Divergent enantioselective total synthesis of siphonarienal, siphonarienone, and pectinatone

Article abstract of DOI:10.1002/hlca.201300035

A divergent synthesis of siphonarienal, siphonarienone, and pectinatone has been achieved from a common precursor 4, which was synthesized by using an enzymatic desymmetrization approach. The major key steps involved were Grignard reaction, Wittig reactio

Full text of DOI:10.1002/hlca.201300035

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Helvetica Chimica Acta – Vol. 96 (2013)
Divergent Enantioselective Total Synthesis of Siphonarienal, Siphonarienone,
and Pectinatone
by Jhillu Singh Yadav*a), D. Narasimha Charya)b), Nagendra Nath Yadava), Sandip Senguptaa),
Basi V. Subba Reddya)
a) Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India
(fax: þ 91-40-27160512; e-mail:yadavpub@iict.res.in)
b) An Associate Institution of University of Hyderabad, Gachibowli, Hyderabad, Andhra Pradesh
500046, India
A divergent synthesis of siphonarienal, siphonarienone, and pectinatone has been achieved from a
common precursor 4, which was synthesized by using an enzymatic desymmetrization approach. The
major key steps involved were Grignard reaction, Wittig reaction, Evansꢀ asymmetric alkylation, and
base-catalyzed cyclization.
Introduction. – The siphonarienes belong to a class of polypropionates [1], which
includes polyether antibiotics [2] and macrolides [3]. Of these, deoxypropionate is a
common recurring motif in many deoxygenated polyketide-type natural products [4].
A syn/syn-deoxypropionate unit is found in many natural products, e.g., TMC-151A
[5], pectinatone [6], and siphonarienes (and its congeners) [7]. The siphonarienes 1, 2,
and pectinatone (3; Fig.) are marine polypropionate natural products and were
isolated from the genus Siphonaria such as Siphonariea grisea [8] and S. pectinata [6a],
respectively.
Figure. Representative structures of deoxypolypropionate-containing natural products
ꢁ 2013 Verlag Helvetica Chimica Acta AG, Zꢂrich

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The polydeoxypropionates are known to exhibit various biological activities. They
are active against Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis),
yeast (Candida albicaans and Sacchoromyces cervisiae), and several human cancer cell
lines [6b][9]. The structures of 1 [8], 2 [7a], and 3 [6b] were established on the basis of
their spectroscopic data. Furthermore, the structure of 3 was confirmed by X-ray
diffraction analysis [10].
In earlier studies, for the installation of new Me-bearing stereogenic centers mainly
iterative alkylations or diastereoselective aldol reactions were used [11]. Other
methods for the introduction of a Me group involved chiral auxiliaries [8][12], allylic
substitutions [13], or substrate-controlled methods. Catalytic asymmetric methods have
also been employed for the generation of stereogenic centers bearing a Me group,
which include Negishiꢀs Zr-catalyzed carboalumination [7b], Burgessꢀs Ir-catalyzed
hydrogenation [14], and Feringaꢀs Josiphos-catalyzed conjugate addition [15]. Of these,
conjugate addition of MeMgBr to a commercially available a,b-unsaturated ester is one
of the most direct entries into these structural elements. Recently, the total synthesis of
the marine polypropionates siphonarienal (1), siphonarienone (2), and pectinatone (3)
has been reported by our group by employing a desymmetrization strategy, i.e.,
asymmetric hydroboration of the known meso-olefin using (ꢀ)-IPC2BH (¼diisopino-
camphenylborane), PCC (¼ pyridinium chlorochromate), and BaeyerꢀVilliger oxida-
tion reactions [7c]. Herein, we report an enantioselective total synthesis of 1, 2, and 3
by using enzymatic desymmetrization of a meso-diol and Evansꢀ alkylation protocol.
Results and Discussion. – Retrosynthetically, we envisaged that the target
molecules 1 – 3 could be synthesized from a common chiral precursor 4. The latter
was then proposed to be synthesized from 5 in two steps involving oxidation and C3-
homologation reactions. The intermediate 5 was assumed to be prepared from 6 in a
stereoselective manner involving Wittig reaction and Evansꢀ asymmetric alkylation.
The key intermediate 6 was obtained from diketone 7 by NaIO4 oxidation and LiAlH4
reduction, followed by enzymatic desymmetrization (Scheme 1).
Scheme 1. Retrosynthetic Analysis of Siphonarienal (1), Siphonarienone (2), and Pectinatone (3).
TBS ¼ tBuMe2Si.
Accordingly, we started our synthesis from cis-4,6-dimethylcyclohexan-1,3-dione
(7), which was obtained by the condensation of methyl methacrylate with butan-2-one
in the presence of MeONa [16a]. Thus obtained 1,3-dione was then converted to the
corresponding diacid by means of periodate oxidation [16b]. Reduction of the diacid
with LiAlH4 in THF at 08 gave the meso-diol in 98% yield. Desymmetrization of the
latter using Lipase-AK and vinyl acetate (as acylating agent) in THF at ambient

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Helvetica Chimica Acta – Vol. 96 (2013)
conditions [17] gave the mono acetate 6 in 74% yield with > 95% ee along with the
meso-diacetate, which was again converted to meso-diol using K2CO3 in MeOH. The
t
mono acetate 6 was protected as its silyl ether using BuMe2SiCl (TBS-Cl) and 1H-
imidazole in CH2Cl2 and then treated with K2CO3 in MeOH to furnish the desired
terminal alcohol 8. Subsequent oxidation of 8, followed by elongation by C2 using
Wittig reaction gave the a,b-unsaturated ester 9 in 86% yield over two steps.
