Stereoselective total synthesis of stagonolide C

Article abstract of DOI:10.1002/hlca.201100190

A convergent and efficient total synthesis of stagonolide C (1), a phytotoxic metabolite, was achieved (Schemes 2 and 3) The synthesis exploited the high configuration control in the Prins cyclization along with alkene rearrangement and ring-closing metat

Full text of DOI:10.1002/hlca.201100190

Helvetica Chimica Acta – Vol. 95 (2012)
227
Stereoselective Total Synthesis of Stagonolide C
by Jhillu S. Yadav*a)b), Nimmakayala Mallikarjuna Reddya), N. Venkateswar Raoa),
Md. Ataur Rahmana), and Attaluri R. Prasada)
a) Organic Division-I, Indian Institute of Chemical Technology, Hyderabad-500007, India
(fax: þ 91-40-27160512; e-mail: yadavpub@iict.res.in)
b) King Saud University, Riyadh-11451, Saudi Arabia
A convergent and efficient total synthesis of stagonolide C (1), a phytotoxic metabolite, was
achieved (Schemes 2 and 3) The synthesis exploited the high configuration control in the Prins
cyclization along with alkene rearrangement and ring-closing metathesis as key steps.
Introduction. – Naturally occurring ten-membered lactones from fungal metabo-
lites present a wide variety of potent biological properties [1]. Among them,
stagonolides A – I [2][3] (Fig.) represent a novel family isolated recently from
Stagonospora cirsii, a fungal pathogen of Cirsium arvense causing necrotic lesions on
leaves, with interesting phytotoxic properties. When tested by a leaf disk puncture assay
at a concentration of 1 mg/ml, stagonolide B – I showed no toxicity to C. arvense and
Sonchus arvensis, whereas stagonolide A was highly toxic. Stagonolides A – I possess
interesting structural features, as they are compact, bearing properly placed olefin
moieties with well-defined geometry and, therefore, are attractive synthetic targets.
Figure. Phytotoxic nonenolides
In continuation of our ongoing program towards synthesis of biologically active
compounds, we showed interest in developing a simple and flexible route to the total
synthesis of stagonolide C (1) [4]. Our group has made a significant effort to explore
the utility of the Prins cyclization in the synthesis of various polyketide intermediates as
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 95 (2012)
well as for the synthesis of some complex natural products [5][6]. As a part of this
program, we now accomplished a stereoselective total synthesis of stagonolide C.
The retrosynthetic analysis delineated in Scheme 1 indicated that stagonolide C (1)
could be synthesized by utilizing a ring-closing-metathesis (RCM) protocol from bis-
olefin 2, which in turn could be prepared by esterification of acid 3 with alcohol 4 [4a].
We anticipated that alcohol 4 would be derived from 2H-pyran-2-methanol 6, which in
turn could be easily constructed via Prins cyclization, in analogy to our previous
approach. The second fragment, acid 3, could easily be derived from (þ)-diethyl l-
tartrate (5).
Scheme 1
Results and Discussion. – Prins cyclization between the known homoallylic alcohol
7 [6d] and acetaldehyde in the presence of trifluoroacetic acid [5] resulted in the
trifluoroacetate salt of 6, which on treatment with K2CO3 in MeOH gave tetrahydro-4-
hydroxy-2H-pyran-2-methanol 6 as the only isolable diastereoisomer in 55% yield
(Scheme 2). The stereochemical aspects of such Prins cyclizations and compounds
structurally similar to 6 have been discussed in detail previously (for the Prins
cyclization, see, e.g., [5]) [6]. The primary OH group present in 6 was transformed to its
tosylate 8 with TsCl and Et3N in anhydrous CH2Cl2, and the secondary OH group was
protected as its methoxymethyl (MeOCH2) ether with MeOCH2Cl and N,N-
diisopropylethylamine (iPr2EtN) in anhydrous CH2Cl2 to give 9. The tosylate group
of 9 was substituted by an I-atom on treatment with NaI to give 10, and subsequent
elimination of HI [7] by using NaH in DMF affording the exocyclic alkene 11, which on
column chromatography (CC; SiO2) revealed the rearranged product 12 in 72% yield.
To confirm that the HI elimination did not result in the rearranged product, we
analyzed the 1H-NMR spectrum of the crude product of the elimination reaction, which
clearly revealed the presence of two d at d(H) 4.33 and 4.09 (J ¼ 2.2 Hz, geminal
coupling) and the absence of any characteristic signal for the rearranged product. The
substrate 12 was then subjected to ozonolysis to obtain the corresponding (acetyloxy)-
substituted aldehyde, which on treatment with methylenetriphenylphosphorane
furnished the open-chain olefinic acetate 13 [6e]. Hydrolysis of the acetate group in
13 with K2CO3 in MeOH provided the corresponding key alcohol 4.

