Enantioselective synthesis of (3R,4E)-19-methylicos-4-en-1-yn-3-ol, a bioactive metabolite of the marine sponge Cribrochalina vasculum

Article abstract of DOI:10.1016/S0957-4166(99)00251-7

The first stereoselective synthesis of (3R,4E)-19-methylicos-4-en-1-yn- 3-ol, an immunosuppressive and antitumoral metabolite isolated from the Caribbean sponge Cribrochalina vasculum, has been achieved and its stereostructure has been confirmed. The key step of the synthesis involves a borane-mediated reduction of the parent (E)- 19-methyl-1-trimethylsilylicos- 4-en-1-yn-3-one in the presence of a chiral oxazaborolidine.

Full text of DOI:10.1016/S0957-4166(99)00251-7

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2617–2626
Enantioselective synthesis of (3R,4E)-19-methylicos-4-en-1-yn-
3-ol, a bioactive metabolite of the marine sponge Cribrochalina
vasculum
Jordi Garcia,∗ Marta López and Joan Romeu
Departament de Química Orgànica, Div. III, Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain
Received 26 May 1999; accepted 17 June 1999
Abstract
The first stereoselective synthesis of (3R,4E)-19-methylicos-4-en-1-yn-3-ol, an immunosuppressive and anti-
tumoral metabolite isolated from the Caribbean sponge Cribrochalina vasculum, has been achieved and its
stereostructure has been confirmed. The key step of the synthesis involves a borane-mediated reduction of the
parent (E)-19-methyl-1-trimethylsilylicos-4-en-1-yn-3-one in the presence of a chiral oxazaborolidine. © 1999
Elsevier Science Ltd. All rights reserved.
1. Introduction
Marine sponges are rich sources of long-chain acetylenic metabolites.1 Many of these compounds,
frequently isolated from sponges of the genera Siphonochaline,2 Petrosia,3–10 Cribrochalina,11,12
Xestospongia,13 Pellina14 and Haliclona,15 show a variety of interesting biological activities (antimicro-
bial, antitumoral, enzyme inhibitory) as well as important ecological roles.16 Recently, some acetylenic
alcohols (1–5, Fig. 1) which exhibit remarkable immunosuppressive and antitumoral activities, were
isolated in minute amounts from samples of the sponge Cribrochalina vasculum collected by Gunasekera
et al.11 in Belize and also by Aiello et al.12 near the Bahamas Islands. From a structural point of view,
these compounds possess unsaturated, long-chain backbones with a characteristic, terminal 4-alkene-1-
yn-3-ol moiety. As far as the stereochemistry is concerned, Aiello et al.12 assigned the configuration at
C-3 of these compounds as R based on the CD spectra of the corresponding p-bromobenzoate derivatives.
However, Hallock et al.17 suggested that some acetylenic alcohols from C. vasculum collected at the
Bahamas coast at much greater depths, including (+)-1, had the S configuration using the modified
Mosher’s NMR method; since they obtained a CD spectrum opposite in sign to that previously reported
∗
Corresponding author. E-mail: jgg@gsaa1.qo.ub.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00251-7

2618
J. Garcia et al. / Tetrahedron: Asymmetry 10 (1999) 2617–2626
Figure 1.
by Aiello et al.,12 it was concluded that these metabolites can present either R or S configurations
depending on the origin of the collection of C. vasculum.
Although these natural products appear to be attractive synthetic targets owing to their structural
novelty and the strong bioactivity displayed, only a few stereoselective approaches to this kind of product
have been very recently reported in which sugars are used as chiral pool starting materials,17 or the
stereocenters arise from an enzymatic resolution.18–20
In the context of studies directed toward the synthesis of marine natural products,21,22 we wish to
report herein the first stereoselective synthesis of (3R,4E)-19-methylicos-4-en-1-yn-3-ol, (R)-1, based
on the stereoselective reduction of the parent (E)-19-methyl-1-trimethylsilylicos-4-en-1-yn-3-one, 6. As
a result, the stereochemistry proposed by Hallock et al.17 for natural compound 1 has eventually been
confirmed.
2. Results and discussion
In our retrosynthetic analysis, compound 1 could arise from ketone 6 which, in turn, can be obtained
from the α,β-unsaturated acid chloride 7 and bis(trimethylsilyl)acetylene by a Friedel–Crafts process.
Compound 7, as outlined in Scheme 1, could be further disconnected into three readily available
fragments.
Scheme 1.
The synthesis of ketone 6 is summarised in Scheme 2. 12-Bromododecan-1-ol, easily obtained from
dodecane-1,12-diol as described in the literature,23 was protected as its O-benzyl derivative 9 and was
then heated under nitrogen with triphenylphosphine to obtain the phosphonium salt 10 as a viscous oil.