Chemoselective reduction of the C¼C bond with Pd/C in AcOEt afforded the saturated
ester 10 in 96% yield, which was then subjected to hydrolysis under basic conditions to
furnish the corresponding carboxylic acid 11 in 93% yield. The coupling of the latter
with Evansꢀ chiral oxazolidinone using pivaloyl chloride in the presence of Et3N and
LiCl gave the required compound 12 in 93% yield [18]. Diastereoselective methylation
of the Li-enolate of 12 was achieved with MeI using a freshly prepared LDA (1.0m) to
furnish the desired compound 13 with a diastereoselectivity of > 97:3 [18c], which was
1
confirmed by H-NMR. Reduction of 13 with LiBH4 in MeOH gave the primary
alcohol 5 in 92% yield with three stereogenic centers (Scheme 2).
Scheme 2. Synthesis of Alcohol 5. TBS ¼ tBuMe2Si; Piv-Cl ¼ 2,2-Dimethylpropanoyl chloride; LDA ¼
LiNiPr2.
The alcohol 5 was then protected as its Bn derivative using NaH and BnBr in the
presence of a catalytic amount of Bu4NI (TBAI), followed by removal of the silyl group
using HF-pyridine in THF to give the alcohol 14. Tosylation of 14 with TsCl in the
presence of Et3N in dry CH2Cl2, at 08, followed by Grignard reaction [17b] with
EtMgBr in dry Et2O at ꢀ 208 in the presence of a catalytic amount of Li2CuCl4,

Helvetica Chimica Acta – Vol. 96 (2013)
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furnished the Grignard product 15 in 82% yield. Removal of the Bn group of 15 with
Pd/C in AcOEt under H2 afforded the primary alcohol 16 in good yield. Swern
oxidation of 16 gave the required aldehyde, which was then subjected to C3 Wittig
reaction to afford the a,b-unsaturated ester 4 ((E)-isomer), as the major product in
86% yield over two steps [19], which was the common precursor for the synthesis of all
the three natural products 1, 2, and 3.
The target molecule, siphonarienal (1) was readily achieved in 88% yield by the
partial reduction of 4 with DIBAL-H at ꢀ 788. Grignard reaction of 1 with EtMgBr
followed by oxidation with DessꢀMartin periodinane gave the siphonarienone (2) in
85% yield over two steps (isomeric purity was 99%; Scheme 3). The spectroscopic data
of 1 and 2 were in good agreement with those reported [8][20].
Scheme 3. Synthesis of Siphonarienal (1) and Siphonarienone (2). DMAP ¼ 4-(Dimethylamino)pyr-
idine; DIBAL-H ¼ diisobutylaluminium hydride.
To achieve the synthesis of our next target molecule 3, the ester 4 was treated with
(methoxy)(methyl)ammonium chloride and iPrMgCl in THFat ꢀ 20 to 08 to afford the
Weinreb amide 17 in 71% yield. Treatment of the latter with ethyl 2-methyl-3-
oxopentanoate (18; prepared by treating pentan-3-one with (EtO)2CO in the presence
of LiHMDS (lithium bis(trimethylsilyl)amide) in dry THF), followed by base-
catalyzed cyclization of the resulting b,d-diketo ester 19 in the presence of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) under refluxing toluene [21], gave pectinatone
(3) in 30% yield (Scheme 4).
In summary, we have developed a highly enantioselective, divergent total synthesis
of siphonarienal (1), siphonarinone (2), and pectinatone (3). This approach involves a
lower number of steps in comparison with our earlier approach [7c]. The present
synthesis includes an enzymatic desymmetrization of a meso-diol, Wittig olefination,
Evansꢀ asymmetric alkylation, and base-catalyzed cyclization as key steps.

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Helvetica Chimica Acta – Vol. 96 (2013)
Scheme 4. Synthesis of Pectinatone (3). DBU ¼ 1,8-Diazabicyclo[5.4.0]undec-7-ene.
D. N. C thanks UGC, N. N. Y and S. S. G. thank CSIR, New Delhi, for the financial support in the
form of fellowships.
Experimental Part
General. All reactions were performed under Ar. All glassware used for reactions are oven/flame-
dried. Anh. solvents were distilled prior to use: THF from Na and benzophenone; CH2Cl2 and DMSO
from CaH2 ; and MeOH from Mg cake. Commercial reagents were used without purification. Column
chromatography (CC): silica gel (60 – 120 mesh), unless otherwise mentioned. Anal. TLC: silica gel
60F 254 pre-coated plates (250 mm thickness). Optical rotations: Perkin-Elmer 343 polarimeter; in
10ꢀ1 Deg cm2 gꢀ1. IR Spectra: Perkin-Elmer Infrared-683 spectrometer; in CHCl3 or KBr; n˜ in cmꢀ1
.
NMR Spectra: Varian Gemini 200, Varian Unity 400, Varian Inova 500, or Bruker Avance 300
spectrometers; at 300, 400, and 500 MHz (1H), and 75 MHz (13C); in CDCl3 soln., unless otherwise
mentioned, chemical shifts (d) in ppm downfield from Me4Si; coupling constants (J) in Hz. ESI- or HR-
ESI-MS: Finnigan MAT 1020B or Micro Mass 70 – 70H spectrometers; at 70 eV; m/z (rel. %).
