Asymmetric synthesis of the (2S,4S,6S)-2,4,6-trimethylnonyl subunit of siphonarienes

Article abstract of DOI:10.1560/y4cf-ym5a-n6fe-qbwf

The paper describes an asymmetric approach to the synthesis of the (2S,4S,6S)-2,4,6-trimethylnonyl segment of siphonarienes. The key step used is a newly developed methodology to obtain sec-dialkyl acetylenes based on the intra-molecular hydride transfer

Full text of DOI:10.1560/y4cf-ym5a-n6fe-qbwf

Asymmetric Synthesis of the (2S,4S,6S)-2,4,6-Trimethylnonyl Subunit
of Siphonarienes
DAVID D. DíAZ, FERNANDO R. P. CRISÓSTOMO, AND VíCTOR S. MARTíN*
Instituto Universitario de Bio-Orgánica “Antonio González”, Universidad de La Laguna, C/Astrofísico Francisco Sánchez, 2,
38206 La Laguna, Tenerife, Spain
(Received 25 February 2002)
Abstract: The paper describes an asymmetric approach to the synthesis of the
(2S,4S,6S)-2,4,6-trimethylnonyl segment of siphonarienes. The key step used is a
newly developed methodology to obtain sec-dialkyl acetylenes based on the intra-
molecular hydride transfer from a secondary γ-benzyloxy group with well-defined
absolute stereochemistry, ensured by a Sharpless asymmetric epoxidation reaction,
to a cation generated by Lewis acid treatment of a tertiary Co2(CO)6-complexed
propargylic alcohol.
1. INTRODUCTION
oped for the construction of such polypropionates; by
iterative alkylations of chiral nucleophiles7 and by
deoxygenation of polypropionates obtained by asym-
metric aldol condensations.4c,8
We speculated that an alternative methodology to
gain access to this kind of molecule could make use of
an alkyne such as 2 in which the three stereocenters of
the alkynyl moiety are defined (Fig. 2).
Recently, we reported on a very efficient protocol to
obtain sec-dialkyl acetylenes with absolute stereo-
chemical control in which the key step is the intramo-
lecular hydride transfer from a secondary γ-benzyloxy
group with defined absolute stereochemistry to a cation
generated by Lewis acid treatment of a tertiary
Co2(CO)6-complexed propargylic alcohol (Fig. 3).9 We
report herein on our efforts to achieve the asymmetric
total synthesis of 2, taking advantage of this new stereo-
selective reduction.
Polypropionates have been reported from a number of
marine pulmonate mollusks belonging to the genera
Siphonaria,1 Tridachia,2 and Onchidium.3 The siphona-
rienes (1) are fully reduced polypropionates produced
by Siphonaria characterized by possessing a (2S,4S,6S)-
2,4,6-trimethylnonyl fragment connected through an
olefinic linker to a more polar, oxygen-containing
group.4 These animals are air-breathing gastropod mol-
lusks found in the high intertidal region, which may
represent an evolutionary link between marine and ter-
restrial gastropods.5 The secondary metabolites pro-
duced are believed to be employed in chemical defense
against predators, and most are active against gram-
positive bacteria, yeast, and several human cancer cell
lines.4b,d Selected examples of these types of metabolites
are given in Fig. 1.
In the course of our studies on the synthesis of marine
natural products,6 we addressed our attention to the
siphonarienes. Two main approaches have been devel-
*Authortowhomcorrespondenceshouldbeaddressed. E-mail:
vmartin@ull.es
Israel Journal of Chemistry
Vol. 41
2001 pp. 297–302

298
O
O
O
OH
O
Siphonarienone
O
Siphonariendione
Pectinatone
1
3
X
9
Siphonarienes
1 1
O
OH
O
O
HO
Siphonarienfuranone
Siphonarienolone
Fig. 1. Representative metabolites isolated from Siphonaria grisea.
X
2
Siphonarienes
2
Fig. 2. Plausible general strategy to obtain the (2S,4S,6S)-2,4,6-trimethylnonyl segment of siphonarienes.
Ph
R2
HO H H R2
O H
R3
BF3·OEt2
H
O
Co2(CO)6
R3
R1
Co2(CO)6
R3
R1
R1
Co2(CO)6
OH
H
H
R2
Fig. 3. Stereoselective hydride transfer to Co2(CO)6-propargylic cations.
