Synthesis of α-conhydrine

Article abstract of DOI:10.1016/j.tet.2006.09.004

A synthesis of α-conhydrine has been achieved from trans-(2S,4R)-4-hydroxyproline via diastereoselective Grignard addition, regioselective Baeyer-Villiger reaction, and ring-closing metathesis as the key steps.

Full text of DOI:10.1016/j.tet.2006.09.004

Tetrahedron 62 (2006) 10843–10848
Synthesis of a-conhydrine
a
b
Meng-Yang Chang,a, Yung-Hua Kung and Shui-Tein Chen
*
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan, ROC
bInstitute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan, ROC
Received 24 July 2006; revised 1 September 2006; accepted 1 September 2006
Available online 20 September 2006
Abstract—A synthesis of a-conhydrine has been achieved from trans-(2S,4R)-4-hydroxyproline via diastereoselective Grignard addition,
regioselective Baeyer–Villiger reaction, and ring-closing metathesis as the key steps.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
connection with our studies on the trans-(2S,4R)-4-hydroxy-
proline (2) as the chiral material, we are interested in
developing a feasible and straightforward approach to
a-conhydrine (1a) via diastereoselective Grignard addition,
regioselective Baeyer–Villiger reaction, and ring-closing
metathesis.
Based on the structural framework of trans-(2S,4R)-4-
hydroxyproline, it possesses three functional groups that can
be easily modified, and these are 1-amino, 2-carboxylate,
and 4-hydroxy groups.1 The skeleton represents the signifi-
cant feature for producing a series of different carbon frame-
works using an efficient modification technique.2 Recently
we have introduced a straightforward approach toward ani-
somycin,2h epibatidine,2i pancracine,2j and streptorubin B
core2k employing trans-(2S,4R)-4-hydroxyproline as the
starting material. To explore a new application, synthetic
studies toward a-conhydrine were further investigated.
2. Results and discussion
The synthesis of a-conhydrine (1a) began from prolinol 3
as illustrated in Scheme 1. The four-step preparation of
compound 3 with 90% overall yield was reported from
trans-(2S,4R)-4-hydroxyproline (2).2i–k First, prolinol 3 was
treated with Swern oxidation and followed by Grignard
addition to give compound 4 as a single isomer at ꢀ78 ꢁC.6
The diastereoselective addition occurred in favor of the anti
isomer through a chelated intermediate.5a,6 Subsequently,
alcohol 4 was treated with O-benzylation, desilylation, and
oxidation to afford ketone 5. The relative anti configurations
of compound 5 were based upon the single-crystal X-ray
analysis (Fig. 2).7
These alkaloids containing a 2-(1-hydroxyalkyl)piperidine
unit with biological activities are abundant in nature.3 Con-
hydrine is one of the alkaloids of the hemlock, isolated from
the seeds and leaves of the poisonous alkaloids plant Conium
maculatum, whose extracts were used in the ancient Greece
for execution of criminals (Fig. 1).4 Various methods for the
asymmetric synthesis of a-conhydrine (1a) and b-conhy-
drine (1b) and mainly based on auxiliary-supported or chiral
pool approaches have been documented in the literature.5 In
TBSO
TBSO
HO
1) Swern ox.
2) EtMgBr
(two steps 90%)
1) NaH, BnBr (86%)
2) TBAF, THF (92%)
3) PCC, DCM (83%)
OH
R
N
Ts
N
Ts
R
N
H
N
H
R
S
S
CO2H
OH
N
H
OH
OH
3
4
2
α-conhydrine (1a)
Figure 1.
β-conhydrine (1b)
OH
O
1) MCPBA, Na2CO3 (82%)
2) LAH, THF (94%)
N
Ts
HN
Ts OBn
OBn
Keywords: trans-(2S,4R)-4-Hydroxyproline; a-Conhydrine; Grignard addi-
tion; Regioselective Baeyer–Villiger reaction; Ring-closing metathesis.
* Corresponding author. Tel.: +886 7 591 9464; fax: +886 7 591 9348;
e-mail: mychang@nuk.edu.tw
5
6
Scheme 1.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.004

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M.-Y. Chang et al. / Tetrahedron 62 (2006) 10843–10848
3. Conclusion
In summary, we succeeded in accomplishing the synthesis of
a-conhydrine (1a) from trans-(2S,4R)-4-hydroxyproline (2)
in moderate yields (ca. 18%) via diastereoselective Grignard
addition, regioselective Baeyer–Villiger reaction, and ring-
closing metathesis as the key steps. Currently studies are
in progress in this direction.
4. Experimental
4.1. General
Figure 2. X-ray crystallography of compound 5.
Dichloromethane (DCM) and tetrahydrofuran (THF) were
distilled prior to use. All other reagents and solvents were
obtained from commercial sources and used without further
purification. Reactions were routinely carried out under an
atmosphere of dry nitrogen with magnetic stirring. Products
in organic solvents were dried with anhydrous magnesium
sulfate before concentration in vacuo.