(2S,4R)-5-Hydroxy-2,4-dimethylpentyl Acetate (6). A stirred soln. of meso-2,4-dimethylpentane-1,5-
diol (4.0 g, 30.3 mmol, 1.0 equiv.) in THF (40 ml) was cooled to 08. At this temp., Amano Lipase AK
(220 mg) and vinyl acetate (4.20 ml, 3.90 g, 45.4 mmol, 1.50 equiv.) were added. The mixture was stirred
for 30 min at 08 and 7 h at 58. The enzyme was removed by suction filtration through Celite. The residue
was further washed with Et2O (2 ꢁ 30 ml) and dried (Na2SO4). The homogeneous filtrate was
concentrated in vacuo and purified by CC (AcOEt/hexane 1:5) to afford 6 (3.902 g, 74%). Colorless oil.
[a]2D5 ¼ þ10.5 (c ¼ 1.2, CHCl3). 1H-NMR (300 MHz, CDCl3): 3.97 (dd, J ¼ 10.5, 5.2, 1 H); 3.85 (dd, J ¼
10.5, 6.7, 1 H); 3.49 (dd, J ¼ 10.5, 6.0, 1 H); 3.42 (dd, J ¼ 10.5, 6.0, 1 H); 2.05 (s, 3 H); 1.82 – 1.96 (m, 1 H);
1.64 – 1.78 (m, 1 H); 1.43 (br. s, 1 H); 1.39 – 1.49 (m, 1 H); 1.15 – 1.30 (m, 1 H); 0.96 (d, J ¼ 6.7, 3 H); 0.95
(d, J ¼ 6.7, 3 H). 13C-NMR (CDCl3, 75 MHz): 171.3; 69.1; 67.9; 37.2; 32.9; 29.9; 20.9; 17.8; 17.2.
(2S,4R)-5-{[(tert-Butyl)(dimethyl)silyl]oxy}-2,4-dimethylpentan-1-ol (8). To a cold (08) soln. of 6
(6.0 g, 34.4 mmol) in dry CH2Cl2 (80 ml) were added 1H-imidazole (4.69 g, 68.9 mmol) and TBS-Cl
(6.20 g, 41.32 mmol). The resulting mixture was stirred at r.t. for 3 h. After completion of the reaction
(TLC), the reaction was quenched with sat. aq. NH4Cl, and the mixture was extracted with CH2Cl2 (3 ꢁ
50 ml). The combined org. layers were washed with brine, dried (Na2SO4), and concentrated under
reduced pressure to furnish the crude acetate. To the above mixture in MeOH (80 ml), K2CO3 (9.5 g,
68.0 mmol) was added at r.t. The mixture was stirred for 1 h at r.t. and then concentrated under reduced
pressure. The residue was treated with sat. NH4Cl and extracted with AcOEt (3 ꢁ 100 ml). The combined
org. layers were washed with H2O, brine, dried (Na2SO4), and concentrated in vacuo. The resulting crude
product was purified by CC (AcOEt/hexane 1:9) to give 8 (8.143 g, 96%). Colorless oil. [a]2D5 ¼ þ0.9
(c ¼ 1.2, CHCl3). IR (KBr): 3348, 2954, 2928, 2857, 1466, 1252, 1097, 837, 775. 1H-NMR (300 MHz,

Helvetica Chimica Acta – Vol. 96 (2013)
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CDCl3): 3.32 – 3.50 (m, 4 H); 1.60 – 1.77 (m, 2 H); 1.36 – 1.50 (m, 2 H); 0.93 (d, J ¼ 6.7, 3 H); 0.90 (d, J ¼
6.7, 3 H); 0.89 (s, 9 H); 0.03 (s, 6 H). 13C-NMR (CDCl3, 75 MHz): 68.2; 67.9; 37.2; 33.1; 25.8; 18.2; 17.7;
17.6; ꢀ 5.4.
Ethyl (2E,4S,6R)-7-{[(tert-Butyl)(dimethyl)silyl]oxy}-4,6-dimethylhept-2-enoate (9). To a stirred
soln. of DMSO (1.4 ml, 20.32 mmol) in CH2Cl2 (30 ml) was added oxalyl chloride (1.1 ml, 12.7 mmol) at
ꢀ 788, and the resulting soln. was stirred for 15 min. A soln. of 8 (2.5 g, 10.16 mmol) in CH2Cl2 (10 ml)
was added dropwise at ꢀ 788 over 30 min. After stirring the mixture for an additional 30 min, Et3N
(4.20 ml, 30.48 mmol) was added, and the mixture was stirred for 0.5 h at ꢀ 788 and then for 0.5 h at 08.
The reaction was then quenched with sat. aq. NH4Cl soln. (20 ml), and then the mixture was extracted
with CH2Cl2 (2 ꢁ 30 ml). The combined org. layers were washed with H2O (30 ml), brine (20 ml), dried
(Na2SO4), and concentrated in vacuo. To a stirred soln. of crude aldehyde in benzene was added the
stabilized ylide Ph3PCHCO2Et (5.60 g, 15.2 mmol), and the mixture was refluxed for 12 h and then
concentrated in vacuo. Solvent was removed under reduced pressure, followed by purification of the
residue by CC (AcOEt/hexane 5 :95) to give 9. Colorless liquid. [a]2D5 ¼ þ17.9 (c ¼ 1.0, CHCl3). IR
(KBr): 2957, 2859, 1722, 1652, 1465, 1367, 1259, 1180, 1094, 1042, 840, 775. 1H-NMR (300 MHz, CDCl3):
6.76 (dd, J ¼ 15.8, 8.3, 1 H); 5.75 (d, J ¼ 15.8, 1 H); 4.17 (q, J ¼ 14.3, 6.7, 2 H); 3.37 (dd, J ¼ 5.2, 1.5, 2 H);
2.32 – 2.51 (m, 1 H); 1.44 – 1.67 (m, 2 H); 1.29 (t, J ¼ 6.7, 3 H); 1.06 – 1.15 (m, 1 H); 1.06 (d, J ¼ 6.7, 3 H);
0.89 (s, 9 H); 0.86 (d, J ¼ 6.7, 3 H); 0.03 (s, 6 H). 13C-NMR (CDCl3, 75 MHz): 166.7; 154.3; 119.7; 68.3;
60.0; 39.8; 34.1; 33.3; 25.8; 20.4; 18.2; 16.5; 14.2; ꢀ 5.4. ESI-MS: 337 ([M þ Na]þ). HR-ESI-MS: 337.2174
([M þ Na]þ, C17H34NaO3Siþ; calc. 337.2175).