Helvetica Chimica Acta – Vol. 95 (2012)
229
Scheme 2
a) MeCHO, CF3COOH, CH2Cl2, then K2CO3, MeOH, r.t, 5 h; 55%. b) TsCl, Et3N, CH2Cl2, 08 to r.t., 3 h;
i
90%. c) MeOCH2Cl, Pr2EtN, CH2Cl2, 08 to r.t., 6 h; 94%. d) NaI, acetone, reflux, 24 h; 95%. e) NaH,
DMF, r.t., 6 h. f) SiO2; 72%. g) O3, Ph3P, CH2Cl2, then Ph3P¼CH2, THF, ꢀ 788 to 08; 74%. h) K2CO3,
MeOH, r.t., 2 h; 96%.
The synthesis of the other key fragment, acid 3, commenced with a known
intermediate 14 [8] (Scheme 3). Deprotection of the benzyl ether moiety followed by
reduction of the C¼C bond of 14 was achieved with Pd/C in the presence of H2 to
furnish hydroxy ester 15 in 90% yield. Its primary-alcohol group was successfully
converted into an iodo group of 16, and subsequent reductive elimination was
promoted by Zn/EtOH to afford secondary-alcohol derivative 17 [9]. The free OH
group of 17 was protected as its MeOCH2 ether 18, and subsequent saponification of
the ester group with 2n NaOH and MeOH afforded acid 3 [10] in 85% yield
(Scheme 3).
The synthesis of the target compound was successfully completed by combining the
two fragments 3 and 4 in a three-step sequence (Scheme 3). In analogy to [4a], alcohol
4 was acylated with acid 3 in the presence of dicyclohexylcarbodimide/N,N-dimethyl-
pyridin-4-amine (DCC/DMAP) to obtain ester 2 [11] in 80% yield. Ester 2 underwent
ring-closing metathesis with Grubbs 2nd-generation catalyst [12] in boiling CH2Cl2 to
yield (E)-diastereoisomer 19 in 60% yield, which was characterized by the usual
spectroscopic techniques. The coupling constant of 15.6 Hz between HꢀC(5) and
HꢀC(6) clearly demonstrated the (E)-configuration of the C¼C bond. Deprotection of
both MeOCH2 ether moieties [13] was carried out with Me3SiBr in CH2Cl2 to afford the
natural product stagonolide C (1). The spectroscopic (1H- and 13C-NMR) and
analytical data were in good agreement with those of the natural product [2][3].
In conclusion, a flexible and efficient synthesis of stagonolide C (1) was performed
involving Prins cyclization and RCM as the key steps. Further applications of the Prins
cyclization to the synthesis of natural products are in progress and will be disclosed in
due course.
N. M. R and N. V. R thank CSIR, New Delhi, for the award of a fellowship. J. S. Y. acknowledges the
partial support by the King Saud University for Global Research Network for Organic Synthesis
(GRNOS)

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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 3
a) H2, Pd/C, AcOEt, reflux, 2 h; 90%. b) I2, Ph3P, 1H-imidazole, THF, 08 to r.t., 4 h; 80%. c) Zn, EtOH,
reflux, 2 h; 86%. d) MeOCH2Cl, iPr2EtN, N,N-dimethylpyridin-4-amine DMAP (cat.), CH2Cl2, 08 to r.t.,
3 h; 82%. e) 2n NaOH, MeOH, r.t., 6 h; 85%. f) 4, DCC, DMAP, CH2Cl2, 08 to r.t., 2 h; 80%. g) Grubbs
2nd-gen. catalyst, CH2Cl2, reflux, 24 h; 60%. h) Me3SiBr, CH2Cl2, ꢀ 408, 15 min; 76%.
Experimental Part
General. All reactions were carried out under inert atmosphere unless mentioned otherwise
following standard syringe septa techniques. Solvents were dried and purified by conventional methods
prior to use. The progress of all the reactions were monitored by TLC. Column (CC) and flash
chromatography (FC): silica gel (SiO2; 60 – 120 mesh) and neutral alumina, Et2O, AcOEt, and hexane as
eluents. TLC: precoated SiO2 60 F254 glass plates (0.5 mm; Merck). Optical rotations: Perkin-Elmer P241
polarimeter and Jasco-DIP-360 digital polarimeter. IR Spectra: Perkin-Elmer FT-IR spectrophotometer;
.
