Samarium diiodide promoted generation and asymmetric hydroxyalkylation of N,O-diprotected (3S)-3-pyrrolidinol 2-carbanions

Article abstract of DOI:10.1021/ol047733z

(Chemical Equation Presented) The N,O-diprotected chiral nonracemic 2-pyridyl 3-pyrrolidinol-2-yl sulfide 5a undergoes efficient SmI₂ mediated reduction to give the N,O-diprotected 3-pyrrolidinol 2-carbanion intermediate D, which reacted under

Full text of DOI:10.1021/ol047733z

ORGANIC
LETTERS
2005
Vol. 7, No. 4
553-556
Samarium Diiodide Promoted Generation
and Asymmetric Hydroxyalkylation of
N,O-Diprotected (3S)-3-Pyrrolidinol
2-Carbanions
Xiao Zheng, Chen-Guo Feng, Jian-Liang Ye, and Pei-Qiang Huang*
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian
ProVince, College of Chemistry and Chemical Engineering, Xiamen UniVersity,
Xiamen, Fujian 361005, P. R. China
pqhuang@xmu.edu.cn
Received November 4, 2004
ABSTRACT
The N,O-diprotected chiral nonracemic 2-pyridyl 3-pyrrolidinol-2-yl sulfide 5a undergoes efficient SmI2 mediated reduction to give the N,O-
diprotected 3-pyrrolidinol 2-carbanion intermediate D, which reacted under Barbier-type conditions with ketones and aldehydes to afford the
protected N-r-hydroxyalkyl-3-pyrrolidines 10b−h with excellent diastereoselectivity at the newly formed chiral center in the pyrrolidine ring.
Application of the present method led to the formal asymmetric syntheses of (2R,3S)-2-hydroxymethyl-3-pyrrolidinol (2) and (2S,3S)-3-
hydroxyproline (12).
2-Hydroxyalkyl-3-pyrrolidinols 1a and their higher homo-
logues 1b are key structural features found in a number of
polyhydroxylated bioactive natural products, which include
pyrrolidine, pyrrolizidine, and indolizidine alkaloids.1 For
example, (2R,3S)-2-hydroxymethyl-3-pyrrolidinol (2) (CYB-
3)2 and castanospermine (3) are alkaloids isolated from the
seeds of Castanospermum australe.3a Castanospermine has
also been isolated from the dried pod of Alexa leiopetala,3b
and was found to be a powerful inhibitor of R- and
â-glucosidases.4 The important bioactivities exhibited by
these alkaloids and/or azasugars have stimulated considerable
synthetic interest and a number of strategies have been
developed for the syntheses of these natural products.1
However, efficient and straightforward approaches continue
to be highly desirable.
(1) For recent reviews of synthesis and biological activity, see: (a) Nemr,
A. E. Tetrahedron 2000, 56, 8579. (b) Asano, N.; Nash, R. J.; Molyneux,
R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645. (c) Sears,
P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300. (d) Michael, J. P.
Nat. Prod. Rep. 1999, 16, 675. (e) Elbein, A. D.; Molyneux, R. J. In
Iminosugars as Glycosidase Inhibitors; Stutz, A. E., Ed.; Wiley-VCH:
Weinheim, Germany, 1999; p 216. (f) Michael, J. P. Nat. Prod. Rep. 1997,
14, 619. (g) Takahata, H.; Momose, T. In The Alkaloids; Cordell, G. A.,
Ed.; Academic: San Diego, CA, 1993; Vol. 44, Chapter 3. (h) Elbein, A.
D.; Molyneux, R. In Alkaloids: Chemical and Biological PerspectiVes;
Pelletier, S. W., Ed.; Wiley and Sons: New York, 1987; Vol. 5.
(2) Nash, R. J.; Bell, E. A.; Fleet, G. W. J.; Jones, R. H.; Williams, J.
M. J. Chem. Soc., Chem. Commun. 1985, 738.
A conceptually attractive approach to 2-hydroxyalkyl-3-
pyrrolidinols involves generation of the chiral nonracemic
(4) (a) Campbell, B. C.; Molyneux, R. J.; Jones, K. C. J. Chem. Ecol.