Ethyl (4R,6R)-7-{[(tert-Butyl)(dimethyl)silyl]oxy}-4,6-dimethylheptanoate (10). To a stirred soln. of
9 (2.0 g, 6.36 mmol) in AcOEt (10 ml), under N2 was added Pd/C (10%; 35 mg). The mixture was flushed
with N2 and then stirred under H2 for ca. 2 h until complete consumption of the starting material. The
resulting mixture was diluted with Et2O (20 ml) and then filtered through a pad of Celite and
concentrated in vacuo. The crude product was purified by CC (5% AcOEt/hexane) to give 10 (1.93 g,
96% yield). Colorless oil. [a]2D5 ¼ þ3.8 (c ¼ 1.2, CHCl3). IR (KBr): 2956, 1738, 1636, 1253, 1094, 772, 570.
1H-NMR (300 MHz, CDCl3): 4.10 (q, J ¼ 14.3, 6.7, 2 H); 3.41 (dd, J ¼ 9.8, 6.0, 1 H); 3.33 (dd, J ¼ 9.8, 6.0,
1 H); 2.18 – 2.34 (m, 2 H); 1.28 – 1.75 (m, 6 H); 1.26 (t, J ¼ 6.7, 3 H); 0.90 (d, J ¼ 6.0, 3 H); 0.89 (s, 9 H);
0.87 (d, J ¼ 6.0, 3 H); 0.02 (s, 6 H). 13C-NMR (CDCl3, 75 MHz): 174.0; 68.2; 60.1; 40.7; 33.0; 31.8; 31.5;
29.6; 25.9; 20.0; 18.2; 17.3; 14.2; ꢀ 5.4. ESI-MS: 339 ([M þ Na]þ). HR-ESI-MS: 339.2321 ([M þ Na]þ,
C17H36NaO3Siþ; calc. 339.2331).
(4R,6R)-7-{[(tert-Butyl)(dimethyl)silyl]oxy}-4,6-dimethylheptanoic acid (11). LiOH · H2O (0.79 g,
18.9 mmol) was added in portions to a cooled soln. (08) of 10 (2.0 g, 6.32 mmol) in 30 ml of MeOH/H2O
(3 :1), and stirring was continued for 2 h at r.t. The mixture was then concentrated in vacuo, and the
residue was diluted with AcOEt (30 ml), washed with sat. aq. NH4Cl and extracted with AcOEt (3 ꢁ
20 ml). The combined org. layers were washed with brine, dried (Na2SO4), and concentrated under
reduced pressure. Removal of solvent, followed by CC (20% AcOEt/hexane) afforded 11 (1.70 g, 93%
yield). Colorless liquid. [a]2D5 ¼ þ5.0 (c ¼ 0.7, CHCl3). IR (KBr): 2956, 2930, 2858, 1711, 1464, 1414, 1253,
1094, 938, 839, 775, 667. 1H-NMR (300 MHz, CDCl3): 3.30 – 3.45 (m, 2 H); 2.24 – 2.42 (m, 2 H); 1.06 – 1.78
(m, 6 H); 0.92 (d, J ¼ 6.7, 3 H); 0.89 (s, 9 H); 0.88 (d, J ¼ 6.7, 3 H); 0.03 (s, 6 H). 13C-NMR (CDCl3,
75 MHz): 180.2; 68.1; 40.6; 33.0; 31.5; 31.2; 29.6; 25.9; 19.9; 18.3; 17.4; ꢀ 5.3 . ESI-MS: 311 ([M þ Na]þ).
HR-ESI-MS: 311.2028 (C15H32NaO3Siþ, [M þ Na]þ; calc. 311.2018).
(4S)-4-Benzyl-3-[(4R,6R)-7-{[(tert-butyl)(dimethyl)silyl]oxy}-4,6-dimethylheptanoyl]-1,3-oxazoli-
din-2-one (12). To a stirred soln. of 11 (3.0 g, 10.41 mmol) in THF (35 ml) at ꢀ 208 was added Et3N
(3.50 ml, 26.04 mmol), followed by PivCl (1.3 ml, 10.41 mmol). After stirring for 1 h at ꢀ 208, LiCl
(0.66 g, 15.62 mmol), and then by (S)-1,3-oxazolidin-2-one (2.0 g, 11.45 mmol) were added at the same
temp. The stirring was continued for 1 h at ꢀ 208 and then 2 h at 08. The reaction was then quenched with
sat. NH4Cl soln. (20 ml), and the mixture was extracted with AcOEt (2 ꢁ 30 ml). The combined org.
