the
This intramolecular Sm(II) reductive coupling process
thus appeared to be selective for the formation of δ-lac-
tones. This was confirmed by treating, under our reductive
samariation conditions, anomeric acetates 15–17, which
expected five- or seven-membered lactones 22 or 23 (Ta-
provided the corresponding δ-lactones 24–26 in 77–84%
ble 2, entries 2 or 4). Again, complex mixtures were pro-
Table 1 Esterification of Acids 1 and 2 with Keto-Alcohols and 1,3-Propanediol
Entry
Alcohol
Ester
Conditionsa
Yield (%)b
OAc
O
OAc
O
AcO
O
HO
O
Me
AcHN
AcO
Me
n
n
O
OAc
1
5 (n = 1)
6 (n = 2)
7 (n = 3)
12 (n = 1)
13 (n = 2)
14 (n = 3)
A
61 (n = 1)
60 (n = 2)
68 (n = 3)
OAc
OAc
AcO
HO
Et
O
O
Et
O
AcHN
AcO
O
O
O
O
O
OAc
2
3
8
15
A
A
77
60
OAc
AcHN
OAc
AcO
HO
i-Pr
i-Pr
O
AcO
O
OAc
9
16
OAc
OAc
AcO
O
HO
O
AcHN
AcO
O
O
O
OAc
4
5
6
10
17
A
B
B
50
O
O
O
O
O
OAc
Me
AcO
n
HO
Me
S(2-Py)
n
AcHN
AcO
OAc
6 (n = 2)
7 (n = 3)
18 (n = 2)
19 (n = 3)
53 (n = 2)
78 (n = 3)
O
O
O
O
OAc
AcO
HO
OH
S(2-Py)
AcHN
AcO
OAc
11
20c
72d
a Conditions A: trichlorobenzoylchloride (1.5 equiv), Et3N (1.5 equiv), DMAP (0.5 equiv), CH2Cl2. Conditions B: diphenylphosphorylazide
(DPPA; 1.2 equiv), Et3N (1.2 equiv), DMF.
b Isolated yields after silica gel chromatography.
c Compound 20 (76%) was obtained after Dess–Martin oxidation of the mono-ester of 1,3-propanediol (see text).
d Isolated yield of the mono-ester of 11.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 375–380

378
J. Pezzotta et al.
LETTER
Table 2 Synthesis of Spirolactone C-Sialosides by Reductive Cyclizationa
Entry
Substrate
Spiro-C-sialoside
Yield (%)b
1
O
O
O
OAc
3'
AcO
9
2
1'
AcHN
AcO
HO Me
OAc
18
19
1
21c
–
90
–
O
O
OAc
AcO
n
O
AcHN
AcO
Me
HO
OAc
2
3
4
12 (n = 1)
13 (n = 2)
14 (n = 3)
22 (n = 1)
21 (n = 2)
23 (n = 3)
–
70
–
O
O
OAc
AcO
O
AcHN
AcO
HO
R
OAc
5
6
7
15
16
17
24 (R = Et)
25 (R = i-Pr)
26 (R = c-Hex)
77
84
80
a Reaction conditions: SmI2 (3.0 equiv), THF, r.t., 0.5–2 h.
b Isolated yield as a 1:1 mixture of diastereomers.
c The two diastereomers 21R (first eluted isomer) and 21S (second eluted isomer) were separated by silica gel column chromatography.
yields as 1:1 mixtures of stereoisomers (Table 2, entries
5–7).
Acknowledgment
We thank the French Agency for Research (grant No. ANR-2010-
BLAN-708-1) and the Institut Universitaire de France (IUF) for the
financial support of this study. The CHARM3AT program is also
acknowledged for its support. We warmly thank Jean-Pierre Baltaze
(services communs, ICMMO) for his assistance in the HMBC NMR
experiments.
As previously demonstrated in the intermolecular process,
this intramolecular version provides the equatorial (‘α’
orientation) carbon–carbon bond at the anomeric center
with high selectivity with either an α-precursor (2-thio-
pyridyl glycoside 18) or a β-substrate (β-anomeric ace-
tates), pointing to a common intermediate. There is,
however, no control of the facial attack on the carbonyl,
giving rise to δ-lactones 21 and 24–26 as 1:1 mixtures of
diastereomers. The unsuccessful formation of five- and
seven-membered-ring spirolactones might be due to the
severe steric constraints in the pre-cyclizing structures of
the samarium enolate intermediate. Excellent results were
obtained for the formation of six-membered-ring products
even starting from the anomeric acetates, which were eas-
ily accessible in two steps from commercial Neu5Ac.