1987, 13, 1759. (b) Pan, Y. T.; Hori, H.; Saul, R.; Sanford, B. A.; Molyneux,
R. J.; Elbein, A. D. Biochemistry 1983, 22, 3975. (c) Saul, R.; Chambers,
J. P.; Molyneux, R. J.; Elbein, A. D. Arch. Biochem. Biophys. 1983, 221,
593. (d) Szumilo, T.; Kaushal, G. P.; Elbein, A. D. Arch. Biochem. Biophys.
1986, 247, 261.
(3) (a) Hohenschutz, L. D.; Bell, E. A.; Jewess, P. J.; Leworthy, D. P.;
Pryce, R. J.; Arnold, E.; Clardy, J. Phytochemistry 1981, 20, 811. (b) Nash,
R. J.; Fellows, L. E.; Dring, J. V.; Stirton, C. H.; Carter, D.; Hegarty, M.
P.; Bell, E. A. Phytochemistry 1988, 27, 1403.
10.1021/ol047733z CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/21/2005

R-hydroxyalkylation method7 using N,O-diprotected 2-
pyrrolidinyl sulfides 5 as the synthetic equivalents of the
chiral nonracemic 3-pyrrolidinol 2-carbanion synthons A.
Inspired by the SmI2-mediated14 C-glycosylation chemistry
developed by Beau15 and Skrydstrup,16 the sulfones 4 and
sulfides 5 were designed as the synthetic equivalents of A
(P ) TBDMS, Bn) (Figure 1).
Scheme 1. Retrosynthetic Analysis of 2-Hydroxyalkyl
3-Pyrrolidinols 1a and Their Higher Homologues 1b
3-pyrrolidinol 2-carbanion synthon A (Scheme 1). However,
this remains a challenging problem in carbanion chemistry
despite much effort having been paid, and a number of
umpoled methods having been developed, for the generation
of N-R-carbanions in general,5 in particular 2-lithio-
pyrrolidines or 2-lithiopiperidines.6,7 Past attempts at generat-
ing the R-carbanion synthons A, B, or C suffered from
â-elimination (for A, P ) Me),8 or wrong regioselectivity
(for B),9 or quick proton exchange (for C).10 Only in a
specific case, where a coordinating group (methoxycarbonyl)
was present in the C-2 position, was the 3-hydroxylate
2-lithiopyrrolidine generated.11 Alternatively, both achiral12
and chiral nonracemic13 synthetic equivalents of A have been
reported. In continuation of our interests in developing
substituted 2-lithiopyrrolidine-based synthetic methodologies
for alkaloid synthesis,10,13 we wish to report herein our results
on the development of a samarium diiodide (SmI2) mediated
Figure 1. Synthetic equivalents of synthons A.
We first selected sulfone 4a (P ) TBDMS) as a precursor
of synthon A. However, the failure to prepare 4a17 led us to
give up sulfones 4 (P ) TBDMS, Bn) and turn to sulfides
5 (P ) TBDMS, Bn) as the synthetic equivalents of A. The
synthesis of 5a is depicted in Scheme 2. Known (S)-3-
Scheme 2. Synthesis of N,O-Diprotected 2-Pyrrolidinyl
Sulfide 5a
(5) For reviews involving the generation and application of R-lithioam-
ines, see: (a) Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152. (b)
Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297. (c) Beak, P.; Basu,
A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996,
29, 552. (d) Yus, M. Chem. Soc. ReV. 1996, 25, 155. (e) Cohen, T. Pure
Appl. Chem. 1996, 68, 913. (f) Gawley, R. E. Curr. Org. Chem. 1997, 1,
71. (g) Kessar, S. V.; Singh, P. Chem. ReV. 1997, 97, 721. (h) Katritzky,
A.; Qi, M. Tetrahedron 1998, 54, 2647. (i) Husson, H. P.; Royer, J. Chem.
Soc. ReV. 1999, 28, 383. (j) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi,
G. Chem. Soc. ReV. 2000, 29, 109.
(6) For representative approaches to optically active R-lithiopyrrolidines
and R-lithiopiperidines, see: (a) Meyers, A. I.; Dickman, D. A.; Bailey, T.