layers were washed with brine (30 ml), dried (Na2SO4), and concentrated under reduced pressure. The
crude product was purified by CC (AcOEt/hexane 1:16) to give 12 (4.33 g, 93%). Viscous liquid. [a]D25
¼
þ38.8 (c ¼ 1.0, CHCl3). IR (KBr): 2954, 2928, 2857, 1784, 1700, 1461, 1386, 1353, 1251, 1208, 1093, 839,
772, 701, 591. 1H-NMR (300 MHz, CDCl3): 7.15 – 7.38 (m, 5 H); 4.54 – 4.67 (m, 1 H); 4.09 – 4.23 (m, 2 H);
3.43 (dd, J ¼ 9.8, 5.2, 1 H); 3.25 – 3.40 (m, 2 H); 2.78 – 3.03 (m, 2 H); 2.69 (dd, J ¼ 13.5, 9.8, 1 H); 1.08 –

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Helvetica Chimica Acta – Vol. 96 (2013)
1.80 (m, 6 H); 0.95 (d, J ¼ 6.0, 3 H); 0.89 (s, 9 H); 0.88 (d, J ¼ 6.7, 3 H); 0.03 (s, 6 H). 13C-NMR (CDCl3,
75 MHz): 173.6; 153.3; 135.3; 129.3; 128.8; 127.2; 68.2; 66.0; 55.1; 40.8; 37.8; 33.1; 33.0; 30.8; 29.7; 25.9;
20.0; 18.3; 17.4; ꢀ 5.3. ESI-MS: 470 ([M þ Na]þ). HR-ESI-MS: 470.2714 ([M þ Na]þ, C25H41NNaO4Siþ;
calc. 470.2703).
(4S)-4-Benzyl-3-[(2S,4S,6R)-7-{[(tert-butyl)(dimethyl)silyl]oxy}-2,4,6-trimethylheptanoyl]-1,3-oxa-
zolidin-2-one (13). To a stirred soln. of 12 (2.0 g, 4.47 mmol) in dry THF (20 ml) at ꢀ 788, LDA (1m soln.
in THF, 6.75 ml, 6.75 mmol) was added slowly dropwise with stirring under N2. After stirring at ꢀ 788 for
30 min, MeI (0.83 ml, 13.42 mmol) was added dropwise and then stirring was continued for another 2 h at
ꢀ 788. Then, the reaction was quenched with sat. NH4Cl (10 ml), and the mixture was warmed to r.t. and
then extracted with AcOEt (2 ꢁ 30 ml). The combined org. extracts were washed with brine (30 ml),
dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by CC
(AcOEt/hexane 1:19) to afford 13 (1.87 g, 91%). Colorless liquid. [a]2D5 ¼ þ41.6 (c ¼ 1.3, CHCl3). IR
(KBr): 2956, 2928, 2857, 1783, 1699, 1460, 1385, 1351, 1249, 1208, 1096, 839, 774, 700. 1H-NMR (300 MHz,
CDCl3): 7.17 – 7.37 (m, 5 H); 4.55 – 4.68 (m, 1 H); 4.08 – 4.22 (m, 2 H); 3.77 – 3.93 (m, 1 H); 3.22 – 3.47 (m,
3 H); 2.70 (dd, J ¼ 12.8, 9.8, 1 H); 1.25 – 1.98 (m, 5 H); 1.20 (d, J ¼ 6.7, 3 H); 0.96 – 1.12 (m, 1 H); 0.89 (s,
9 H); 0.88 (d, J ¼ 6.7, 6 H); 0.03 (s, 6 H). 13C-NMR (CDCl3, 75 MHz): 177.2; 152.9; 135.2; 129.4; 128.8;
127.2; 68.3; 65.9; 55.2; 41.2; 40.4; 37.8; 35.2; 33.0; 28.1; 25.9; 20.7; 18.5; 18.3; 17.4; ꢀ 5.3. ESI-MS: 484
([M þ Na]þ). HR-ESI-MS: 484.2875 ([M þ Na]þ, C26H43NaO4Siþ; calc. 484.2859).
(2S,4R,6R)-7-{[(tert-Butyl)(dimethyl)silyl]oxy}-2,4,6-trimethylheptan-1-ol (5). To a stirred soln. of
13 (1.80 g, 3.90 mmol) in THF (20 ml) at 08 was added LiBH4 (258 mg, 11.72 mmol) portionwise. The
mixture was stirred for 2 h at the same temp., and then, the reaction was quenched with sat. aq. NH4Cl,
and the mixture was extracted with AcOEt (3 ꢁ 20 ml). The combined org. layers were dried (Na2SO4)
and concentrated under reduced pressure, and the crude product was purified by CC (10%, AcOEt/
hexane) to afford 5 (1.03 g, 92%). Viscous liquid. [a]2D5 ¼ ꢀ5.8 (c ¼ 1.0, CHCl3). IR (KBr): 3351, 2956,
2928, 2858, 1465, 1383, 1253, 1098, 1040, 838, 775, 667. 1H-NMR (300 MHz, CDCl3): 3.29 – 3.55 (m, 4 H);
2.60 (s, 1 H); 0.96 – 1.88 (m, 7 H); 0.93 (d, J ¼ 7.5, 3 H); 0.90 (d, J ¼ 6.7, 3 H); 0.89 (s, 9 H); 0.88 (d, J ¼ 6.7,
3 H); 0.03 (s, 6 H). 13C-NMR (CDCl3, 75 MHz): 68.1; 67.9; 41.2; 41.0; 33.0; 27.6; 25.9; 21.0; 18.3; 17.9;
17.5; ꢀ 5.3. ESI-MS: 289 ([M þ H]þ). HR-ESI-MS: 311.2398 ([M þ Na]þ, C16H36NaO2Siþ; calc.
311.2382).
