Formal synthesis of (+)-α-conhydrine and stereoselective synthesis of pyrrolidine analogue via the diastereoselective chelation-controlled hydride reduction and wittig reaction

Article abstract of DOI:10.1080/00397911.2014.899605

Asymmetric syntheses of (+)-α-conhydrine and its pyrrolidine analogue were achieved from readily available L-serine. The key step involved highly diastereoselective chelation-controlled hydride reduction of the amino ketone to give the anti-amino alcohol

Full text of DOI:10.1080/00397911.2014.899605

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Formal Synthesis of (+)-α-Conhydrine
and Stereoselective Synthesis
of Pyrrolidine Analogue via the
Diastereoselective Chelation-Controlled
Hydride Reduction and Wittig Reaction
Tian Jin a , Yu Mu a , Jin-Seok Kim a , Seok-Hwi Park a , Xiangdan Jin
a , Jong-Cheol Kang a , Chang-Young Oh a b & Won-Hun Ham a
a School of Pharmacy , Sungkyunkwan University , Suwon-si ,
Gyeonggi-do , Republic of Korea
b Yonsung Fine Chemicals Co., Ltd., Jangan-myeon , Hwaseong-si ,
Gyeonggi-do , Republic of Korea
Accepted author version posted online: 08 May 2014.Published
online: 01 Jul 2014.
To cite this article: Tian Jin , Yu Mu , Jin-Seok Kim , Seok-Hwi Park , Xiangdan Jin , Jong-Cheol Kang ,
Chang-Young Oh & Won-Hun Ham (2014) Formal Synthesis of (+)-α-Conhydrine and Stereoselective
Synthesis of Pyrrolidine Analogue via the Diastereoselective Chelation-Controlled Hydride Reduction
and Wittig Reaction, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 44:16, 2401-2408, DOI: 10.1080/00397911.2014.899605
To link to this article: http://dx.doi.org/10.1080/00397911.2014.899605
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Synthetic Communications1, 44: 2401–2408, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.899605
FORMAL SYNTHESIS OF (þ)-a-CONHYDRINE AND
STEREOSELECTIVE SYNTHESIS OF PYRROLIDINE
ANALOGUE VIA THE DIASTEREOSELECTIVE
CHELATION-CONTROLLED HYDRIDE REDUCTION AND
WITTIG REACTION
Tian Jin,1 Yu Mu,1 Jin-Seok Kim,1 Seok-Hwi Park,1
Xiangdan Jin,1 Jong-Cheol Kang,1 Chang-Young Oh,1,2 and
Won-Hun Ham1
1School of Pharmacy, Sungkyunkwan University, Suwon-si, Gyeonggi-do,
Republic of Korea
2Yonsung Fine Chemicals Co., Ltd., Jangan-myeon, Hwaseong-si,
Gyeonggi-do, Republic of Korea
GRAPHICAL ABSTRACT
Abstract Asymmetric syntheses of (þ)-a-conhydrine and its pyrrolidine analogue were
achieved from readily available L-serine. The key step involved highly diastereoselective
chelation-controlled hydride reduction of the amino ketone to give the anti-amino alcohol
and Wittig reaction.
Keywords Asymmetric synthesis; natural products; piperidines; reduction; Wittig
reaction
INTRODUCTION
Alkaloids containing 2-(1-hydroxyalkyl)piperidines are abundant in nature
and have attracted much attention because of their potent antiviral, antitumor, and
Received October 11, 2013.
Address correspondence to Won-Hun Ham, School of Pharmacy, Sungkyunkwan University,
Suwon-si, Gyeonggi-do, 440-746, Republic of Korea. E-mail: whham@skku.edu
2401