2. RESULTS AND DISCUSSION
being easily available from the corresponding (4S)-4,6-
Iterative application in both directions of the above- bis(phenylmethoxy)hexan-2-one 7 synthesized previ-
described procedure, taking a central benzyloxy group ously by our group,10 where the stereocenter configura-
as the stereochemical director, could allow the enantio- tion is ensured by a Katsuki–Sharpless asymmetric
meric synthesis of reduced polypropionates such as 2. In epoxidation reaction (>95% ee).11
this sense, the stereocontrolled synthesis of 2 could be
In order to perform the above-mentioned intramo-
envisioned from a secondary alcohol such as 3, avail- lecular reduction, the necessary Co2(CO)6-diastereo-
able by application of our methodology to a Co2(CO)6- meric mixture of tertiary propargylic alcohols 8 (ca.
complexed tertiary carbinol such as 4 (Fig. 4). The 1.5:1) was obtained by addition of lithium trimethylsilyl
synthesis of an additional tertiary alcohol forces us to acetylide to the ketone 7 and further complexation with
perform the first reductive process over a substrate with Co2(CO)8. The key reduction was performed by Lewis
an additional protected hydroxyl group 6, this molecule acid treatment, affording 9 as the only detected isomer
Israel Journal of Chemistry
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2001

299
OBn
OH
Co2(CO)6
2
OH
4
3
TMS
O
OBn
OBn O
OBn
BnO
TMS
PO
OH
5
6
7
From Sharpless
Asymmetric Epoxidation
Fig. 4. Suggested protocol for the synthesis of (3S,5S,7S)-3,5,7-trimethyl-1-decyne (2).
OH
OBn
a
b
Co2(CO)6
TMS
BnO
7
BnO
OH
8
9
OBn
OH
c
d
e
BnO
HO
10
11
OBn
O
OBn
f
a
b
4
3
HO
12
13
Scheme 1. (a) (i) LiC≡CTMS, THF, –78 °C; (ii) Co2(CO)8, CH2Cl2, rt; (b) (i) BF3·OEt2, CH2Cl2, –20 °C, (ii) CAN, acetone, 0 °C,
(iii) n-Bu4NF, THF, rt, 62% overall from 7; (c) (i) PhCH2Br, NaH, n-Bu4NI (cat), THF, rt, 94%, (ii) MeI, n-BuLi, THF, 0 °C,
98%; (d) H2, Pd/C, MeOH, 99%; (e) (i) PhCH(OMe)2, CSA (cat), CH2Cl2, (ii) DIBAL-H, CH2Cl2, 0 °C, 82% overall; (f) (i)
Oxalyl chloride, DMSO, Et3N, –78 °C, (ii) MeMgCl, THF, –78 °C, (iii) Oxalyl chloride, DMSO, Et3N, –78 ºC, 73% overall.
OH
a
2
3
Scheme 2. (a) (i) TsCl, Py, 45 °C, (ii) (CH3)2CuLi, THF, 50 °C, 63% overall.
after CAN and fluoride treatments.12 Reprotection of the zylidene obtained from 11. The primary alcohol was
secondary alcohol and homologation of one carbon pro- oxidized to the corresponding aldehyde, which, after
vided the correct terminal carbon framework. Catalytic Grignard addition and further oxidation, provided the
hydrogenation produced simultaneous reduction of the methyl ketone 13. An iterative process similar to that
triple bond and deprotection of the two benzyl ethers, applied to 7 yielded the free alcohol 3 (63% overall
affording the saturated diol 11. At this point in the yield) with the stereochemically well-defined methyl
synthesis and considering the necessity to apply a new groups located at the α-position relative to the triple
intramolecular reduction, we obtained the secondary bond (Scheme 1).
benzyloxy ether 12 by reduction of the suitable ben-
In order to introduce the additional methyl group of
Diaz et al. / Synthesis of (3S,5S,7S)-3,5,7-Trimethyl-1-decyne

300
To a stirred solution of the crude Co2(CO)6 complex in dry
CH2Cl2 (16 mL), BF3·OEt2 (0.13 mL, 1.65 mmol) was slowly
added at –20 °C. The reaction mixture was stirred for 5 min
and poured into saturated aqueous NaHCO3 at 0 °C. The
resulting mixture was vigorously stirred for 15 min and ex-
tracted with CH2Cl2. The combined organic layers were
washed with brine, dried (MgSO4), filtered, and concentrated
to give a complexed acetylene that was employed in the next
step without further purification.
the alkyl chain of 2, we took advantage of the existence of
the secondary alcohol with the opposed stereochemistry
in the carbinolic carbon carrying out a nucleophilic
displacement with inversion of the configuration of this
stereocenter. Thus, the alcohol 3 was tosylated and
treated with the suitable dimethylcuprate,13 affording 2
1
as the sole detected stereoisomer by H and 13 C NMR
analysis (Scheme 2).