(2R,4S,6S)-7-(Benzyloxy)-2,4,6-trimethylheptan-1-ol (14). To a stirred soln. of NaH (0.55g (50%
with mineral oil), 11.46 mmol) in dry THF (10 ml) was added 5 (3.0 g, 10.42 mmol) in dry THF (20 ml) at
08. The mixture was stirred for 20 min, and then a soln. of BnBr (1.3 ml, 10.42 mmol) in excess anh. THF
was added slowly dropwise. The resulting mixture was allowed to be stirred at r.t. for 2 h. Upon
completion, the reaction was quenched with H2O, and the mixture was extracted with AcOEt (3 ꢁ
20 ml). The org. extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent,
followed by purification of the crude product by flash chromatography (FC; 4% AcOEt/ hexane)
afforded the benzyl ether (3.62 g, 92%) as a colorless liquid.
The crude product was dissolved in dry THF (20 ml) at 08, and then 9.6 ml of Bu4NF (1m in THF) was
added. The resulting mixture was stirred at r.t. for 6 h. After completion, the reaction was quenched with
sat. NH4Cl soln. (10 ml), and the mixture was extracted with AcOEt (2 ꢁ 30 ml). The combined org.
layers were washed with brine (30 ml), dried (Na2SO4), and concentrated under reduced pressure. The
crude product was purified by CC (AcOEt/hexane 1:9) to give 5 (2.3 g, 90%). Viscous liquid. [a]D25
¼
þ7.5 (c ¼ 2.5, CHCl3). IR (KBr): 3418, 2956, 2919, 2869, 1457, 1370, 1101, 1034, 740. 1H-NMR
(300 MHz, CDCl3): 7.34 – 7.19 (m, 5 H); 4.50 – 4.42 (m, 2 H); 3.46 (dd, J ¼ 4.9, 9.8, 1 H); 3.36 – 3.27 (m,
2 H); 3.23 – 3.18 (m, 2 H); 1.87 – 1.80 (m, 1 H); 1.61 – 1.55 (m, 1 H); 1.40 – 1.26 (m, 2 H); 0.97 – 0.84 (m,
12 H). 13C-NMR (CDCl3, 75 MHz): 138.6; 128.2; 127.4; 127.3; 75.7; 72.93; 68.0; 41.5; 41.0; 32.9; 30.8; 27.6;
20.9; 18.2; 17.5. ESI-MS: 282 ([M þ NH4]þ).
Benzyl (2S,4S,6S)-2,4,6-Trimethylnonyl Ether (15). To a stirred soln. of 14 (2.0 g, 7.6 mmol) in dry
CH2Cl2(20 ml) were added Et3N (1.3 ml, 9.1 mmol), TsCl (1.50g, 7.6 mmol), and a cat. amount of DMAP
(46 mg, 0.37 mmol). The resulting mixture was stirred for 3 h. After complete conversion (TLC), the
reaction was quenched with NH4Cl soln., and the mixture was extracted with AcOEt (3 ꢁ 20 ml).
Removal of the solvent, followed by purification on CC (5% AcOEt/hexane), gave the pure tosyl
derivative. To a round-bottom flask equipped with an activated Mg turnings (0.59 g, 24.0 mmol,

Helvetica Chimica Acta – Vol. 96 (2013)
1975
3.4 equiv.), EtBr (1.86 ml, 25.2 mmol, 3.5 equiv.) in Et2O (20 ml) was added slowly. After complete
addition, the mixture was heated to reflux (ca. 30 min) until initiation of the reaction. The mixture was
cooled to ꢀ 208, and then tosylate (3.0 g, 7.18 mmol) was added slowly. To this mixture, a soln. of
Li2CuCl4 (0.1m in THF, 7 ml, 0.718 mmol, 0.1 equiv.) was slowly added at ꢀ 208. The resulting mixture
was stirred vigorously overnight at r.t., and the reaction was quenched with sat. aq. NH4Cl (20 ml) at 08,
and the mixture was extracted with Et2O (3 ꢁ 20 ml). Removal of the solvent, followed by CC gave 15
(82%). Colorless liquid. [a]2D5 ¼ þ2.0. (c ¼ 1.0, CHCl3). IR (KBr): 3449, 2955, 2919, 2857, 1637, 1457,
1371, 1101, 760. 1H-NMR (300 MHz, CDCl3): 7.35 – 7.21 (m, 5 H); 4.51 – 4.42 (m, 2 H); 3.30 (dd, J ¼ 5.2,
1 H); 3.18 (dd, J ¼ 6.7, 1 H); 1.90 – 1.78 (m, 1 H); 1.65 – 1.44 (m, 2 H); 1.44 – 1.15 (m, 6 H); 1.03 – 0.79 (m,
14 H). 13C-NMR (CDCl3, 75 MHz): 138.8; 128.2; 127.4; 127.3; 75.9; 73.0; 45.2; 41.8; 38.9; 30.9; 29.7; 27.6;
20.9; 20.4; 20.0; 18.4; 14.5. ESI-MS: 294 ([M þ NH4]þ).