2402
T. JIN ET AL.
Figure 1. Structures of (þ)-a-conhydrine 1 and its pyrrolidine analogue 2.
anti-HIV properties.[1] Conhydrine was isolated from the seeds and leaves of the
poisonous plant Coniummaculatum L. in 1856, whose extracts were used in ancient
Greece for the execution of criminals,[2] and its structure was elucidated in 1933
(Fig. 1).[3]
To date, several syntheses of a- and b-conhydrine have been reported employ-
ing chiral starting materials,[4] use of chiral auxiliaries,[5] or catalytic asymmetric syn-
thesis.[6] In recent representative publications, Dong et al reported the concise total
synthesis of (ꢀ)-a-conhydrine, starting from readily available D-erythronolactone,
via the regioselective and diastereoseletive allylic amination of anti-1,2-dibenzyl ether
by using chlorosulfonyl isocyanate and intramolecular olefin metathesis.[4a] Louvel
et al. reported synthesis of (þ)-b-conhydrine, via stereoselective synthesis of syn-b-
amino propargylic ethers as a key step.[5a] We have also recently reported a facile
strategy for the construction of (þ)-a-conhydrine and its pyrrolidine analogue based
on the highly diastereoselective chelation-controlled hydride reduction and RCM
(ring-closing metathesis).[7a]
As a continuation of our previous work on highly diastereoselective chelation-
controlled hydride reduction, we became interested in developing a more practical
and efficient synthetic route to (þ)-a-conhydrine 1 and its pyrrolidine analogue 2.
Herein, we report the asymmetric syntheses of (þ)-a-conhydrine 1 and its pyrrolidine
analogue 2 via highly diastereoselective chelation-controlled hydride reduction and
Wittig reaction as the key steps.
RESULTS AND DISCUSSION
Retrosynthetically, we envisioned that (þ)-a-conhydrine 1 could be generated
from 8 through an intramolecular cyclization after deprotection of Boc group. The
olefin compound 7 could be generated from benzylated 1,2-anti-amino alcohol 6
through Wittig olefination. In turn, the common intermediate 6 could be prepared
by the diastereoselective reduction of amino ketone 4. Thus, our synthetic plan for
asymmetric synthesis of (þ)-a-conhydrine 1 could be traced back to the construction
of amino ketone 4, which we envisaged could be easily achieved from commercially
available L-serine (Scheme 1).
We envisioned that pyrrolidine analogue 2 could be prepared from compound
10 by intramolecular cyclization after palladium-catalyzed hydrogenation under
acidic conditions. Compound 10 would come from hydrogenation of olefin 9 with
platinum(IV) oxide, followed by reduction of ester with lithium aluminium hydride
(LAH). It was envisaged that the construction of compound 9 could be afforded
from L-serine according to a similar process to that descried for the construction
of (þ)-a-conhydrine via intermediate 6.

STEREOSELECTIVE SYNTHESES OF CONHYDRINE
2403
Scheme 1. Retrosynthetic analysis of (þ)-a-conhydrine 1 and its pyrrolidine analogue 2.
The asymmetric synthesis of (þ)-a-conhydrine is described in Scheme 2. Reac-
tion of 3 with NH(OMe)Me ꢁ HCl in the presence of AlMe3 gave Weinreb amide in
quantitative yield. Treatment of the Weinreb amide with EtMgBr in tetrahydrofuran
(THF) at 0 ꢂC provided 4 in 92% yield. Reduction of 4 with LiAlH(OtBu)3 in EtOH
at ꢀ78 ꢂC gave the desired anti-amino alcohol as the major compound with excellent
1
yield and stereoselectivity (anti=syn > 10:1 by H NMR spectroscopy). The diaster-
eoselectivity of this reduction resulted from a chelation-controlled process.[7,8] The
secondary alcohol was protected as benzyl ether and the TBS group was deprotected
Scheme 2. Reagents and conditions: (a) NH(OMe)Me ꢁ HCl, AlMe3, CH2Cl2, 0 ꢂC, 95%; (b) EtMgBr,
THF, 0 ꢂC, 92%; (c) LiAlH(OtBu)3, EtOH, ꢀ78 ꢂC, 89%; (d) BnBr, NaH, TBAI, THF, rt, 85%; (e) TBAF,
THF, rt, 92%; (f) (i) Dess–Martin periodinane, CH2Cl2, rt; (ii) (3-benzyloxypropyl)triphenylphosphonium
bromide, n-BuLi, THF, 0 ꢂC to rt, 72% (2 steps); (g) Pd=C, H2, MeOH, rt, 87%.