˜n in cmꢀ1 1H- and 13C-NMR Spectra: Varian-Gemini-200, Bruker-Avance-300, Varian-Unity-400, or
Varian-Inova-500 spectrometer; in CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz. MS:
Micro-Mass-VG-7070 H (EI) and VG-Autospec-M (FAB-MS) spectrometer; in m/z.
(2R,4S,6R)-Tetrahydro-4-hydroxy-6-methyl-2H-pyran-2-methanol (6). CF3COOH (25 ml) was add-
ed slowly to a soln. of the homoallylic alcohol 7 [6d] (2.0 g, 19.60 mmol) and acetaldehyde (3.45 g,
78.40 mmol) in CH2Cl2 (60 ml) at 258 under N2. The mixture was stirred for 3.0 h, and then sat. aq.
NaHCO3 soln. (150 ml) was added and the pH adjusted to > 7 by addition of Et3N. The aq. layer was
extracted with CH2Cl2 (4 ꢁ 50 ml) and the combined org. layer concentrated. The trifluoroacetate
obtained was directly used in the next reaction without purification, i.e., the residue was dissolved in
MeOH (50 ml) and stirred in the presence of K2CO3 (4.50 g) for 0.5 h. The MeOH was then evaporated,
and H2O (30 ml) was added. The mixture was extracted with CH2Cl2 (3 ꢁ 30 ml), the combined org. layer
dried (Na2SO4) and concentrated, and the residue purified by CC SiO2, AcOEt/hexane): 6 (1.57 g, 55%).
Colorless liquid. Rf (AcOEt/hexane 6 :4) 0.3. [a]2D7 ¼ ꢀ13.7 (c ¼ 1.34, CHCl3). IR (neat): 3398, 2925,
1
2856, 1452, 1363, 1178, 1030, 976. H-NMR (CDCl3, 200 MHz): 1.09 – 1.20 (m, 2 H); 1.22 (d, J ¼ 6.04,
3 H); 1.78 – 1.99 (m, 2 H); 3.38 – 3.62 (m, 4 H); 3.75 – 3.86 (m, 1 H). 13C-NMR (50 MHz, CDCl3): 21.6;
36.5; 42.3; 65.8; 67.3; 67.8; 72.1. HR-ESI-MS: 169.0839 ([M þ Na]þ, C7H14NaO3þ ; calc. 169.0840)

Helvetica Chimica Acta – Vol. 95 (2012)
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(2R,4S,6R)-Tetrahydro-4-hydroxy-6-methyl-2H-pyran-2-methanol 4-Methylbenzenesulfonate (8). To
a soln. of 6 (1.5 g, 10.27 mmol) in dry CH2Cl2 (20 ml), Et3N (2.87 ml, 20.49 mmol) was added at 08,
followed by TsCl (2.34 g, 12.23 mmol) over 2 h. The mixture was allowed to warm to r.t. and stirred for
3 h. Then, the mixture was treated with aq. 1n HCl (7 ml) and extracted with CH2Cl2 (3 ꢁ 25 ml). The
org. layer was washed with sat. aq. NaHCO3 soln. (20 ml) and H2O (20 ml), the combined org. phase
dried (Na2SO4) and concentrated, and the residue subjected to FC (SiO2, AcOEt/hexane): 8 (2.76 g,
90%). Gummy liquid. Rf (AcOEt/hexane 6 :4) 0.6. [a]2D7 ¼ ꢀ3.5 (c ¼ 0.93, CHCl3). IR (neat): 3410, 2926,
2855, 1741, 1597, 1451, 1358, 1176, 974 . 1H-NMR (300 MHz, CDCl3): 1.15 (d, J ¼ 5.8, 3 H); 1.37 – 1.41 (m,
2 H); 1.83 – 1.96 (m, 2 H); 2.46 (m, 3 H); 3.32 – 3.45 (m, 1 H); 3.48 – 3.61 (m, 1 H); 3.67 – 3.83 (m, 1 H);
3.90 – 4.02 (m, 2 H); 7.32 (d, J ¼ 8.08, 2 H); 7.79 (d, J ¼ 8.08, 2 H). 13C-NMR (75 MHz, CDCl3): 21.32;
21.51; 36.45; 42.26; 67.30; 71.78; 72.02; 72.71; 127.84; 129.70; 132.73; 144.75. HR-ESI-MS: 301.1097 ([M þ
H]þ, C14H21O5Sþ; calc. 301.1104).