With the result in hand, regioselective Baeyer–Villiger reac-
tion of ketone 5 was next examined. While poring over the
related literature, we found that Young’s group had devel-
oped the copper(II) acetate-mediated expansion of 4-keto-
prolines with m-chloroperoxybenzoic acid.8 We believe
that the nitrogen atom can play an important factor to initiate
the regiospecific ring expansion.8c According to the reports,
compound 5 was first treated with the combination of
copper(II) acetate and m-chloroperoxybenzoic acid. The result-
ing tetrahydro-1,3-oxazin-6-one skeleton was provided in
moderate (42%) yield. In order to increase higher yields,
other commercial available reagents and reaction conditions
were tested. When the reaction was treated with the combi-
nation of sodium carbonate and m-chloroperoxybenzoic
acid, the yield was increased to 82% yield without other re-
gioisomers. For the synthetic efficiency, sodium carbonate is
better than copper(II) acetate in our cases during the regio-
specific ring expansion. The difference between sodium car-
bonate and copper(II) acetate was not clear. Next, reduction
of the corresponding regioisomer provided aminoalcohol 6.
4.1.1. 2-(1-Hydroxypropyl)-4-(tert-butyldimethylsil-
anyloxy)-1-(4-methylphenylsulfonyl)pyrrolidine (4). A
stirred solution of oxalyl chloride (400 mg, 3.15 mmol) in
dichloromethane (20 mL) was mixed with dimethyl sulf-
oxide (400 mg, 5.1 mmol) at ꢀ78 ꢁC. The solution was
warmed to ꢀ40 ꢁC for 15 min and recooled to ꢀ78 ꢁC,
and then a solution of prolinol 3 (385 mg, 1.0 mmol) in
dichloromethane (10 mL) was added dropwise for 90 min
followed by excess triethylamine (4 mL, 28.5 mmol) for
30 min. The reaction mixture was warmed to rt and poured
into aqueous ammonium chloride solution (15%, 2 mL),
and concentrated under reduced pressure. The residue was
diluted with water (15 mL) and extracted with ethyl acetate
(3ꢂ30 mL). The organic layer was washed with brine and
water, dried, filtered, and concentrated under reduced pres-
sure to produce crude aldehyde. Without further purification,
a solution of ethylmagnesium bromide (1.0 M in tetrahydro-
furan, 1.5 mL, 1.5 mmol) was added to a stirred solution of
resulting aldehyde in tetrahydrofuran (20 mL) at ꢀ78 ꢁC.
The reaction mixture was stirred at rt for 2 h. Saturated so-
dium bicarbonate solution (1 mL) was added to the reaction
mixture and the solvent was concentrated under reduced
pressure. Water (3 mL) and ethyl acetate (10 mL) was added
to the residue and the mixture was filtered through a short
plug of Celite. The filtrate was concentrated under reduced
pressure. The residue was extracted with ethyl acetate
(3ꢂ20 mL). The combined organic layers were washed
with brine, dried, filtered, and evaporated to afford crude
product under reduced pressure. Purification on silica gel
(hexane/ethyl acetate¼4/1) afforded alcohol 4 (372 mg,
90% of two steps). [a]2D9 ꢀ46.54 (c 0.104, CHCl3); IR
(CHCl3) 3503, 2955, 1598, 1343, 1090, 836 cmꢀ1; HRMS
(ESI) m/z calcd for C20H36NO4SSi (M++1) 414.2134, found
414.2133; 1H NMR (500 MHz, CDCl3) d 7.72 (d, J¼8.0 Hz,
2H), 7.30 (d, J¼8.0 Hz, 2H), 4.28–4.25 (m, 1H), 4.14–4.11
(m, 1H), 3.60 (dd, J¼4.0, 11.5 Hz, 1H), 3.60–3.57 (m, 1H),
3.27 (ddd, J¼2.0, 4.0, 11.5 Hz, 1H), 2.46 (d, J¼4.0 Hz, 1H),
2.42 (s, 3H), 2.07–2.01 (m, 1H), 1.61–1.57 (m, 1H), 1.47–
1.40 (m, 1H), 1.38–1.30 (m, 1H), 1.02 (t, J¼7.0 Hz, 3H),
0.71 (s, 9H), ꢀ0.08 (s, 3H), ꢀ0.11 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 143.54, 133.84, 129.66 (2ꢂ), 127.83
As shown in Scheme 2, compound 7 was synthesized via
silylation of compound 6 and N-allylation of the resultant
product. Further, in order to achieve the synthesis of target
compound 1a, we required a reasonable intermediate 8 for
the synthetic manipulation. To this end, compound 7 was
treated with desilylation, oxidation, and Wittig olefination
to afford diene 8. To build up the piperidine skeleton, diene
8 was subjected to a ring-closing metathesis employing
Grubbs’ second catalyst, the expected piperidine ring 9
was generated.9 Finally, synthesis of a-conhydrine (1a)
was accomplished via hydrogenation and desulfonation.
OTBS
1) TBAF, THF (99%)
1) TBSCl, Im. (96%)
2) NaH, allylBr (97%)
6
2) PCC, DCM (87%)
3) Ph3P=CH2 (82%)
N
N
Ts OBn
Ts OBn
7
8
Grubbs' 2nd (92%)
1) H2, Pd/C (94%)
N
N
2) Na/Hg, MeOH (80%)
H
OH
1a
Ts OBn
9
Scheme 2.

