Enantioselective synthesis of herbarumin III by using a chelation-controlled reduction

Article abstract of DOI:10.1002/hlca.200900427

The total synthesis of herbarumin III (1) was achieved via an alkynide ion addition onto a chiral aldehyde and LiAlH₄/LiI reduction as key steps (Scheme 2).

Full text of DOI:10.1002/hlca.200900427

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Helvetica Chimica Acta – Vol. 93 (2010)
Enantioselective Synthesis of Herbarumin III by Using a Chelation-
Controlled Reduction
by Gowravaram Sabitha*, Chitti Srinivas, Chittapragada Maruthi, and Jhillu Singh Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500007, India
(phone: þ 91-40-27160512; fax: þ 91-40-27160512; e-mail: gowravaramsr@yahoo.com)
The total synthesis of herbarumin III (1) was achieved via an alkynide ion addition onto a chiral
aldehyde and LiAlH4/LiI reduction as key steps (Scheme 2).
Introduction. – Natural lactones with a medium ring size between eight to eleven [1]
are attracting the attention of several groups because of their significant biological
importance, but their syntheses are challenging. The phytotoxic lactone herbarumin III
(1) was isolated by Mata and co-workers from the fermentation broth and mycelium of
the fungus Phoma herbarum along with herbarumin I (2) and II (3) [2]. The structure
of 1 was elucidated by spectroscopic methods combined with molecular modeling.
Herbarumin III showed significant phytotoxic effects when tested against seedlings of
A. hypochondriacus [3]. The herbarumin macrolides 1 – 3 interact with bovine-brain
calmodulin and inhibited the activation of the calmodulin-dependent enzyme camp
phosphodiesterase. Considering its structure and selective biological profile, herbar-
umin III has attracted a great deal of interest among synthetic organic chemists.
Consequently, the synthesis of 1 has been reported by various research groups [4].
Herein, we report a protocol for the synthesis of herbarumin III based on an alkynide
ion addition onto a chiral aldehyde and reagent-controlled synthesis.
Retrosynthetically (Scheme 1), the macrolactone ring of 1 could be constructed by
Yamaguchiꢀs lactonization method at the final stage, and the corresponding hydroxy
acid 4 would be prepared from aldehyde 5 and PMB-protected 5-hexyn-1-ol 6 by
alkynide ion addition onto the chiral aldehyde (PMB ¼ 4-methoxybenzyl). Aldehyde 5
could be made from the known chiral oxirane 7. The syn-1,3-diol moiety of 4 could be
introduced by using a chelation-controlled reduction reaction.
ꢁ 2010 Verlag Helvetica Chimica Acta AG, Zꢂrich

Helvetica Chimica Acta – Vol. 93 (2010)
Scheme 1. Retrosynthetic Analysis
1635
Results and Discussion. – Accordingly, the synthesis started with the known chiral
oxirane 7 (Scheme 2). Ring opening of 7 with EtMgBr in the presence of CuI in THF
t
gave alcohol 8, which was protected as its BuMe2Si ether 9, and subsequent
debenzylation with Li in liquid NH3 afforded compound 10. Further oxidation of
alcohol 10 with iodoxybenzoic acid (¼1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide;
IBX) in DMSO furnished aldehyde 5 which was taken to the next step without
purification. To prepare alkynol 11, alkyne 61) was treated with BuLi in THF at ꢀ 788,
and the resulting alkynide was quenched with aldehyde 5 to furnish 11 as a
diastereomer mixture. Oxidation of alkynol 11 with IBX in DMSO gave ketone 12,
which on subsequent removal of the silyl protecting group furnished compound 13. A
highly syn-stereoselective 1,3-asymmetric reduction was carried out with LiAlH4/LiI
[5] in Et2O at ꢀ 1008 to provide the desired syn-diol 14 in 85% yield (syn/anti 95 :5).
