Total synthesis of (+)-pseudohygroline

Article abstract of DOI:10.1016/j.tetlet.2010.01.060

A simple and efficient total synthesis of five-membered pyrrolidine, (+)-pseudohygroline is described. The key steps involved in this synthesis are highly stereoselective Prins cyclisation followed by reductive ring opening and hydroboration.

Full text of DOI:10.1016/j.tetlet.2010.01.060

Tetrahedron Letters 51 (2010) 1574–1577
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Total synthesis of (+)-pseudohygroline
*
J. S. Yadav , G. Narasimhulu, N. Mallikarjuna Reddy, B. V. Subba Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient total synthesis of five-membered pyrrolidine, (+)-pseudohygroline is described.
The key steps involved in this synthesis are highly stereoselective Prins cyclisation followed by reductive
ring opening and hydroboration.
Received 18 December 2009
Revised 9 January 2010
Accepted 17 January 2010
Available online 22 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
(+)-Pseudohygroline
Prins cyclisation
Hydroboration
Pyrrolidine alkaloids
Pyrrolidine ring is frequently found in a large number of natural
products, many of which exhibit a wide range of biological and
pharmacological activity, hence pyrrolidine alkaloids make them
attractive targets to synthetic chemists.1 (+)-Pseudohygroline and
hygroline were isolated from Carallia brachiata,2a Erythroxylon
coca2b andSchizanthushookeri.2c Structurally, thesenaturalproducts
constitute 2-substituted pyrrolidine.2 This small molecule occupies
a significant place in alkaloid chemistry as it was prepared as part of
the first chemical proof of the absolute stereochemistry of the
biosynthetically important (+)-hygroline and (+)-hygrine.3 (+)-
Pseudohygroline and hygroline are found to exhibit a potent phar-
macological activity.4 Considering its potent biological activity and
fascinating structural features, several approaches have been re-
ported for the synthesis of (+)-pseudohygroline (Fig. 1).5
The Prins cyclisation is a powerful synthetic tool for the con-
struction of multi-substituted tetrahydropyran systems and has
been utilised in the synthesis of several natural products.6 Our
group has made a significant effort to explore the utility of Prins
cyclisation in the synthesis of various polyketide intermediates
and applied it to the total synthesis of some natural products.7
As a part of our interest on the total synthesis of biologically active
natural products, we herein report a total synthesis of (+)-pseud-
ohygroline (2) by means of Prins cyclisation (Scheme 1).
lysis of the resulting trifluoroacetate gave the tetrahydropyranol 6
in 52% yield.9 The stereochemistry of 6 was assumed to be in antic-
ipated line with previous results.6–8 It was later proved after elab-
orating the compound 6 to the target molecule which in all
respects was identical with the reported one.10 The chemoselective
tosylation of primary alcohol 6 with 1.1 equiv of tosyl chloride in
the presence of TEA in DCM gave the corresponding tosylate 7 in
96% yield.11 Protection of secondary alcohol 7 with TBSCl, DMAP
and imidazole gave the TBS ether 8 in 91% yield. Treatment of tos-
ylate 8 with NaI in refluxing acetone afforded iodo compound 9 in
94% yield, which on exposure to activated zinc in refluxing ethanol
furnished the key intermediate 10 with a required anti-1,3-diol
system in 96% yield. The newly created secondary alcohol 10 was
protected as its MOM ether 11 in the presence of DIPEA and
MOM chloride in dichloromethane in 98% yield. Hydroboration of
compound 11 using BH3ꢀDMS in THF furnished the primary alcohol
12 in 80% yield.12 Treatment of compound 12 with TBAF in THF
produced the diol 13 in 85% yield. Mesylation of diol 13 with mesyl
chloride in the presence of TEA gave the dimesylate, which was
subsequently treated with 40% aqueous methylamine in DMF at
60 °C to afford the N-methyl pyrrolidine 14.13 Deprotection of
MOM ether using TMS chloride in methanol gave the pure (+)-
pseudohygroline (2) in 96% yield (Scheme 2), the data of which
were in good agreement with the reported values.5
Accordingly, the synthesis of (+)-pseudohygroline (2) began
with a chiral homoallyl alcohol (5).8 Prins cyclisation of 5 with
acetaldehyde in the presence of TFA (10 equiv), followed by hydro-
In conclusion, we have demonstrated a simple and concise total
synthesis of (+)-pseudohygroline (2)14 by stereoselective Prins
cyclization, reductive ring opening of tetrahydropyran and sequen-
tial intermolecular and intramolecular substitution reactions. Fur-
ther application of Prins cyclisation in the synthesis of natural
products is in progress, and will be disclosed in due course.