M.-Y. Chang et al. / Tetrahedron 62 (2006) 10843–10848
10845
(2ꢂ), 72.92, 69.80, 63.62, 58.62, 35.08, 25.76, 25.65 (3ꢂ),
21.49, 17.94, 10.79, ꢀ4.93, ꢀ5.05; Anal. Calcd for
C20H35NO4SSi: C, 58.07; H, 8.53; N, 3.39. Found: C,
58.39; H, 8.21; N, 3.58.
(5 mL) was added to a mixture of pyridinium chlorochro-
mate (431 mg, 2.0 mmol) and Celite (1.0 g) in dichloro-
methane (20 mL). After being stirred at rt for 20 h, the
mixture was filtered through a short silica gel column. The
filtrate was dried, filtered, and evaporated to yield crude
compound. Purification on silica gel (hexane/ethyl
acetate¼5/1) afforded ketone 5 (320 mg, 83%). [a]D29
+32.47 (c 0.023, CHCl3); IR (CHCl3) 2955, 1763, 1307,
1158, 1063, 697 cmꢀ1; HRMS (ESI) m/z calcd for
4.1.2. 2-(1-Benzyloxypropyl)-1-(4-methylphenylsulfonyl)
pyrrolidin-4-one (5). A solution of compound 4 (415 mg,
1.0 mmol) in tetrahydrofuran (5 mL) was added to a rapidly
stirred suspension of sodium hydride (60%, 100 mg,
2.5 mmol) in tetrahydrofuran (10 mL). After the reaction
mixture was stirred at rt for 10 min, a solution of benzyl bro-
mide (200 mg, 1.16 mmol) in tetrahydrofuran (2 mL) was
added. The reaction mixture was stirred at rt for 20 h, and
poured into aqueous ammonium chloride solution (15%,
2 mL), and concentrated under reduced pressure. The resi-
due was extracted with ethyl acetate (3ꢂ20 mL). The com-
bined organic layers were washed with brine, dried,
filtered, and evaporated to afford crude product under re-
duced pressure. Purification on silica gel (hexane/ethyl
acetate¼10/1) afforded benzyl product (432 mg, 86%).
[a]2D8 ꢀ18.89 (c 0.01, CHCl3); IR (CHCl3) 2927, 1342,
1090, 755 cmꢀ1; HRMS (ESI) m/z calcd for C27H42NO4SSi
1
C21H26NO4S (M++1) 388.1583, found 388.1586; H NMR
(500 MHz, CDCl3) d 7.72 (d, J¼8.5 Hz, 2H), 7.34–7.25
(m, 5H), 7.18 (d, J¼7.0 Hz, 2H), 4.60 (d, J¼12.0 Hz, 1H),
4.44 (d, J¼12.0 Hz, 1H), 4.29 (dt, J¼2.0, 9.5 Hz,
1H), 3.81 (td, J¼2.0, 7.0 Hz, 1H), 3.69 (d, J¼17.5 Hz,
1H), 3.64 (d, J¼17.5 Hz, 1H), 2.50 (d, J¼17.5 Hz, 1H),
2.44 (s, 3H), 2.10 (dd, J¼9.5, 17.0 Hz, 1H), 1.65–1.58 (m,
1H), 1.42–1.33 (m, 1H), 0.98 (t, J¼7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 209.13, 144.16, 138.05, 135.31,
130.12 (2ꢂ), 128.38 (2ꢂ), 127.59, 127.13 (2ꢂ), 127.09
(2ꢂ), 84.11, 72.89, 59.87, 53.37, 37.10, 24.60, 21.55,
10.06; Anal. Calcd for C21H25NO4S: C, 65.09; H, 6.50; N,
3.61. Found: C, 65.48; H, 6.78; N, 3.32. Single-crystal
X-ray diagram: crystal of ketone 5 was grown by slow dif-
fusion of ethyl acetate into a solution of ketone 5 in dichloro-
methane to yield colorless prism. The compound crystallizes
in the monoclinic crystal system. space group P21(#4),
1
(M++1) 504.2604, found 504.2608; H NMR (500 MHz,
CDCl3) d 7.73 (d, J¼8.0 Hz, 2H), 7.38–7.26 (m, 7H), 4.81
(d, J¼11.5 Hz, 1H), 4.72 (d, J¼11.5 Hz, 1H), 4.39–4.35
(td, J¼4.5, 10.0 Hz, 1H), 4.08 (t, J¼7.0 Hz, 1H), 3.69 (t,
J¼7.0 Hz, 1H), 3.56 (dd, J¼4.5, 10.0 Hz, 1H), 3.07 (dd,
J¼4.5, 10.0 Hz, 1H), 2.43 (s, 3H), 2.21–2.16 (m, 1H),
1.51–1.45 (m, 2H), 1.40–1.33 (m, 1H), 0.99 (t, J¼7.5 Hz,
3H), 0.72 (s, 9H), ꢀ0.12 (s, 3H), ꢀ0.15 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 143.25, 139.21, 134.33, 129.60 (2ꢂ),
128.23 (2ꢂ), 127.82 (2ꢂ), 127.78 (2ꢂ), 127.36, 82.48,
74.38, 70.39, 62.62, 56.69, 34.74, 26.06, 25.72 (3ꢂ),
21.49, 18.03, 10.68, ꢀ5.01, ꢀ5.10; Anal. Calcd for
C27H41NO4SSi: C, 64.37; H, 8.20; N, 2.78. Found: C,
64.66; H, 8.08; N, 2.98. A solution of tetra-n-butyl-
ammonium fluoride (1.0 M in tetrahydrofuran, 1.2 mL,
1.2 mmol) in tetrahydrofuran (2 mL) was added to a solution
of benzyl compound (400 mg, 0.8 mmol) in tetrahydrofuran
(5 mL) at rt. The reaction mixture was stirred at rt for 2 h,
and poured into aqueous ammonium chloride solution
(15%, 2 mL), and concentrated under reduced pressure.