Alkenediol 14 was selectively protected as tBuMe2Si ether at the allylic position leaving
the other OH group intact (!15). The next task was to release the PMB group (4,5-
dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (DDQ) [6], CH2Cl2/H2O,
room temp.; 91%) in order to oxidize the ensuing alcohol 16 into an acid. Accordingly,
the primary alcohol 16 was oxidized to the corresponding acid by a two-step process,
firstly to an aldehyde with 2,2,6,6-tetramethylpiperidin-1-yloxy (TEMPO) and
bis(acetoxy)iodobenzene (BAIB) in CH2Cl2, followed by further oxidation with
perchlorite/dihydrogen orthophosphate (NaClO2, NaH2PO4 · 2 H2O, DMSO) [7] to
afford the acid 4 (83% over two steps). Lactonization was achieved by applying
Yamaguchiꢀs protocol. The hydroxy acid 4 when treated with 2,4,6-trichlorobenzoyl
chloride in refluxing toluene in the presence of Et3N and N,N-dimethylpyridin-4-amine
(DMAP), gave, the required lactone 17 in 70% yield.
t
Finally, BuMe2Si deprotection was carried out with Bu4NF to furnish the target
1
molecule 1 in 90% yield. The H- and 13C-NMR data and optical-rotation value of
synthetic 1 were in good accordance with those of the natural product.
1
)
Hex-5-yn-1-ol was protected as its PMB ether by the standard procedure:

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Helvetica Chimica Acta – Vol. 93 (2010)
Scheme 2
Conclusions. – In conclusion, an enantioselective total synthesis of herbarumin III
(1) was achieved via an alkynide ion addition onto a chiral aldehyde, a LiAlH4/LiI
reduction, and the Yamaguchiꢀs protocol as key steps.
C. S. thanks UGC, and C. M. thanks CSIR, New Delhi, for the award of fellowships.
Experimental Part
General. Reactions were conducted under N2 in anh. solvents such as CH2Cl2, THF, and AcOEt
(TLC monitoring). Light petroleum ether (b.p. 60 – 808) was used. Yields refer to chromatographically
and spectroscopically (1H- and 13C-NMR) homogeneous material. Air-sensitive reagents were trans-
ferred by syringe or double-ended needle. TLC: Merck 60 F254 SiO2 plates; visualization under UV light.
Column chromatography (CC): SiO2 (60 – 120 mesh; Acme Chemical Co., India). Optical rotations:
JASCO-DIP-370 polarimeter; at 258. IR: Thermo Nicolet Nexus-670 FT-IR spectrometer; ˜n in cmꢀ1. 1H-

Helvetica Chimica Acta – Vol. 93 (2010)
1637
and 13C-NMR Spectra: Varian-FT-200 (Gemini) and Bruker-UXNMR-FT-300 (Avance) spectrometers;
in CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz. MS: LC-MSD spectrometers (Agilent
Technologies) under EI conditions at 70 eV; in m/z (rel. %). HR-MS: QSTAR-XL hybrid MS/MS system
(Applied Biosystems/MDS Sciex, Foster City, CA, USA), equipped with an ESI source (IICT,
Hyderabad).
(3R)-1-(Benzyloxy)hexan-3-ol (8). To a suspension of Mg (1.08 g, 44.88 mmol) in dry THF (30 ml),
EtBr (3.46 ml, 44.88 mmol) was added dropwise under N2 at 08. The mixture was stirred for 1 h at r.t. A
catalytic amount of CuI was then added at 08 to the suspension of Grignard reagent, and the mixture was
stirred at 08 for 30 min. Oxirane 7 (4 g, 22.44 mmol) in dry THF (15 ml) was then added dropwise at 08
and stirred at r.t. for ca. 30 min. After completion of the reaction, the mixture was quenched with sat. aq.