References and Notes
(1) Biology of Sialic Acids; Rosenberg, A., Ed.; Plenum: New
York, 1995.
(2) (a) Schauer, R. In Carbohydrates in Chemistry and Biology;
Vol. 3; Ernst, B.; Hart, G. W.; Sinaÿ, P., Eds.; Wiley-VHC:
Weinheim, 2000, 227. (b) Angata, T.; Varki, A. Chem. Rev.
2002, 102, 439.
(3) (a) Lingwood, C. A. Curr. Opin. Chem. Biol. 1998, 2, 695.
(b) Varki, A. Nature 2007, 446, 1023.
(4) Selected reviews on C-glycosides, see: (a) Beau, J.-M.;
Gallagher, T. Top. Curr. Chem. 1997, 187, 1. (b) Du, Y.;
Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998, 54, 9913.
(c) Dondoni, A.; Marra, A. Chem. Rev. 2000, 100, 4395.
(d) Somsák, L. Chem. Rev. 2001, 101, 81. (e) Liu, L.;
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1133.
(5) Reviews: (a) Skrydstrup, T.; Vauzeilles, B.; Beau, J.-M. In
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Glycoscience; Vol. 3; Fraser-Reid, B.; Tatsuta, K.; Thiem,
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Linhardt, R. J. Curr. Top. Med. Chem. 2005, 5, 1393.
In conclusion, the reductive samariation for the intramo-
lecular coupling reaction in the sialic acid series was suc-
cessfully developed for the α-selective preparation of
anomeric δ-spirolactones. Work is in progress to provide
more details on this transformation and to extend this pro-
cedure to the preparation of more complex cyclic C-sialo-
sides, which should be useful for exploring molecular
interactions with relevant binding proteins.
Synlett 2014, 25, 375–380
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Spirolactonic C-Sialosides
379
(6) (a) Vlahov, I. R.; Vlahova, P. I.; Linhardt, R. J. J. Am. Chem.
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= 5.5 Hz, JH8–H9a = 2.8 Hz, 1 H, H-8), 4.19 (q, JH5–H6 = JH5–H4
= JH5–NH = 10.1 Hz, 1 H, H-5), 4.09 (dd, JH9a–H9b = 12.2 Hz,
JH9a–H8 = 2.8 Hz, 1 H, H-9a), 4.04 (dd, JH6–H5 = 10.1 Hz, JH6–H7
(7) For reductive samariation on neutral hexoses, see:
(a) Mazéas, D.; Skrydstrup, T.; Beau, J.-M. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 909. (b) Miquel, N.; Doisneau, G.;
Beau, J.-M. Angew. Chem. Int. Ed. 2000, 39, 4111.
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Sodeoka, M. J. Am. Chem. Soc. 2007, 129, 15420.
(b) Watanabe, T.; Hirai, G.; Kato, M.; Hashizume, D.;
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(b) Sannigrahi, M. Tetrahedron 1999, 55, 9007.
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2012, 48, 756.
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Hengeveld, J.; Rosenbrook, W. Jr.; Whittern, D.; Wideburg,
N. Carbohydr. Res. 1990, 201, 209.
(15) (a) For SmI2-promoted Reformatsky reaction, see: Namy,
J.-L.; Girard, P.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102,
2693. For intramolecular versions, see: (b) Molander, G. A.;
Etter, J. B. J. Am. Chem. Soc. 1987, 109, 6556. (c) Molander,
G. A.; Etter, J. B.; Harring, L. S.; Thorel, P.-J. J. Am. Chem.
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3889. (e) Inanaga, J.; Yokoyama, Y.; Handa, Y.;
= 1.8 Hz, 1 H, H-6), 3.89 (dd, JH9b–H9a = 12.2 Hz, JH9b–H8
5.5 Hz, 1 H, H-9b), 2.88 (dd, JH3eq–H3ax = 12.3 Hz, JH3eq–H4
=
=
5.4 Hz, 1 H, H-3eq), 2.17, 2.10, 2.07 (s, 3 × 3 H, 3OAc), 2.05
(m, 1 H, H-3ax), 2.04 (s, 3 H, OAc), 1.94 (s, 3 H, NHAc). 13C
NMR (CDCl3, 90 MHz): δ = 170.9, 170.6, 170.5, 170.4,
169.9, 169.7 (6C, 6CO), 153.7, 147.3, 139.3, 124.6, 121.8
(5C, 5C-Ar), 85.7 (C-2), 74.8 (C-6), 69.9 (C-4), 68.8 (C-8),
66.8 (C-7), 61.6 (C-9), 49.3 (C-5), 37.8 (C-3), 23.1 (NHAc),
20.7–21.0 (4C, 4OAc). HRMS: m/z calcd for
C24H30N2NaO12S: 593.1417; found: 593.1405.