(2S,4S,6S)-2,4,6-Trimethylnonan-1-ol (16). To a stirred soln. of 15 (1.6 g, 5.8 mmol) in AcOEt
(10 ml) under N2 was added Pd/C (10%, 35 mg). The soln. was flushed with N2 and then stirred under H2
for ca. 2 h until complete consumption of the starting material. The resulting mixture was diluted with
Et2O (60 ml), filtered through a pad of Celite, and concentrated in vacuo. The crude product was purified
by CC (AcOEt/hexane 1:9) to yield 16 (1.1g, 95% yield). Colorless oil. [a]2D5 ¼ ꢀ7.7 (c ¼ 2.1, CHCl3). IR
(KBr): 3450, 2924, 2855, 1633, 1376, 1215, 1085, 759. 1H-NMR (300 MHz, CDCl3): 3.54 – 3.32 (m, 2 H);
2.06 – 1.96 (m, 1 H); 1.77 – 1.42 (m, 3 H); 1.37 – 1.11 (m, 6 H); 0.95 – 0.79 (m, 14 H). 13C-NMR (CDCl3,
75 MHz): 68.2; 45.1; 41.2; 38.7; 33.0; 29.7; 27.4; 20.8; 20.4; 19.9; 17.5; 14.4.
Ethyl (2E,4S,6S,8S)-2,4,6,8-Tetramethylundec-2-enoate (4). To a stirred soln. of 2-iodobenzoic acid
(IBX; 2.48 g, 8.85 mmol) in DMSO (6 ml) at 258, was added slowly dropwise a soln. of 16 (1.1 g,
5.9 mmol) in CH2Cl2 (15 ml). The resulting mixture was stirred at 258 for 3 h. The solid was filtered and
washed with Et2O. The filtrate was washed with sat. aq. NaHCO3 soln., H2O, and brine, and then dried
(Na2SO4). The solvent was removed under reduced pressure to furnish the crude aldehyde. To this
aldehyde in CH2Cl2 (20 ml) was added ethyl 2-(triphenylphosphoranylidene)propanoate (3.30 g,
9.46 mmol), and the resulting mixture was stirred for 12 h at r.t. The solvent was concentrated under
reduced pressure and purified by CC (3% AcOEt/hexane) to afford 4 (1.3 g, 86%). Colorless liquid.
[a]2D5 ¼ þ17.9 (c ¼ 1.0, CHCl3). IR (KBr): 3449, 2958, 2924, 2871, 1713, 1648, 1457, 1268, 1101, 1035, 751.
1H-NMR (300 MHz, CDCl3): 6.44 (d, J ¼ 10.1, 1 H); 4.20 (q, J ¼ 7.1, 2 H); 2.66 – 2.53 (m, 1 H); 1.84 (s,
3 H); 1.46 – 1.14 (m, 10 H); 1.12 – 0.77 (m, 15 H). 13C-NMR (CDCl3, 75 MHz): 168.3; 148.0; 126.1; 60.2;
45.5; 44.3; 39.2; 30.8; 29.6; 28.1; 20.5; 20.4; 19.9; 14.3; 14.2; 12.3. ESI-MS: 291 ([M þ Na]þ). HR-ESI-MS:
291.2322 ([M þ Na]þ, C17H32NaOþ2 ; calc. 291.2300).
(2E,4S,6S,8S)-2,4,6,8-Tetramethylundec-2-enal (1) [8]. To a cooled (ꢀ 788) soln. of 4 (250 mg,
0.93 mmol) in dry CH2Cl2 (3 ml), DIBAL-H (1.0 ml, 1.0 mmol, 20% soln. in toluene) was added slowly
over 5 min. The resulting mixture was stirred for 30 min at ꢀ 788, before quenching the reaction with
sodium potassium tartarate soln. (5 ml). The mixture was then stirred at r.t. until it became clear soln.
The aq. layer was extracted with CH2Cl2 (3 ꢁ 10 ml), and the combined org. layers were concentrated
in vacuo. Purification of the residue (FC; AcOEt/hexane 2 :98) gave siphonarienal (1; 80%). Color-
less liquid. [a]2D5 ¼ þ15.8 (c ¼ 1.0, CHCl3). IR (KBr): 3447, 2959, 2924, 2871, 2706, 1690, 1644, 1459,
1
1378, 1014, 809. H-NMR (300 MHz, CDCl3): 9.39 (s, 1 H); 6.22 (d, J ¼ 9.8, 1 H); 2.91 – 2.76 (m, 1 H);
1.77 (s, 3 H); 1.53 – 1.25 (m, 4 H); 1.24 – 1.10 (m, 3 H); 1.04 (d, J ¼ 6.7, 3 H); 0.95 – 0.78 (m, 12 H).
13C-NMR (CDCl3, 75 MHz): 195.4; 160.6; 137.93; 45.5; 44.2; 39.2; 31.2; 29.6; 28.2; 20.4; 20.3; 20.0; 19.9;
14.3; 9.3.
(4E,6S,8S,10S)-4,6,8,10-Tetramethyltridec-4-en-3-one (2) [20]. To a stirred soln. of 1 (150 mg,
0.66 mmol) in dry THF was added EtMgBr (0.4 ml of 2m soln.), at ꢀ 788, and the mixture was stirred for
2 h. The reaction was then quenched with sat. NH4Cl, and the mixture was extracted with AcOEt (3 ꢁ
5 ml). The combined org. extracts were washed sequentially with H2O and brine, dried (Na2SO4), and
filtered. Evaporation of the solvent under reduced pressure afforded the diastereoisomer mixture of
allylic alcohol (1:1), which was then dissolved in dry CH2Cl2 (6 ml) and treated with DessꢀMartin
periodinane (450 mg) at 08 for 30 min. The mixture was filtered through a pad of Celite, washed with
CH2Cl2, and the reaction was quenched with sat. aq. NaHCO3 soln. The aq. layer was then extracted with
CH2Cl2 (3 ꢁ 5 ml), and washed with H2O and then brine. The org. extracts were dried (Na2SO4), filtered,
and concentrated in vacuo to furnish the crude product which was then purified by CC (AcOEt/hexane

1976
Helvetica Chimica Acta – Vol. 96 (2013)
2 :98) to yield 2 (90%). [a]2D5 ¼ þ25.2 (c ¼ 1.0, CHCl3). IR (KBr): 3451, 2958, 2925, 2871, 1672, 1639,
1458, 1376, 1256, 1047, 799. 1H-NMR (300 MHz, CDCl3): 6.34 (d, J ¼ 9.2, 1 H); 2.75 – 2.64 (m, 3 H); 1.80
(s, 3 H); 1.54 – 1.15 (m, 10 H); 1.10 (t, J ¼ 7.3, 3 H); 1.05 (d, J ¼ 6.6, 3 H); 0.87 (t, J ¼ 7.3, 3 H); 0.83 (d, J ¼
6.6, 3 H); 0.81 (d, J ¼ 6.6, 3 H). 13C-NMR (CDCl3, 75 MHz): 202.8; 148.2; 135.3; 45.5; 44.4; 39.2; 31.2;
30.3; 29.6; 28.2; 20.6; 20.4; 19.9; 19.9; 14.3; 11.5; 8.9. ESI-MS: 253 ([M þ H]þ).