Treatment of 10 with BuLi, followed by addition of 3-methybutanal gave an olefin mixture, with the
Z-isomer as the major product, which was hydrogenated without further purification to obtain saturated
alcohol 11. Swern oxidation of 11 followed by treatment of the resulting aldehyde with Ph3P=CHCO2Et
1
afforded (E)-α,β-unsaturated ester 13 in an E/Z ratio >30:1 according to the H NMR spectrum of
the crude product. Hydrolysis of ester 13 was accomplished with LiOH in refluxing dioxane:H2O (3:1)
overnight, which gave the unsaturated acid 14. Finally, ketone 6 was readily obtained by transformation of
14 into its corresponding acid chloride followed by reaction of the crude product with Me3SiC^CSiMe3
in the presence of AlCl3.
Taking advantage of our previous experience of the enantioselective reduction of α,β-unsaturated
ketones using chiral oxazaborolidines,21,22,24,25 we assumed that treatment of 6 with BH3:SMe2 in the

J. Garcia et al. / Tetrahedron: Asymmetry 10 (1999) 2617–2626
2619
Scheme 2. (i) PhCH2Br, NaH, Et2O, reflux; (ii) PPh3, 120°C, neat; (iii) BuLi, THF, 0°C and then (CH3)2CHCH2CHO; (iv) H2,
Pd/C, MeOH, rt; (v) Swern oxidn; (vi) Ph3P_CHCO2Et, CH2Cl2, rt; (vii) LiOH, dioxane:H2O, 3:1, reflux; (viii) (COCl)2, DMF
cat., hexane; (ix) Me3SiC^CSiMe3, AlCl3, CH2Cl2, −20°C
presence of oxazaborolidines (R)-15a or (R)-15b would lead to the 1-trimethylsilyl-4-alken-1-yn-3-
ol with the proper R configuration at C-3. In order to assess this assumption, reduction of the easily
obtained (E)-1-trimethylsilyl-4-octen-1-yn-3-one, 16, was first attempted since its derived chiral alcohol
is known.19b As expected, 16 was efficiently transformed into (R)-17 with BH3:SMe2 in the presence of 1
equiv. of either (R)-15a or (R)-15b (85–90% yield, 95% e.e.) in a few minutes.22 As shown in Scheme 3,
the configuration at C-3 in alcohol 17 was determined by comparison of its specific rotation, as well as
the specific rotation of the 3-octanol derivative arising from 17, with those described in the literature.
It is noteworthy that long reaction times led to poorer chemical yields by concomitant side reactions,
mainly hydroboration, of the alcohol first formed. Similarly, when only 0.2 equiv. of 15 were used the
reaction became slower and the chemical yield also dropped. On the other hand, reduction of 16 with
(−)-Alpine-Borane® proved to be as efficient as with 15 (93% yield, 92% e.e.) but longer reaction times
were required.26
Scheme 3. (i) BH3:SMe2, (R)-15, THF, 0°C, 10 min (85−90%, 95% e.e.); (ii) (R)-Alpine-Borane®, neat, overnight (93%, 92%
e.e.); (iii) K2CO3, MeOH, t.a., 1 h; (iv) H2, Pt/C cat., MeOH (82% overall yield)
As far as the stereochemical course of the reaction is concerned, the observed configuration of
alcohol 17 arising from reduction with oxazaborolidines was that expected according to the mechanism
proposed by Corey et al.27 for similar processes, by an arrangement such as 19 in which the double bond
moiety — acting as a bigger group than C^CSiMe3 — is located far from the Me group on the boron atom
(see Fig. 2). In a similar way, the stereochemical course of the reduction of 16 with Alpine-Borane® can
be explained through a transition state such as 20 where the ethylene moiety also acts as a group ‘larger’
than the acetylenic one.

2620
J. Garcia et al. / Tetrahedron: Asymmetry 10 (1999) 2617–2626
Figure 2.
Finally, we turned our attention to the synthesis of (+)-1. Reduction of ketone 6 was performed with
BH3:SMe2 and (R)-15b to afford (R)-21 (90% yield, 94% e.e.), which was easily desilylated by treatment
with K2CO3 in MeOH/H2O to obtain the desired unsaturated alcohol (−)-(R)-1 (Scheme 4).
Scheme 4. (i) BH3:SMe2, (R)-15, THF, 0°C, 10 min (90%); (ii) K2CO3, MeOH, t.a., 1 h (82%)
3. Conclusions
In conclusion, we have disclosed an efficient approach to highly enantioenriched 4-alken-1-yn-
3-ol moiety, present in many acetylenic metabolites isolated from sponges, which is based on the
enantioselective reduction of the parent 1-trimethylsilyl-4-alken-1-yn-3-one followed by desilylation of
the resulting alcohol. This strategy, obviously amenable to obtain either R or S enantiomers, has been
applied to the first enantioselective synthesis of (3R,4E)-19-methylicos-4-en-1-yn-3-ol, (−)-(R)-1, an
immunosuppressive and antitumoral acetylenic alcohol isolated from samples of the sponge C. vasculum.
It is also worth noting that the correlation between the absolute configuration and the specific rotation
determined in the present work confirm the S configuration proposed by Hallock et al. for samples of
natural dextrorotatory 1.