To a stirred solution of the complexed acetylene in dry
acetone (4 mL), CAN (10 g, 3.29 mmol) was added in one
portion at 0 °C. The reaction mixture was stirred at 0 °C until
TLC showed completion of the reaction (ca. 5 min). The
mixture was evaporated and the residue diluted with water and
extracted with Et2O. The combined organic solutions were
dried (MgSO4), filtered, and concentrated. To a solution of the
crude obtained in dry THF (30 mL), n-Bu4NF (1 M in THF,
1.5 mL, 1.5 mmol) was slowly added at 0 °C. After this
addition, the mixture was allowed to warm to rt for 1 h with
stirring, diluted with Et2O, and H2O was added. The resulting
mixture was extracted with Et2O. The combined organic layers
were washed with brine, dried, filtered, concentrated and puri-
fied by column chromatography to afford 9 (230 mg, 62%
overall yield) as a colorless oil: [α]25D = –5.8 (c 4.65, CHCl3);
1H NMR (CDCl3) δ 1.20 (d, J = 7.7 Hz, 3H), 1.22–1.56 (m,
1H), 1.70–1.80 (m, 3H), 2.07 (br s, 1H), 2.59–2.63 (m, 1H),
3.04 (br s, 1H), 3.64–3.74 (m, 2H), 3.98 (m, 1H), 4.52 (br s,
2H), 7.25–7.40 (m, 5H); 13C NMR (CDCl3) δ 20.7 (q), 22.4
(d), 36.4 (t), 43.9 (t), 68.6 (d), 68.8 (t), 69.2 (d), 73.2 (t), 89.1
3. CONCLUSION
In summary, a new asymmetric synthesis of the
(2S,4S,6S)-2,4,6-trimethylnonyl segment of siphonarienes
has been achieved, starting from readily available (4S)-
4,6-bis(phenylmethoxy)hexan-2-one 7 and using alkyne–
cobalt complexes chemistry. The method is very efficient
for the stereocontrolled synthesis of highly-branched alkyl
chains, and considering that the source of chirality is the
Katsuki–Sharpless asymmetric epoxidation, the alterna-
tive choice of the tartrate auxiliary easily permits control
of the absolute configuration in the final product.
4. EXPERIMENTAL
4.1. General Methods and Materials
1H and 13C NMR spectra were recorded at 400 and 75 MHz,
respectively, and chemical shifts were reported relative to
internal Me4Si. Optical rotations were determined for solu-
tions in chloroform. Column chromatography was performed
on Merck silica gel, 60 Å and 230–400 mesh. Compounds
were visualized by use of UV light and/or 2.5% phosphomo-
lybdic acid in ethanol with heating. All solvents were purified
by standard techniques.14 Reactions requiring anhydrous con-
ditions were performed under nitrogen. Anhydrous magne-
sium sulfate was used for drying solutions.
~
(s), 127.7 (d), 128.4 (d), 137.9 (s); IR (film) νmax (cm–1) 3440,
3298, 2970, 1454, 1096; MS m/z (relative intensity) 233
(M + 1)+ (0.5), 232 (M)+ (2.4), 155 (M – C6H5)+ (0.5), 141 (M –
C7H7O)+ (1.5), 120 (6.0), 107 (22.0), 91 (100). Anal. Calcd for
C15H20O2: C, 77.55; H, 8.68. Found: C, 77.29; H, 8.84.