* Corresponding author. Tel.: +91 40 27193030; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.060

J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 1574–1577
1575
OH
OH
OH
OH
N
N
N
N
CH3
CH3
CH3
CH3
(+)-hygroline
1,
2,
(+)-pseudohygroline
(-)-pseudohygroline
4,
(-)-hygroline
3,
Figure 1. (+)-Hygroline (1), (+)-pseudohygroline (2), (ꢁ)-hygroline (3) and (ꢁ)-pseudohygroline (4).
OTBSOH
OH OMOM
OH
HO
N
CH3
13
10
2
OH
OH
OH
OH
O
5
6
Scheme 1. Retrosynthetic analysis of (+)-pseudohygroline.
OH
OH
CH3CHO,TFA, CH2Cl2
TEA, TsCl, CH2Cl2
OH
OTs
OH
O
°
OH
K2CO3,MeOH
r.t., 4h, 52%
0 C, r.t., 3h, 96%
O
7
6
5 (99% ee)
OTBS
OTBS
reflux, 1h
Zn, EtOH,
NaI, acetone,
reflux, 24h.
TBSCl, DMAP
OTs
I
96%
O
imidazole, CH2Cl2
O
94%
9
8
.
BH3 DMS,THF, 8h, 0 C
°
1)
OTBSOMOM
OTBSOMOM
OTBSOH
MOMCl, DIPEA
HO
2) H2O2, NaOH, H2O, 3h, 80%
°
0 C-r.t., 4h,
98%
12
Regioselectivity 91:9
11
10
OH OMOM
OMOM
°
, 0 C,1h
°
1)
2)
TEA, DMAP, MsCl
TBAF,THF, 0 C,-r.t., 4h
HO
N
85%
MeNH2, DMF-H2O
CH3
13
14
°
60 C, 7h, 76%
Diastereoselectivity 93:7
TMSCl, MeOH
OH
r.t., 2h, NaHCO3
96%
N
CH3
2
Scheme 2. Synthetic sequence of pseudohygroline.

1576
J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 1574–1577
(3.04 mL, 21.9 mmol) was added at 0 °C. Then tosyl chloride (2.28 g, 12 mmol)
Acknowledgements
was added over 2 h. The resulting mixture was allowed to warm to room
temperature and stirred for 3 h. Then mixture was treated with aqueous 1 N
HCl (10 mL) and extracted with CH2Cl2 (3 ꢂ 30 mL). The organic layer was
washed with NaHCO3 (15 mL), and water (15 mL).The combined organic layers
were dried over Na2SO4 and concentrated under reduced pressure. Flash
chromatography of the crude product afforded tosylate (3.12 g, 95%) as a
G.N.L. and N.M.R. thanks CSIR, New Delhi, for the award of fel-
lowship and also we thank DST for the financial assistance under J.
C. Bose fellowship scheme.
gummy liquid. Rf = 0.4 (SiO2, 60% EtOAc in hexane). ½a D25
ꢃ
+34.8 (c 1.0, CHCl3);
1H NMR (200 MHz, CDCl3): d 7.78 (d, 2H, J = 8.0 Hz), 7.33 (d, 2H, J = 8.0 Hz),
4.07–3.89 (m, 2H), 3.86–3.65 (m, 1H), 3.64–3.47 (m, 1H), 3.47–3.31 (m, 1H),
2.46 (s, 3H), 1.98–1.79 (m, 2H), 1.52–1.33 (m, 2H), 1.15 (d, 3H, J = 5.8 Hz); 13C
NMR (75 MHz, CDCl3): d 144.7, 132.8, 129.7, 127.9, 72.7, 71.9, 71.8, 67.4, 42.3,
References and notes
1. (a) Massio, G.; Delaude, C.. In The Alkaloids; Brossi, A., Ed.; Academic Press: San
Diego, 1986; Vol. 27, p 270; (b) Pinder, A. R. Nat. Prod. Rep. 1992, 17.