(2R,4S,6R)-Tetrahydro-4-(methoxymethoxy)-6-methyl-2H-pyran-2-methanol 4-Methylbenzenesulfo-
nate (9). To a soln. of 8 (2.5 g, 9.13 mmol) in anh. CH2Cl2 (25 ml) at 08 were successively added iPr2EtN
(8.77 ml, 50.15 mmol), DMAP (cat.), and MeOCH2Cl (0.8 ml, 25 mmol). The resulting mixture was
stirred for 3 h at r.t., the reaction quenched by adding H2O (15 ml), and the mixture extracted with
CH2Cl2 (3 ꢁ 30 ml). The org. extract was washed with brine (15 ml), dried (Na2SO4), and concentrated
and the crude purified by CC (SiO2, AcOEt/hexane): pure 9 (2.68 g, 94%). Liquid Rf (AcOEt/hexane
1:9) 0.5. [a]2D7 ¼ ꢀ8.10 (c ¼ 1.35, CHCl3). IR (neat): 2924, 2852, 1598, 1451, 1361, 1178, 1039, 977, 817, 668,
1
555. H-NMR (300 MHz, CDCl3): 1.12 (d, J ¼ 6.23, 3 H); 1.16 – 1.26 (m, 2 H); 1.90 (dd, J ¼ 1.88, 4.53,
1 H); 1.94 (dd, J ¼ 1.70, 4.15, 1 H); 2.43 (s, 3 H); 3.33 (s, 3 H); 3.35 – 3.43 (m, 2 H); 3.51 – 3.74 (m, 2 H);
3.93 – 4.04 (m, 2 H); 4.64 (s, 2 H); 7.32 (d, J ¼ 7.93, 2 H); 7.77 (d, J ¼ 8.49, 2 H). 13C-NMR (75 MHz,
CDCl3): 21.44; 21.56; 34.15; 39.86; 55.24; 71.90; 72.02; 72.31; 72.86; 94.40; 127.95; 129.71; 132.98; 144.70.
ESI-MS: 345 ([M þ H]þ); 362 ([M þ NH4]þ).
(2R,4S,6R)-Tetrahydro-2-(iodomethyl)-4-(methoxymethoxy)-6-methyl-2H-pyran (10). NaI (10.0 g,
67 mmol) was added to a soln. of 9 (2.3 g, 6.70 mmol) in acetone (40 ml) and the mixture heated to reflux
for 24 h. The acetone was then evaporated, and to the residue were added H2O and CH2Cl2 (60 ml). The
org. layer was dried (Na2SO4) and concentrated and the residue subjected to CC (SiO2, AcOEt/hexane):
10 (1.90 g, 95%). Colorless liquid. Rf (AcOEt/hexane 1:9) 0.7. IR (neat): 2939, 2885, 1379, 1144, 1099,
914. 1H-NMR (300 MHz, CDCl3): 1.26 (d, J ¼ 6.04, 3 H); 1.88 – 1.97 (m, 2 H); 2.16 – 2.25 (m, 2 H); 3.16 –
3.21 (dd, J ¼ 2.45, 5.85, 2 H); 3.31 – 3.34 (m, 1 H); 3.36 (s, 3 H); 3.45 – 3.56 (m, 1 H); 3.63 – 3.80 (m, 1 H);
4.69 (s, 2 H). 13C-NMR (CDCl3, 75 MHz): 8.84; 21.57; 37.92; 39.83; 55.32; 72.10; 72.51; 75.02; 94.48. ESI-
MS: 318 ([M þ NH4]þ).
(2R,4S)-3,4-Dihydro-4-(methoxymethoxy)-2,6-dimethyl-2H-pyran (12). To a soln. of 10 (1.8 g,
6.0 mmol) in DMF (100 ml) at 08 was added NaH (60% in oil; 0.57 g, 24.0 mmol). After 6 h stirring at r.t.,
the reaction was quenched with H2O at 08. The resulting mixture was diluted with AcOEt, the org. phase
washed with H2O and brine, dried (Na2SO4), and concentrated and the residue purified by CC (SiO2,
AcOEt/hexane1:9): 12 (1.26 g, 72%). Colorless clear oil. Rf (AcOEt/hexane 1:9) 0.6. 1H-NMR
(300 MHz, CDCl3): 1.29 (d, 3 H); 1.52 – 1.63 (m, 1 H); 1.73 (s, 3 H); 2.06 – 2.16 (m, 1 H); 3.35 (s, 3 H);
3.96 – 4.05 (m, 1 H); 4.24 – 4.31 (m, 1 H); 4.53 (m, 1 H); 4.66 (s, 2 H). 13C-NMR (75 MHz, CDCl3): 19.90;
21.00; 36.46; 55.25; 69.50; 70.95; 95.19; 98.04; 153.44. ESI-MS: 173 ([M þ H]þ).