4. Experimental
All the solvents were distilled from an appropriate drying agent and stored under nitrogen atmosphere.
The crude products were purified by column chromatography on silica gel of 230–400 mesh (flash
chromatography). Thin-layer chromatograms were performed on HF 254 silica gel plates (using the
1
eluents indicated after the Rf values). Melting points are uncorrected. H and 13C NMR spectra were
obtained in CDCl3 at 200 MHz and 50.3 MHz, respectively; chemical shifts are given in ppm with respect
to internal TMS, and J values are quoted in hertz. Infrared spectra were measured on a Perkin–Elmer
681 on NaCl plates (film) or in KBr; only the most significant absorptions, in cm−1, are indicated.
Microanalyses were performed by the Serveis Científico-Tècnics (Universitat de Barcelona). Chemical
ionisation mass spectra (NH3) are given in m/z. Oxazaborolidines 15a28 and 15b25 were prepared
according to published procedures.

J. Garcia et al. / Tetrahedron: Asymmetry 10 (1999) 2617–2626
2621
4.1. Benzyl 12-bromododecyl ether 929
A solution of 1.75 g (6.57 mmol) of alcohol 8 in 5 mL of dry diethyl ether were carefully added via
cannula to a suspension of NaH (375 mg of 60% dispersion in mineral oil, 9.7 mmol), previously washed
with dry hexane, in 5 mL of dry diethyl ether. The mixture was heated at reflux for 45 min and then
allowed to cool to room temperature. Afterwards, 1.12 mL (9.4 mmol) of neat benzyl bromide were
added dropwise and the resulting suspension was stirred at room temperature. Twenty-four hours later,
TLC showed that the starting alcohol 8 had almost disappeared and the reaction mixture was poured into
diethyl ether and H2O. The organic layer was separated and washed with brine. After drying (Na2SO4),
the solvent was eliminated in vacuo and the crude product was purified by flash chromatography (2:1,
hexane:CH2Cl2) to yield 2.052 g (88%) of 9. Colourless oil. Rf 0.30 (1:2, hexane:CH2Cl2); 1H NMR δ
1.27 (m, 16H), 1.60 (m, 2H), 1.86 (m, 2H), 3.40 (t, 2H, J=6.6 Hz), 3.46 (t, 2H, J=6.6 Hz), 4.50 (s, 2H),
7.30–7.40 (m, 5H); 13C NMR δ 26.2, 28.2, 28.7, 29.5, 29.6, 32.8, 34.1, 70.5, 72.8, 127.4, 128.3, 129.0,
137.0; IR (film) 2900, 2820, 1440, 1100.
4.2. (12-Benzyloxidodecyl)triphenylphosphonium bromide 10
A mixture of 170 mg (0.48 mmol) of 9 and 138 mg (0.53 mmol) of triphenylphosphine was heated in an
oil bath at 120°C under N2. The melt mixture was magnetically stirred for 3 h and then it was allowed to
cool to room temperature. The crude product was purified by flash chromatography (9:1, CH2Cl2:MeOH)
to afford 281 mg (95%) of phosphonium salt 10 as a thick oil. Rf 0.30 (9:1, CH2Cl2:MeOH); 1H NMR
δ 1.20 (m, 16H), 1.50–1.60 (m, 4H), 3.40 (t, 2H, J=6.6 Hz), 3.80 (m, 2H), 4.50 (s, 2H), 7.08–7.40 (m,
5H), 7.60–7.85 (m, 15H); 13C NMR δ 22.3 (d, JCP=52 Hz), 22.8, 25.6, 28.6, 28.9, 29.1, 29.7, 30.0,
30.9 (d, JCP=16 Hz), 69.9, 72.2, 117.6 (d, JCP=86 Hz), 126.9, 127.7, 128.5, 130.0 (d, JCP=12.4 Hz),
133.1 (d, JCP=9.8 Hz), 134.8 (d, JCP=2.9 Hz), 138.1; IR (KBr) 3000, 2760, 1440, 1100. Anal. calcd for
C37H46BrOP: C, 71.95; H, 7.51. Found: C, 71.71; H, 7.34.
4.3. 15-Methylhexadecan-1-ol 11
To a magnetically stirred mixture of 444 mg (0.72 mmol) of phosphonium salt 10 in 10 mL of dry
THF, 0.63 mL (1.0 mmol) of BuLi in hexanes were added dropwise at 0°C under N2. After 45 min, 3-
methybutanal (110 µL, 1.0 mmol) was added to the resulting red solution and the stirring was continued
for a further 2 h at room temperature. The progress of the reaction was monitored by TLC. Work-up was
done at 0°C by addition of 5 mL of saturated aqueous NH4Cl. The reaction mixture was diluted with
CH2Cl2 (25 mL) and washed with brine (5 mL). The organic layer was dried (MgSO4) and concentrated
to afford a crude product which was hydrogenated without further purification. To a solution of the crude
product in MeOH (25 mL), 230 mg of 5% Pt/C were added, and the suspension was shaken under 1 atm
of hydrogen. After 6 h, the mixture was filtered through a pad of Celite®. The solvent was eliminated
in vacuo and the residue was purified by flash chromatography on silica gel (CH2Cl2) to yield 136 mg
(74% overall yield) of 11: mp 42–44°C; Rf 0.20 (CH2Cl2); 1H NMR δ 0.86 (d, 6H, J=6.6 Hz), 1.20–1.45
(m, 24H), 1.53 (m, 3H), 2.05 (bs, 1H), 3.63 (t, 2H, J=6.6 Hz); 13C NMR δ 22.6, 25.7, 27.4, 27.9, 29.5,
29.6, 29.7, 29.9, 32.7, 39.0, 62.8; IR (KBr) 3360, 2920, 2840, 1460. Anal. calcd for C17H36O: C, 79.61;
H, 14.15. Found: C, 79.88; H, 14.10.