2. (a) Platonava, T. F.; Kuzovkov, A. D. Med. Prom. SSSR 1963, 17, 19; (b) Fitzgerald,
J. S. Aust. J. Chem. 1965, 18, 589; (c) Martin, S. A.; Rovirosa, J.; Gambaro, V.;
Castillo, M. Phytochemistry 1980, 19, 2007.
36.6, 21.6, 21.3; IR (neat):
1096, 975, 816, 667 cmꢁ1; ESI-MS: 301 [M+H]+; HRMS calcd for C14H21O5S:
301.1104. Found: 301.1097. (2S,4R,6S)-4-(tert-Butyldimethylsilyloxy)-6-
methyltetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (8): To
m 3399, 2923, 2853, 1723, 1598, 1453, 1358, 1177,
a
3. Lukes, R.; Kovar, J.; Kjoubek, J.; Blaha, K. Coll. Czech. Chem. Commun. 1960, 25,
483.
4. (a) Schulz, S. Eur. J. Org. Chem. 1998, 1, 13; (b) Hartmann, T. Planta 1999, 207,
483; (c) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. Tetrahedron:
Asymmetry 2000, 11, 1645.
solution of 7 (3.0 g, 10 mmol) in dry CH2Cl2 (30 mL) was added DMAP (5 mg)
and imidazole (1.36 g, 20 mmol) in one portion followed by TBDMSCl (1.8 g,
12 mmol) in three portions. The reaction mixture was stirred for 3 h with the
temperature slowly reaching to room temperature. It was quenched with the
saturated NH4Cl solution (30 mL), diluted with EtOAc (100 mL), washed with
brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the
5. (a) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981, 103, 1172; (b)
Shono, T.; Matsumura, Y.; Tsubata, K.; Uchida, K. J. Org. Chem. 1986, 51, 2590;
(c) Knight, D. W.; Salter, R. Tetrahedron Lett. 1999, 40, 5915; (d) Takahata, H.;
Kubota, M.; Momose, T. Tetrahedron: Asymmetry 1997, 8, 2801; (e) Enierga, G.;
Hockless, D. C. R.; Perlmutter, P.; Rose, M.; Sjoberg, S.; Wong, K. Tetrahedron
Lett. 1998, 39, 2813; (f) Enierga, G.; Espiritu, M.; Perlmutter, P.; Pham, N.; Rose,
M.; Sjoberg, S.; Thienthong, N.; Wong, K. Tetrahedron: Asymmetry 2001, 12, 597.
6. (a) Barry, C. St.; Crosby, S. R.; Harding, J. R.; Hughes, R. A.; King, C. D.; Parker, G.
D.; Willis, C. L. Org. Lett. 2003, 5, 2429; (b) Yang, X. F.; Mague, J. T.; Li, C. J. Org.
Chem. 2001, 66, 739; (c) Yadav, J. S.; Reddy, B. V. S.; Sekar, K. C.; Gunasekar, D.
Synthesis 2001, 6, 885; (d) Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S.; Niranjan, N.
J. Mol. Catal. A: Chem. 2004, 210, 99; (e) Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S.;
Niranjan, N.; Prasad, A. R. Eur. J. Org. Chem. 2003, 1779; (f) Kwon, M. S.; Woo, S.
K.; Na, S. W.; Lee, E. Angew. Chem., Int. Ed. 2008, 47, 1733.
7. (a) Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem, Int. Ed. 2005, 44, 3485;
(b) Barry, C. S.; Bushby, N.; Harding, J. R.; Willis, C. S. Org. Lett. 2005, 7, 2683; (c)
Cossey, K. N.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 12216; (d) Crosby, S. R.;
Harding, J. R.; King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2002, 4, 3407; (e)
Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett. 2002, 4, 3919;
(f) Kozmin, S. A. Org. Lett. 2001, 3, 755; (g) Jaber, J. J.; Mitsui, K.; Rychnovsky, S.