(2R,4S)-4-(Methoxymethoxy)hex-5-en-2-ol Acetate (13). Ozone was bubbled through a soln. of 12
(0.7 g, 4.06 mmol) in CH2Cl2 (12 ml) at ꢀ 788 until no starting material was observed by TLC. The
mixture was purged with N2 to remove the excess ozone and cooled to 08, Ph3P (2.13 g, 8.13 mmol) was
added, and the mixture was stirred for 2 h and then concentrated. After adding hexane, the mixture was
filtered through a Celite pad, which was washed with hexane. The filtrate was dried (Na2SO4) and
concentrated and the crude aldehyde subjected to the next reaction without further purification. A soln.
of this aldehyde in dry THF (10 ml) was added at 08 to the ylide generated from methyltriphenylphos-
t
phonium chloride (3.36 g, 12.17 mmol) and BuOK (2.73 g, 24.30 mmol) in dry THF. The mixture was
stirred for 2 h at 08 and then the THF was evaporated. AcOEt was (15 ml) added to the residue, the
mixture washed with brine (5 ml), the org. phase dried (Na2SO4) and concentrated and the residue
purified by CC (SiO2, AcOEt/hexane): 13 (0.606, 74%, 2 steps). Colorless oil. Rf (AcOEt/hexane 1:9)
1
0.7. [a]2D7 ¼ ꢀ83.4 (c ¼ 0.52, CHCl3). IR (neat): 2929, 1738, 1373, 1244, 1096, 1031. H-NMR (200 MHz,

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Helvetica Chimica Acta – Vol. 95 (2012)
CDCl3): 1.23 (d, J ¼ 6.23, 3 H); 1.66 – 1.82 (m, 2 H); 2.02 (s, 3 H); 3.32 (s, 3 H); 4.02 – 4.10 (m, 1 H); 4.46
(d, J ¼ 6.98, 1 H); 4.67 (d, J ¼ 6.98, 1 H); 5.01 – 5.11 (m, 1 H); 5.16 – 5.24 (m, 2 H); 5.60 – 5.72 (m, 2 H).
13C-NMR (CDCl3, 75 MHz): 20.50; 21.23; 41.95; 55.62; 67.72; 73.66; 93.67; 117.35; 137.84. ESI-MS: 225
([M þ Na]þ).
(2R,4S)-4-(Methoxymethoxy)hex-5-en-2-ol (4). To a soln. of 13 (0.5 g, 2.47 mmol) in MeOH (10 ml),
K2CO3 (0.6 g, 4.94 mmol) was added. After stirring for 4 h at r.t., the mixture was diluted with H2O
(15 ml) and extracted with CH2Cl2 (3 ꢁ 10 ml). Evaporation of CH2Cl2 followed by FC (SiO2, AcOEt/
hexane): afforded 4 (0.39 g, 96%). Colorless liquid. Rf (AcOEt/hexane 3 :7) 0.4. [a]2D7 ¼ ꢀ109.2 (c ¼ 1.50,
1
CHCl3). IR (neat): 3414, 2922, 2854, 1460, 1030. H-NMR (CDCl3, 300 MHz): 1.19 (d, J ¼ 6.23, 3 H);
1.60 – 1.66 (m, 2 H); 2.55 (br., 1 H, OH); 3.38 (s, 3 H); 3.98 – 4.09 (m, 1 H); 4.22 – 4.20 (m, 1 H); 4.52 (d,
J ¼ 6.61, 1 H); 4.65 (d, J ¼ 6.79, 1 H); 5.15 – 5.26 (m, 2 H); 5.67 – 5.79 (m, 1 H). 13C-NMR (75 MHz,
CDCl3): 23.30; 43.87; 55.68; 64.20; 75.32; 94.25; 116.80; 137.66. ESI-MS: 183 ([M þ Na]þ).
Ethyl (4S,5S)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxolane-4-propanoate (15). To a soln. of 14
(2.0 g, 6.25 mmol) in AcOEt (30 ml) was added 10% Pd/C, and the mixture was stirred under H2 for 6 h.
