Enantiopure alkaloid analogues and iminosugars from proline derivatives: stereocontrol in sequential processes

Article abstract of DOI:10.1016/j.tetlet.2009.04.082

An alternative to the use of expensive auxiliaries or catalysts in the synthesis of chiral 2-substituted pyrrolidines is described. Thus, commercial, cheap 4-(S)-hydroxyproline was readily transformed into optically pure pyrrolidines, using a one-pot deca

Full text of DOI:10.1016/j.tetlet.2009.04.082

Tetrahedron Letters 50 (2009) 3974–3977
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantiopure alkaloid analogues and iminosugars from proline derivatives:
stereocontrol in sequential processes
*
*
Alicia Boto , Dácil Hernández, Rosendo Hernández
Instituto de Productos Naturales y Agrobiología CSIC, Avda. Astrofísico Fco. Sánchez 3, 38206-La Laguna, Tenerife, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
An alternative to the use of expensive auxiliaries or catalysts in the synthesis of chiral 2-substituted pyr-
rolidines is described. Thus, commercial, cheap 4-(S)-hydroxyproline was readily transformed into opti-
cally pure pyrrolidines, using a one-pot decarboxylation–alkylation reaction as the key step. In this
reaction, an acyliminium intermediate was generated, which was trapped by carbon nucleophiles. As
postulated by Woerpel, the addition of the nucleophiles to the five-membered ring iminium ions took
place stereoselectively, affording 2,4-cis-disubstituted pyrrolidines in high de. The hydroxy group at C-
4 can then be removed, or alternatively, it can be used to create new functionalities in the molecule.
In this way, optically pure alkaloid analogues and iminosugars were prepared.
Received 17 March 2009
Revised 21 April 2009
Accepted 22 April 2009
Available online 3 May 2009
Keywords:
Azanucleosides
Nucleoside analogues
Radical reactions
Decarboxylation
Iminium ions
Ó 2009 Elsevier Ltd. All rights reserved.
The preparation of optically pure pyrrolidine derivatives has
elicited much interest, since these heterocycles are present in
many bioactive compounds (such as alkaloids or iminosugars),1
whose biological activity is often related to the stereochemistry
of the product. Among the asymmetric methodologies to prepare
substituted pyrrolidines or pyrrolidinones, the addition of nucleo-
philes to cyclic iminium ions2 bearing chiral auxiliaries has been a
key step in the synthesis of different bioactive compounds [e.g.,
conversion 1?2 (Scheme 1), in the preparation of alkaloid (ꢀ)-
205A].3 The use of chiral catalysts instead of chiral auxiliaries
avoids the protection–deprotection steps. The appropriate cata-
lysts or auxiliaries could vary for even related substrates.4
On the other hand, when five-membered ring iminium or oxo-
nium ions (such as 3a and 3b, Scheme 2) present stereogenic cen-
ters, the addition of nucleophiles is stereoselective, and the
preferred face for the addition depends on the nature of the substi-
tuent.5 Thus, Woerpel postulated that alkyl groups (such as Me) fa-
vor an envelop conformation 3a where the alkyl substituent is
equatorial. On the contrary, the alkoxy or acyloxy functions favor
an envelop conformation 3b, with a pseudoaxial OR group, due
to stabilizing electrostatic interactions between the oxygen lone
electron pairs and the iminium ion.5b In both cases, the nucleophile
adds from the inner face, to avoid eclipsing interactions on the for-
mation of the product.6
H
H
O
MgCl
S
O
O
Ph
N
N
N
O
ZnI2, THF,
0 oC, 99%
Ar
Ar
2
H
H
1
2
Alkaloid
(−)-205A
Precursor of the
acyliminium ion
Ar = 2,6-Cl2-Ph
Scheme 1. Addition of nucleophiles to iminium ions.
TMS
4
X
+
X
2
H
4a
3a X = N-acyl, O
2,4-trans-product
TMS
4
+
X
2
X
OBn
H
Therefore, the intermediate 3a would yield a 2,4-trans product
while the intermediate 3b would afford a 2,4-cis product.
BnO
4b
3b X = N-acyl, O
2,4-cis-product
* Corresponding authors. Tel.: +34 922 260112; fax: +34 922 260135 (A.B.).