D. J. Org. Chem. 2001, 66, 4679; (h) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem.
Soc. 2001, 123, 8420; (i) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2,
1217; (j) Rychnovsky, S. D.; Yang, G.; Hu, Y.; Khire, U. R. J. Org. Chem. 1997, 62,
3022; (k) Su, Q.; Panek, J. S. J. Am. Chem. Soc. 2004, 126, 2425.
crude product by column chromatography afforded
8
ꢃ
(4.09 g, 99%) as
+8.3 (c 1.0, CHCl3);
a
colourless liquid. Rf = 0.2 (SiO2, 10% EtOAc in hexane). ½a D20
1H NMR (200 MHz, CDCl3): d 7.79 (d, 2H, J = 8.0 Hz), 7.32 (d, 2H, J = 8.0 Hz),
4.00–3.88 (m, 2H), 3.81–3.61 (m, 1H), 3.60–3.27 (m, 2H), 2.45 (s, 3H), 1.81–
1.65 (m, 2H), 1.24–1.00 (m, 2H), 1.13 (d, 3H, J = 5.8 Hz), 0.86 (s, 9H), 0.03 (s,
6H); 13C NMR (75 MHz, CDCl3): d 129.7, 127.9, 72.8, 72.1, 71.8, 68.0, 43.0, 37.1,
25.7, 21.5, 21.4, ꢁ4.6; IR (neat):
1073, 981, 836, 776 cmꢁ1; ESI-MS: 415 [M+H]+; HRMS calcd for C20H35O5SSi:
415.1969. Found: 415.1985. tert-Butyl((2S,4R,6S)-2-(iodomethyl)-6-
methyltetrahydro-2H-pyran-4-yloxy)dimethylsilane (9): NaI (6.7 g, 45 mmol)
was added to solution of (3.72 g, 9 mmol) in 60 mL of acetone and
m 2931, 2856, 1598, 1465, 1363, 1254, 1181,
a
8
heated to reflux for 24 h. Acetone was removed under reduced pressure. To the
residue was added water and EtOAc and the organic layer was separated, dried
over Na2SO4, concentrated and chromatographed to afford 9 (3.23 g, 97%) as a
colourless liquid. Rf = 0.7 (SiO2, 10% EtOAc in hexane). ½a D20
ꢃ
+15.6 (c 1.05,
CHCl3); 1H NMR (300 MHz, CDCl3): d 3.83–3.69 (m, 1H), 3.52–3.39 (m, 1H),
3.38–3.27 (m, 1H), 3.23–3.10 (m, 2H), 2.07–1.98 (m, 1H), 1.79–1.69 (m, 1H),
1.32–1.08 (m, 2H), 1.23 (d, 3H, J = 6.0 Hz), 0.88 (s, 9H), 0.05 (s, 6H); 13C NMR
(75 MHz, CDCl3): d 75.0, 72.0, 68.2, 42.9, 40.9, 21.7, 21.5, 18.0, 9.0, ꢁ4.5; IR
(neat):
m 2951, 2932, 2856, 1466, 1383, 1253, 1157, 1120, 1071, 878, 836,
775 cmꢁ1; ESI-MS: 371 [M+H]+. HRMS calcd for C13H28O2ISi: 371.0898. Found:
371.0910. (2S,4S)-4-(tert-Butyldimethylsilyloxy)hept-6-en-2-ol (10): To the
iodide 9 (3.0 g, 8.1 mmol) in ethanol (106 mL), commercial zinc dust (7.89 g,
121.5 mmol) was added. The resulting mixture was refluxed for 1 h, and then
cooled to 25 °C. Addition of solid ammonium chloride (11.0 g) and ether
(160 mL) followed by stirring for 5 min gave a grey suspension. The suspension
was filtered through Celite and the filtrate was concentrated in vacuo.
Purification by flash chromatography gave 10 (1.84 g, 93%) as a colourless
8. Bonini, C.; Chiummiento, L.; Lopardo, M. T.; Pullex, M.; Colobert, F.; Solladie, G.
Tetrahedron Lett. 2003, 44, 2695.
9. Yadav, J. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron Lett. 2005, 46, 2133.
10. Yadav, J. S.; Trimurthulu, N.; Gayathri, K. U.; Reddy, B. V. S.; Prasad, A. R.
Tetrahedron Lett. 2008, 49, 6617.
11. Yadav, J. S.; Sridhar Reddy, M.; Purushothama Rao, P.; Prasad, A. R. Tetrahedron
Lett. 2006, 47, 4397.
12. Yadav, J. S.; Jayaprakash, S.; Gangadhar, Y. Tetrahedron: Asymmetry 2005, 16,
2722–2728.
liquid. Rf = 0.45 (SiO2, 20% EtOAc in hexane). ½a D25
ꢃ
+39.5 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d 5.83–5.65 (m, 1H), 5.14–4.99 (m, 2H), 4.19–3.85 (m, 2H),
3.04–2.70 (br s, 1H), 2.40–2.30 (m, 2H), 1.62–1.52 (m, 2H), 1.16 (d, 3H,
J = 6.0 Hz), 0.92 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); 13C NMR (75 MHz, CDCl3): d
13. (a) Mehta, G.; Reddy, M. S.; Thomas, A. Tetrahedron 1998, 54, 7865; (b) Masaki,
Y.; Oda, H.; Kozuta, K.; Usui, A.; Itoh, A.; Xu, F. Tetrahedron Lett. 1992, 33, 5089.