R. J. Am. Chem. Soc. 1985, 107, 7974. (b) Huang, P.-Q.; Arseniyadis, S.;
Husson, H.-P. Tetrahedron Lett. 1987, 28, 547. (c) Gawley, R. E.; Hart, G.
C.; Bartolotti, L. J. J. Org. Chem. 1989, 54, 175. (d) Pearson, W. H.;
Lindbeck, A. C.; Kampf, J. W. J. Am. Chem. Soc. 1993, 115, 2622. (e)
Wu, S.; Lee, S.; Beak, P. J. Am. Chem. Soc. 1996, 118, 715. (f) Coldham,
I.; Hufton, R.; Snowden, D. J. Am. Chem. Soc. 1996, 118, 5322. (g) Wiberg,
K. B.; Bailey, W. F. Angew. Chem., Int. Ed. 2000, 39, 2127. (h) Dearden,
M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P. J. Am. Chem. Soc. 2002,
124, 11870. (i) Watson, R. T.; Gore, V. K.; Chandupatla, K. R.; Dieter, R.
K.; Snyder, J. P. J. Org. Chem. 2004, 69, 6105.
(7) For samarium diiodide mediated generation of pyrrolidine and
piperidine R-carbanions, see: (a) Collin, J.; Namy, J. L.; Kagan, H. B.
Tetrahedron Lett. 1992, 33, 2973. (b) Murakami, M.; Hayashi, M.; Ito, Y.
J. Org. Chem. 1992, 57, 794. (c) Booth, S. E.; Benneche, T.; Undheim, K.
Tetrahedron 1995, 51, 3665.
hydroxy-2-pyrrolidinone18 (6) was silylated (TBDMSCl,
imidazole, DMAP, CH2Cl2, room temperature, 24 h) to give
(S)-7 in 95% yield. Treatment of (S)-7 with di-tert-butyl
dicarbonate in the presence of both triethylamine and a
(8) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
(9) (a) Sunose, M.; Peakman, T. M.; Charmant, J. P. H.; Gallagher, T.;
Macdonald, S. J. F. Chem. Commun. 1998, 1723. (b) Pandey, G.;
Chakrabarti, D. Tetrahedron Lett. 1998, 39, 8371 and references therein.
(10) Huang, P.-Q.; Zheng, X.; Wang, S.-L.; Ye, J.-L.; Jin, L.-R.; Chen,
Z. Tetrahedron: Asymmetry 1999, 10, 3309.
(14) For an excellent review, see: Kagan, H. B. Tetrahedron 2003, 59,
10351.
(11) (a) Williams, R. M.; Cao, J. Tetrahedron Lett. 1996, 37, 5441. (b)
Williams, R. M.; Cao, J.; Tsujishima, H. Angew. Chem., Int. Ed. 2000, 39,
2540.
(12) (a) Gallagher, T.; Giles, M.; Subramanian, R. S.; Hadley, M. S. J.
Chem. Soc., Chem. Commun. 1992, 166. (b) S. H. J.; Subramanian, R. S.;
Roberts, J. K.; Hadley, M. S. J. Chem. Soc., Chem. Commun. 1994, 933.
(13) (a) Huang, P.-Q.; Wu, T.-J.; Ruan, Y.-P. Org. Lett. 2003, 5, 4341.
(b) Huang, P.-Q.; Deng, J. Synlett 2004, 247. (c) Tang, T.; Ruan, Y.-P.;
Ye; J.-L.; Huang, P.-Q. Synlett 2005, 231.
(15) (a) Miquel, N.; Doisneau, G.; Beau, J. M. Angew. Chem., Int. Ed.
2000, 39, 4111. (b) Skrydstrup, T.; Jarreton, O.; Mazeas, D.; Urban, D.;
Beau, J. M. Chem. Eur. J. 1998, 4, 655. (c) Urban, D.; Skrydstrup, T.;
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(16) Mikkelsen, L. M.; Krintel, S. L.; Jimenez-Barbero, J.; Skrydstrup,
T. Chem. Commun. 2000, 2319.
(17) Attempts to oxidize 5a to sulfone 4a with either m-CPBA or oxone
failed. Instead, the hydrolyzed product was always obtained.