4.3. Preparation of [(3R,5R)-3-(benzyloxy)-5-methyl-6-
heptynyl]oxy(methyl)benzene (10)
To a stirred suspension of NaH (60% in mineral oil, 52 mg,
1.29 mmol) in dry THF (10 mL), at 0 ºC, a solution of 9 (230 mg,
0.99 mmol) in THF (5 mL), a catalytic amount of n-Bu4NI,
4.2. Preparation of (3R,5R)-1-(benzyloxy)-5-methyl-6-
heptyn-3-ol (9)
n-BuLi (1.01 mL, 1.9 M in hexanes, 1.92 mmol) was added and benzyl bromide (0.18 mL, 1.5 mmol) were sequentially
to a solution of trimethylsilylacetylene (0.24 mL, 2.07 mmol) and slowly added. The reaction mixture was stirred at room
in dry THF (7 mL) at –78 °C. After the addition, the mixture temperature for 24 h. Then, the mixture was diluted with Et2O,
was warmed to 0 °C for 0.5 h. Then, this mixture was cooled to washed with brine, dried, concentrated, and purified by column
–78 °C and a solution of 7 (500 mg, 1.60 mmol) in dry THF chromatography yielding the corresponding dibenzyl ether
(12 mL) was added dropwise. The mixture was stirred at (300 mg, 94%) as a colorless oil: [α]25D= –14.3 (c 5.00, CHCl3);
–78 °C for 1 h, whereupon it was quenched with saturated 1H NMR (CDCl3) δ 1.16 (d, J = 6.9 Hz, 3H), 1.52–1.60 (m, 1H),
NH4Cl solution and Et2O. The organic layer was washed with 1.85–1.94 (m, 3H), 2.04 (br s, 1H), 2.54–2.62 (m, 1H), 3.6 (t, J =
brine, dried (MgSO4), filtered, and concentrated to give a 6.1 Hz, 2H), 3.72–3.80 (m, 1H), 4.48 (br s, 2H), 4.50 (br s, 2H),
mixture of alcohols in which one diastereoisomer slightly 7.20–7.37 (m, 10H);13C NMR (CDCl3) δ 21.0 (q), 22.2 (d), 34.1
predominated (ca. 1.5:1).
(t), 41.2 (t), 66.8 (d), 68.4 (d), 71.0 (t), 73.0 (t), 74.3 (d), 88.9 (s),
To a solution of the above-obtained mixture in dry CH2Cl2 127.0 (d), 127.5 (d), 127.7 (d), 127.9 (d), 128.0 (d), 128.1 (d),
(16 mL), Co2(CO)8 (715 mg, 2.08 mmol) was added at room 128.3 (d), 129.0 (d), 129.7 (d), 138.5 (s), 138.7 (s); IR (film)
~
temperature. The reaction mixture was stirred at room tem- νmax (cm–1) 3294, 2968, 1745, 1454, 1097; MS m / z (relative
perature until TLC showed complete conversion to the intensity) 322 (M)+ (0.2), 321 (M – 1)+ (0.5), 231 (3.0), 230
hexacarbonyldicobalt complex (ca. 1 h). The mixture was (M – C6H5 – CH3) + (1.0), 169 (2.0), 91 (100). Anal. Calcd for
filtered through a pad of silica gel and concentrated to yield 8 C22H26O2: C, 81.95; H, 8.13. Found: C, 81.92; H, 8.31.
as a brown solid that was used without any purification.
To a solution of the above dibenzyl ether (300 mg,
Israel Journal of Chemistry 41 2001

301
0.93 mmol) in THF (10 mL) under nitrogen, n-BuLi (1.9 M in concentrated, and purified by column chromatography to yield
hexanes, 0.54 mL, 1.03 mmol) was added dropwise at 0 °C. 12 (320 mg, 82% overall yield) as a colorless oil: [α]25D= –14.1
The reaction mixture was stirred for 15 min and then CH3I (c 1.46, CHCl3); 1H NMR (CDCl3) δ 0.87 (br s, 3H), 0.89 (br s,
(0.09 mL, 1.40 mmol) was added. The reaction was allowed to 3H), 0.90–1.58 (m, 1H), 1.2–1.35 (m, 5H), 1.58–1.63 (m, 1H),
warm to rt and stirred for 1 h, after which the reaction mixture 1.67–1.78 (m, 2H), 1.82–1.92 (m, 1H), 3.69–3.74 (m, 2H),
was added to a saturated aqueous solution of NH4Cl and 3.76–3.82 (m, 1H), 4.54 (m, 2H), 7.27–7.34 (m, 5H);13C NMR
extracted with Et2O. The combined organic phases were (CDCl3) δ 14.3 (q), 19.9 (q), 20.0 (t), 29.1 (d), 36.3 (t), 39.5 (t),
washed with brine, dried over MgSO4, concentrated, and puri- 41.6 (t), 60.5 (t), 70.9 (t), 76.6 (d), 127.7 (d), 127.9 (d), 128.4
~
fied by column chromatography yielding 10 (287 mg, 98%) as (d), 138.4 (s); IR (film) νmax (cm–1) 3368, 2928, 1717, 1455,
a colorless oil: [α]25D= –8.5 (c 1.91, CHCl3); 1H NMR (CDCl3) 1067; MS m/z (relative intensity) 250 (M)+ (0.3), 249 (M – 1)+
δ 0.84 (d, J = 7.3 Hz, 3H), 1.45–1.55 (m, 1H), 1.75 (br s, 3H), (0.2), 232 (M – H2O)+ (2.7), 205 (0.6), 147 (7.0), 91 (100).