14. Experimental data: IR spectra were recorded on a Perkin–Elmer FT-IR 240-c
spectrophotometer using KBr optics. 1H NMR and 13C spectra were recorded on
a Gemini-200 and a Varian Bruker-300 spectrometer in CDCl3 using TMS as an
internal standard. Mass spectra were recorded on a Finnigan MAT 1020 mass
134.6, 117.3, 71.1, 64.3, 43.0, 41.0, 25.7, 23.8, ꢁ4.5, ꢁ4.8; IR (neat):
m 3443,
2957, 2932, 2858, 1640, 1466, 1371, 1254, 1063, 1001, 912, 834, 775 cmꢁ1
;
ESI-MS: 245 (M+H)+; HRMS calcd for C13H29O2Si: 245.1931. Found: 245.1941.
(5S,7S)-7-Allyl-5,9,9,10,10-pentamethyl-2,4,8-trioxa-9-silaundecane (11): To
alcohol 10 (1.6 g, 6.55 mmol) in anhydrous CH2Cl2 (20 mL) at 0 °C were
added diisopropylethylamine (3.4 mL, 19.65 mmol) and MOMCl (1.04 g,
13 mmol) successively and the mixture was stirred for 3 h at room
temperature and then quenched by adding water (10 mL) and extracted with
CH2Cl2 (3 ꢂ 15 mL). The organic extracts were washed with brine (10 mL),
dried over anhydrous Na2SO4 and concentrated under vacuum to remove the
solvent and the crude was purified by column chromatography to afford the
spectrometer
methyltetrahydro-2H-pyran-4-ol (6): Trifluoroacetic acid (38.0 mL) was added
slowly to solution of the homoallylic alcohol (2.5 g, 24.5 mmol) and
operating
at
70 eV.
(2S,4R,6S)-2-(4Hydroxymethyl)-6-
a
5
acetaldehyde (3.2 g, 73.5 mmol) in CH2Cl2 (90 mL) at room temperature under
nitrogen atmosphere. The resulting mixture was stirred for 3 h and then
quenched with saturated sodium hydrogen carbonate solution (200 mL) and
the pH was adjusted to >7 by addition of triethylamine. The layers were
separated and the aqueous layer was extracted with CH2Cl2 (4 ꢂ 70 mL). The
combined organic layers were dried over anhydrous Na2SO4 and the solvent
was removed under reduced pressure. The trifluoroacetate thus obtained in
this reaction was directly used in the next reaction without purification. The
residue was dissolved in methanol (40 mL) and stirred over potassium
carbonate (6.77 g) for 0.5 h. Then methanol was removed under reduced
pressure and water (30 mL) was added. The mixture was extracted with
dichloromethane (3 ꢂ 30 mL) and the combined organic layers were dried over
anhydrous Na2SO4 and the solvent was removed under reduced pressure. The
resulting crude product was purified by column chromatography on silica gel
to give compound 6 (1.86 g, 52%) as a liquid. Rf = 0.2 (SiO2, 60% EtOAc in
pure product 11 (1.85 g, 98%). Rf = 0.8 (SiO2, 20% EtOAc in hexane). ½a D20
ꢃ
+69.4
(c 2.1, CHCl3), 1H NMR (300 MHz, CDCl3): d 5.90–5.72 (m, 1H), 5.10–4.99 (m,
2H), 4.63 (ddd, 2H, J = 6.7, 5.2, 12 Hz), 3.95–3.70 (m, 2H), 3.36 (s, 3H), 2.24 (t,
2H, J = 6.7, 5.2 Hz), 1.81–1.60 (m, 1H), 1.50–1.40 (m, 1H), 1.20 (d, 3H,
J = 6.0 Hz), 0.91 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3): d
134.7, 117.0, 95.5, 71.4, 68.9, 55.3, 44.8, 42.4, 25.8, 21.5, ꢁ4.0, ꢁ4.5; IR (neat):
m
3076, 2931, 2890, 2858, 2361, 1641, 1467, 1378, 1253, 1215, 1100, 1042, 1001,
915, 834, 772 cmꢁ1; ESI-MS: 311 (M+Na)+; HRMS calcd for C15H32O3SiNa:
311.2013.