2622
J. Garcia et al. / Tetrahedron: Asymmetry 10 (1999) 2617–2626
4.4. 15-Methylhexadecanal 12
DMSO (110 µL, 1.55 mmol) was added slowly to a solution of oxalyl chloride (70 µL, 0.80 mmol)
in 2 mL of anh. CH2Cl2 at −40°C under Ar. After 10 min at this temperature, a solution of alcohol
11 (164 mg, 0.64 mmol) in 1 mL of anh. CH2Cl2 was added dropwise and the solution was stirred for
45 min. Afterwards, 418 µL (3.0 mmol) of Et3N were added and the mixture was stirred for a further
15 min and then it was allowed to warm to room temperature. The suspension was poured into 130
mL of Et2O:hexane (1:4) and 50 mL of saturated aqueous NaHCO3. The organic layer was washed
with brine, dried (MgSO4), and the solvent was eliminated in vacuo. The residue was purified by flash
chromatography (CH2Cl2) to afford 153 mg (94%) of aldehyde 12: mp 36–37°C; Rf 0.65 (CH2Cl2); 1H
NMR δ 0.86 (d, 6H, J=6.6 Hz), 1.20–1.45 (m, 22H), 1.53 (m, 1H), 1.63 (m, 2H), 2.42 (td, 2H, J=7.4, 1.8
Hz), 9.77 (t, 1H, J=1.8 Hz); 13C NMR δ 22.6, 27.4, 28.0, 29.3, 29.5, 29.6, 29.7, 29.8, 29.9, 39.0, 43.9,
202.9; IR (KBr) 2920, 2840, 1730. Anal. calcd for C17H34O: C, 80.24; H, 13.47. Found: C, 80.01; H,
13.63.
4.5. Ethyl (E)-17-methyl-2-octadecenoate 13
A solution of 153 mg (0.60 mmol) of 12 and 251 mg (0.72 mmol) of ethyl(triphenylphosphoranyl-
idene)acetate (previously dried at 50°C under vacuum for 2 days) in 1 mL of anh. CH2Cl2 was stirred at
room temperature under N2. The progress of the reaction was monitored by TLC. When full conversion
of starting 12 was obtained (14 h), the solvent was removed and the crude product was purified by
flash chromatography (CH2Cl2) to obtain 185 mg (95%) of unsaturated ester 13. Colourless oil. Rf 0.72
(CH2Cl2); 1H NMR δ 0.86 (d, 6H, J=6.6 Hz), 1.20–1.45 (m, 22H), 1.50 (m, 3H), 2.19 (dtd, 2H, J=7.0,
6.6, 1.6 Hz), 4.18 (q, 2H, J=7.2 Hz), 5.81 (dt, 1H, J=15.8, 1.6 Hz), 6.97 (dt, 1H, J=15.8, 7.0 Hz); 13C
NMR δ 14.3, 22.6, 27.4, 27.9, 28.0, 29.1, 29.4, 29.5, 29.7, 29.9, 32.2, 39.1, 60.1, 121.2, 149.5, 166.7; IR
(film) 2900, 2820, 1720, 1650. Anal. calcd for C21H40O2: C, 77.72; H, 12.42. Found: C, 77.96; H, 12.40.
4.6. (E)-17-Methyl-2-octadecenoic acid 14
A solution of 185 mg (0.57 mmol) of ester 13 and 41 mg (1.71 mmol) of LiOH in 3 mL of dioxane
and 1 mL of water was heated to reflux overnight. The solution was allowed to cool to room temperature
and 2 M HCl was then added until the mixture reached pH 1. Afterwards, the mixture was extracted
with CH2Cl2 (2×50 mL) and AcOEt (2×50 mL). The organic layers were washed with 0.2 M HCl (10
mL). After drying (Na2SO4), the solvent was eliminated in vacuo and the crude product was purified by
flash chromatography (98:2, CH2Cl2:MeOH) to yield 150 mg (89%) of 14: mp 58–59°C; Rf 0.55 (9:1,
1
CH2Cl2:MeOH); H NMR δ 0.86 (d, 6H, J=6.6 Hz), 1.20–1.45 (m, 22H), 1.50 (m, 3H), 2.22 (dt, 2H,
J=7.0, 6.8 Hz), 5.82 (dt, 1H, J=15.8, 1.6 Hz), 7.08 (dt, 1H, J=15.8, 7.0 Hz); 13C NMR δ 22.6, 27.6, 27.8,
29.1, 29.3, 29.6, 29.7, 29.9, 32.2, 39.0, 120.2, 153.0, 173.0; IR (KBr) 3300–3000, 2920, 2840, 1690,