E-mail addresses: alicia@ipna.csic.es (A. Boto), rhernandez@ipna.csic.es (R.
Hernández).
Scheme 2. Woerpel’s stereoselectivity rules for the addition of nucleophiles to
cyclic iminium or oxonium ions.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.082

A. Boto et al. / Tetrahedron Letters 50 (2009) 3974–3977
3975
We reasoned that this stereocontrol effect could be used to ob-
reducing the waste. Thus,
achieved.
a
more sustainable chemistry is
tain optically pure pyrrolidines from inexpensive 4-(S)-hydroxy-
proline derivatives (such as the methyl carbamate 5, Scheme 3),
using a sequential process that would couple a decarboxylation
to an alkylation reaction. By using sequential processes,7 the isola-
tion of intermediates is avoided, saving materials and time and
Our group has developed different sequential processes8a–c ini-
tiated by radical reactions,8 and we are currently exploring stereo-
selective versions of these processes. For instance, we have studied
the decarboxylation of proline derivatives where a chiral auxiliary
is attached to the nitrogen. However, these auxiliaries are expen-
sive and in many cases the stereoselectivity was not satisfactory.9
An alternative would be the use of chiral substrates where the ste-
reogenic centers could be later removed or transformed. This Letter
explores the feasibility of this approach.
One-pot
radical
scission−
MeO2C
N
MeO2C
N
CO2Me
N
CO2H
Nu
Nu
2
2
Thus, 4-(S)-hydroxyproline 5 was readily converted into ether
or silyl ether derivatives 6, which were treated with (diacetoxy-
iodo)benzene and iodine under irradiation with visible light (sun-
light or commercial lamps).10 Under these conditions, a radical
decarboxylation took place, followed by oxidation of the resulting
C-radicals 7 to the acyliminium intermediates 8, which were
trapped by allylsilanes or silyl enolethers. The nucleophiles added
preferentially from the inner face of the envelop conformation,
affording 2,4-cis-pyrrolidines 9. The OR group at C-4 can be re-
moved or replaced by other functionalities, affording optically pure
substituted pyrrolidines 10.
4
oxidation−
alkylation
X
RO
5 R = H
RO
9
10
X = H, OH, N3,
NH2, etc
6 R = alkyl, silyl
Optically pure
Nu−
CO2Me
OR
N
[Ox]
H
.
CO2Me
N
+
RO
H
To study the influence of the protecting group on the yield and
stereoselectivity, the hydroxyproline derivatives 11–14 (Table 1)
were used as substrates. Their R groups, which differ in volume,
are easily introduced and removed.
7
8
Scheme 3. Stereoselective decarboxylation–oxidation–alkylation.
Table 1
Stereoselective decarboxylation–oxidation–alkylation
Substrate
Decarboxylation–allylation products, yieldsa (%)
Decarboxylation–alkylation products, yieldsb (%)
CO2Me
CO2Me
N
CO2Me
N
N
CO2H
2'
5
5
Ph
1'
1'
2
2
3'
2'
4
4
O
BnO
BnO
BnO
15 (72)
19 (84)
11
CO2Me
CO2Me
N
CO2Me
N
CO2Me
N
N
CO2H
Ph
Ph
+
O
O
Ph3CO
Ph3CO
Ph3CO
Ph3CO
c
16 (91)
20
21
12
c
20:21, 2:1 mixture, 68%
CO2Me
CO2Me
N
CO2Me
N
N
CO2H
Ph
O
Si
O
TBSO
TBSO
17 (77)
13
22 (66)
CO2Me
N
CO2Me
N
CO2Me
CO2Me
N
N
CO2H
Ph
TBDPSO
Ph
+
Ph
Ph
O
O
Si
O
TBDPSO
TBDPSO
14
18 (78)
23 (63)
24 (25)
a
b
c
PhI(OAc)2 (2 equiv) I2 (0.5 equiv), CH2Cl2, h
PhI(OAc) (2 equiv) I (0.5 equiv), CH2Cl , h
, 3 h; then 0 °C, BF3ꢁOEt (2 equiv), PhC(OTMS)@CH (3 equiv), 1 h.