Pyridylsulfide 18: 1H NMR (CDCl3, 400 MHz): δ = 8.46
(ddd, J = 4.8, 1.8, 0.9 Hz, 1 H, ArH), 7.67 (dt, J = 7.8,
1.8 Hz, 1 H, ArH), 7.58 (dt, J = 7.8, 0.9 Hz, 1 H, ArH), 7.19
(ddd, J = 7.8, 4.8, 0.9 Hz, 1 H, ArH), 5.56 (d, JNH–H5
= 9.2 Hz, 1 H, NH), 5.32 (dd, JH7–H8 = 8.0 Hz, JH7–H6
= 1.2 Hz, 1 H, H-7), 5.21 (ddd, JH8–H7 = 8.0 Hz, JH8–H9b
= 5.2 Hz, JH8–H9a = 2.7 Hz, 1 H, H-8), 4.85 (ddd, JH4–H3ax or H5
= 11.4 Hz, JH4–H5 or H3ax = 10.1 Hz, JH4–H3eq = 4.7 Hz, 1 H, H-
4), 4.56–4.50 (m, 1 H, CH2-O), 4.29 (dd, JH9a–H9b = 12.4 Hz,
JH9a–H8 = 2.7 Hz, 1 H, H-9a), 4.20–4.05 (m, 4 H, H-9b, H-6,
H-5, CH2-O), 2.90-2.80 (m, 2 H, H-3eq, CH2), 2.74–2.64 (m,
1 H, CH2), 2.17, 2.12 (s, 2 × 3 H, 2OAc) 2.07 (m, 1 H, H-
3ax), 2.05, 2.02 (s, 2 × 3 H, 2OAc), 2.01 (s, 3 H, Me), 1.98 (s,
3 H, NHAc). 13C NMR (CDCl3, 100 MHz): δ = 206.1
(ketone), 170.6, 170.2, 170.0, 167.3 (6C, 6CO), 153.1,
149.7, 137.2, 129.1, 122.8 (5C, 5C-Ar), 86.0 (C-2), 74.6
(C-6), 69.5 (C-4), 69.4 (C-8), 67.5 (C-7), 62.0 (C-9), 60.5
(CH2), 48.8 (C-5), 41.8 (CH2), 38.3 (C-3), 30.1 (Me), 23.2
(NHAc), 20.8–21.0 (4C, 4OAc). HRMS: m/z calcd for
C28H36N2NaO13S: 663.1836; found: 663.1857.
Lactones 21: First eluted isomer 21R: 1H NMR (CDCl3,
400 MHz): δ = 5.75 (d, JNH–H5 = 10.0 Hz, 1 H, NH), 5.62
(ddd, JH4–H3ax = 10.7 Hz, JH4–H5 = 10.0 Hz, JH4–H3eq = 5.7 Hz,
1 H, H-4), 5.32 (dd, JH7–H8 = 9.6 Hz, JH7–H6 = 2.4 Hz, 1 H, H-
7), 5.23 (ddd, JH8–H7 = 9.6 Hz, JH8–H9b = 5.5 Hz, JH8–H9a
= 2.7 Hz, 1 H, H-8), 4.48 (ddd, J = 11.2, 10.7, 4.7 Hz, 1 H,
CH2-O), 4.26 (ddd, J = 11.2, 6.2, 2.7 Hz, 1 H, CH2-O), 4.26
(dd, JH9a–H9b = 12.8 Hz, JH9a–H8 = 2.7 Hz, 1 H, H-9a), 4.07 (q,
JH5–H6 = JH5–H4 = JH5–NH = 10.0 Hz, 1 H, H-5), 3.97 (dd, JH9b–H9a
= 12.8 Hz, JH9b–H8 = 5.5 Hz, 1 H, H-9b), 3.95 (dd, JH6–H5
= 10.0 Hz, JH6–H7 = 2.4 Hz, 1 H, H-6), 2.52 (s, 1 H, OH),
2.44 (ddd, J = 14.3, 10.7, 6.2 Hz, 1 H, CH2), 2.32 (dd,
JH3eq–H3ax = 13.6 Hz, JH3eq–H4 = 5.7 Hz, 1 H, H-3eq), 2.11,
2.08, 2.03, 2.01 (s, 4 × 3 H, 4OAc), 1.95 (dd, JH3ax–H3eq
= 13.6 Hz, JH3ax–H4 = 10.7 Hz, 1 H, H-3ax), 1.89 (s, 3 H,
NHAc), 1.68 (ddd, J = 14.3, 4.7, 2.7 Hz, 1 H, CH2), 1.42 (s,
3 H, Me). 13C NMR (CDCl3, 100 MHz): δ = 171.0, 170.7,
170.6, 170.0, 169.8 (6C, 6CO), 79.7 (C-2), 73.2 (C-OH),
72.7 (C-6), 70.8 (C-4), 68.0 (C-8), 67.0 (C-7), 66.2 (CH2),
62.3 (C-9), 49.2 (C-5), 32.0 (CH2), 30.5 (C-3), 23.5 (CH3),
23.1 (NHAc), 20.7, 20.8, 21.0 (4C, 4OAc). HRMS: m/z
calcd for C23H33NNaO13: 554.1850; found: 554.1831.
