Stereodivergent total asymmetric synthesis of polyhydroxylated pyrrolidines via tandem allylic epoxidation and intramolecular cyclization reactions

Article abstract of DOI:10.1016/j.tetlet.2004.06.048

Epoxidation of the allylic alcohols 10 and 11 using the VO(acac) ₂/t-BuOOH system followed by an intramolecular 5-exo cyclization of the resulting δ-epoxycarbamates 12, 13, 18, and 19 has been shown to provide a general and efficient solution f

Full text of DOI:10.1016/j.tetlet.2004.06.048

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6349–6352
Stereodivergent total asymmetric synthesis of polyhydroxylated
pyrrolidines via tandem allylic epoxidation and
intramolecular cyclization reactions
Satwinder Singh and Hyunsoo Han*
Department of Chemistry, The University of Texas at San Antonio, 6900 N. Loop 1604 West, San Antonio, TX 78249, USA
Received 3 June 2004; revised 9 June 2004; accepted 11 June 2004
Abstract—Epoxidation of the allylic alcohols 10 and 11 using the VO(acac)2/t-BuOOH system followed by an intramolecular 5-exo
cyclization of the resulting d-epoxycarbamates 12, 13, 18, and 19 has been shown to provide a general and efficient solution for the
asymmetric synthesis of polyhydroxy pyrrolidines. The requisite vicinal amino alcohol functionality was enantio-/regio-selectively
installed by the Os-catalyzed asymmetric aminohydroxylation reaction of the designed achiral olefin 6.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Pyrrolidines have been found in a large number of
biologically active natural and artificial compounds.1
Among them, a certain class of polyhydroxylated pyrro-
lidines such as shown in Figure 1 has drawn consider-
able interest in recent years, primarily due to their ability
to inhibit glycosidases.2 Considering the implication of
glycosidases in many serious diseases like diabetes,3
cancers,4 and viral infections including HIV,5 such
compounds and their derivatives may find useful ther-
apeutic applications for treating these medical condi-
tions. Furthermore, chiral polyhydroxylated pyrro-
lidines have been used as catalysts/ligands in asymmetric
synthesis.6 As a result, a range of strategies for the
asymmetric synthesis of polyhydroxylated pyrrolidines
have been developed, most of which have relied on use
of chirons derived from carbohydrates, tartaric acid,
pyrroles, and a-amino acids.7 Recently, we developed
the first true asymmetric methodology for the synthesis
of polyhydroxylated pyrrolidines, which used the readily
available olefin 6 as a starting material, and utilized the
regioselective asymmetric aminohydroxylation (RAA)
and amidomercuration reactions for installing the vici-
nal amino alcohol functionality and five-membered ring,
respectively.8 Herein, we now report that the RAA
reaction as well as the epoxidation–intramolecular
cyclization cascade of allylic alcohols can provide a
more general and efficient solution for the complete
asymmetric synthesis of polyhydroxylated pyrrolidines.
H
3
HO
N
HO
OH
OH1 or 2
OH
9
N
O
OH
OH
HO
H
H
N
3, broussonetine C
HO
OH
2
5
4
HO
3
2, hyacinthacines
X
R
HO
1, DMDP
OH
O
OH1 or 2
N
N
OH
H
HO
HO
OH
From a synthetic point of view, it would not be unrea-
sonable to think that 2–5 are the more complex deriv-
atives of 1, and thus can be synthesized by elaborating 1.
Therefore, any general and unified methodology for the
asymmetric synthesis of these compounds should
involve the asymmetric synthesis of 1 and its stereo-
isomers. Figure 2 describes a retrosynthetic analysis for
the asymmetric synthesis of polyhydroxylated pyrrol-
idines including 1. In this strategy, the RAA reaction (V
to IV) and allylic epoxidation–cyclization reactions (III
HO
OH
(X = O, S, N)
4, alexine & casuarine
5, glycomimetics
Figure 1.
Keywords: Polyhydroxylated pyrrolidines; Regioselective asymmetric
aminohydroxylation; Allylic epoxidation; Intramolecular cyclization.