1650. Anal. calcd for C19H36O2: C, 76.97; H, 12.24. Found: C, 77.21; H, 12.26.
4.7. (E)-19-Methyl-1-trimethylsilyl-4-icosen-1-yn-3-one 6
Oxalyl chloride (46 µL, 0.52 mmol) was added to 141 mg (0.48 mmol) of acid 14 in 3 mL of anh.
hexane at room temperature. A drop of anh. DMF was added and the mixture was stirred at room
temperature overnight. The volatiles were removed under vacuum. The residue containing the crude acid
chloride and 120 µL (0.53 mmol) of bis(trimethylsilyl)acetylene was dissolved in 1 mL of anh. CH2Cl2

J. Garcia et al. / Tetrahedron: Asymmetry 10 (1999) 2617–2626
2623
and the solution was added dropwise to a suspension of 75 mg (0.56 mmol) AlCl3 in 2 mL of anh.
CH2Cl2 at −20°C. Thirty minutes later the mixture was warmed to 0°C and then stirred for a further 3 h
at this temperature. The reaction was quenched by pouring the mixture into ice and pH 7 phosphate buffer
followed by extractions with CH2Cl2 (2×50 mL). The organic layer was dried over Na2SO4, filtered and
concentrated in vacuo. The crude product was purified by a short flash chromatography (CH2Cl2) to yield
155 mg (87%) of ketone 6 which was used immediately. Pale yellowish oil. Rf 0.64 (CH2Cl2); 1H NMR
δ 0.26 (s, 9H), 0.88 (d, 6H, J=6.6 Hz), 1.20–1.45 (m, 22H), 1.50 (m, 3H), 2.30 (dt, 2H, J=7.0, 6.6 Hz),
6.15 (dt, 1H, J=15.8, 1.4 Hz), 7.20 (dt, 1H, J=15.8, 7.0 Hz); 13C NMR δ −0.7, 22.6, 27.4, 27.9, 28.0,
29.2, 29.3, 29.5, 29.6, 29.9, 32.6, 39.0, 99.0, 102.0, 132.0, 155.0, 179.0; IR (film) 2920, 2840, 2140,
1640. Anal. calcd for C24H44OSi: C, 76.52; H, 11.77. Found: C, 76.29; H, 11.84.
4.8. (E)-1-Trimethylsilyl-4-octen-1-yn-3-one 16
To a stirred solution of 0.83 mL (5.9 mmol) of trimethylsilylacetylene in 10 mL of anh. THF at
−78°C, 3.47 mL (5.0 mmol) of a solution of BuLi in hexanes was added dropwise followed by 0.70
mL (6.0 mmol) of (E)-2-hexenal 10 min later. The reaction mixture was stirred for a further 10 min and
then allowed to warm to room temperature. Then, the mixture was poured into pH 7 phosphate buffer
and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered and
concentrated in vacuo to yield 0.94 g (96%) of crude, almost pure, (ꢀ)-17 by TLC. The crude product
was dissolved in 10 mL of dry hexane and 2.1 g of activated MnO2 were added at once under N2 and the
suspension was stirred at room temperature. The progress of the reaction was monitored by TLC. After
1 h, a further 3.6 g of MnO2 was added and the mixture was stirred overnight. Afterwards, TLC revealed
the disappearance of the starting alkene. Filtration through a pad of Celite® and evaporation of the
solvent gave a crude product which was purified by a short flash chromatography (2:1, CH2Cl2:hexane)
to yield 783 mg (84%) of ketone 16 which was used immediately. Pale yellowish oil. Rf 0.48 (2:1,
1
CH2Cl2:hexane); H NMR δ 0.27 (s, 9H), 0.97 (t, 3H, J=7.3 Hz), 1.55 (m, 2H), 2.29 (m, 2H), 6.16 (dt,
1H, J=15.6, 1.5 Hz), 7.20 (dt, 1H, J=15.6, 6.8 Hz); 13C NMR δ −0.7, 13.6, 21.1, 34.5, 98.0, 100.3, 132.1,
154.6, 178.2; IR (film) 2960, 2160, 1640. Anal. calcd for C11H18OSi: C, 67.98; H, 9.33. Found: C, 68.26;
H, 9.51. MS (CI) m/z (rel. int. %): 195 (M++1, 100%).
4.9. Reduction of ketone 16 with BH3:SME2 catalysed by (R)-15a
A solution of 16 (155 mg, 0.80 mmol) in THF (1 mL) was added dropwise in ∼10 min to a
solution of (R)-15a (0.80 mmol) and BH3:SMe2 (91 µL, 0.91 mmol) in THF (3 mL) at 0°C under Ar.