NH4Cl soln. and extracted with AcOEt (3 ꢁ 50 ml). The org. layer was washed with brine, dried
(Na2SO4), and concentrated. Purification by CC (SiO2) afforded 8 (4.02 g, 86%). Viscous liquid. [a]D25
¼
1
þ3.88 (c ¼ 6, CHCl3). IR (neat): 3433, 2946, 2866, 1715, 1454, 1275, 1099, 738, 699. H-NMR (CDCl3,
300 MHz): 7.24 – 7.35 (m, 5 H); 4.51 (s, 2 H); 3.73 – 3.82 (m, 1 H); 3.57 – 3.73 (m, 2 H); 2.69 (br. s, 1 H);
1.66 – 1.74 (m, 2 H); 1.32 – 1.50 (m, 4 H); 0.93 (t, J ¼ 7.5, 3 H). 13C-NMR (CDCl3, 50 MHz): 137.8; 129.5;
128.3; 127.6; 73.2; 71.0; 69.1; 39.5; 36.3; 18.7; 14.1. ESI-MS: 209 ([M þ Na]þ). HR-ESI-MS: 231.1349
([M þ Na]þ, C13H20NaOþ2 ; calc. 231.1361).
{(1R)-1-[2-(Benzyloxy)ethyl]butoxy}(tert-butyl)dimethylsilane (9). To a stirred soln. of 8 (3.8 g,
t
18.24 mmol) and 1H-imidazole (2.48 g, 36.48 mmol) in dry CH2Cl2 (50 ml) was added BuMe2SiCl
(4.12 g, 27.36 mmol), portionwise at 08. The mixture was stirred at 08 for 2 h and then quenched with sat.
aq. NH4Cl soln. and extracted with CH2Cl2 (3 ꢁ 50 ml). The extract was washed with H2O (50 ml) and
brine (50 ml), dried (Na2SO4), and concentrated and the residue purified by CC (SiO2): 9 (5.58 g, 95%).
Colorless liquid. [a]2D5 ¼ ꢀ6.24 (c ¼ 5, CHCl3). IR (neat): 2954, 2931, 2858, 1744, 1462, 1252, 1109, 1073,
1
835, 774, 697. H-NMR (CDCl3, 300 MHz): 7.24 – 7.31 (m, 5 H); 4.45 (AB q, J ¼ 12.1, 18.1, 2 H); 3.79 –
3.86 (m, 1 H); 3.42 – 3.52 (m, 2 H); 1.63 – 1.77 (m, 2 H); 1.26 – 1.46 (m, 4 H); 0.90 (t, J ¼ 7.4, 3 H); 0.86
(s, 9 H); 0.03 (s, 3 H); 0.02 (s, 3 H). 13C-NMR (CDCl3, 50 MHz): 138.6; 128.3; 127.6; 127.4; 72.9; 69.3;
67.2; 39.8; 36.9; 25.9; 18.3; 18.1; 14.3; ꢀ 4.4; ꢀ 4.6. ESI-MS: 345 ([M þ Na]þ). HR-ESI-MS: 345.2213
([M þ Na]þ, C19H34NaO2Siþ; calc. 345.2226).
(3R)-3-{[(tert-Butyl)dimethylsilyl]oxy}hexan-1-ol (10). Lithium metal (0.325 g, 46.5 mmol) was
added to a stirred soln. of freshly dist. NH3 (50 ml) and 9 (5 g, 15.5 mmol) in dry THF (15 ml) (250 ml
two-necked round-bottomed flask fitted with a cold-finger condenser at ꢀ 338). The mixture was then
stirred for another 10 min at ꢀ 338 and quenched by the addition of solid NH4Cl, and NH3 was then
allowed to diffuse. The residue left was partitioned between H2O (50 ml) and Et2O (50 ml), and the aq.