When substrate 12 was used, the nucleophilic addition was carried out at ꢀ50 °C to avoid trityl ether cleavage.
m, 3 h; then 0 °C, BF3ꢁOEt2 (2 equiv), allylTMS (3 equiv), 1 h.
m

3976
A. Boto et al. / Tetrahedron Letters 50 (2009) 3974–3977
The substrates underwent the scission–alkylation procedure,11
CO2Me
N
CO2Me
N
OsO4, NMO,
acetone, H2O
using allylTMS or silyl enol ethers as nucleophiles, affording 2-allyl
derivatives 15–1812,13 and 2-acetophenone derivatives 19–2412 in
good yields (66–91%) and in most cases, high diastereomeric ex-
cess. With relatively small-size nucleophiles such as allylTMS,
excellent stereoselectivities were observed in all cases. However,
with bulkier reagents such as PhC(OTMS)@CH2 and larger R pro-
tecting groups such as trityl and TBDPS, a mixture of diastereomers
was obtained, with the cis isomer as the major one. The attack from
the inner face would be less favored due to steric interactions be-
tween the protecting group and the nucleophile.
The 2-allyl derivatives 15–18 are ring-contracted analogues of
the poisonous coniine,14 while the 2-acetophenone derivatives
19–24 are ring-contracted analogues of sedamine.15 This method
would also allow the introduction of other substituents, affording
other alkaloid analogues.1
62%
HO
OH
27
29
1. MCPBA, CH2Cl2
75%
2. NaN3, acetone/H2O
76%
CO2Me
N
CO2Me
H2, Pd(OH)2/C,
MeOH, 25 oC
N
90%
H2N
OH
N3
OH
30
31
After the asymmetric scission–alkylation reaction, the 4-OR
group could be deprotected, and the resulting OH was removed
by radical deoxygenation, or elimination/reduction, as illustrated
with the synthesis of (+)-norconiine methyl carbamate (Scheme
4).16 Thus, the decarboxylation–allylation product 17 was desily-
lated to the alcohol 25, and the lateral chain was reduced, giving
compound 26. The removal of the 4-hydroxy group took place in
two steps and afforded the olefin 27 in good overall yield. The lat-
ter was hydrogenated, affording the pure (+)-norconiine methyl
carbamate 28.
Alternatively, the hydroxy group at C-4 could be used to intro-
duce new functionalities in the molecule. Thus, the elimination
product 27 was transformed into iminosugar derivatives 29–31
(Scheme 5). Many iminosugars are potent glycosidase inhibitors,
and display cytotoxic, antiviral, or hypoglucemic activities.17 They
are also precursors to azanucleosides, which have been used as
inhibitors of enzymes, antitumoral agents, etc.18 As a result, the
development of procedures to obtain a variety of azasugars has
an ongoing interest.
As shown in Scheme 5, the enantiopure pyrrolidine 27 was
readily converted into iminosugar 29 using a dihydroxylation reac-
tion.19 Also, the epoxidation of substrate 27, followed by ring open-
ing with sodium azide, generated compound 30. The azide group
was reduced by hydrogenation,20 yielding the iminosugar 31.21
Other functionalities can be introduced using similar strategies.
Since commercial 4-(S)-hydroxyproline can be easily trans-
formed into 4-(R)-hydroxy, alkoxy or acyloxy derivatives, this
methodology would also afford the opposite series of enantio-
mers.22 We are currently exploring the stereoselective formation
of new alkaloid and iminosugar derivatives, which will be pub-
lished in due time.
Scheme 5. Stereoselective decarboxylation–oxidation–alkylation.
Acknowledgments
This work was supported by the Research Program CTQ2006-
14260/PPQ (Plan Nacional de Investigación Científica, Desarrollo
e Innovación Tecnológica, Ministerio de Educación y Ciencia,
Spain). We also acknowledge financial support from FEDER funds.
D.H. thanks the Gobierno de Canarias (Consejería de Industria)-
CSIC for a research contract.
References and notes
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Prod. Rep. 2009, 26, 363–381; (b) Blunt, J. W.; Copp, B. R.; Hu, W. P.; Munro, M.