(18) Huang, P.-Q.; Zheng, X.; Wei, H. Heterocycles 2003, 60, 1833.
554
Org. Lett., Vol. 7, No. 4, 2005

catalytic amount of DMAP provided (S)-8 in 96% yield.
Controlled regioselective reduction19 of (S)-8 with NaBH4
at 0 °C yielded a diastereomeric mixture of N,O-hemiacetal
9 in 95% yield. TLC monitoring of the reaction showed that
9 was formed as only one diastereomer, which partially and
readily epimerized during the workup procedure and also
upon standing. Reaction of 9 with 2-mercaptopyridine in the
presence of 1% (w/w) of a 1:1 mixture of PPTS and TsOH
yielded the desired 5a in nearly diastereomerically pure form,
which epimerized and hydrolyzed readily.
Table 1. The Results for the Reductive Coupling of 5a/5b
with Electrophiles (Scheme 3)20
With multigram quantities of 5a available, SmI2-mediated
hydroxyalkylations were investigated. To test the possibility
of using 5a as a synthetic equivalent of A, a THF solution
of 5a was treated, at 20 °C and in the presence of an excess
of MeOH, with 2.2 molar equiv of SmI2 (0.1 M in THF) for
10 min. In such a way, the desired protected (S)-3-
pyrrolidinol (10a) was isolated in 95% yield (Scheme 3,
Scheme 3. SmI2-Mediated Hydroxyalkylations of 5a and 5b
Table 1, entry 1). The formation of 10a in high yield implied
that the reductive samariation of 5a occurred smoothly, and
the presumed organosamarium (III) intermediate D was stable
to â-elimination.
Encouraged by this result, we then proceeded to study the
reductive hydroxyalkylation of 5a under Barbier-type condi-
tions. Happily, treatment of a mixture of cyclohexanone (1.5
molar equiv) and 5a in THF with freshly prepared SmI2 (0.1
M in THF, 2.2 molar equiv) at room temperature, followed
by stirring at room temperature for 10 min (protocol A),
afforded the desired reductive coupling product 10b in 50%
yield, alongside the protonated product 10a in 33% yield
(Table 1, entry 2). Better yields (62%) of 10b could be
obtained by using an alternative procedure (protocol B),
which consisted of adding freshly prepared SmI2 (0.1 M in
THF, 4.0 molar equiv) to a mixture of cyclohexanone (2.0
molar equiv) and 5a in THF at 0 °C, followed by warming
the reaction mixture to room temperature over 10 min (Table
1, entry 3).
a Isolated yield. b Diastereoselectivity (at the carbinolic center) determined
by chromatographic separation. c With protocol A. d Using protocol B.
by HPLC analysis; however, its 1H (500 MHz) and 13C NMR
(125 MHz) spectra (measured at room temperature in CDCl3)
clearly indicated the presence of two isomers. Keeping in
mind that extensive rotamerism exists in carbamates such
as 10a, and to verify the nature of the isomerism of 10b, 1H
and 13C NMR experiments of 10b were performed in
deuterated DMSO at a range of temperatures. Indeed, at 25
The desired product 10b was formed exclusively according
to TLC analysis and chromatographic separation of the crude
reaction mixture. The homogeneity of 10b was confirmed
(19) Wunberg, J. B. P. A.; Schoemaker, H. E.; Speckamp, W. N.
Tetrahedron 1978, 34, 179.
Org. Lett., Vol. 7, No. 4, 2005
555

1
°C, the H and 13C spectra of 10b showed the presence of
(2R,3S)-10h.22 Since 10h has been converted to (2R,3S)-2-
hydroxymethyl-3-pyrrolidinol23 (2) and its oxidized form,
(2S,3S)-3-hydroxyproline22 (12), a nonproteinogenic amino
acid isolated from the hydrolysates of Mediterranean sponge,24
and the seeds of Delonix regia,25 our synthesis of 10h thus
constitutes formal asymmetric syntheses of 2 and 12.26 It is
noteworthy that the present synthesis of 10h also confirmed
the 2,3-trans-diastereoselectivity of the reductive hydroxy-
alkylation of 5a in the pyrrolidine ring.
