Synthesis of cis-3-hydroxypipecolic acid via SmI2-mediated cyclization of aldehydo β-aminovinyl sulfoxides

Article abstract of DOI:10.1016/j.tetlet.2009.11.116

Stereoselective synthesis of cis-3-hydroxypipecolic acid was achieved via chirality transfer in the SmI₂-mediated cyclization reactions of aldehydo β-aminovinyl sulfoxides.

Full text of DOI:10.1016/j.tetlet.2009.11.116

Tetrahedron Letters 51 (2010) 707–708
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of cis-3-hydroxypipecolic acid via SmI2-mediated cyclization of
aldehydo b-aminovinyl sulfoxides
*
Hea Seung Chung, Won Kyo Shin, Soo Young Choi, Young Keun Chung, Eun Lee
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective synthesis of cis-3-hydroxypipecolic acid was achieved via chirality transfer in the SmI2-
mediated cyclization reactions of aldehydo b-aminovinyl sulfoxides.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 30 October 2009
Revised 24 November 2009
Accepted 26 November 2009
Available online 29 November 2009
Recently, SmI2-mediated cyclization of aldehydo b-alkoxyvinyl
sulfoxides emerged as a viable method for construction of 3-hydrox-
yoxolanes and 3-hydroxyoxanes.1,2 Cyclizations of aldehydo b-alk-
oxyvinyl sulfoxides derived from primary and tertiary alcohols
appear to proceed under sulfoxide chirality control, and the stereo-
chemistry of the major products may be predicted on the basis of
the olefin geometry and sulfoxide chirality. For example, the reac-
tion of b-alkoxyvinyl sulfoxide 1 with SmI2 in the presence of meth-
anol proceeded smoothly to yield a single 3-hydroxyoxane product
3. Reaction of the (Z)-(S)-isomer 2 also produced a single cyclization
product 4 (Scheme 1). We were curious whether the same kind of
stereoselectivity and stereospecificity may be maintained in the
cyclization of aldehydo b-aminovinyl sulfoxides, and wish to report
here the results of our recent studies in this area of research.
At the outset, we settled on the Ses-protection of the amino
group considering the efficiency in the substrate preparation and
the final deprotection steps.3 The 4-aminobutan-1-ol derivative 5
was obtained from butane-1,4-diol in three steps involving TBS
monoprotection, Mitsunobu reaction with SesNHBoc, and acid
deprotection.
Pummerer rearrangement of the TBS derivatives of the products
11 and 12 and sodium borohydride reduction led to an enantio-
SmI2
MeOH
S
S
S
S
E
R
O
O
O
O
O
Tol
Tol
R
3
S
OH
S
S
O
O
O
Tol
1
S
S
Z
Z
O
O
Tol
R OH
O
2
4
S
S
Tol
P
P
N
P
N
S
S
E
S
S
N
O
O
Tol
Tol
OH
O
O
?
Scheme 1. Stereoselectivity in the SmI2-mediated cyclization of b-alkoxyvinyl
sulfoxides.
Reaction of 5 with alkynyl sulfoxide 6 in the presence of TEA
and DMAP produced a mixture of the (Z)-(S)- and (E)-(S)-b-amino-
vinyl sulfoxides 7 (81%) and 8 (16%). The (E)-(S)-isomer 8 was also
obtained from 7 via acetylation, treatment with iodine, and basic
hydrolysis. IBX oxidation4 of 7 and 8 yielded the corresponding
aldehydes 9 and 10, respectively (Scheme 2).
In the presence of SmI2 and methanol in THF, the (Z)-(S)-alde-
hyde 9 was converted smoothly into the 3-hydroxypiperidine
product 11. No other stereoisomers were detected. The reaction
of the (E)-(S)-isomer 10 proceeded more quickly producing another
3-hydroxypiperidine product 12 (Scheme 3). The structures of the
products 11 and 12 were elucidated by X-ray diffraction studies5
(Fig. 1).
S
S
S
S
O
O
6
TEA
DMAP
Tol
Tol
Ses
Ses
NH
Ses
Z
Z
N
N
IBX
98%
81%
OH
OH
O
O
7
9
5
1) Ac2O, TEA, DMAP
2) I2
3) K2CO3
75%
Tol
S
S
Ses
N
Ses
S
S
E
S
S
E
6
O
N
O
IBX
Tol
Tol
Ses=SO2CH2CH2TMS
86%
OH
O
8
10
* Corresponding author. Tel.: +82 2 880 6646; fax: +82 2 889 1568.
E-mail address: eunlee@snu.ac.kr (E. Lee).
Scheme 2. Synthesis of Ses-protected b-aminovinyl sulfoxides.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.116

708
H. S. Chung et al. / Tetrahedron Letters 51 (2010) 707–708
oxidation of 13, Pinnick oxidation and cesium fluoride deprotec-
Ses
N
Ses
N
1) DMP
2) NaClO2
H
S
S
S
R
S
tion. 3-Hydroxypipecolic acids are important building blocks in
O
N
CO2H
OH
OH
9
biologically important compounds.6
Tol
65%
72%
3) CsF
51%
R
11
R
13
R
15
Formation of the 3-hydroxypiperidine derivative 11 from 9 may
be explained by invoking the transition state structure A, which is
analogous to the transition state structure suggested in the forma-
tion of the 3-hydroxyoxane 4. On the contrary, we were surprised
to find that the samarium ketyl from aldehyde 10 cyclized to form
the 2,3-cis product 12, presumably through the transition state
structure B. We had expected formation of the 2,3-trans product
16 through the transition state C, but 12 was the sole product.
The transition state structures A0 and B0 may also be considered
in which the sulfone oxygens assume active roles in coordination
at samarium (Scheme 4).
OH
OTBS
SmI2
MeOH
1) TBSCl, imidazole, DMAP
2) TFAA, pyridine; NaBH4
Ses
Ses
N
S
S
S
R
N
O
OH
10
Tol
52%
80%
S OTBS
14
S
12
OH
Scheme 3. SmI2-mediated cyclization of b-aminovinyl sulfoxides.
In these studies, we found that SmI2-mediated cyclization of
aldehydo b-aminovinyl sulfoxides proceeds with high stereoselec-
tivity and unique stereospecificity. Future studies will focus on the
synthesis of more complex azacycles using the present concept.
Acknowledgments
This work was supported by a grant from Marine Biotechnology
Program funded by Ministry of Land, Transport and Maritime
Affairs, Republic of Korea, and a grant from the Center for Bioactive
Molecular Hybrids (Yonsei University and KOSEF). A BK21 graduate
fellowship grant to H. S. Chung is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.11.116.
Figure 1. X-ray diffraction structures of 11 and 12.
References and notes
I2
SmI2
O
O
Sm
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O
S
O
O
O
RS
RO2S
N
Ar
Ar or
9
S
11
12
H
H
N
H
A'
H
3. For example, the Cbz-protected derivative did not react with 6. Ms- and Ts-
protection caused problems in the later steps.
A
I2
Sm
SmI2
O
O
O
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Ar
Ar
RO2S
N
RS
or
O
O
O
10
S
S
N
H
H
H
H
B'
B
RO2S
Ar
RO2S
S
S
R
R
N
O
H
O
S
10
N
SmI2
Tol
O
OH
H
C (?)
16 (Not found)
Scheme 4. Possible transition state structures in the SmI2-mediated cyclization of
b-aminovinyl sulfoxides.
meric pair of primary alcohols 13 and 14. Further conversion to
(2S,3R)-3-hydroxypipecolic acid (15) involved Dess–Martin