H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2009, 26, 170–244; (c)
Butler, M. S. Nat. Prod. Rep. 2008, 25, 475–516; (d) Michael, J. P. Nat. Prod. Rep.
2008, 25, 139–165; (e) Jin, Z. Nat. Prod. Rep. 2007, 24, 886–905; (f) Felpin, F. X.;
Lebreton, J. Eur. J. Org. Chem. 2003, 3693–3712; (g) O’Hagan, D. Nat. Prod. Rep.
2000, 17, 435–446; (h) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645–1680; (i) Pichon, M.; Figadere, B.
Tetrahedron: Asymmetry 1996, 7, 927–964 and references cited therein.
2. (a) Petrini, M. Chem. Rev. 2005, 105, 3949–3977; (b) Royer, J.; Bonin, M.;
Micouin, L. Chem. Rev. 2004, 104, 2311–2352; (c) Maryanoff, B. E.; Zhang, H. C.;
Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431–1628.
3. (a) Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1991, 56, 4868–4874; For a
recent example using chiral catalysts, see: (b) Raheem, I. T.; Thiara, P. S.;
Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404–13405.
4. For recent reviews on the Mannich reaction and related processes, see: (a)
Ferraris, D. Tetrahedron 2007, 63, 9581–9597; (b) Friestad, G. K.; Mathies, A. K.
Tetrahedron 2007, 63, 2541–2569; (c) Schaus, S. E.; Ting, A. Eur. J. Org. Chem.
2007, 5797–5815; (d) Petrini, M.; Torregiani, E. Synthesis 2007, 159–186 and
references cited therein.
5. (a) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem. Soc.
1999, 121, 12208–12209; (b) Smith, D. M.; Tran, M. B.; Woerpel, K. A. J. Am.
Chem. Soc. 2003, 125, 14149–14152; (c) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.;
Smith, D. M.; Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 10879–10884; (d)
Smith, D.; Woerpel, K. A. Org. Biomol. Chem. 2006, 4, 1195–1201; (e) Bonger, K.
M.; Wennekes, T.; Filippov, D. V.; Lodder, G.; van der Marel, G. A.; Overkleeft, H.
S. Eur. J. Org. Chem. 2008, 3678–3688; For similar studies in six-membered-ring
oxycarbenium ions, see: (f) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am.
Chem. Soc. 2000, 122, 168–169; (g) Shenoy, S. R.; Woerpel, K. A. Org. Lett. 2005,
7, 1157–1160.
CO2Me
N
CO2Me
N
H
2, Pd(OH)2/C,
MeOH, 25 o
C
99%
HO
RO
26
17 R = TBS
25 R = H
TBAF,
THF
88%
6. The nucleophile adds from the inner face of the envelope, giving the cis
product. Attack from this face generates a staggered structure, where the
substituents at C-2 and C-3 (or C-5) are not eclipsed. On the contrary, the attack
from the outside face is disfavored, due to the eclipsing interactions developed
between the substituents at C-2 and C-3 in the transition structure leading to
the first-formed trans product.
7. (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino reactions in Organic Synthesis;
Wiley-VCH: Weinheim, 2006; (b) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew.
Chem., Int. Ed. 2007, 46, 1570–1581; (c) Nicolaou, K. C.; Edmons, D. J.; Bulger, P.
G. Angew. Chem., Int. Ed. 2006, 45, 7134–7186; (d) Pellissier, H. Tetrahedron
2006, 62, 1619–1665 (Part A) and Tetrahedron 2006, 62, 2143–2173 (Part B)
and references cited therein.
1. TsCl, Py
2. (PhSe)2,
NaBH4,
62%
MeOH;
then H2O2
CO2Me
N
H2, Pd(OH)2/C,
CO2Me
N
MeOH, 25 o
C
97%
8. For recent work on the subject, see: (a) Boto, A.; Gallardo, J. A.; Hernández, D.;
Hernández, R. J. Org. Chem. 2007, 72, 7260–7269; (b) Boto, A.; Hernández, D.;
Hernández, R.; Montoya, A.; Suárez, E. Eur. J. Org. Chem. 2007, 325–334; (c)
Saavedra, C. J.; Hernández, R.; Boto, A.; Álvarez, E. Tetrahedron Lett. 2006, 47,
28
27
Scheme 4. Synthesis of (+)-norconiine methyl carbamate 28.