* Corresponding author. Tel./fax: +1-210-458-4958; e-mail: hhan@
utsa.edu
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.048

6350
S. Singh, H. Han / Tetrahedron Letters 45 (2004) 6349–6352
PG
NH
reaction with vinylmagnesium bromide at )50 ꢁC gen-
erated the requisite allylic alcohols 10 and 11 in a 7:3
diastereoselectivity.
PG
NH
H
N
HO
OH
PGO
PGO
PGO
PGO
O
OH
HO
OH
OH
I
III
II
With the stage now set for the allylic epoxidation, 10
was treated with various epoxidation reagents including
peracetic acid, MCPBA, VO(acac)2/ROOH, and
Sharpless asymmetric epoxidation reagents, among
which the VO(acac)2/t-BuOOH(TBHP) system gave the
best results. After some experiments with VO(acac)2/
t-BuOOH/solvents, it was found that the reaction con-
ditions using two-fold excess of TBHP in the presence of
4 mol % of VO(acac)2 in toluene solvent at ambient
temperature were optimal for the epoxidation of 10.12
Thus, under these conditions, 10 was smoothly trans-
formed to a mixture of the epoxide 12 and the pyrroli-
dine 15 in 40% and 44% isolated yield, respectively
(Scheme 2). The compound 15 is formed by the ring
opening and concomitant intramolecular cyclization
reactions of the initially formed epoxide 13 under the
reaction conditions. After separation, cyclization of the
surviving epoxide 12 in the presence of TFA (1.0 equiv)
at 4 ꢁC afforded the other diastereomeric pyrrolidine 14.
Deprotection of the PMP group of 14 and 15 by CAN13
followed by exhaustive acidic hydrolysis of the resulting
triols furnished the polyhydroxylated pyrrolidine 16 and
17 as their HCl salt, respectively.14
PG
NH
O
O
PGO
PGO
OEt
OEt
V
IV
OH
Figure 2. A retrosynthetic route to polyhydroxylated pyrrolidines.
to I through II) are used to establish two key structural
features of polyhydroxylated pyrrolidines, the vicinal
amino alcohol functionality and five-membered ring
containing a nitrogen atom, respectively. Enantio- and
regio-selective transformation of V to IV has been well
established,8 and a variety of reagents and catalysts are
available for the stereoselective epoxidation of allylic
alcohols.9 In the allylic epoxidation reaction, it was
hoped that the initially formed epoxide with right ste-
reochemistry would spontaneously undergo an 5-exo
intramolecular cyclization to give the corresponding
pyrrolidine compound (direct conversion of III to I),
making it easy to separate the other epoxide (if any) and
the pyrrolidine compound.10
Scheme 1 delineates the synthesis of the optically pure
substrates 10 and 11 required for the allylic epoxidation
Epoxidation of the allylic alcohol 11 under the similar
conditions was substantially slower compared to that of
10, and thus most of the starting material remained even
after 3 days. However, upon increasing temperature to
step. The RAA reaction of the olefin
6 using
(DHQD)2PHAL and N-bromoacetamide afforded the
syn-aminoalcohol 7 with an excellent regio- (>20:1) and
enantio-selectivity (>99%). After protection of the hy-
droxyl group of 7 with p-methoxybenzyl (PMB) chloride
and sodium hydride, the N-acetyl group of the resulting
ester was transformed into tert-butyl carbamate (Boc)
group employing di-tert-butyl carbonate in the presence
of catalytic DMAP followed by a hydrazinolysis to
provide 8.11 The partial reduction of the ester 8 with
DIBAL at )78 ꢁC afforded the aldehyde 9, which upon
Boc
NH
PMPO
10
OH
PMBO
a
Boc
NH
Boc
NH
Ac
O
NH O
PMPO
PMBO
PMPO
a
O
O
OH
PMPO
OEt
OH
OEt
PMBO
O
7
OH
b
13
12 (isolated)
6
OMe
b
Boc
N
Boc
N
Boc
Boc
NH O
NH O
c
PMPO
PMPO
OH
OH
OH
OEt
H
PMPO
PMBO
PMPO
PMBO
8
OPMB
OPMB
9
OH
OH
d
14
15 (isolated)
c
c
Boc
Boc
NH
NH
.