Upon completion of the addition, TLC revealed the disappearance of the starting ketone. Reaction was
cautiously quenched by slow addition of MeOH (1 mL) at 0°C. The solution was stirred for 15 min at
room temperature and the volatiles were then removed under vacuum. The residue was purified by flash
chromatography (1:1, CH2Cl2:hexane) to yield 134 mg (85%) of alcohol (R)-17. Colourless oil; Rf 0.33
(2:1, CH2Cl2:hexane); [α]20 −39.5 (c 2, CHCl3), [lit.19b [α]20 +38.5 (c 1, CHCl3) for isomer 3S]; H
1
D
D
NMR δ 0.23 (s, 9H), 0.92 (t, 3H, J=7.2 Hz), 1.34–1.55 (m, 2H), 2.05 (m, 2H), 4.83 (m, 1H), 5.59 (ddt,
1H, J=15.3, 6.2, 1.4 Hz), 5.89 (dtd, 1H, J=15.3, 6.6, 1.0 Hz); 13C NMR δ −0.2, 13.6, 22.0, 34.0, 63.3,
90.4, 105.0, 128.8, 133.8; IR (film) 3320, 2940, 2160, 1670. MS (CI) m/z (rel. int. %): 196 (M+, 100%),
197 (M++1, 19%). An analytical sample of the crude product was treated with an excess of (S)-Mosher
acid chloride (derived from (R)-acid) to give the Mosher ester. The analysis by GC (Supelco Beta-DEX®)
120 capillary column, 130°C, tR (S)=13.44 min, tR (R)=14.01 min) as well as by 19F NMR revealed a
95% e.e.

2624
J. Garcia et al. / Tetrahedron: Asymmetry 10 (1999) 2617–2626
4.10. Reduction of ketone 16 with BH3:SME2 catalysed by (R)-15b
The reaction was performed as described above for (R)-15a to yield (R)-17 in 90% yield and 95% e.e.
4.11. Reduction of ketone 16 with Alpine-Borane®
A commercial 0.5 M solution of (R)-Alpine-Borane® (5.2 mL, 2.60 mmol) in THF was placed in
a round-bottom flask provided with a magnetic bar and the solvent was removed under vacuum in a
vacuum manifold. The flask was then refilled with N2, cooled in an ice bath and 181 mg (0.93 mmol) of
neat ketone 16 were added dropwise. After 15 h, TLC revealed the disappearance of the starting ketone.
To the crude product, 0.8 mL (14.3 mmol) of acetaldehyde in 2 mL of dry THF were added and the
mixture was stirred at room temperature for 6 h before removing the solvents in vacuo. The residue was
stirred with 0.10 mL of 2-aminoethanol in 2 mL of Et2O. After 1 h, the precipitate was removed by
filtration and washed with more diethyl ether. The organic layers were dried (MgSO4) and concentrated
in vacuo. Flash chromatography (1:2, CH2Cl2:hexane) yielded 169 mg (93%) of (R)-17. The analysis of
an analytical sample by 19F NMR of the corresponding Mosher ester revealed a 92% e.e.
4.12. (S)-3-Octanol (S)-1826
To a solution of 120 mg (0.62 mmol) of (R)-17 (95% e.e.) in 4 mL of MeOH:H2O (10:1), K2CO3 (170
mg, 1.23 mmol) was added and the mixture was stirred at room temperature. The progress of the reaction
was monitored by TLC (CH2Cl2, appearance of spot at Rf 0.29). When the reaction was completed (45
min), the mixture was poured into pH 7 phosphate buffer (8 mL) and extracted with CH2Cl2 (3×25 mL).
The organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was dissolved in 30
mL of MeOH, 50 mg of 5% Pt/C was added, and the suspension was shaken under 50 atm of hydrogen
for 3 h. Afterwards, the mixture was filtered through a pad of Celite®. The solvent was eliminated in
vacuo and the residue was purified by flash chromatography through a short path of silica gel (9:1,
CH2Cl2:AcOEt) to yield 66 mg (82%) of (S)-18, which was compared to a sample of commercial (ꢀ)-
3-octanol. Rf 0.63 (9:1, CH2Cl2:AcOEt); [α]20 +11.5 (c 0.6, Et2O) [lit.26 [α]20 +12.9 (c 6, Et2O) for
D
D
isomer 3S]; 1H NMR δ 0.79–1.00 (m, 6H), 1.20–1.60 (m, 10H), 1.72 (bs, 1H), 3.55 (m, 1H); 13C NMR
δ 9.9, 14.1, 22.7, 25.5, 30.2, 32.0, 36.1, 73.3.