A. Boto et al. / Tetrahedron Letters 50 (2009) 3974–3977
3977
8757–8760. and references cited therein; For related work, see: (d) Díaz-
Sánchez, B. R.; Iglesias-Arteaga, M. A.; Melgar-Fernández, R.; Juaristi, E. J. Org.
Chem. 2007, 72, 4822–4825; (e) Maruyama, T.; Mizuno, Y.; Shimizu, I.; Suga, S.;
Yoshida, J. I. J. Am. Chem. Soc. 2007, 129, 1902–1903. and references cited
therein; For a review on the modification of amino acids and carbohydrates
through radical chemistry, see: (f) Hansen, S. G.; Skrydstrup, T. Top. Curr. Chem.
2006, 264, 135–162.
43.4 (CH2, 10-C), 52.0 (CH3, OMe), 52.4 (CH2, 5-C), 54.1 (CH, 2-C), 71.0 (CH2,
CH2Ph), 77.5 (CH, 4-C), 127.5 (2 ꢂ CH, Ph), 128.2 (2 ꢂ CH, Ph), 128.5 (2 ꢂ CH,
Ph), 128.6 (3 ꢂ CH, Ph), 132.8 (CH, Ph), 137. 4 (C, Ph), 138.0 (C, Ph), 155.2 (C,
CO2), 199.0 (C, 20-C). As in the previous case, the 1H NMR coupling constants
showed a cis relationship 2-H/3-Hb/4-H and a trans relationship 2-H/3-Ha and
4-H/3-Ha (J3b = 5.4, 8.2 Hz, while J3a = 0.0 Hz).
13. (a) Substrate 17 is known: Renaud, P.; Seebach, D. Helv. Chim. Acta 1986, 69,
9. Unpublished results on the stereoselective scission–alkylation process using
menthyl carbamoyl, camphorsulfonyl, camphanyl, and amino acyl groups as
chiral auxiliaries. In many cases, the stereoselectivity was low or moderate. In
others, unseparable mixtures of the major and minor diastereomers were
formed.
10. Any source of visible light can be used. However, to obtain reproducible results,
we carried out the scission with 80-W tungsten-filament lamps, available in
DIY shops.
1704–1710; ½a lDit
ꢃ
+22.9 (c 1.4, CHCl3); (b) For compound 17: ½a Dobs
ꢃ
+21.2 (c 0.40,
CHCl3). (c) As comparison, for compound 23: [a] +13.6 (c 0.43, CHCl3), while
D
its epimer 24: [
a
]
D
ꢀ17.3 (c 0.45, CHCl3).
14. (a) Passarella, D.; Barilli, A.; Belinghieri, F.; Fassi, P.; Riva, S.; Sacchetti, A.;
Silvani, A.; Danieli, B. Tetrahedron: Asymmetry 2005, 16, 2225–2230; (b) Amat,
M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem. 2003, 68, 1919–1928.
15. (a) Tirel, P. J.; Vaultier, M.; Carrié, R. Tetrahedron Lett. 1989, 30, 1947–1950; For
a review, see: (b) Bates, R. W.; Kanicha, S. E. Tetrahedron 2002, 58, 5957–5978.
11. General procedure for the scission–rearrangement process: To a solution of the
hydroxyproline derivative (0.1 mmol) in dry dichloromethane (1.5 mL) were
added iodine (13 mg, 0.05 mmol) and DIB (64 mg, 0.2 mmol). The resulting
mixture was stirred for 3 h at 26 °C, under irradiation with visible light (80 W
tungsten-filament lamp). Then the reaction mixture was cooled to 0 °C (ꢀ50 °C
16. (a) For compound 28 [(+)-norconiine methyl carbamate], [
CHCl3). (b) For
very related compound (the (ꢀ)-norconiine t-butyl
carbamate) see: Blarer, S. J.; Seebach, D. Chem. Berich. 1983, 116, 2250–2260;
a
]
+26 (c 0.3,
D
a
[a
]
D
ꢀ34.1 (c 1.1, CHCl3).