The residue was extracted with ethyl acetate (3ꢂ20 mL).
The combined organic layers were washed with brine, dried,
filtered, and evaporated to afford crude product under re-
duced pressure. Purification on silica gel (hexane/ethyl
acetate¼2/1) afforded alcohol product (285 mg, 92%).
[a]2D9 ꢀ32.35 (c 0.011, CHCl3); IR (CHCl3) 3501, 2933,
1338, 1156, 1090 cmꢀ1; HRMS (ESI) m/z calcd for
˚
˚
˚
a¼7.9147(16) A, b¼6.1920(12) A, c¼21.110(4) A, V¼
1033.5(4) A , Z¼2, dcalcd¼1.245 mg/m3, absorption coef-
3
˚
ficient¼0.182 mmꢀ1, F(000)¼412, 2q range (1.93–26.00ꢁ).
4.1.3. 4-Benzyloxy-3-(4-methylphenylsulfonylamino)
hexan-1-ol (6). A solution of m-chloroperoxybenzoic acid
(75%, 600 mg, 2.6 mmol) in dichloromethane (10 mL) was
added to a solution of ketone 5 (390 mg, 1.0 mmol) and
sodium carbonate (420 mg, 4.0 mmol) in dichloromethane
(20 mL) at 0 ꢁC. The reaction mixture was stirred at rt for
20 h. Saturated sodium carbonate solution (10 mL) was
added to the reaction mixture and the solvent was concen-
trated under reduced pressure. The residue was extracted
with ethyl acetate (3ꢂ20 mL). The combined organic layers
were washed with brine, dried, filtered, and evaporated to af-
ford crude product under reduced pressure. Purification on
silica gel (hexane/ethyl acetate¼4/1 to 2/1) afforded lactone
product (330 mg, 82%). [a]2D9 ꢀ102.74 (c 0.008, CHCl3); IR
(CHCl3) 2923, 1764, 1352, 1156, 998 cmꢀ1; HRMS (ESI,
M++1) calcd for C21H26NO5S 404.1532, found 404.1538;
1H NMR (500 MHz, CDCl3) d 7.74 (d, J¼8.5 Hz, 2H),
7.39–7.31 (m, 7H), 5.79 (d, J¼11.5 Hz, 1H), 5.17 (d,
J¼11.5 Hz, 1H), 4.76 (d, J¼11.0 Hz, 1H), 4.67 (d, J¼
11.0 Hz, 1H), 3.97 (td, J¼2.0, 7.0 Hz, 1H), 3.73 (ddd,
J¼2.0, 7.0, 10.0 Hz, 1H), 2.96 (dd, J¼11.0, 16.0 Hz, 1H),
2.43 (s, 3H), 2.42 (dd, J¼7.0, 16.0 Hz, 1H), 1.64–1.55 (m,
1H), 1.39–1.30 (m, 1H), 0.98 (t, J¼7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 169.11, 144.94, 138.05, 134.53,
130.14 (2ꢂ), 128.55 (2ꢂ), 127.96, 127.93 (2ꢂ), 127.86
(2ꢂ), 83.47, 75.76, 74.32, 53.95, 28.19, 24.08, 21.64,
10.13; Anal. Calcd for C21H25NO5S: C, 62.51; H, 6.25; N,
3.47. Found: C, 62.83; H, 6.58; N, 3.60. A solution of the
resulting product (310 mg, 0.77 mmol) in tetrahydrofuran
(10 mL) was added to a rapidly stirred suspension of lithium
aluminum hydride (76 mg, 2.0 mmol) at 0 ꢁC. The reaction
mixture was stirred at rt for 2 h. Aqueous ammonium chlo-
ride solution (15%, 2 mL) was added to the reaction mixture
1
C21H28NO4S (M++1) 390.1739, found 390.1741; H NMR
(500 MHz, CDCl3) d 7.76 (d, J¼8.5 Hz, 2H), 7.35–7.26
(m, 7H), 4.79 (d, J¼11.5 Hz, 1H), 4.71 (d, J¼11.5 Hz,
1H), 4.33 (br s, 1H), 4.03 (ddd, J¼2.0, 5.5, 8.0 Hz, 1H),
3.85 (td, J¼2.0, 8.0 Hz, 1H), 3.48 (dd, J¼4.0, 12.0 Hz,
1H), 3.36 (dt, J¼2.0, 12.0 Hz, 1H), 2.43 (s, 3H), 2.25
(ddd, J¼4.5, 7.0, 12.5 Hz, 1H), 1.69–1.64 (m, 1H), 1.51–
1.32 (m, 2H), 1.13–1.11 (m, 1H), 0.96 (t, J¼7.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 143.65, 139.07, 134.69,
129.64 (2ꢂ), 128.29 (2ꢂ), 127.83 (2ꢂ), 127.75 (2ꢂ),
127.45, 82.35, 74.35, 70.61, 62.43, 56.95, 34.08, 25.82,
21.55, 10.61; Anal. Calcd for C21H27NO4S: C, 64.75; H,
6.99; N, 3.60. Found: C, 64.58; H, 7.20; N, 3.88. A solution
of alcohol product (390 mg, 1.0 mmol) in dichloromethane

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M.-Y. Chang et al. / Tetrahedron 62 (2006) 10843–10848
1
and filtered through a short silica gel column. The filtrate
was dried, filtered, and evaporated to yield crude compound.