phase was extracted with Et2O (2 ꢁ 50 ml). The combined org. layers were washed with H2O (50 ml) and
brine (50 ml), dried (Na2SO4), and concentrated. The residue was purified by CC (SiO2): pure 10 (3.27 g,
91%). Clear colorless liquid. [a]2D5 ¼ ꢀ11.27 (c ¼ 5, CHCl3). IR (neat): 3362, 2948, 2863, 1464, 1474, 1253,
1
1051, 835, 755, 716, 699. H-NMR (CDCl3, 300 MHz): 3.86 – 3.95 (m, 1 H); 3.74 – 3.85 (m, 1 H); 3.61 –
3.71 (m, 1 H); 2.15 (t, J ¼ 5.3, 1 H); 1.73 – 1.85 (m, 1 H); 1.56 – 1.67 (m, 1 H); 1.45 – 1.55 (m, 2 H);
1.24 – 1.37 (m, 2 H); 0.92 (t, J ¼ 6.8, 3 H); 0.90 (s, 9 H); 0.09 (s, 3 H); 0.07 (s, 3 H). 13C-NMR (CDCl3,
50 MHz): 71.7; 60.2; 39.1; 37.4; 25.8; 18.5; 17.93; 14.2; ꢀ 4.5; ꢀ 4.8. ESI-MS: 233 ([M þ 1]þ). HR-ESI-
MS: 255.1764 ([M þ Na]þ, C12H28NaO2Siþ; calc. 255.1756).
(3R)-3-{[(tert-Butyl)dimethylsilyl]oxy}hexanal (5). To an ice-cooled soln. of 2-iodoxybenzoic acid
(5.42 g, 19.36 mmol) in dry DMSO (5.5 ml, 77.44 mmol) was added a soln. of 10 (3 g, 12.90 mmol) in dry
CH2Cl2 (50 ml). The mixture was stirred at r.t. for 2 h and then filtered through a Celite pad and washed
with Et2O. The combined org. filtrates were washed with H2O (40 ml) and brine (40 ml), dried (Na2SO4),
and concentrated. The unstable crude aldehyde 5 was immediately used for the next reaction.
(4R)-4-{[(tert-Butyl)dimethylsilyl]oxy}-12-[(4-methoxybenzyl)oxy]dodec-7-yn-6-ol (11). To a soln.
of 6 (2.7 g, 12.36 mmol) in dry THF (40 ml) was slowly added 2.5m BuLi in hexanes (5.44 ml,
13.59 mmol) at ꢀ 788 under N2. The mixture was stirred for 30 min at ꢀ 788, and a soln. (2.85 g,
12.36 mmol) of 5 in THF (10 ml) was added dropwise under stirring. The mixture was kept at ꢀ 788 for
2 h and then allowed to warm to r.t. for 2 h. The reaction was quenched with sat. aq. NH4Cl soln., the
mixture extracted with AcOEt (3 ꢁ 50 ml), the extract dried (Na2SO4) and concentrated, and the crude
product purified by CC (SiO2): 4.98 g (86% over two steps) of 11.

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Helvetica Chimica Acta – Vol. 93 (2010)
(4R)-4-{[(tert-Butyl)dimethylsilyl]oxy}-12-[(4-methoxybenzyl)oxy]dodec-7-yn-6-one (12). As de-
scribed for 5, with 2-iodoxybenzoic acid (3.55 g, 12.70 mmol), DMSO (3.6 ml, 50.81 mmol), 11 (3.8 g,
8.47 mmol), and CH2Cl2 (40 ml). Washing with H2O (50 ml) and brine (50 ml) and CC (SiO2) afforded
12 (3.55 g, 94%). Viscous liquid. [a]2D5 ¼ ꢀ8.7 (c ¼ 3, CHCl3). IR (neat): 3453, 2955, 2931, 2856, 2211,
1673, 1612, 1512, 1463, 1248, 1101, 1038, 834, 755. 1H-NMR (CDCl3, 300 MHz): 7.19 (d, J ¼ 9.1, 2 H); 6.82
(d, J ¼ 9.1, 2 H); 4.40 (s, 2 H); 4.18 – 4.26 (m, 1 H); 3.80 (s, 3 H); 3.43 (t, J ¼ 6.0, 2 H); 2.67 (dd, J ¼ 6.8,
15.1, 1 H); 2.55 (dd, J ¼ 5.3, 15.1, 1 H); 2.39 (t, J ¼ 6.8, 2 H); 1.66 – 1.73 (m, 4 H); 1.27 – 1.51 (m, 4 H); 0.92
(t, J ¼ 7.5, 3 H); 0.87 (s, 9 H); 0.06 (s, 3 H); 0.04 (s, 3 H). 13C-NMR (CDCl3, 50 MHz): 186.5; 159.1; 130.5;
129.2; 113.7; 94.1; 81.6; 72.6; 69.1; 68.8; 55.2; 53.3; 39.9; 28.9; 25.7; 24.6; 18.7; 18.2; 18.0; 14.1; ꢀ 4.5; ꢀ 4.7.