Then, the mixture was filtered through a small Celite pad and the filtrate concentrated. The crude residue
thus obtained was purified by CC (SiO2, AcOEt/hexane): 15 (1.30 g, 90%). Colorless liquid. Rf (AcOEt/
hexane 3 :7) 0.3. [a]D27 ¼ þ20.3 (c ¼ 1.26, CHCl3). IR (neat): 3453, 2985, 2933,1731, 1375, 1219, 1166, 1070,
1040. 1H-NMR (300 MHz, CDCl3): 1.23 (t, J ¼ 6.98, 3 H); 1.37 (s, 3 H); 1.38 (s, 3 H); 1.75 – 2.00 (m, 2 H);
2.25 (br., 1 H, OH); 2.36 – 2.56 (m, 2 H); 3.37 – 3.64 (m, 1 H); 3.70 – 3.80 (m, 2 H); 3.84 – 3.92 (m, 1 H);
4.08 – 4.15 (q, J ¼ 7.17, 14.35, 2 H). 13C-NMR (75 MHz, CDCl3): 14.11; 26.92; 27.18; 27.91; 30.56; 60.43;
61.86; 76.13; 80.98; 108.82; 173.20. ESI-MS: 233 ([M þ H]þ), 250 ([M þ NH4]þ).
Ethyl (4S,5R)-5-(Iodomethyl)-2,2-dimethyl-1,3-dioxolane-4-propanoate (16). To a stirred soln. of 15
(1.2 g, 5.17 mmol) in dry THF (20 ml) were added successively, at 08, 1H-imidazole (0.84 g, 12.35 mmol),
Ph3P (1.62 g, 6.40 mmol), and I2 (1.57 g, 6.20 mmol). The resulting mixture was stirred for 2 h at r.t. and
then quenched by H2O (15 ml), and extracted with CH2Cl2 (3 ꢁ 30 ml). The org. layers were washed with
brine (15 ml), dried (anh. Na2SO4), and concentrated. Purification of the crude residue by CC (SiO2,
AcOEt/hexane) gave pure 16 (1.41 g, 92%). Colorless liquid. Rf (AcOEt/hexane 1:9) 0.5. [a]2D7 ¼ ꢀ19.1
(c ¼ 1.55, CHCl3). IR (neat): 2985, 2934, 1734, 1371, 1242, 1178, 1065, 878. 1H-NMR (300 MHz, CDCl3):
1.24 (t, J ¼ 7.17, 3 H); 1.37 (s, 3 H); 1.38 (s, 3 H); 1.71 – 2.02 (m, 2 H); 2.36 – 2.58 (m, 2 H); 3.58 – 3.80 (m,
3 H); 3.85 – 3.93 (m, 1 H); 4.12 (q, J ¼ 7.17, 14.35, 2 H). 13C-NMR (75 MHz, CDCl3): 14.17; 26.98; 27.23;
27.95; 30.61; 60.46; 61.89; 76.15; 80.98; 108.86; 173.21. ESI-MS: 342 ([M þ H]þ), 365 ([M þ NH4]þ).
Ethyl (4S)-4-Hydroxyhex-5-enoate (17). To a soln. of 16 (1.3 g, 3.80 mmol) in EtOH (60 ml),
commercial Zn dust (4.79 g, 76.03 mmol) was added. The mixture was refluxed for 2 h and then cooled to
258. Addition of solid NH4Cl (6.0 g) and Et2O (100 ml) followed by stirring for 5 min gave a gray
suspension. The suspension was filtered through a pad of Celite and the filtrate was concentrated.
Purification by FC (SiO2, AcOEt/hexane) gave 17 (0.516 g, 92%). Colorless liquid. Rf (AcOEt/hexane
3 :7) 0.4. [a]2D7 ¼ þ15.14 (c ¼ 2.85, CHCl3). IR (neat): 3453, 2983, 2929, 1776, 1729, 1424, 1375, 1176, 1018,
930. 1H-NMR (300 MHz, CDCl3): 1.17 (t, J ¼ 6.98, 3 H); 1.89 – 2.02 (m, 2 H); 2.5 (br., OH); 2.31 – 2.43
(m, 2 H); 3.63 (q, J ¼ 6.98, 13.97, 2 H); 4.85 – 4.93 (m, 1 H); 5.18 – 5.34 (m, 2 H); 5.78 – 5.89 (m, 1 H).
13C-NMR (75 MHz, CDCl3): 13.99; 18.15; 28.10; 80.40; 117.20; 135.46; 176.90. EI-MS: 158 (Mþ).