Purification on silica gel (hexane/ethyl acetate¼5/1) af-
forded aminoalcohol 6 (273 mg, 94%). [a]2D9 ꢀ46.75 (c
0.015, CHCl3); IR (CHCl3) 3290, 2962, 1598, 1325, 1160,
815 cmꢀ1; HRMS (ESI, M++1) calcd for C20H28NO4S
(M++1) 532.2917, found 532.2920; H NMR (500 MHz,
CDCl3) d 7.72 (d, J¼8.0 Hz, 2H), 7.34–7.25 (m, 7H),
5.81–5.73 (m, 1H), 5.10 (d, J¼17.0 Hz, 1H), 5.02 (d,
J¼10.0 Hz, 1H), 4.55 (d, J¼11.5 Hz, 1H), 4.36 (d, J¼
11.5 Hz, 1H), 4.02 (dd, J¼6.5, 16.0 Hz, 1H), 3.97 (dt, J¼
4.0, 9.5 Hz, 1H), 3.89 (dd, J¼6.5, 16.0 Hz, 1H), 3.49–3.46
(m, 1H), 3.44–3.40 (m, 1H), 3.36–3.31 (m, 1H), 2.42 (s,
3H), 1.88–1.82 (m, 1H), 1.80–1.73 (m, 1H), 1.70–1.63 (m,
1H), 1.60–1.52 (m, 1H), 0.94 (t, J¼7.5 Hz, 3H), 0.87 (s,
9H), ꢀ0.01 (s, 3H), ꢀ0.02 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 142.94, 138.44, 138.33, 136.06, 129.41 (2ꢂ),
128.29 (2ꢂ), 127.50 (2ꢂ), 127.48, 127.45 (2ꢂ), 117.01,
84.10, 71.48, 60.50, 56.50, 47.32, 30.75, 25.88 (3ꢂ),
24.01, 21.49, 18.20, 9.78, ꢀ5.38, ꢀ5.42; Anal. Calcd for
C29H45NO4SSi: C, 65.49; H, 8.53; N, 2.63. Found: C,
65.83; H, 8.62; N, 2.44.
1
378.1739, found 378.1742; H NMR (500 MHz, CDCl3)
d 7.52 (d, J¼8.0 Hz, 2H), 7.41–7.34 (m, 4H), 7.25–7.22
(m, 3H), 4.89 (d, J¼9.5 Hz, 1H), 4.55 (d, J¼12.0 Hz, 1H),
4.18 (d, J¼12.0 Hz, 1H), 3.88–3.82 (m, 1H), 3.69–3.64
(m, 1H), 3.49–3.43 (m, 1H), 2.89–2.86 (m, 1H), 2.64 (dd,
J¼6.0, 7.0 Hz, 1H), 2.42 (s, 3H), 1.74–1.67 (m, 1H), 1.65–
1.55 (m, 2H), 1.38–1.29 (m, 1H), 0.70 (t, J¼7.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 143.39, 138.08, 137.38,
129.62 (2ꢂ), 128.70 (2ꢂ), 128.03, 127.76 (2ꢂ), 126.97
(2ꢂ), 81.57, 71.36, 58.18, 51.67, 30.38, 22.56, 21.51,
9.58; Anal. Calcd for C20H27NO4S: C, 63.63; H, 7.21; N,
3.71. Found: C, 63.28; H, 7.56; N, 3.46.
4.1.5. N-Allyl-N-[1-(1-benzyloxypropyl)but-3-enyl]-4-
methylbenzenesulfonamide (8). A solution of tetra-n-butyl-
ammonium fluoride (1.0 M in tetrahydrofuran, 1.2 mL,
1.2 mmol) in tetrahydrofuran (2 mL) was added to a solution
of compound 7 (530 mg, 1.0 mmol) in tetrahydrofuran
(20 mL) at rt. The reaction mixture was stirred at rt for
2 h, and poured into aqueous ammonium chloride solution
(15%, 2 mL), and concentrated under reduced pressure.
The residue was extracted with ethyl acetate (3ꢂ20 mL).