Second eluted isomer 21S: 1H NMR (CDCl3, 400 MHz):
δ = 5.87 (d, JNH–H5 = 10.8 Hz, 1 H, NH), 5.40 (ddd, JH8–H7
= 9.6 Hz, JH8–H9b = 5.6 Hz, JH8–H9a = 2.4 Hz, 1 H, H-8), 5.34
(dd, JH7–H8 = 9.6 Hz, JH7–H6 = 2.5 Hz, 1 H, H-7), 5.21 (ddd,
JH4–H3ax = 11.6 Hz, JH4–H5 = 10.8 Hz, JH4–H3eq = 4.8 Hz, 1 H,
H-4), 4.73 (dd, JH6–H5 = 10.8 Hz, JH6–H7 = 2.5 Hz, 1 H, H-6),
4.56 (ddd, J = 11.3, 8.7, 6.0 Hz, 1 H, CH2-O), 4.27 (ddd,
J = 11.3, 6.6, 4.5 Hz, 1 H, CH2-O), 4.23 (dd, JH9a–H9b
= 12.4 Hz, JH9a,H8 = 2.4 Hz, 1 H, H-9a), 4.12 (q, JH5–H4
= JH5,H6 = JH5,NHAc = 10.8 Hz, 1 H, H-5), 4.02 (dd, JH9b–H9a
= 12.4 Hz, JH9b–H8 = 5.6 Hz, 1 H, H-9b), 3.39 (s, 1 H, OH),
2.29 (dd, JH3eq–H3ax = 13.2 Hz, JH3eq–H4 = 4.8 Hz, 1 H, H-3eq),
Yamaguchi, M. Tetrahedron Lett. 1991, 32, 6371.
(f) Rudkin, I. M.; Miller, L. C.; Procter, D. J. Organomet.
Chem. 2008, 34, 19. (g) Ocampo, R.; Dolbier, W. R. Jr.
Tetrahedron 2004, 60, 9325.
(16) For selected reviews, see: (a) Molander, G. A. Chem. Rev.
1992, 92, 29. (b) Edmonds, D. J.; Johnston, D.; Procter, D. J.
Chem. Rev. 2004, 104, 3371. (c) Procter, D. J.; Flowers, R.
A. II.; Skrydstrup, T. In Organic Synthesis using Samarium
Diiodide: A Practical Guide; RSC Publishing: Cambridge,
2009.
(17) (a) Chénedé, A.; Perrin, E.; Rekaï, E. D.; Sinaÿ, P. Synlett
1994, 420. (b) Mazéas, D.; Skrydstrup, T.; Doumeix, O.;
Beau, J.-M. Angew. Chem., Int. Ed. Engl. 1994, 33, 1383.
(c) Skrydstrup, T.; Mazéas, D.; Elmouchir, M.; Doisneau,
G.; Riche, C.; Chiaroni, A.; Beau, J.-M. Chem. Eur. J. 1997,
3, 1342.
(18) Meindl, P.; Tuppy, H. Monatsh. Chem. 1965, 96, 802.