ESI-MS: 469 ([M þ Na]þ). HR-ESI-MS: 469.2738 ([M þ Na]þ, C26H42NaO4Siþ; calc. 469.2750).
(4R)-4-Hydroxy-12-[(4-methoxybenzyl)oxy]dodec-7-yn-6-one (13). To a soln. of 12 (3.4 g,
7.61 mmol) in THF (30 ml) was added 1.0m Bu4NF in THF (11.41 ml, 11.41 mmol) at 08. The mixture
was stirred for 8 h and then diluted with H2O and extracted with AcOEt (3 ꢁ 50 ml). The org. layer was
washed with H2O (50 ml) and brine (50 ml), dried (Na2SO4), and concentrated and the crude product
purified by CC (SiO2): 13 (2.22 g, 88%). Colorless oil. [a]2D5 ¼ þ29.9 (c ¼ 3, CHCl3). IR (neat): 3445,
1
2956, 2869, 2211, 1717, 1665, 1602, 1512, 1250, 1168, 1101, 1030, 824, 769. H-NMR (CDCl3, 300 MHz):
7.19 (d, J ¼ 8.3, 2 H); 6.82 (d, J ¼ 8.3, 2 H); 4.39 (s, 2 H); 4.25 – 4.36 (m, 1 H); 3.79 (s, 3 H); 3.40 (t, J ¼ 6.1,
2 H); 2.55 – 2.72 (m, 1 H); 2.18 – 2.43 (m, 3 H); 1.24 – 1.82 (m, 8 H); 0.97 (t, J ¼ 6.8, 3 H). 13C-NMR
(CDCl3, 50 MHz): 193.4; 159.1; 131.9; 129.2; 113.7; 95.1; 81.1; 78.9; 72.5; 69.3; 55.2; 52.3; 40.9; 34.5; 29.0;
18.7; 18.1; 13.7. HR-ESI-MS: 355.1875 ([M þ Na]þ, C20H28NaO4þ ; calc. 355.1885).
(4R,6R,7E)-12-[(4-Methoxybenzyl)oxy]dodec-7-ene-4,6-diol (14). To a stirred soln. of 13 (2.1 g,
6.32 mmol) in Et2O (100 ml) was added LiI (8.45 g, 63.16 mmol), and the resulting mixture was stirred at
ꢀ 408 for 30 min. Then, the mixture was cooled to ꢀ 1008, and LiAlH4 (2.87 g, 75.80 mmol) was added.
The mixture was stirred for 1 h at ꢀ 1008 and then for 3 h at r.t. After quenching with 10% aq. potassium
sodium tartrate soln., the aq. layer was extracted with Et2O (4 ꢁ 50 ml), the combined org. layer dried
(Na2SO4) and concentrated, and the residue purified by CC (SiO2): 14 (1.83 g, 85%). Colorless oil.
[a]2D5 ¼ þ2.94 (c ¼ 4, CHCl3). IR (neat): 3392, 2934, 2860, 1611, 1513, 1453, 1247, 1094, 1034, 825.