The combined organic layers were washed with brine, dried,
filtered, and evaporated to afford crude product under
reduced pressure. Purification on silica gel (hexane/ethyl
acetate¼4/1) afforded alcohol product (410 mg, 99%).
HRMS (ESI) m/z calcd for C23H32NO4S (M++1) 418.2052,
4.1.4. N-Allyl-N-{2-benzyloxy-1-[2-(tert-butyldimethyl-
silanyloxy)ethyl]butyl}-4-methylbenzenesulfonamide
(7). tert-Butyldimethylsilyl chloride (150 mg, 1.0 mmol)
and imidazole (136 mg, 2.0 mmol) were added to a stirred
solution of compound 6 (300 mg, 0.8 mmol) in dimethylfor-
amide (5 mL) at rt. The reaction mixture was stirred at rt for
2 h. The reaction mixture was concentrated under reduced
pressure. The residue was diluted with water (10 mL) and
the mixture was extracted with ethyl acetate (3ꢂ20 mL).
The combined organic layers were washed with saturated
sodium bicarbonate solution and brine, dried, filtered, and
evaporated under reduced pressure to yield crude product.
Purification on silica gel (hexane/ethyl acetate¼5/1)
afforded silyl product (375 mg, 96%). HRMS (ESI) m/z
calcd for C26H42NO4SSi (M++1) 492.2604, found
492.2606; 1H NMR (500 MHz, CDCl3) d 7.68 (d,
J¼8.0 Hz, 2H), 7.37–7.24 (m, 7H), 5.31 (d, J¼7.5 Hz,
1H), 4.54 (d, J¼11.5 Hz, 1H), 4.35 (d, J¼11.5 Hz, 1H),
3.62–3.57 (m, 1H), 3.53–3.48 (m, 1H), 3.46–3.41 (m, 1H),
3.36–3.33 (m, 1H), 2.42 (s, 3H), 1.69–1.54 (m, 3H), 1.49–
1.40 (m, 1H), 0.89 (s, 9H), 0.85 (t, J¼7.5 Hz, 3H), 0.02 (s,
6H); 13C NMR (125 MHz, CDCl3) d 143.06, 138.54,
137.93, 129.52 (2ꢂ), 128.42 (2ꢂ), 127.65 (3ꢂ), 127.16
(2ꢂ), 81.88, 72.02, 60.21, 53.68, 31.03, 25.86 (3ꢂ),
23.08, 21.51, 18.11, 9.63, ꢀ5.49, ꢀ5.53; Anal. Calcd for
C26H41NO4SSi: C, 63.50; H, 8.40; N, 2.85. Found: C,
63.77; H, 8.22; N, 2.70. A solution of silyl compound
(350 mg, 0.71 mmol) in dimethylforamide (2 mL) was
added to a rapidly stirred suspension of sodium hydride
(60%, 100 mg, 2.5 mmol) in dimethylforamide (3 mL). Af-
ter the reaction mixture was stirred at ice bath for 5 min, allyl
bromide (250 mg, 2.1 mmol) was added at ice bath. The re-
sulting mixture was stirred at rt for 3 h. The reaction was
quenched with 15% ammonium chloride solution (1 mL)
and the mixture was concentrated under reduced pressure.
The residue was diluted with water (10 mL) and the mixture
was extracted with ethyl acetate (3ꢂ20 mL). The combined
organic layers were washed with saturated sodium bicarbon-
ate solution and brine, dried, filtered, and evaporated under
reduced pressure to yield crude product. Purification on
silica gel (hexane/ethyl acetate¼10/1) afforded compound
7 (367 mg, 97%) as viscous oil. [a]2D9 ꢀ27.78 (c 0.011,
CHCl3); IR (CHCl3) 2928, 1462, 1340, 1255, 1162, 1027,
835 cmꢀ1; HRMS (ESI) m/z calcd for C29H46NO4SSi
1
found 418.2055; H NMR (500 MHz, CDCl3) d 7.70 (d,
J¼8.5 Hz, 2H), 7.34–7.24 (m, 7H), 5.88–5.80 (m, 1H),
5.09 (dd, J¼1.5, 17.5 Hz, 1H), 5.05 (dd, J¼1.0, 10.0 Hz,
1H), 4.54 (d, J¼11.5 Hz, 1H), 4.27 (d, J¼11.5 Hz, 1H),
4.06 (dd, J¼7.5, 16.0 Hz, 1H), 3.96 (dt, J¼3.5, 10.0 Hz,
1H), 3.92 (dd, J¼10.0, 16.0 Hz, 1H), 3.71–3.65 (m, 1H),
3.64–3.58 (m, 1H), 3.19 (dt, J¼4.5, 8.5 Hz, 1H), 2.56 (dd,
J¼5.0, 7.5 Hz, 1H), 2.44 (s, 3H), 1.89–1.77 (m, 2H), 1.61–
1.53 (m, 1H), 1.16–1.37 (m, 1H), 0.48 (t, J¼7.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 143.37, 138.02, 137.97,
136.02, 129.60 (2ꢂ), 128.37 (2ꢂ), 127.66, 127.51 (2ꢂ),
127.29 (2ꢂ), 117.43, 82.91, 71.00, 58.59, 55.95, 47.29,
29.58, 23.56, 21.53, 9.80; Anal. Calcd for C23H31NO4S: C,
66.16; H, 7.48; N, 3.35. Found: C, 66.39; H, 7.62; N, 3.71.