.
H
N
HCl
OH
+
PMPO
PMPO
H
N
HCl
OH
OH
OPMB
OH
OPMB
11
OH
10
HO
:
HO
7
3
HO
HO
Scheme 1. Reagents and conditions: (a) K2OsO4ꢀ2H2O (5 mol %),
(DHQD)2PHAL (6 mol %), LiOH, N-bromoacetamide, t-BuOH–H2O
2:1, 4 ꢁC, 8 h, 70%; (b) (i) NaH, PMBCl, DMF, 0 ꢁC, 10 h, 78%, (ii)
(Boc)2O, DMAP, THF, reflux, 4 h, then H2NNH2, MeOH, 4 h, 82%;
(c) DIBAL, CH2Cl2, )78 ꢁC, 3 h, 90%; (d) vinylmagnesium bromide,
THF, )50 ꢁC, 1 h, then room temp. 1 h, 88%.
17
16
Scheme 2. Reagents and conditions: (a) VO(acac)2 (4 mol %), TBHP
(2.0 equiv), toluene, rt, 16 h, 40% for 12 and 44% for 15; (b) TFA
(1.0 equiv), CH2Cl2, 4 ꢁC, 3 h, 82%; (c) (i) CAN, CH3CN–H2O 4:1,
4 ꢁC, 10 min, (ii) 3 N HCl, 3 h, 76% for two steps.

S. Singh, H. Han / Tetrahedron Letters 45 (2004) 6349–6352
6351
Acknowledgements
Boc
NH
Financial support from National Institute of Health
(GM 08194) and The Welch Foundation (AX-1534) is
gratefully acknowledged.
PMPO
PMBO
11
OH
a
Boc
NH
Boc
NH
References and notes
PMPO
PMBO
PMPO
PMPO
O
OH
O
OH
18 (isolated)
1. (a) Pearson, W. H. In Studies in Natural Product
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dez, J. M. J. Org. Chem. 2004, 69, 3578–3581.
PMBO
19
b
Boc
N
R
N
OH
OR
c
PMPO
PMBO
OH
OR
PMBO
22 (isolated)
20: R = H-
21: R = Ac-
d
d
.
.
H
N
HCl
OH
H
N
HCl
OH
OH
OH
HO
HO
HO
HO
24
23
Scheme 3. Reagents and conditions: (a) VO(acac)2 (4 mol %), TBHP
(2.0 equiv), toluene, 60 ꢁC, 32 h, 38% for 18 and 42% for 22; (b) TFA
(2.5 equiv), CH2Cl2, rt, 32 h; (c) Ac2O, Et3N, CH2Cl2, 82%; (d) (i)
CAN, CH3CN–H2O 4:1, 4 ꢁC, 10 min, (ii) 3 N HCl, 3 h, 76% for two
steps.
3. Johnson, P. S.; Lebovitz, H. E.; Coniff, R. F.; Simonson,
D. C.; Raskin, P.; Munera, C. L. J. Clin. Endocrinol.
Metab. 1998, 83, 1515, and references cited therein.
4. Bernaki, R. J.; Korytnyk, W. Cancer Metastasis Rev.
1985, 4, 81.
60 ꢁC, the reaction completed in 32 h giving a mixture of
the epoxide 18 and cyclized product 22 in 38% and 42%
isolated yield, respectively (Scheme 3). Cyclization of the
epoxide 18 needed more demanding conditions, where
2.5 equiv of TFA and ambient temperature were re-
quired. As a result, deprotection of the N-Boc group
occurred to give the cyclic amine 20. Even though ion-
exchange column chromatography could be used for
purification, the amine 20 was more conveniently puri-
fied by silica gel column chromatography after conver-
sion to the corresponding tri-acetate 21. Finally, upon
successive CAN deprotection and acidic hydrolysis, 21
and 22 generated the polyhydroxylated pyrrolidines 23
and 24 as HCl salt, respectively.15
5. (a) Fleet, G. W. J.; Karpas, A.; Dwek, R. A.; Fellows,
L. E.; Tyms, A. S.; Petursson, S.; Namgoong, S. K.;
Ramsden, N. G.; Smith, P. W.; Son, J. C.; Wilson, F. X.;
Witty, D. R.; Jacob, G. S.; Rademacher, T. W. FEBS Lett.