1H-NMR (CDCl3, 300 MHz): 7.19 (d, J ¼ 8.3, 2 H); 6.82 (d, J ¼ 8.3, 2 H); 5.61 (dt, J ¼ 6.8, 15.5, 1 H); 5.45
(dd, J ¼ 6.8, 15.5, 1 H); 4.39 (s, 2 H); 4.24 – 4.30 (m, 1 H); 3.78 – 3.86 (m, 1 H); 3.79 (s, 3 H); 3.39 (t, J ¼
6.8, 2 H); 2.04 (t, J ¼ 6.8, 2 H); 1.52 – 1.66 (m, 2 H); 1.25 – 1.50 (m, 8 H); 0.93 (t, J ¼ 6.8, 3 H). 13C-NMR
(CDCl3, 50 MHz): 157.9; 154.8; 132.8; 131.4; 129.2; 113.7; 73.7; 72.5; 72.1; 69.9; 55.3; 43.4; 40.2; 31.8; 29.1;
25.6; 18.5; 14.1. ESI-MS: 355 ([M þ Na]þ). HR-ESI-MS: 359.2187 ([M þ Na]þ, C20H32NaOþ4 ; calc.
359.2198).
(4R,6R,7E)-6-{[(tert-Butyl)dimethylsilyl]oxy}-12-[(4-methoxybenzyl)oxy]dodec-7-en-4-ol (15). As
described for 9, with 14 (1.6 g, 4.75 mmol), 1H-imidazole (0.667 g, 9.51 mmol), CH2Cl2 (20 ml), and
tBuMe2SiCl (1.07 g, 7.13 mmol); for 4 h. Extraction with CH2Cl2 (3 ꢁ 40 ml and then 2 ꢁ 30 ml), washing
with H2O (30 ml) and brine (30 ml), and purification by CC (SiO2) afforded 15 (1.84 g, 86%). Colorless
liquid. [a]2D5 ¼ þ12.56 (c ¼ 5, CHCl3). IR (neat): 3472, 2929, 2856, 1743, 1613, 1513, 1463, 1249, 1092,
1039, 835. 1H-NMR (CDCl3, 300 MHz): 7.18 (d, J ¼ 8.3, 2 H); 6.81 (d, J ¼ 8.3, 2 H); 5.52 (dt, J ¼ 7.3, 15.6,
1 H); 5.39 (dd, J ¼ 7.3, 15.6, 1 H); 4.38 (s, 2 H); 4.24 – 4.30 (m, 1 H); 3.78 (s, 3 H); 3.69 – 3.75 (m, 1 H);
3.39 (t, J ¼ 6.2, 2 H); 1.98 – 2.07 (m, 2 H); 1.54 – 1.62 (m, 3 H); 1.40 – 1.49 (m, 3 H); 1.31 – 1.39 (m, 4 H);
0.92 (t, J ¼ 7.3, 3 H); 0.89 (s, 9 H); 0.08 (s, 3 H); 0.03 (s, 3 H). 13C-NMR (CDCl3, 50 MHz): 159.1; 133.5;
132.1; 130.9; 129.2; 113.7; 75.3; 72.5; 70.8; 69.8; 55.2; 44.7; 39.8; 31.8; 29.3; 25.8; 25.7; 18.5; 18.0; 14.1; ꢀ
3.6; ꢀ 4.7. ESI-MS: 473 ([M þ Na]þ). HR-ESI-MS: 473.3052 ([M þ Na]þ, C26H46NaO4Siþ; calc.
473.3063).