(2E,4S,6S,8S)-N-Methoxy-N,2,4,6,8-pentamethylundec-2-enamide (17). To a stirred soln. of
4
(300 mg, 1.34 mmol) and Me(MeO)NH · HCl (4.0 g, 4.0 mmol) in anh. THF (10 ml) was added iPrMgCl
(2.68 ml, 5.36 mmol, 2m soln. in THF) at ꢀ 208, and the mixture was stirred for 1 h. Upon completion, the
reaction was quenched with sat. aq. NH4Cl (5 ml), and the mixture was washed with AcOEt (2 ꢁ 5 ml).
The combined org. layers were dried (Na2SO4), concentrated in vacuo, and purified by CC (AcOEt/
hexanes 5 :95) to give 17 (280 mg, 75%). Liquid. [a]D ¼ þ11.1 (c ¼ 1.0, CHCl3). IR (KBr): 3448, 2923,
2855, 1624, 1456, 1219, 769, 668. 1H-NMR (300 MHz, CDCl3): 5.44 (d, J ¼ 10.3, 1 H); 3.38 (s, 3 H); 2.69 –
2.54 (m, 1 H); 1.88 (s, 3 H); 1.55 – 0.93 (m, 14 H); 0.99 (d, J ¼ 6.7, 3 H); 0.88 (t, J ¼ 6.7, 2 H); 0.86 (d, J ¼
6.7, 3 H); 0.82 (d, J ¼ 6.7, 3 H). 13C-NMR (75 MHz, CDCl3): 168.7; 141.7; 126.5; 45.6; 44.4; 39.1; 37.8; 30.2;
29.6; 29.5; 28.2; 28.8; 20.2; 20.1; 19.9; 14.3; 13.9. ESI-MS: 284 ([M þ H]þ).
4-Hydroxy-3,5-dimethyl-6-[(2E,4S,6S,8S)-4,6,8-trimethylundec-2-en-2-yl]-2H-pyran-2-one (3) [22].
To a freshly prepared 1.0m soln. of LDA (1.20 ml) in anh. THF at ꢀ 208 was added a soln. of 17 (150 mg,
0.53 mmol) in anh. THF (5 ml) dropwise, and the mixture was stirred for 30 min at 08. To this mixture, a
soln. of 18 (252 mg, 1.59 mmol) in anh. THF (5 ml) was added dropwise at 08, the resulting mixture was
stirred for another 30 min at the same temp. After completion, the reaction was quenched with sat. aq.
NH4Cl (6 ml) at 08, and the mixture was allowed to warm to r.t. The aq. layer was separated and washed
with AcOEt (2 ꢁ 5 ml). The combined org. layers were dried (Na2SO4) and concentrated in vacuo to
afford crude 19 (415 mg) as a liquid. Without further purification, the compound 19 was treated with
DBU (1.0 ml, 6.811 mmol) in anh. toluene under reflux for 4 h. The solvent was removed under reduced
pressure, then the residue was diluted with CH2Cl2 (10 ml) and washed with H2O (3 ml). The aq. layer
was again washed with CH2Cl2 (2 ꢁ 10 ml). The combined org. layers were dried (Na2SO4) , concentrated
in vacuo, and purified by CC (AcOEt/hexane 1:4) to give 3. Solid. M.p. 126 – 1288. [a]D ¼ þ58 (c ¼ 0.2,
CHCl3). IR (KBr): 3201, 2923, 2858, 1655, 1455, 1375, 1226, 755. 1H-NMR (300 MHz, CDCl3): 5.37 – 5.32
(m, 1 H); 2.68 – 2.58 (m, 1 H); 2.03 (s, 3 H); 1.97 (s, 3 H); 1.86 (s, 3 H); 1.52 – 1.42 (m, 2 H); 1.40 – 1.01 (m,
8 H); 0.91 (t, J ¼ 6.4, 3 H); 0.86 (d, J ¼ 6.0, 3 H); 0.85 (d, J ¼ 6.0, 3 H); 0.80 (d, J ¼ 6.4, 3 H). 13C-NMR
(CDCl3, 75 MHz): 165.2; 164.5; 159.6; 146.9; 126.2; 105.4; 98.7; 45.9; 44.8; 39.4; 30.6; 29.5; 28.3; 21.4;
20.2; 20.1; 20.0; 14.8; 14.4; 11.5; 8.5. ESI-MS: 352 ([M þ NH4]þ).
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Received January 17, 2013