2404
T. JIN ET AL.
Scheme 3. Reagents and conditions: (a) (i) Dess–Martin periodinane, CH2Cl2, rt; (ii) (carbethoxymethy-
lene)triphenylphosphorane, THF, 0 ꢂC to rt, 79% (2 steps); (b) PtO2, H2, MeOH, rt, 90%; (c) LAH, THF,
0 ꢂC to rt, 85%; (d) (i) MsCl, Et3N, CH2Cl2, 0 ꢂC; (ii) NaH, THF, 0 ꢂC to rt, 92% (2 steps); (e) Pd=C, H2,
MeOH, 6 N HCl, rt, 92%.
with tetra-n-butylammonium fluoride (TBAF), leading to the corresponding primary
alcohol in good yield. Dess–Martin oxidation of primary alcohol afforded corre-
sponding aldehyde, which was treated with (3-benzyloxypropyl)triphenylphospho-
nium bromide and n-BuLi in tetrahydrofuran (THF) at 0 ꢂC to afford olefin 7 in
moderate yield.[9a,9b]
Catalytic hydrogenation of 7 with Pd=C furnished 8 by simultaneous
deprotection of the benzyl group and reduction of the double bond. Compound 8
had previously been transformed into (þ)-a-conhydrine 1, thus completing the
formal total synthesis.[10]
Oxidation of primary alcohol 6 with the Dess–Martin periodinane afforded the
corresponding aldehyde, which was treated with (carbethoxymethylene)triphenyl-
phosphorane in THF at 0 ꢂC to room temperature provided the olefinic ester 9.[9c,9d]
Hydrogenation of the olefin 9 with platinum(IV) oxide gave ester in good
yield.[11] Reduction of ester with LAH to afford alcohol 10. Treatment of 10 with
methanesulfonyl chloride and triethylamine afforded the corresponding mesylate,
which was subjected to cyclization using NaH furnished compound 11 (Scheme 3).
Further, catalytic hydrogenation of 11 with Pd=C under acidic conditions furnished
2 by simultaneous deprotection of the benzyl and Boc groups. The spectroscopic
data for synthetic 2 agreed with those reported.[5d,7a]
CONCLUSION
We have developed asymmetric syntheses of (þ)-a-conhydrine 1 and its pyr-
rolidine analogue 2 and demonstrated the usefulness of the highly diastereoselective
chelation-controlled hydride reduction of the amino ketone to give the anti-amino
alcohol. This article described practical and efficient SN2-type cyclization procedure,
which employed a reaction using mesylates instead of that used for the RCM pro-
cedure in our previous work. In addition, the substrate for the cyclization reaction
was easily obtained from the intermediate 6 via the Wittig reaction. The net results
was the syntheses from linear sequence of eight steps from N-Boc-L-serine-methyl
ester 3 in 38.1% overall yield for compound 8, which has previously been trans-
formed to (þ)-a-conhydrine 1 in two steps, and to pyrrolidine analogue 2 in