17. (a) Iminosugars: from Synthesis to Therapeutic Applications; Compain, P.; Martin,
O.R., Eds.; Wiley-VCH: Chichester, ISBN: 978-0-470-03391-3, 2007.; For
pyrrolidine-based iminosugars, see: (b) Doddi, V. R.; Vankar, Y. D. Eur. J. Org.
Chem. 2007, 5583–5589; (c) Hakansson, A. E.; van Ameijde, J.; Guglielmini, L.;
Horne, G.; Nash, R. J.; Evinson, E. L.; Kato, A.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2007, 18, 282–289; (d) Zhou, X.; Liu, W. J.; Ye, J. L.; Huang, P. Q.
Tetrahedron 2007, 63, 6346–6357.
when substrate 12 was used) and then BF3ꢁOEt2 (25
lL, 29 mg, 0.2 mmol) and
the nucleophile (3 equiv) were added. The mixture was stirred for 1 h; then
was poured into 10% aqueous Na2S2O3/saturated aqueous NaHCO3 (1:1,
10 mL), and extracted with CH2Cl2. The organic layer was dried on sodium
sulfate, filtered, and evaporated under vacuum. The residue was purified by
chromatography on silica gel (hexanes/ethyl acetate mixtures) to give the
products.
18. For a review article, see: (a) Yokoyama, M.; Momotake, A. Synthesis 1999,
ˇ
12. (a) All the products were characterized using NMR, HRMS, and elemental
analysis. The proposed stereochemistry was deduced from the value of the 1H
NMR coupling constants and it was supported by NOESY experiments. As
representative examples, the NMR experiments for the allyl compound 15 and
1541–1554; For articles on the subject: (b) Kocalka, P.; Pohl, R.; Rejman, D.;
Rosenberg, I. Tetrahedron 2006, 62, 5763–5774; (c) Evans, G. B.; Furneaux, R.
H.; Hausler, H.; Larsen, J. S.; Tyler, P. C. J. Org. Chem. 2004, 69, 2217–2220; (d)
Kamath, V. P.; Ananth, S.; Bantia, S.; Morris, P. E., Jr. J. Med. Chem. 2004, 47,
1322–1324; (e) Deng, L.; Scharer, O. D.; Verdine, G. L. J. Am. Chem. Soc. 1997,
119, 7865–7866; (f) Mayer, A.; Häberli, A.; Leumann, C. J. Org. Biomol. Chem.
2005, 3, 1653–1658.
the phenone derivative 19 are described; (b) Product 15: [a] +20.6 (c 1.11,
D
CHCl3); 1H NMR (500 MHz, CDCl3 with TMS, 70 °C) dY 1.97 (ddd, J = 3.8, 3.8,
13.6 Hz, 3-Ha), 2.05 (ddd, J = 6.0, 8.2, 13.6 Hz, 1H, 3-Hb), 2.38 (ddd, J = 7.9, 9.1,
13.6 Hz, 1H, 10-Ha), 2.64 (m, 1H, 10-Hb), 3.42 (dd, J = 3.8, 12 Hz, 1H, 5-Ha), 3.67
(s, 3H, OMe), 3.70 (m, 1H, 5-Hb), 3.90 (m, 1H, 2-H), 4.06 (m, 1H, 4-H), 4.47 (d,
J = 12.2 Hz, 1H, CHaPh), 4.50 (d, J = 12.6 Hz, 1H, CHbPh), 5.04 (J = 10 Hz, 1H, 30-
Ha), 5.06 (J = 17 Hz, 1H, 30-Hb), 5.75 (m, 1H, 20-H), 7.26–7.34 (m, 4H, Ph), 7.24
(m, 1H, Ph); 13C NMR (125.7 MHz, CDCl3, 70 °C) dC 35.2 (CH2, 3-C), 38.9 (CH2,
10-C), 52.0 (CH3, OMe), 52.2 (CH2, 5-C), 56.6 (CH, 2-C), 71.3 (CH2, CH2Ph), 77.2
(CH, 4-C), 117.0 (CH2, 30-C), 127.5 (2 ꢂ CH, Ph), 127.6 (CH, Ph), 128.4 (2 ꢂ CH,
Ph), 135.2 (CH, 20-C), 138.3 (C, Ph), 155.4 (C, CO2). The NOESY experiment
showed strong spatial interactions between the benzylic protons (dY 4.50/4.47)
and the 10-H2 (dY 2.64/2.38), between the 10-H2 and the 3-Ha (dY 1.97) and a
weaker spatial interaction between 2-H (dY 3.90) and 4-H (dY 4.06). The 1H
NMR coupling constants also showed a cis relationship 2-H/3-Hb/4-H and a
trans relationship 2-H/3-Ha and 4-H/3-Ha (J3b = 6.0, 8.2 Hz, while J3a = 3.8,
19. For related compounds and their uses, see: Murruzzu, C.; Riera, A. Tetrahedron:
Asymmetry 2007, 18, 149–154.