To summarize, through the present work, we were able
to demonstrate that sulfide 5a is a valuable synthetic
equivalent of the samarium intermediate D, which can
function synthetically as the hitherto unknown chiral non-
racemic synthon A. Application of the present reductive
coupling reaction to the asymmetric synthesis of more
complex natural products is in progress.
two isomers as did those recorded in CDCl3 at 25 °C. At 80
°C, however, the 1H and 13C NMR spectra of 10b in
deuterated DMSO simplified and only one isomer was
observed. When the temperature was lowered to 25 °C, the
1H and 13C NMR spectra of 10b were identical with those
taken prior to heating. These experiments clearly demon-
strated that the isomers observed at room temperature were
rotamers instead of diastereomers. Thus, the reductive N-R-
hydroxyalkylation of 5a led to only one isolable diastere-
omer. Consequently, the reductive hydroxyalkylation of 5a
was highly diastereoselective in establishing the C-2 chiral
center of the pyrrolidine ring. As regarding the stereochem-
istry of the product, although the flexibility of the pyrrolidine
ring does not allow the determination of stereochemistry,
we have assumed that the trans-isomer is formed for steric
reasons. This assumption was confirmed by the R-hy-
droxymethylation of 5a with formaldehyde, which led to a
known compound (Vide infra).
We next examined the reductive couplings of 5a with other
ketones and aldehydes, and the results are summarized in
Table 1. As can be seen, the reductive hydroxyalkylation of
5a with symmetric ketones gave, in each case, only one
diastereomer (Table 1, entries 2-5), and when unsymmetrical
ketones or aldehydes were used, a diastereomeric mixture
(originating from the newly formed exocyclic chiral carbinol
center) was obtained (Table 1, entries 6-9). For ketones,
protocol B generally gave better results than protocol A
(Table 1, entries 2/3 and 6/7). The silyl group (TBDMS)
protected pyridyl sulfide 5a generally gave better results than
the benzyl protected sulfide 5b21 did (Table 1, entries 3/10
and 8/11).
Acknowledgment. The authors are grateful to the Na-
tional Science Fund for Distinguished Young Investigators,
the NSF of China (20272048; 203900505; 20402012), and
the Ministry of Education (Key Project 104201) for financial
support. We thank Professor J. M. Beau and Professor Y.
M. Zhang for valuable discussions.
Supporting Information Available: Experimental pro-
1
cedures and spectral data for all new compounds and H
NMR and 13C NMR spectra of compounds 5a, 5b, 7, 8, 10a-
h, 11a, 11b, and 11c. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL047733Z
(20) All new compounds gave satisfactory analytical and spectral data.
(21) Sulfide 5b was prepared in a similar way as that described for 5a.
(22) Herdeis, C.; Hubmann, H. P.; Lotter, H. Tetrahedron: Asymmetry
1994, 5, 119.
To illustrate the utility of the method, and to confirm the
relative stereochemistry of the reaction, the reductive cou-
pling of 5a with formaldehyde was investigated (Scheme
4). The samarium(III) intermediate D reacted with formal-
dehyde to give 10h as the only isolable diastereomer, which
was identical in all respects with the known compound
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1989, 1149. (b) Griffart-Brunet, D.; Langlois, N. Tetrahedron Lett. 1994,
35, 119. (c) Dell’Uomo, N.; Di Giovanni, M. C.; Misiti, D.; Zappia, G.;
Delle Monache, G. Tetrahedron: Asymmetry 1996, 7, 181. (d) Barco, A.;
Benetti, S.; De Risi, C.; Pollini, G. P.; Romagnoli, R.; Zanirato, V.
Tetrahedron Lett. 1996, 37, 7599. (e) Aoyagi, Y.; Inaba, H.; Hiraiwa, Y.;
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Scheme 4. Formal Asymmetric Synthesis of Natural Products
2 and 12
(26) For other syntheses of (2S,3S)- or (2R,3R)-3-hydroxyproline (12)
see: (a) Sheehan, J. C.; Whitney, J. G. J. Am. Chem. Soc. 1963, 85, 3863.
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556
Org. Lett., Vol. 7, No. 4, 2005