STEREOSELECTIVE SYNTHESES OF CONHYDRINE
2405
31.1% overall yield in 12 steps. Further extension of this work to the syntheses of
other structurally related natural products are in progress.
Therefore, we have performed efficient, stereoselective syntheses of (þ)-a-
conhydrine 1 and its pyrrolidine analogue 2. These results are better than those
reported in the previous syntheses of either 1 or its pyrrolidine analogue 2.
EXPERIMENTAL
Optical rotations were measured with a polarimeter in the solvent specified. 1H
and 13C NMR spectroscopic data were recorded on Varian or Bruker FT-NMR 125,
175, 300, 500, and 700 MHz spectrometers at the Cooperative Center for Research
Facilities in Sungkyunkwan University. Chemical shift values are reported in parts
per million relative to TMS or CDCl3 as the internal standard, and coupling con-
stants are reported in hertz. Infrared (IR) spectra were measured with a Bruker
FT-IR spectrometer. High-resolution fast atom bombardment (FAB) mass spectra
were recorded using a Jeol JMS-700 mass spectrometer at the Daegu Center of
KBSI, Korea. Chromatography was performed using mixtures of EtOAc and hex-
anes as eluent. Unless otherwise noted, all nonaqueous reactions were carried out
in an argon atmosphere with commercial-grade reagents and solvents. THF was dis-
tilled from sodium and benzophenone (indicator). CH2Cl2 was distilled from calcium
hydride.
tert-Butyl (3R,4S,E)-3,8-Bis(benzyloxy)oct-5-en-4-ylcarbamate (7)
A solution of the primary alcohol (152 mg, 0.49 mmol) in CH2Cl2 (5 mL) was
added to a solution of Dess–Martin periodinane (250 mg, 0.59 mmol) in anhydrous
CH2Cl2 (3 mL) at rt. The reaction mixture was stirred at rt. for 2 h. The mixture was
diluted with Et2O (20 mL); then saturated aqueous NaHCO3 (5 mL) and Na2S2O3
(0.94 g) were added and the heterogeneous mixture was stirred at rt for 20 min.
The ether layer was washed with brine, dried over MgSO4, and concentrated in
vacuo to give the crude aldehyde. n-BuLi (1.6 M in hexanes, 0.31 mL, 0.50 mmol)
was added dropwise to a mixture of (3-benzyloxypropyl)triphenylphosphonium bro-
mide (251 mg, 0.50 mmol) in anhydrous THF (5 mL) at 0 ꢂC. After 10 min stirring at
0 ꢂC, the crude aldehyde (139 mg, 0.45 mmol) dissolved in anhydrous THF (1 mL)
was added dropwise. After 6 h, the reaction was partitioned between Et2O and
H2O. The organic layer was washed with brine, dried over MgSO4, and concentra-
ted. The residue was purified by chromatography on a silica-gel column (hexanes–
EtOAc, 6:1) to afford 7 (142 mg, 72%, 2 steps) as a colorless oil.
25
½aꢃD ¼ ꢀ14:09 (c 1.3, CHCl3); Rf ¼ 0.73 (hexanes–EtOAc, 2:1); FT-IR (neat)
1
3383, 2948, 2834, 1661, 1452, 1114, 1032, 698 cmꢀ1; H NMR (500 MHz, CDCl3)
d 0.91 (t, J ¼ 7.5 Hz, 3 H), 1.37–1.46 (m, 10 H), 1.53–1.60 (m, 1 H), 2.39–2.56 (m,
2 H), 3.45–3.54 (m, 4 H), 4.48–4.62 (m, 4 H), 4.85 (br, 1 H), 5.48–5.65 (m, 2 H),
7.21–7.33 (m, 10 H); 13C NMR (125 MHz, CDCl3) d 10.57, 24.01, 28.70, 28.79,
50.02, 69.98, 72.59, 73.04, 79.33, 83.03, 127.74, 127.86, 127.88, 127.97, 128.58,
128.66, 130.25, 138.76, 138.99, 155.42. HRMS-FAB m=z [M þH]þ calcd. for
C27H37NO4: 440.2801; found 440.2804.