Ethyl (4S)-4-(Methoxymethoxy)hex-5-enoate (18). To 17 (0.40 g, 2.53 mmol) in anh. CH2Cl2 (10 ml)
i
at 08 were successively added Pr2EtN (2.66 ml, 15.19 mmol), DMAP (cat.), and MeOCH2Cl (0.38 ml,
7.58 mmol). The resulting mixture was stirred for 3 h at r.t., the reaction quenched by adding H2O
(10 ml), and the mixture extracted with CH2Cl2 (3 ꢁ 20 ml). The org. extracts were washed with brine
(10 ml), dried (anh. Na2SO4) and concentrated. The crude was purified by CC (SiO2, AcOEt/hexane):
pure 18 (0.42 g, 82%). Liquid. Rf (AcOEt/hexane 3 :7) 0.7. [a]2D7 ¼ ꢀ77.8 (c ¼ 1.6, CHCl3). IR (neat):
2983, 2935, 1736, 1178, 1151, 1095, 1032, 922. 1H-NMR (300 MHz, CDCl3): 1.23 (t, J ¼ 6.98, 3 H); 1.78 –
1.86 (m, 2 H); 2.33 (t, J ¼ 7.55, 15.10, 2 H); 3.30 (s, 3 H); 3.94 – 4.01 (m, 1 H); 4.04 – 4.11 (q, J ¼ 6.79, 14.35,
2 H); 4.44 (d, J ¼ 6.79, 1 H); 4.60 (d, J ¼ 6.79, 1 H), 5.13 – 5.21 (m, 2 H); 5.56 – 5.67 (m, 1 H). 13C-NMR
(CDCl3, 75 MHz): 14.14; 30.14; 30.25; 55.42; 60.25; 76.13; 93.67; 117.70; 137.54; 173.30. LC/MS: 225
([M þ Na]þ).
(4S)-4-(Methoxymethoxy)hex-5-enoic Acid (3). To a soln. of 18 (0.35 g, 1.73 mmol) in MeOH
(20 ml), 2n NaOH (10 ml) was added. The mixture was stirred for 6 h at r.t., acidified to pH 4 by adding

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1m HCl soln, and extracted with AcOEt (2 ꢁ 15 ml). Evaporation of the solvent followed by FC (SiO2,
AcOEt/hexane) afforded 3 (0.255 g, 85%). Colorless liquid. Rf (AcOEt/hexane 4 :6) 0.3. [a]2D7 ¼ ꢀ102.3
(c ¼ 0.90, CHCl3). IR (neat): 3082, 2936, 1711, 1420, 1150, 1095, 1031, 922. 1H-NMR (300 MHz, CDCl3):
1.85 – 1.93 (m, 2 H); 2.47 (t, J ¼ 6.98, 13.59, 2 H); 3.37 (s,3 H); 4.02 – 4.19 (q, J ¼ 6.98, 13.59, 1 H); 4.53 (d,
J ¼ 6.79, 1 H); 4.69 (d, J ¼ 6.79, 1 H); 5.19 – 5.27 (m, 2 H); 5.60 – 5.72 (m, 1 H). 13C-NMR (75 MHz,
CDCl3): 29.89; 29.95; 55.53; 76.09; 93.7; 117.98; 137.34; 179.27. HR-ESI-MS: 197.0789 ([M þ Na]þ,
C8H14NaOþ4 ; calc. 197.0781).
(1R,3S)-3-(Methoxymethoxy)-1-methylpent-4-en-1-yl) (4S)-(Methoxymethoxy)hex-5-enoate (2). To
a stirred soln. of 4 (0.20 g, 1.25 mmol) in CH2Cl2 (10 ml) was added 3 (0.26 g, 1.50 mmol) followed by
DCC (0.515 g, 2.50 mmol) and DMAP [4a] (0.30 g, 2.50 mmol) at r.t. After 2 h stirring the mixture was
filtered and the resulting filtrate evaporated. The crude residue was purified by CC (SiO2, AcOEt/
hexane): 2 (0.36 mg, 78%). Colorless liquid. Rf (AcOEt/hexane 3 :7) 0.7. [a]2D7 ¼ ꢀ127.6 (c ¼ 0.60,
1
CHCl3). IR (neat): 2937, 2890, 1732, 1152, 1095, 1031, 922. H-NMR (300 MHz, CDCl3): 1.24 (d, 2 H);
1.72 – 1.79 (m, 2 H); 1.82 – 1.97 (m, 2 H); 2.37 – 2.43 (m, 2 H); 3.33 (s, 3 H); 3.38 (s, 3 H); 4.49 (m, 2 H);
4.47 (d, J ¼ 6.79, 1 H); 4.53 (d, J ¼ 6.79, 1 H); 4.67 – 4.70 (m, 2 H); 5.18 – 5.26 (m, 4 H); 5.61 – 5.73 (m,
2 H). 13C-NMR (75 MHz, CDCl3): 20.55; 30.36; 30.47; 42.01; 55.49; 55.49; 67.71; 73.77; 76.28; 93.75;
93.79; 117.34; 117.79; 137.58; 137.89; 172.82. HR-ESI-MS: 339.1770 ([M þ Na]þ, C16H28NaO6þ ; calc.