(19) Selected Spectroscopic Data; Acid 2: 1H NMR (CDCl3,
360 MHz): δ = 8.78 (d, J = 5.2 Hz, 1 H, ArH), 7.81 (t,
J = 7.7 Hz, 1 H, ArH), 7.40 (d, J = 7.7 Hz, 1 H, ArH), 7.31
(dd, J = 7.7, 5.2 Hz, 1 H, ArH), 6.59 (d, JNH–H5 = 10.1 Hz,
1 H, NH), 5.37 (ddd, JH4–H3ax = 10.8 Hz, JH4–H5 = 10.1 Hz,
JH4–H3eq = 5.4 Hz, 1 H, H-4), 5.34 (dd, JH7–H8 = 8.1 Hz, JH7–H6
= 1.8 Hz, 1 H, H-7), 5.08 (ddd, JH8–H7 = 8.1 Hz, JH8–H9b
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 375–380

380
J. Pezzotta et al.
LETTER
2.15, 2.14 (s, 2 × 3 H, 2OAc), 2.09 (m, 1 H, CH2), 2.06, 2.01
(s, 2 × 3 H, 2 × OAc), 1.97 (m, 1 H, CH2), 1.94 (dd, JH3ax–H3eq
= 13.2 Hz, JH3ax–H4 = 11.6 Hz, 1 H, H-3ax), 1.90 (s, 3 H,
NHAc), 1.36 (s, 3 H, Me). 13C NMR (CDCl3, 100 MHz): δ =
172.7, 170.8, 170.7, 170.5, 170.4, 170.0 (6C, 6CO), 80.7 (C-
2), 73.6 (C-6 or C-OH), 73.4 (C-6 or C-OH), 69.6 (C-4), 67.7
(C-8), 67.2 (C-7), 66.6 (CH2), 62.8 (C-9), 49.1 (C-5), 32.9
(C-3), 32.7 (CH2), 23.1 (NHAc), 21.7 (CH3), 20.7, 20.8,
20.9, 21.0 (4C, 4OAc). HRMS: m/z calcd for
under an argon atmosphere. The solution was stirred at r.t.
for 2 h. The initial blue color of the mixture then became
yellow. The reaction was quenched by the addition of a few
drops of a sat. aq NH4Cl. The aqueous layer was extracted
four times with CH2Cl2 and the organics layers were
combined and washed with sat. aq NaHCO3. The aqueous
layers were extracted three times with CH2Cl2 and the
organic layers were combined, dried under Na2SO4, filtered
and concentrated under vacuum. The obtained residue was
purified by silica gel chromatography (toluene–acetone, 3:1
to 2:1), furnishing the separated two stereoisomers of
spirolactones 21 (75 mg total, 0.14 mmol, 90%).
C23H33NNaO13: 554.1850; found: 554.1831.
(20) Kunz, H.; Waldmann, H. J. Chem. Soc., Chem. Commun.
1985, 638.
(21) Shpirt, A. M.; Kononov, L. O.; Torgov, V. I.; Shibaev, V. N.
Russ. Chem. Bull. Int. Ed. 2004, 53, 717.
Spirolactone 21S was recrystallized in CH2Cl2–Et2O (mp
207 °C).
(22) Cao, S.; Meunier, S. J.; Andersson, F. O.; Letellier, M.; Roy,
R. Tetrahedron: Asymmetry 1994, 5, 2303.
(28) The X-ray diffraction data were collected with a Kappa X8
APPEX II Bruker diffractometer with graphite-
(23) Kunz, H.; Waldmann, H.; Klinkhammer, U. Helv. Chim.
Acta 1988, 71, 1868.
(24) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
monochromated MoKα radiation (λ = 0.71073 Å). CCDC
959507 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via
(25) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc.
1972, 94, 6203.
http://www.ccdc.cam.ac.uk/Community/Requestastructure.
(29) For the formation of similar spirocyclic six-membered
lactones by using a SmI2-mediated aldol reaction with
aldehydes, see: (a) Helm, M. D.; Sucunza, D.; Da Silva, M.;
Helliwell, M.; Procter, D. J. Tetrahedron Lett. 2009, 50,
3224. (b) Helm, M. D.; Da Silva, M.; Sucunza, D.; Helliwell,
M.; Procter, D. J. Tetrahedron 2009, 65, 10816.
(26) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(27) Reductive Cyclization of 18; Typical Procedure: A
freshly prepared solution of samarium diiodide (0.1 M in
THF, 4.7 mL, 3.0 equiv) was added to sialyl derivative 18
(100 mg, 0.16 mmol) previously dissolved in THF (0.5 mL)
Synlett 2014, 25, 375–380
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