1988, 237, 128; (b) Gruters, R. A.; Niefies, J. J.; Tersmette,
M. I.; De Groede, R. E.; Tulp, A.; Heisman, H. G.;
Miedema, F.; Ploegh, H. L. Nature 1987, 330, 74.
6. (a) Shi, M.; Satoh, Y.; Makihara, T.; Masaki, Y. Tetra-
hedron: Asymmetry 1995, 6, 2109; (b) Masaki, Y.; Oda, H.;
Kazuta, K.; Usai, A.; Itoh, A.; Xu, F. Tetrahedron Lett.
1992, 33, 5089; (c) Gouverneur, V.; Ghosez, L. Tetrahe-
dron Lett. 1991, 32, 5349; (d) Gouverneur, V.; Ghosez, L.
Tetrahedron: Asymmetry 1990, 1, 363; (e) Ikegami, S.;
Uchiyama, H.; Hayama, T.; Katsuki, T.; Yamaguchi, M.
Tetrahedron 1988, 44, 5333.
7. For reviews see: (a) Pichon, M.; Figadere, B. Tetrahedron:
Asymmetry 1996, 7, 927; (b) Yoda, H. Current Org. Chem.
2002, 6, 223–243; (c) Pearson, W. H.; Stoy, P. Synlett
2003, 903–921; For more recent articles, see: (c) Izquierdo,
I.; Plaza, M. T.; Franco, F. Tetrahedron: Asymmetry 2004,
15, 1465–1469; (e) Izquierdo, I.; Plaza, M. T.; Franco, F.
Tetrahedron: Asymmetry 2002, 13, 1581; (f) Izquierdo, I.;
Plaza, M. T.; Robles, R.; Franco, F. Tetrahedron: Asym-
metry 2001, 12, 2481–2487; (g) Davies, S. G.; Nicholson,
R. L.; Price, P. D.; Roberts, P. M.; Smith, A. D. Synlett
2004, 901; (h) Donohoe, T. J.; Headley, C. E.; Cousins, R.
P. C.; Cowley, A. Org. Lett. 2003, 5, 999–1002; (i) Verma,
S. K.; Atanes, M. N.; Busto, J. H.; Thai, D. L.; Rapoprt,
H. J. Org. Chem. 2002, 67, 1314–1318; (j) Yoda, H.;
Shimojo, T.; Takabe, K. Tetrahedron Lett. 1999, 40, 1335;
(k) Davis, B. G.; Maughan, M. A. T.; Chapman, T. M.;
Villard, R.; Courtney, S. Org Lett. 2002, 4, 1026.
In summary, it has been shown that the RAA reaction
of olefins and the epoxidation–intramolecular cycliza-
tion cascade of allylic alcohols can provide an extremely
convenient tool for the asymmetric synthesis of poly-
hydroxylated pyrrolidines. Coupled with the previous
work from this laboratory where the RAA reaction of
olefins and oxazoline chemistry have been used to con-
trol stereochemistry of the vicinal amino alcohol func-
tionality (stereochemistry at C-1 and C-2; see Fig. 1 for
carbon numbering),8c the methodology reported here
should make it possible to stereoselectively synthesize
DMDP (1) and its all other stereoisomers from the
readily available achiral olefin 6. As an extension and
application of the present methodology, the asymmetric
synthesis of 2, 3, 4, and 5 in Figure 1 are currently being
pursued, and will be reported in due course.
8. (a) Singh, S.; Chikkanna, D.; Singh, O. V.; Han, H.
Synlett 2003, 9, 1279–1282; (b) Singh, O. V.; Han, H.