4.13. Reduction of ketone 6 with BH3:SME2 catalysed by (R)-15b
A solution of 6 (78 mg, 0.21 mmol) in THF (1 mL) was added dropwise in ∼10 min to a solution of (R)-
15b (0.20 mmol) and BH3:SMe2 (30 µL, 0.30 mmol) in THF (2 mL) at 0°C under Ar. Upon completion
of the addition, TLC revealed the disappearance of the starting ketone. Reaction was cautiously quenched
by slow addition of MeOH (0.1 mL) at 0°C. The solution was stirred for 10 min at room temperature
and the volatiles were then removed under vacuum. The residue was purified by flash chromatography
(2:1, CH2Cl2:hexane) to afford 71 mg (90%) of (3R,4E)-19-methyl-1-trimethylsilyl-4-icosen-1-yn-3-ol,
(R)-21. Colourless oil; Rf 0.56 (CH2Cl2); [α]20 −23.3 (c 1, MeOH); 1H NMR δ 0.19 (s, 9H), 0.88 (d,
D
6H, J=6.6 Hz), 1.20–1.45 (m, 22H), 1.50 (m, 3H), 2.08 (dt, 2H, J=6.6, 6.6 Hz), 4.83 (dd, 1H, J=6.0, 1.2
Hz), 5.60 (dd, 1H, J=15.4, 6.0 Hz), 5.90 (dtd, 1H, J=15.4, 6.6, 1.2 Hz); 13C NMR δ −0.1, 22.8 27.6,
28.1, 29.0, 29.4, 29.6, 29.8, 30.1, 32.1, 39.2, 63.5, 90.6, 105.2, 128.8, 134.4; IR (film) 3340, 2940, 2860,
2200. Anal. calcd for C24H46OSi: C, 76.12; H, 12.24. Found: C, 76.22; H, 11.98. An analytical sample

J. Garcia et al. / Tetrahedron: Asymmetry 10 (1999) 2617–2626
2625
of the crude product was treated with an excess of (S)-Mosher acid chloride (derived from (R)-acid) to
give the Mosher ester. The analysis by 19F NMR revealed a 94% e.e.
4.14. (3R,4E)-19-Methyl-4-icosen-1-yn-3-ol (R)-1
A mixture of 48 mg (0.13 mmol) of (R)-21, 35 mg (0.26 mmol) of K2CO3, 2 mL of MeOH and
two drops of water was stirred at room temperature. The progress of the reaction was monitored by
TLC. When the reaction was completed (1 h), the mixture was poured onto a pH 7 phosphate buffer and
extracted with CH2Cl2 (3×25 mL). The organic layer was washed with brine, dried over Na2SO4, filtered
and concentrated in vacuo. The crude product was purified by a short flash chromatography (CH2Cl2) to
yield 33 mg (82%) of (R)-1: mp 35–37°C; Rf 0.42 (CH2Cl2); [α]20 −20.5 (c 1.1, MeOH) [lit.17 [α]20
D
D
+22.2 (c 0.58, MeOH) for isomer 3S]; 1H NMR δ 0.89 (d, 6H, J=6.6 Hz), 1.20–1.35 (m, 22H), 1.43 (m,
2H), 1.55 (m, 1H), 2.11 (dt, 2H, J=6.9, 6.9 Hz), 2.61 (d 1H, J=2.1 Hz), 4.88 (m, 1H), 5.65 (ddt, 1H,
J=15.3, 6.0, 1.4 Hz), 5.96 (dtd, 1H, J=15.3, 6.9, 1.2 Hz); 13C NMR δ 22.7, 27.4, 28.0, 28.8, 29.2, 29.5,
29.6, 29.7, 29.9, 31.9, 39.0, 62.8, 73.9, 83.3, 128.3, 134.6; IR (film) 3260, 2920, 2840, 2120.
Acknowledgements
Financial support from the DGICYT, Ministerio de Educación y Cultura (Grant PM95-0061), and from
the Direcció General de Recerca, Generalitat de Catalunya (1996SGR 00102), is gratefully acknowled-
ged. A doctorate studentship from the Universitat de Barcelona to M.L. is also acknowledged. Thanks
are due to Prof. J. Vilarrasa for reading the manuscript.
References
1. (a) Faulkner, D. J. Nat. Prod. Rep. 1997, 14, 259–299, and references cited therein. (b) Higa, T.; Tanaka, J.; Kitamura, A.;
Koyama, T.; Takahashi, M.; Uchida, T. Pure & Appl. Chem. 1994, 66, 2227–2230.