2406
T. JIN ET AL.
(4S,5R,E)-Ethyl 5-(Benzyloxy)-4-(tert-butoxycarbonylamino)hept-
2-enoate (9)
A solution of the primary alcohol (84 mg, 0.27 mmol) in CH2Cl2 (3 mL) was
added to a solution of Dess–Martin periodinane (138 mg, 0.33 mmol) in anhydrous
CH2Cl2 (3 mL) at rt. The reaction mixture was stirred at rt for 2 h. The mixture was
diluted with Et2O (10 mL ꢄ 2); then saturated aqueous NaHCO3 (5 mL) and
Na2S2O3 (0.52 g) were added and the heterogeneous mixture was stirred at rt for
20 min. The ether layer was washed with brine, dried over MgSO4, and concentrated
in vacuo to give the crude aldehyde, which was used in a further reaction. The crude
aldehyde was dissolved in THF (3 mL) and (carbethoxymethylene)triphenylpho-
sphorane (119 mg, 0.33 mmol) was added. The reaction mixture was stirred for
12 h at rt and quenched with H2O (1 mL). The aqueous layer was extracted with
EtOAc (5 mL ꢄ 2). The organic layer was washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by flash column chro-
matography (hexanes–EtOAc, 6:1) to afford a,b-unsaturated ester 9 (81 mg, 79%,
two steps) as a colorless oil.
25
½aꢃD ¼ þ11:29 (c 1.9, CHCl3); Rf ¼ 0.61 (hexanes–EtOAc, 3:1); FT-IR (neat)
3671, 2974, 2868, 1714, 1520, 1367, 1167, 1066, 1011, 611 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d 0.96 (t, J ¼ 7.5 Hz, 3 H), 1.29 (t, J ¼ 7.0 Hz, 3 H), 1.42 (s, 9 H),
1.44–1.49 (m, 1 H), 1.63–1.69 (m, 1 H), 3.44–3.47 (m, 1 H), 4.19 (dd, J ¼ 7.0,
14.5 Hz, 2 H), 4.49 (s, 1 H), 4.52 (s, 1 H), 4.61 (s, 1 H), 4.63 (s, 1 H), 4.88 (br, 1 H),
5.96 (d, J ¼ 1.5 Hz, 1 H), 6.00 (d, J ¼ 1.0 Hz, 1 H), 6.91 (dd, J ¼ 6.0, 6.5 Hz, 1 H),
7.28–7.37 (m, 5 H); 13C NMR (125MHz, CDCl3) d 10.24, 14.45, 23.68, 28.56,
53.45, 60.64, 72.19, 79.94, 82.24, 123.02, 128.04, 128.71, 138.35, 144.55,
155.38, 166.30. HRMS-FAB m=z [M þH]þ calcd. for C21H31NO5: 378.2280; found
378.2279.
(R)-1-((S)-Pyrrolidin-2-yl)propan-1-ol (2)
A solution of the substrate 11 (42 mg, 0.13 mmol) in a mixture of 6 N HCl
(0.2 mL) and MeOH (2 mL) was refluxed for 12 h and concentrated in vacuo. The
residue was purified by chromatography on a silica-gel column (CHCl3-MeOH,
1:1) to give the HCl salt of 2 (19.8 mg, 92%) as a white solid.
25
Mp 111–113 ꢂC; ½aꢃD ¼ ꢀ38:2 (c 0.9, CHCl3); Rf ¼ 0.10 (CHCl3-MeOH, 1:1);
FT-IR (neat) 3375, 2943, 2830, 1663, 1459, 1110, 1031, 690 cmꢀ1 1H NMR
;
(300 MHz, D2O) d 0.99 (t, J ¼ 7.5 Hz, 3 H), 1.46–1.62 (m, 2 H), 1.84–2.17 (m, 4
H), 3.35 (t, J ¼ 7.2 Hz, 2 H), 3.67–3.73 (m, 1 H), 3.86–3.92 (m, 1 H); 13C NMR
(125 MHz, D2O) d 9.59, 23.34, 23.59, 26.88, 45.98, 63.62, 70.47; HRMS-FAB m=z
[M þH]þ-HCl calcd. for C7H16ClNO: 130.1232; found 130.1230.
FUNDING
This research was supported by the Basic Science Research Program through
the National Research Foundation of Korea (NRF), which is funded by the Ministry
of Education, Science, and Technology (NRF-2010-0022900; NRF-2011-0029199)
and by Yonsung Fine Chemicals Corporation. The Samsung Dream Scholarship

STEREOSELECTIVE SYNTHESES OF CONHYDRINE
2407
Foundation grant to T. J. is gratefully acknowledged, as is the Global Ph.D. Fellow-
ship grant to S. H. P.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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