6352
S. Singh, H. Han / Tetrahedron Letters 45 (2004) 6349–6352
Tetrahedron Lett. 2003, 44, 2387–2391; (c) Singh, O. V.;
Han, H. Tetrahedron Lett. 2003, 44, 5289–5292.
(bs, 1H), 4.43–4.61 (m, 2H), 4.7 (d, 1H, J ¼ 10:7 Hz), 4.98
(d, 1H, J ¼ 9:3 Hz), 6.77–6.81 (m, 6H, ArH), 7.21 (d, 2H,
1
9. For Sharpless asymmetric epoxidation, see: (a) Sharpless,
K. B. CHEMTECH 1985, 15, 692; (b) Finn, M. G.;
Sharpless, K. B. In Asymmetric Synthesis; Morrison, J. D.,
Ed.; Academic: New York, 1985; Vol. 5, p 247; (c)
Hanson, R. M. Chem. Rev. 1991, 91, 437; (d) Katsuki, T.
In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. II, p 621; (e) Johnson, R. A.; Sharpless, K. B. In
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
Wiley-VCH: New York, 2000; p 231; For epoxidation by
vanadium complexes, see: (f) Bolm, C. Coord. Chem. Rev.
2003, 237, 245; (g) Hoshino, Y.; Yamamoto, H. J. Am.
Chem. Soc. 2000, 122, 10452; (h) Bolm, C.; Kuhn, T.
Synlett 2000, 899; For other methods see: (i) Adam, W.;
J ¼ 8:3 Hz). Compound 15: H NMR (500 MHz, CDCl3)
d 1.41 (s, 9H, t-Bu), 3.74 (s, 3H, CH3), 3.76 (s, 3H, CH3),
3.79–3.81 (m, 2H), 3.84–3.89 (m, 1H), 3.92–4.15 (m, 2H),
4.16–4.21 (m, 3H), 4.58–4.62 (m, 2H), 6.76–6.82 (m, 6H),
7.21 (d, 2H, J ¼ 8:3 Hz). Compound 18: 1H NMR
(500 MHz, CDCl3) d 1.43 (s, 9H, t-Bu), 2.69–2.70 (m,
1H), 2.85–2.87 (distorted dd, 1H), 3.18–3.21 (distorted dd,
1H), 3.77 (s, 7H, 2 · CH3 and CH), 3.82–3.88 (m, 2H),
3.95–3.98 (distorted dd, 1H), 4.37–4.44 (m, 1H), 4.50 (d,
1H, J ¼ 11:2 Hz), 4.62 (dd, 1H, J ¼ 10:7 and 13.7 Hz),
5.01 (d, 1H, J ¼ 9:8 Hz), 6.80–6.83 (m, 6H, ArH), 7.21 (d,
2H, J ¼ 8:3 Hz). Compound 22: 1H NMR (500 MHz,
CDCl3) d 1.45 (s, 9H, t-Bu), 3.76 (s, 4H, CH3 and CH),
3.80 (s, 3H, CH3), 3.86–3.90 (m, 2H), 4.40–4.16 (m, 4H),
4.38–4.40 (m, 1H), 4.52–4.57 (m, 1H), 4.68 (d, 1H,
J ¼ 11:2 Hz), 6.80–6.87 (m, 6H), 7.23 (d, 2H, J ¼ 8:3 Hz).
13. Fukuyama, T.; Laird, A. A.; Hotchkiss, L. M. Tetrahe-
dron Lett. 1985, 26, 6291.
€
Korb, M. N.; Roschman, K. J.; Saha-Moller, C. R. J. Org.
Chem. 1998, 63, 3423; (j) Adam, W.; Rao, P. B.; Degen,
H.-G.; Saha-Moller, C. R. J. Am. Chem. Soc. 2000, 122,
5654; (k) Aoki, M.; Seebach, D. Helv. Chim. Acta 2001,
84, 187.
14. The NMR data of 16 and 17 are consistent with those in
the literatures (Zou, W.; Szarek, W. A. Carbohydr. Res.