A solution of alcohol product (420 mg, 1.0 mmol) in di-
chloromethane (5 mL) was added to a mixture of pyridinium
chlorochromate (431 mg, 2.0 mmol) and Celite (1.0 g) in
dichloromethane (20 mL). After being stirred at rt for
20 h, the mixture was filtered through a short silica gel col-
umn. The filtrate was dried, filtered, and evaporated to yield
crude compound. Purification on silica gel (hexane/ethyl
acetate¼5/1) afforded aldehyde product (364 mg, 87%).
[a]2D8 ꢀ35.20 (c 0.013, CHCl3); IR (CHCl3) 3029, 2927,
2733, 1722, 1598, 1398, 1089 cmꢀ1; HRMS (ESI) m/z calcd
for C23H30NO4S (M++1) 416.1896, found 416.1899; 1H
NMR (500 MHz, CDCl3) d 9.45 (dd, J¼1.0, 2.5 Hz, 1H),
7.71 (d, J¼8.0 Hz, 2H), 7.33–7.24 (m, 7H), 5.79–5.71 (m,
1H), 5.10 (d, J¼9.0 Hz, 1H), 5.09 (d, J¼18.0 Hz, 1H),
4.53 (d, J¼11.5 Hz, 1H), 4.42 (dt, J¼5.0, 8.0 Hz, 1H), 4.33
(d, J¼11.5 Hz, 1H), 3.94 (dd, J¼6.0, 16.5 Hz, 1H), 3.65
(dd, J¼7.0, 16.5 Hz, 1H), 3.55 (dt, J¼5.0, 7.5 Hz, 1H),
2.61 (dd, J¼3.0, 8.5, 16.5 Hz, 1H), 2.42 (s, 3H), 2.23 (dd,

M.-Y. Chang et al. / Tetrahedron 62 (2006) 10843–10848
10847
J¼5.0, 16.5 Hz, 1H), 1.73–1.62 (m, 2H), 0.95 (t, J¼7.5 Hz,
3H); 13C NMR (125 MHz, CDCl3) d 198.68, 143.67, 137.58,
137.21, 135.18, 129.77 (2ꢂ), 128.39 (2ꢂ), 127.92 (2ꢂ),
127.79, 127.32 (2ꢂ), 118.01, 80.92, 71.66, 55.12, 48.26,
43.94, 22.70, 21.51, 8.36; Anal. Calcd for C23H29NO4S: C,
66.48; H, 7.03; N, 3.37. Found: C, 66.69; H, 7.09; N, 3.49.
n-Butyllithium (1.6 M in hexane, 1.0 mL, 1.6 mmol) was
added to a stirred solution of methyl triphenylphosphonium
iodide (808 mg, 2.0 mmol) in tetrahydrofuran (20 mL) at
ꢀ78 ꢁC. The orange red colored mixture was stirred at
ꢀ78 ꢁC for 1 h. A solution of aldehyde product (290 mg,
0.7 mmol) in tetrahydrofuran (5 mL) was added to the reac-
tion mixture at ꢀ78 ꢁC via a syringe and further stirred at
ꢀ78 ꢁC for 2 h. The reaction was quenched with aqueous
saturated ammonium chloride (10 mL) and the mixture
was extracted with diethyl ether (3ꢂ20 mL) and the com-
bined organic layers were washed with brine, dried, filtered,
and evaporated. Purification on silica gel (hexane/ethyl
acetate¼2/1) afforded compound 8 (237 mg, 82%). [a]D28
+3.33 (c 0.009, CHCl3); IR (CHCl3) 2925, 1455, 1337,
1090, 662 cmꢀ1; HRMS (ESI) m/z calcd for C24H32NO3S
as catalyst was added. Then hydrogen was bubbled into
the mixture for 10 min, and stirring occurred at rt for 10 h.
The mixture was filtered through a short silica gel column.
The filtrate was dried, filtered, and evaporated to yield crude
compound. Purification on silica gel (hexane/ethyl
acetate¼5/1) afforded alcohol product (58 mg, 94%). [a]D28
ꢀ33.21 (c 0.026, CHCl3); IR (CHCl3) 3516, 2935, 1455,
1332, 1092, 933, 658 cmꢀ1; HRMS (ESI) m/z calcd for
1
C15H23NO3S (M++1) 298.1477, found 298.1481; H NMR
(500 MHz, CDCl3) d 7.74 (d, J¼8.5 Hz, 2H), 7.30 (d,
J¼8.5 Hz, 2H), 3.85–3.74 (m, 3H), 3.03 (ddd, J¼3.0, 13.0,
14.5 Hz, 1H), 2.43 (s, 3H), 1.94–1.91 (m, 1H), 1.82–1.79
(m, 1H), 1.59–1.50 (m, 1H), 1.46–1.37 (m, 3H), 1.26–1.16
(m, 1H), 1.14–1.05 (m, 1H), 1.01 (t, J¼7.5 Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 142.97, 138.75, 129.69 (2ꢂ),
126.99 (2ꢂ), 71.12, 57.14, 42.34, 27.04, 23.42, 23.03,
21.51, 18.84, 10.85; Anal. Calcd for C15H23NO3S: C,
60.58; H, 7.79; N, 4.71. Found: C, 60.68; H, 7.94; N, 4.69.