2. Fusetani, N.; Sugano, M.; Matsunaga, S.; Hashimoto, K. Tetrahedron Lett. 1987, 28, 4311–4312.
3. Fusetani, N.; Kato, Y.; Matsunaga, S.; Hashimoto, K. Tetrahedron Lett. 1983, 24, 2771–2774.
4. Cimino, G.; De Giulio, A.; De Rosa, S.; De Stefano, S.; Sodano, G. J. Nat. Prod. 1985, 48, 22–27.
5. Fusetani, N.; Shiragaki, T.; Matsunaga, S.; Hashimoto, K. Tetrahedron Lett. 1987, 28, 4313–4314.
6. Isaacs, S.; Kashman, Y.; Loya, S.; Hizi, A.; Loya, Y. Tetrahedron 1993, 45, 10435–10438.
7. Ochi, M.; Ariki, S.; Tatsukawa, A.; Kotsuki, H.; Fukuyama, Y.; Shibata, K. Chem. Lett. 1994, 89–92.
8. Seo, Y.; Cho, K. W.; Rho, J.-R.; Shin, J. Tetrahedron 1998, 54, 447–462.
9. Kim, J. S.; Im, K. S.; Jung, J. H.; Kim, Y.-L.; Kim, J.; Shim, C. J.; Lee, C.-O. Tetrahedron 1998, 54, 3151–3158.
10. Guerriero, A.; Debitus, C.; Laurent, D.; D’Ambrosio, M.; Pietra, F. Tetrahedron Lett. 1998, 39, 6395–6398.
11. Gunasekera, S. P.; Faircloth, G. T. J. Org. Chem. 1990, 55, 6223–6225.
12. Aiello, A.; Fattorusso, E.; Menna, M. J. Nat. Prod. 1992, 55, 1275–1280.
13. Quinoa, E.; Crews, P. Tetrahedron Lett. 1988, 29, 2037–2040.
14. Fu, X.; Abbas, S. A.; Schmitz, F. J.; Vidavsky, I.; Groaa, M. L.; Laney, M.; Schatzman, R. C.; Cabuslay, R. D. Tetrahedron
1997, 53, 799–814.
15. Shin, J.; Seo, Y.; Cho, K. W.; Rho, J.-R.; Paul, V. J. Tetrahedron 1998, 54, 8711–8720.
16. Tsukamoto, S.; Kato, H.; Hirota, H.; Fusetani, N. J. Nat. Prod. 1997, 60, 126–130.
17. Hallock, Y. F.; Cardellina II, J. H.; Balaschak, M. R.; Alexander, M. R.; Prather, T. R.; Shoemaker, R. H.; Boyd, M. R. J.
Nat. Prod. 1995, 58, 1801–1807.
18. Lu, W.; Zheng, G.; Cai, J. Tetrahedron 1999, 55, 4649–4654. For a related synthesis, see: Iguchi, K.; Kitade, M.;
Kashiwagi, T.; Yamada, Y. J. Org. Chem. 1993, 58, 5690–5698.

2626
J. Garcia et al. / Tetrahedron: Asymmetry 10 (1999) 2617–2626
19. (a) Ohtani, T.; Kikuchi, K.; Kamezawa, M.; Hamatani, H.; Tachibana, H.; Totani, T.; Naoshima, Y. J. Chem. Soc., Perkin
Trans. 1 1996, 961–962. (b) Morishita, K.; Kamezawa, M.; Ohtani, T.; Tachibana, H.; Kawase, M.; Kishimoto, M.;
Naoshima, Y. J. Chem. Soc., Perkin Trans. 1 1999, 513–518.
20. Sharma, A.; Chattopadhyay, S. J. Org. Chem. 1998, 63, 6128–6131. For a related resolution, see: Allevi, P.; Ciuffreda, P.;
Anastasia, M. Tetrahedron: Asymmetry 1997, 8, 93–99.
21. (a) Bach, J.; Berenguer, R.; Garcia, J.; Vilarrasa, J. Tetrahedron Lett. 1995, 36, 3425–3428. (b) Bach, J.; Garcia, J.
Tetrahedron Lett. 1998, 39, 6761–6764.
22. Garcia, J.; López, M.; Romeu, J. Synlett 1999, 429–431.
23. Kang, S. K.; Kim, W. S.; Moon, B. H. Synthesis 1985, 1161–1162.
24. Reduction of α,β-alkenones: (a) Bach, J.; Berenguer, R.; Farràs, J.; Garcia, J.; Meseguer, J.; Vilarrasa, J. Tetrahedron:
Asymmetry 1995, 6, 2683–2686. (b) Bach, J.; Berenguer, R.; Garcia, J.; López, M.; Manzanal, J.; Vilarrasa, J. Tetrahedron
1998, 54, 14947–14962.
25. Reduction of α,β-alkynones: Bach, J.; Berenguer, R.; Garcia, J.; Loscertales, T.; Vilarrasa, J. J. Org. Chem. 1996, 61,
9021–9025.
26. Brown, H. C.; Pai, G. G. J. Org. Chem. 1985, 50, 1384–1394. The reduction of a sample of (Z)-5-alken-2-yn-4-one with
Alpine-Borane® has been reported: Midland, M. M. Chem. Rev. 1989, 89, 1553–1561.
27. For a review on proline-derived oxazaborolidines, see: Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. Engl. 1998, 37,
1986–2012. For a review on oxazaborolidine-mediated reductions, see: Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry
1992, 3, 1475–1504.
28. Mathre, J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.; Reamer, R. A.; Mohan, J. J.; Jones, E. T.; Hoogsteen, K.; Baum,
M. W.; Grabowski, E. J. J. Org. Chem. 1991, 56, 751–762.
29. Teuber, A.; Gerlach, H. Liebigs Ann. Chem. 1993, 161–165.