1993, 242, 311 for 16 and Wang, Y.-F.; Takaoka, Y.;
Wong, C.-H. Angew. Chem., Int. Ed. 1994, 33, 1242 for
17). Compound 16: 1H NMR (500 MHz, D2O) d 3.45
(quintet, 1H, J ¼ 3:9), 3.70 (dd, 1H, J ¼ 8:3 and 12.2 Hz),
3.73–3.76 (m, 2H), 3.80 (dd, 2H, J ¼ 7:3 and 12.7 Hz),
3.85 (dd, 1H, J ¼ 3:91 and 11.2 Hz), 3.94–3.96 (overlaped
dd, 1H), 4.11–4.13 (overlaped dd, 1H); 13C NMR
(125 MHz, D2O) d 59.37, 61.75, 65.63, 69.31, 77.02,
10. Takahata, H.; Banba, Y.; Tajima, M.; Momose, T. J. Org.
Chem. 1991, 56, 240–245.
11. (a) Burk, M. J.; Allen, J. G. J. Org. Chem. 1997, 62, 7054;
(b) To prepare the N-Boc protected 6 directly from 1: the
AA reaction of 1 with N-chloro-tert-butyl carbamate was
attempted. However, the reaction suffered from a poor
reaction yield, and further the desired product and tert-
butyl carbamate could not be separated by column.
12. General procedure for vanadium-catalyzed epoxidation:
To a stirred solution of 10 (1.19 g, 2.5 mmol) in anhydrous
toluene (30 mL) was added VO(acac)2 (27 mg, 0.1 mmol)
and the atmosphere was replaced with a nitrogen stream.
After 5 min TBHP (0.89 mL of 5.5 M decane solution,
5.0 mmol) was added dropwise. The resulting solution was
stirred at rt for 16 h or until the starting material was
completely consumed. The reaction mixture was poured in
water (10 mL) and the layers were separated. The aqueous
layer was extracted with ethyl acetate (2 · 20 mL). The
combined organic extracts were dried over Na2SO4, and
the resulting solution was concentrated after filtration
through a pad of Celite. The crude reaction mixture was
purified by column chromatography (ethyl acetate–hexane
1
78.49. Compound 17: H NMR (500 MHz, D2O) d 3.73–
3.77 (m, 2H), 3.80–3.86 (m, 4H), 4.20 (d, 2H, J ¼
2:0 Hz); 13C NMR (125 MHz, D2O) d 61.17, 66.58, 78.36.
15. The spectral data of 23 are consistent with those reported
in Wang, Y.-F.; Takaoka, Y.; Wong, C.-H. Angew. Chem.,
Int. Ed. 1994; 33, 1242, and those of 24 agree well with
those of its enantiomer reported in Cubero, I. I.; Lopez-
Espiposa, M. T. P.; Diaz, R. R.; Montalban, F. F.
1
Carbohydr. Res. 2001; 330, 401. Compound 23: H NMR
(500 MHz, D2O) d 3.76–3.81 (m, 2H), 3.92 (dd, 2H,
J ¼ 8:8 and 12.2 Hz), 4.01 (dd, 2H, J ¼ 4:9 and 12.2 Hz),
4.51 (d, J ¼ 4:9 Hz); 13C NMR (125 MHz, D2O) d 60.66,
1
64.30, 72.86. Compound 24: H NMR (500 MHz, D2O) d
1
1:3) to give 12 and 15 as colorless oil. Compound 12: H
3.64–3.68 (m, 2H), 3.78–3.82 (m, 4H), 3.86 (dd,
1H, J ¼ 4:9 and 11.7 Hz), 3.98–4.02 (m, 1H); 13C
NMR (125 MHz, D2O) d 56.49, 62.88, 65.47, 70.30,
74.67, 75.70.
NMR (500 MHz, CDCl3) d 1.40 (s, 9H, t-Bu), 2.61–2.83
(m, 2H), 3.06 (dd, 1H J ¼ 4:4 and 7.3 Hz), 3.60 (br s, 1H),
3.74 (s, 6H, 2 · CH3), 3.90–3.94 (distorted m, 2H), 4.19