20. Choubdar, N.; Pinto, B. M. Carbohydr. Res. 2008, 343, 1766–1777.
21. Product 31: 1H NMR (500 MHz, CD3OD, 70 °C) dY 0.96 (dd, J = 7.4, 7.7 Hz, 30-H3),
1.39–1.45 (m, 2H, 20-H2), 1.69 (m, 1H, 10-Ha), 1.82 (m, 1H, 10-Hb), 3.00 (dd,
J = 7.9, 11.2 Hz, 5-Ha), 3.17 (ddd, J = 7.5, 7.5, 7.6 Hz, 4-H), 3.58 (m, 1H, 2-H),
3.69 (s, 3H, OMe), 3.71 (m, 1H, 3-H), 3.88 (dd, J = 7.2, 11.2 Hz, 1H, 5-Hb); 13C
NMR (125.7 MHz, CD3OD, 26 °C) Rotamer mixture: dC 13.1 (CH3, 30-C), 17.8
(CH2, 20-C), 33.6/34.5 (CH2, 10-C), 50.9/51.6 (CH3, 5-C), 56.6 (CH, 4-C), 63.9 (CH,
2-C), 80.7/81.4 (CH, 3-C).
22. (a) Kamal, A.; Reddy, D. R.; Reddy, P. S. M. M. Bioorg. Med. Chem. Lett. 2007, 17,
803–806; (b) Mandal, A. K.; Hines, J.; Kuramochi, K.; Crews, C. M. Bioorg. Med.
Chem. Lett. 2005, 15, 4043–4047; (c) Doi, M.; Nishi, Y.; Kiritoshi, N.; Iwata, T.;
Nago, M.; Nakano, H.; Uchiyama, S.; Nakazawa, T.; Wakamiya, T.; Kobayashi, Y.
Tetrahedron 2002, 58, 8453–8459; (d) Gómez-Vidal, J. A.; Silverman, R. B. Org.
Lett. 2001, 3, 2481–2484; (e) Bellier, B.; McCort-Tranchepain, I.; Ducos, B.;
Danascimento, S.; Meudal, H.; Noble, F.; Garbay, C.; Roques, B. P. J. Med. Chem.
1997, 40, 3947–3956.
3.8 Hz); (c) Product 19: [a]
+14.1 (c 0.23, CHCl3); 1H NMR (500 MHz, CDCl3
D
with TMS, 70 °C) dY 2.13 (br d, J = 14.2 Hz, 3-Ha), 2.22 (ddd, J = 5.4, 8.2, 14.0 Hz,
1H, 3-Hb), 3.37 (m, 1H, 10-Ha), 3.64 (m, 2H, 5-H2), 3.68 (br b, 1H, 10-Hb), 3.69 (s,
3H, OMe), 4.15 (m, 1H, 4-H), 4.48 (m, 1H, 2-H), 4.51 (s, 2H, CH2Ph), 7.23–7.31
(m, 5H, Ph), 7.43 (dd, J = 7.3, 8.0 Hz, 2H, Ph), 7.52 (dd, J = 6.8, 7.2 Hz, Ph), 7.95
(br d, J = 7.4 Hz, 2-H, Ph); 13C NMR (125.7 MHz, CDCl3, 70 °C) dC 36.2 (CH2, 3-C),