(5E,7R,9R)-7-{[(tert-Butyl)dimethylsilyl]oxy}dodec-5-ene-1,9-diol (16). To a soln. of 15 (1.6 g,
3.55 mmol) in CH2Cl2/H2O 19 :1 (30 ml), DDQ (1.208 g, 5.32 mmol) was added and the soln. stirred for
1 h at r.t. The mixture was filtered off and the filtrate washed with 5% NaHCO3 soln. (30 ml) and brine
(30 ml), dried (Na2SO4), and concentrated. Purification by CC gave 16 (1.06 g, 91%). [a]2D5 ¼ þ0.7 (c ¼
1.8, CHCl3). IR (neat): 3396, 2930, 2854, 1740, 1612, 1515, 1455, 1246, 1093, 1035, 829. 1H-NMR (CDCl3,
500 MHz): 5.55 (dt, J ¼ 6.8, 15.6, 1 H); 5.41 (dd, J ¼ 6.8, 15.6, 1 H); 4.26 – 4.32 (m, 1 H); 3.71 – 3.77 (m,
1 H); 3.62 (t, J ¼ 6.8, 2 H); 2.02 – 2.11 (m, 2 H); 1.24 – 1.70 (m, 10 H); 0.92 (t, J ¼ 6.8, 3 H); 0.90 (s, 9 H);
0.09 (s, 3 H); 0.04 (s, 3 H). 13C-NMR (CDCl3, 50 MHz): 133.6; 130.8; 75.2; 70.8; 62.7; 44.7; 39.8; 32.3;

Helvetica Chimica Acta – Vol. 93 (2010)
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31.8; 25.8; 25.2; 18.5; 18.0; 14.1; ꢀ 3.6; ꢀ 4.7. ESI-MS: 353 ([M þ Na]þ). HR-ESI-MS: 353.2475
([M þ Na]þ, C18H38NaO3Siþ; calc. 353.2488).
(5E,7R,9R)-7-{[(tert-Butyl)dimethylsilyl]oxy}-9-hydroxydodec-5-enoic Acid (4). BAIB (0.847g,
2.66 mmol) was added to a soln. of 16 (0.8 g, 2.42 mmol) and TEMPO (0.038 g, 0.242 mmol) in CH2Cl2
(1 ml). The mixture was stirred until 16 was no longer detectable (TLC). Then the mixture was diluted
with CH2Cl2 (20 ml), washed with sat. aq. Na2S2O3 soln. (20 ml), and extracted with CH2Cl2 (4 ꢁ 20 ml).
The combined org. extracts were washed with aq. NaHCO3 soln. (30 ml) and brine (30 ml), dried
(Na2SO4), and concentrated. The unstable crude aldehyde was immediately used for the next reaction.
A soln. of NaClO2 (0.33 g, 3.65 mmol) in H2O (2 ml) was added dropwise within 5 min at r.t. to a
stirred soln. of the above crude aldehyde (0.8 g, 2.43 mmol) in DMSO (5 ml) and NaH2PO4 (0.759 g,
4.869 mmol) in H2O (5 ml). The mixture was left overnight at r.t., and then 5% aq. NaHCO3 soln. was
added. The aq. phase was extracted with CH2Cl2 (3 ꢁ 30 ml), the extract washed with brine (30 ml), dried
(Na2SO4), and concentrated, and the residue purified by CC (SiO2). 4 (0.692 g, 83% over two steps).
Yellowish liquid. [a]2D5 ¼ þ14.0 (c ¼ 5, CHCl3). IR (neat): 3397, 2956, 2930, 2858, 1711, 1613, 1460, 1251,
1
1074, 977, 837. H-NMR (CDCl3, 500 MHz): 5.53 (dt, J ¼ 6.8, 15.6, 1 H); 5.44 (dd, J ¼ 6.8, 15.6, 1 H);
4.27 – 4.33 (m, 1 H); 3.70 – 3.78 (m, 1 H); 2.35 (t, J ¼ 6.8, 2 H); 2.06 – 2.18 (m, 2 H); 1.69 – 1.78 (m, 2 H);
1.25 – 1.64 (m, 6 H); 0.93 (t, J ¼ 5.8, 3 H); 0.90 (s, 9 H); 0.10 (s, 3 H); 0.04 (s, 3 H). 13C-NMR (CDCl3,
50 MHz): 178.9; 134.4; 129.7; 75.1; 70.9; 44.6; 39.7; 33.3; 31.3; 25.8; 24.0; 18.5; 18.1; 14.1; ꢀ 3.6; ꢀ 4.7.
ESI-MS: 367 ([M þ Na]þ). HR-ESI-MS: 367.2272 ([M þ Na]þ, C18H36NaO4Siþ; calc. 367.2281).