(methoxymethoxy)heptan-1-ol (12): To
5.2 mmol) in dry THF (15 mL) was added BH3ꢀDMS (0.592 g, 7.8 mmol) for
over period of 15 min while maintaining the temperature at 0 °C. The
Found:
311.2027.
(4S,6S)-4-(tert-Butyldimethylsilyoxy)-6-
a
stirred solution of 11 (1.5 g,
a
reaction mixture was brought to room temperature and stirred for a period of
8 h. This was then treated with the very slow addition of 3 M NaOH until the
reaction mixture was basic while maintaining the temperature at 0 °C. To this
was added H2O2 (30%, 1.17 mL, 10.4 mmol) and the reaction mixture stirred
over a period of 3 h, and then extracted with ethyl acetate (6 ꢂ 20 mL). The
combined organic layers were washed with brine, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The resulting residue was
purified by column chromatography to afford 12 (1.27 g, 80%) as a colourless
hexane). ½a 2D0
ꢃ
+9.7 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 3.88–3.72 (m,
1H), 3.66–3.37 (m, 4H), 2.43–1.36 (m, 4H), 1.30–1.08 (m, 2H), 1.23 (d, 3H,
J = 6.0 Hz); 13C NMR (75 MHz, CDCl3): d 72.9, 71.7, 67.6, 65.7, 42.7, 36.4, 21.5
IR (neat):
m 3398, 2925, 2855, 1724, 1599, 1453, 1364, 1178, 1116, 1030, 976,
818, 668 cmꢁ1; ESI-MS: (m/z): 147 (M+H)+, 129, 111, 102, 93, 67. HRMS calcd
for C7H14O3Na 169.0840. Found: 169.0839. (2S,4R,6S)-4-Hydroxy-6-
methyltetrahydro-2H-pyran-2-yl)methyl-4-methylbenzenesulfonate (7): To
a
solution of diol 6 (1.6 g, 10.95 mmol) in dry CH2Cl2 (15.0 mL), triethyl amine
liquid. Rf = 0.35 (SiO2, 20% EtOAc in hexane). ½a D20
ꢃ
+7.2 (c 2.0, CHCl3); 1H NMR

J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 1574–1577
1577
(300 MHz, CDCl3): d 4.67–4.58 (ddd, 2H, J = 6.7, 5.2, 12.0 Hz), 3.94–3.85 (m,
1H), 3.78–3.66 (m, 1H), 3.66–3.54 (m, 2H), 3.34 (s, 3H), 1.73–1.45 (m, 7H), 1.18
(d, 3H, J = 6.0 Hz), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3): d 95.3,
purification. A mixture of dimesylate and methylamine (4.04 mL, 40%
solution in H2O, 52 mmol) in DMF (17 mL) were maintained at 60 °C for 6 h.
After dilution with ethyl acetate (50 mL), the mixture was washed with brine
(20 mL) and water (20 mL), dried and evaporated. Chromatography on silica
afforded pyrrolidine derivative 14 (370 mg, 76%) as a colourless oil. Rf = 0.4
71.3, 69.1, 62.9, 55.2, 44.6, 34.0, 27.7, 25.8, 21.2, ꢁ4.2, ꢁ4.6; IR (KBr):
m 3401,
2932, 2857, 1461, 1377, 1253, 1040, 917, 835, 774, 664 cmꢁ1; ESI-MS: 307
[M+H]+. HRMS calcd for C15H35O4Si: 307.2299. Found: 307.2313. (4S,6S)-6-
(Methoxymethoxy)heptane-1,4-diol (13): To an ice cold solution of silyl ether 12
(1 g, 3.26 mmol) in dry THF (20 mL) was added TBAF (3.91 mL, 1 M in THF,
3.91 mmol). After 15 min of stirring, the reaction mixture was brought to room
temperature and stirred for another 4 h. The reaction mixture was cooled and
quenched with saturated NH4Cl solution (5 mL), extracted with ethyl acetate
(2 ꢂ 10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography to afford the alcohol 13
(0.596 g, 95% yield) as a colourless liquid. Rf = 0.2 (SiO2, 40% EtOAc in hexane).