339.1783).
(5S,6E,8S,10R)-3,4,5,8,9,10-Hexahydro-5,8-bis(methoxymethoxy)-10-methyl-2H-oxecin-2-one (19).
A soln. of Grubbsꢂ 2nd-generation catalyst [4a] (13.4 mg, 20 mol-%) in CH2Cl2 (10 ml) was added
dropwise to a soln. of 2 (0.25 g, 0.79 mmol) in CH2Cl2 (700 ml). The mixture was stirred under reflux at
458 for 12 h. The solvent was evaporated and the crude product purified by CC (SiO2, AcOEt/hexane):
19 (0.136 mg, 60%). Colorless oil. Rf (AcOEt/hexane 3 :7) 0.5. [a]2D7 ¼ ꢀ42.8 (c ¼ 1.21, CHCl3). IR
(neat): 2928, 2854, 1949, 1859, 1727, 1447, 1372, 1264, 1099, 1033, 801, 756. 1H-NMR (300 MHz, CDCl3):
1.22 (d, J ¼ 6.83, 3 H); 1.78 – 1.90 (m, 2 H); 1.98 – 2.10 (m, 3 H); 2.26 – 2.33 (m, 1 H); 3.33 (s, 3 H); 3.34 (s,
3 H); 4.49 (m, 2 H); 4.49 (d, J ¼ 6.83, 1 H); 4.53 (d, J ¼ 6.83, 1 H); 4.67 – 4.70 (m, 2 H); 5.37 – 5.41 (dd, J ¼
8.90, 15.61, 2 H); 5.48 – 5.54 (dd, J ¼ 9.70, 15.61, 2 H). 13C-NMR (75 MHz, CDCl3): 21.37; 31.47; 31.97;
41.57; 55.27. 55.39; 67.71; 75.17; 77.85; 92.80; 93.85; 133.24; 135.30; 173.53. HR-ESI-MS: 311.1461 ([M þ
Na]þ, C14H24NaOþ6 ; calc. 311.1470).
Stagonolide C (¼(5S,6E,8S,10R)-3,4,5,8,9,10-Hexahydro-5,8-dihydroxy-10-methyl-2H-oxecin-2-one;
1). Me3SiBr (1.60 ml, 1.86 mmol) was added dropwise to a cold (ꢀ408) stirred soln. of 19 (90 mg,
0.31 mmol) in CH2Cl2 (250 ml). The mixture was stirred at ꢀ 408 for 0.5 h and at 08 for an additional 4 h,
poured into sat. aq. NaHCO3 soln., and extracted with CH2Cl2. The extract was dried (Na2SO4), and
concentrated and the residue subjected to CC (SiO2, AcOEt/hexane): 1 (0.041 mg, 76%). Colorless
liquid . Rf (AcOEt/hexane 6 :4) 0.3. [a]2D7 ¼ þ45.6 (c ¼ 1.0, CHCl3). IR (neat): 3391, 2926, 2856, 1718,
1
1439, 1368, 1237, 1113, 1043. H-NMR (300 MHz, CDCl3): 1.22 (d, J ¼ 6.04, 3 H); 1.71 – 1.92 (m, 2 H);
1.98 – 2.06 (m, 3 H); 2.23 – 2.32 (m, 1 H); 4.05 – 4.16 (m, 2 H); 5.09 – 5.19 (m, 1 H); 5.42 (dd, J ¼ 9.06,
15.86, 1 H); 5.58 (dd, J ¼ 9.06, 15.86, 1 H). 13C-NMR (75 MHz, CDCl3): 21.38; 31.47; 34.41; 43.37; 67.64;
72.07; 74.47; 133.0; 174.0. HR-ESI-MS: 223.0937 ([M þ Na]þ, C10H16NaO4þ ; calc. 223.0946).
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Received May 5, 2011