Sodium amalgam (Na/Hg, 0.5 g, 6%) and sodium phosphate
(71 mg, 0.5 mmol) were added to a stirred solution of N-tosyl-
conhydrine (30 mg, 0.1 mmol) in methanol (10 mL), and
vigorously stirred for 5 h at rt. The residue was filtered
and washed with methanol (2ꢂ10 mL) and the combined or-
ganic layers were evaporated to afford the crude products.
Purification on silica gel (hexane/ethyl acetate¼1/1 to 1/2)
afforded a-conhydrine (1a) (12 mg, 80%). The NMR spec-
tral data of a-conhydrine (1a) were in accordance with those
reported in the literature.5g
1
(M++1) 414.2103, found 414.2104; H NMR (500 MHz,
CDCl3) d 7.70 (d, J¼8.5 Hz, 2H), 7.33–7.26 (m, 7H),
5.95–5.77 (m, 1H), 5.52–5.44 (m, 1H), 5.10 (dd, J¼1.5,
17.5 Hz, 1H), 5.04 (dd, J¼1.5, 10.0 Hz, 1H), 4.92 (dd,
J¼1.5, 17.5 Hz, 1H), 4.81 (d, J¼10.0 Hz, 1H), 4.56 (d, J¼
11.0 Hz, 1H), 4.38 (d, J¼11.0 Hz, 1H), 3.99 (dd, J¼6.0,
16.5 Hz, 1H), 3.92 (td, J¼5.0, 10.0 Hz, 1H), 3.80 (dd,
J¼6.5, 16.5 Hz, 1H), 3.47 (dd, J¼5.5, 11.5 Hz, 1H), 2.49–
2.42 (m, 1H), 2.43 (s, 3H), 2.35–2.28 (m, 1H), 1.71–1.59
(m, 2H), 0.96 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 143.03, 138.35, 138.16, 136.15, 135.69, 129.32
(2ꢂ), 128.33 (2ꢂ), 127.60 (2ꢂ), 127.55, 127.54 (2ꢂ),
116.98, 116.78, 83.20, 71.62, 60.12, 47.39, 32.39, 23.90,
21.49, 9.65; Anal. Calcd for C24H31NO3S: C, 69.70; H,
7.56; N, 3.39. Found: C, 66.91; H, 7.82; N, 3.58.
Acknowledgements
The authors would like to thank the National Science Coun-
cil (NSC-95-2113-M-390-003-MY2) of the Republic of
China for financial support. We also thank Prof. Michael
Y. Chiang (National Sun Yat-Sen University) for structural
determination of compound 5 by X-ray diffraction analysis.
4.1.6. 2-(1-Benzyloxypropyl)-1-(4-methylphenylsul-
fonyl)-1,2,3,6-tetrahydropyridine (9). Grubbs’ second
generation catalyst (30 mg) was added to a solution of com-
pound 8 (210 mg, 0.51 mmol) in dichloromethane (50 mL)
at rt. The reaction mixture was refluxed under nitrogen atmo-
sphere for 2 h. The mixture was concentrated and purified by
flash column chromatography (hexane/ethyl acetate¼4/1) to
yield compound 9 (180 mg, 92%). [a]2D8 ꢀ56.00 (c 0.005,
Supplementary data
Photocopies of NMR (1H and 13C) spectral data for new
compounds were supported. Supplementary data associated
with this article can be found in the online version, at
doi:10.1016/j.tet.2006.09.004.
CHCl3); IR (CHCl3) 2924, 1598, 1342, 1091, 754 cmꢀ1
;
HRMS (ESI) m/z calcd for C22H28NO3S (M++1) 386.1790,
found 386.1795; H NMR (500 MHz, CDCl3) d 7.67 (d,
1
References and notes
J¼9.0 Hz, 2H), 7.34–7.24 (m, 7H), 5.55–5.52 (m, 2H),
4.59 (d, J¼11.5 Hz, 1H), 4.35 (d, J¼11.5 Hz, 1H), 4.17
(19.0 Hz, 1H), 4.05 (dd, J¼6.5, 9.5 Hz, 1H), 3.60 (dt,
J¼3.0, 19.0 Hz, 1H), 3.52–3.48 (m, 1H), 2.41 (s, 3H), 2.25
(d, J¼18.0 Hz, 1H), 1.89–1.82 (m, 1H), 1.80–1.75 (m,
1H), 1.72–1.63 (m, 1H), 1.04 (t, J¼7.5 Hz, 3H); 13C NMR
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128.36 (2ꢂ), 127.66 (2ꢂ), 127.62, 126.93 (2ꢂ), 124.22,
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8.26; Anal. Calcd for C22H27NO3S: C, 68.54; H, 7.06; N,
3.63. Found: C, 68.78; H, 6.91; N, 3.44.
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