(6E,8R,10R)-8-{[(tert-Butyl)dimethylsilyl]oxy}-3,4,5,8,9,10-hexahydro-10-propyl-2 H-oxecin-2-one
(17). The 2,4,6-trichlorobenzoyl chloride (0.272 ml, 1.74 mmol) was added to a soln. of 4 (0.4 g,
1.16 mmol) and Et3N (0.245 mg, 1.74 mmol) in THF (3 ml). The soln. was stirred at r.t. for 3 h, diluted
with toluene (6 ml), and added into a refluxing soln. of DMAP (0.709 g, 5.80 mmol) and toluene (50 ml).
The mixture was refluxed for 6 h and cooled to r.t. Sat. aq. NaHCO3 soln. was added, the aq. layer further
extracted with AcOEt (3 ꢁ 20 ml), the combined org. layer washed with H2O (20 ml) and brine (20 ml),
dried (Na2SO4), and concentrated, and the crude product purified by CC: 17 (0.265 g, 70%). Colorless
oil. [a]2D5 ¼ þ5.0 (c ¼ 5, CHCl3). IR (neat): 2956, 2929, 2856, 1732, 1485, 1341, 1252, 1199, 1100, 940, 836.
1H-NMR (CDCl3, 500 MHz): 5.45 – 5.52 (m, 2 H); 5.24 – 5.32 (m, 1 H); 4.35 – 4.41 (m, 1 H); 2.20 – 2.38
(m, 2 H); 1.89 – 2.02 (m, 2 H); 1.67 – 1.79 (m, 2 H); 1.23 – 1.48 (m, 6 H); 0.94 (s, 9 H); 0.92 (t, J ¼ 6.9, 3 H);
0.03 (s, 6 H). 13C-NMR (CDCl3, 50 MHz): 178.9; 134.4; 129.7; 75.1; 70.9; 44.6; 39.7; 33.3; 31.3; 25.8; 24.0;
18.5; 18.1; 14.1; ꢀ 3.6; ꢀ 4.7. ESI-MS: 349 ([M þ Na]þ). HR-ESI-MS: 349.2159 ([M þ Na]þ,
C18H34NaO3Siþ; calc. 349.2175).
(6E,8R,10R)-3,4,5,8,9,10-Hexahydro-8-hydroxy-10-propyl-2H-oxecin-2-one (1). As described for 13,
with 17 (0.15 g, 0.459 mmol), THF (10 ml), and 1m Bu4NF in THF (0.689 ml, 0.689 mmol); for 6 h.
Workup with AcOEt (3 ꢁ 10 ml), H2O (20 ml), and brine (20 ml). CC (SiO2) gave 1 (0.087 g, 90%).
Colorless oil. [a]2D5 ¼ þ20.9 (c ¼ 2.5, EtOH). IR (neat): 3443, 2930, 2859, 1731, 1636, 1452, 1253, 1205,
1094, 770. 1H-NMR (CDCl3, 500 MHz): 5.57 (d, J ¼ 16.1, 1 H); 5.38 – 5.48 (m, 1 H); 5.19 – 5.27 (m, 1 H);
4.33 – 4.40 (m, 1 H); 2.34 – 2.44 (m, 1 H); 2.22 – 2.31 (m, 1 H); 1.88 – 2.03 (m, 3 H); 1.84 – 1.87 (m, 1 H);
1.80 – 1.84 (m, 1 H); 1.72 – 1.79 (m, 1 H); 1.49 – 1.58 (m, 1 H); 1.37 – 1.47 (m, 1 H); 1.28 – 1.36 (m, 2 H);
0.91 (t, J ¼ 7.2, 3 H). 13C-NMR (CDCl3, 50 MHz): 176.8; 134.5; 124.8; 67.9; 67.8; 40.5; 37.4; 34.6; 33.6;
25.9; 18.4; 13.8. ESI-MS: 235 ([M þ Na]þ). HR-ESI-MS: 235.1309 ([M þ Na]þ, C12H20NaOþ3 ; calc.
235.1310).
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Received December 1, 2009