(SiO2, 10% MeOH in CH2Cl2). ½a D25
ꢃ
+69.4 (c 2.1, CHCl3). 1H NMR (300 MHz,
CDCl3): d 4.62 (d, 1H, J = 6.7 Hz), 4.50 (d, 1H, J = 6.7 Hz), 3.71–3.59 (m, 1H), 3.30
(s, 3H), 3.07–2.98 (m, 1H), 2.27 (s, 3H), 2.29–2.17 (m, 1H), 2.15–2.04 (m, 1H),
2.01–1.82 (m, 2H), 1.80–1.56 (m, 2H), 1.53–1.33 (m, H),1.29–1.18 (m, 1H), 1.14
(d, 3H, J = 6.0 Hz); 13C NMR (75 MHz, CDCl3): d 94.8, 71.6, 62.8, 57.0, 55.3, 41.7,
40.1, 30.8, 21.7, 21.2; IR (neat):
m 2917, 2849, 1595, 1462, 1383, 1350, 1260,
1216, 1033, 766 cmꢁ1 ESI-MS: 188 (M+H)+; HRMS calcd for C10H22NO2:
;
188.1650.; found: 188.1646. (S)-1-(R)-1-Methylpyrrolidin-2-yl)propan-2-ol (2):
A solution of pyrrolidine 14 (200 mg, 1.06 mmol) in methanol (10 mL) was
treated with TMS chloride (68 mg, 0.636 mmol). After being stirred at room
temperature for 2 h, the solution was diluted with EtOAc (50 mL) and basified
with aqueous NaHCO3 solution until pH 9–10. The aqueous layer was extracted
with ethyl acetate (2x10 mL). The organic extracts were dried over Na2SO4 and
evaporated under reduced pressure. The crude residue was purified on silica
½ ꢃ
a 2D5 +51.2 (c 2.1, CHCl3); 1H NMR (200 MHz, CDCl3): d 4.63 (dd, 2H, J = 6.2,
7.0 Hz), 4.04–3.82 (m, 2H), 3.69–3.56 (m, 2H), 3.38 (s, 3H), 3.24–2.50 (br s, 1H),
1.79–1.39 (m, 6H), 1.21 (d, 3H, J = 6.2 Hz); 13C NMR (75 MHz, CDCl3): d 95.3,
71.4, 67.8, 62.7, 55.5, 43.6, 34.5, 29.2, 20.2; IR (KBr):
m 3389, 2938, 1655, 1448,
1378, 1211, 1145, 1037, 917, 853, 793, 754 cmꢁ1; ESI-MS: 215 (M+Na)+; HRMS
calcd for C9H20O4Na: 215.1254. Found: 215.1263. (R)-2-((S)-2-(Methoxy-
methoxy)propyl)-1-methylpyrrolidine (14): To a solution of diol 13 (500 mg,
2.6 mmol) and triethylamine (1.08 mL, 7.81 mmol) in CH2Cl2 (42 mL) at 0 °C
was added methanesulfonyl chloride (715 mg, 6.51 mmol). After 1 h, the
mixture was poured into ice-water (35 mL). The layers were separated and the
organic phase was washed with aqueous HCl (1 M, 20 mL), saturated NaHCO3
solution (20 mL) and water (20 mL). The dried organic layer was evaporated
and the crude dimesylate was used in the next step without further
gel to afford 2 (146 mg, 96%). Rf = 0.4 (SiO2, 20% MeOH in CH2Cl2); ½a D26
ꢃ
+53.8 (c
3.0, EtOH); 1H NMR (300 MHz, CDCl3): d 3.93–3.81 (m, 1H), 3.11–2.97 (m, 1H),
2.79–2.66 (m, 1H), 2.39–2.30 (m, 1H), 2.34 (s, 3H), 2.03–1.90 (m, 1H), 1.83–
1.61 (m, 2H), 1.45–1.29 (m, 3H), 1.11 (d, 3H, J = 6.2 Hz); 13C NMR (75 MHz,
CDCl3): d 67.2, 65.9, 55.4, 42.5, 42.3, 30.4, 24.2, 22.6; IR (KBr):
m 3422, 2921,
2851, 1557, 1413, 1075, 617 cmꢁ1; ESI-MS: 144 (M+H)+; HRMS calcd for
C8H18ON: 144.1388. Found: 144.1391.