1.79–1.97 (m, 3H), 2.50 (m, 1H), 3.59 (t, J = 6.5 Hz, 3H, 2H), Anal. Calcd for C16H26O2: C, 76.75; H, 10.47. Found: C, 76.77;
3.75 (m, 1H), 4.43–4.55 (m, 4H), 7.28–7.33 (m, 10H); H, 10.51.
13C NMR (CDCl3) 3.4 (q), 21.5 (q), 22.5 (d), 34.1 (t), 41.7 (t),
4.6. Preparation of (4R,6S)-4-(benzyloxy)-6-methyl-2-
66.9 (t), 70.8 (s), 72.9 (t), 74.5 (t), 75.8 (d), 83.5 (s), 127.5 (d),
nonanone (13)
127.8 (d), 128.0 (d), 128.1 (d), 128.3 (d), 128.4 (d), 128.9 (d),
To a solution of oxalyl chloride(0.11 mL, 1.2 mmol) in dry
CH2Cl2 (2 mL) at –78 °C, DMSO (0.11 mL, 1.5 mmol) was
added. The mixture was stirred for 15 min, and then product
12 (150 mg, 0.60 mmol) was added. The reaction mixture was
stirred for 1 h at –78 °C. After this time, Et3N (0.42 mL,
3 mmol) was added dropwise and the mixture was allowed to
warm to room temperature. After 10 min, it was diluted with
Et2O and a saturated aqueous NH4Cl solution was added. The
mixture was extracted with Et2O and washed with brine. The
combined organic extracts were dried, filtered, and concen-
trated, providing an aldehyde that was suitable for use without
further purification.
To a solution of the crude aldehyde in THF (5 mL),
MeMgCl (0.30 mL, 3 M in THF, 0.90 mmol) was added
dropwise at –78 °C. After the mixture was stirred for 0.5 h,
saturated NH4Cl solution was added, and the resulting slurry
extracted with Et2O. The combined organic extracts were
dried, filtered, and concentrated. The residual oil was used
without further purification.
~
129.0 (d), 138.5 (s), 138.8 (s); IR (film) νmax (cm–1) 2931,
1716, 1453, 1276, 1097; MS m/z (relative intensity) 336 (M)+
(0.1), 335 (M – 1)+ (0.2), 259 (M – C6H5)+ (0.5), 245 (M –
C7H7O)+ (2.3), 243 (1.5), 139.7 (7.0), 91 (100). Anal. Calcd for
C23H28O2: C, 82.10; H, 8.39. Found: C, 82.18; H, 8.60.
4.4. Preparation of (3R, 5S)-5-methyl-1,3-octanediol (11)
To a solution of 10 (250 mg, 0.75 mmol) in MeOH (8 mL),
10% Pd/C (22 mg) was added at room temperature. The
resulting suspension was vigorously stirred under an atmo-
sphere of H2 (1 atmosphere) for 2 h at room temperature. After
removal of the catalyst by filtration through a small pad of
Celite, the filtrate was concentrated and purified by column
chromatography, yielding 11 (136 mg, 99%) as a colorless oil:
1
[α]25D= +10.0 (c 0.81, CHCl3); H NMR (CDCl3) 0.89 (t,
J = 7.2 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H), 1.13–1.35 (m, 5H),
1.55–1.71 (m, 4H), 2.52 (br s, 2H), 3.81–3.98 (m, 3H);
13C NMR (CDCl3) 14.3 (q), 19.2 (q), 20.0 (t), 28.7 (d), 39.1 (t),
–~
40.0 (t), 45.3 (t), 61.8 (t), 69.9 (d); IR (film) νmax (cm–1) 3347,
2956, 1457, 1054; MS m/z (relative intensity) 161 (M + 1)+
(0.1), 160 (M)+ (0.1), 159 (M – 1)+ (0.3), 143 (M – OH)+ (1.6),
124 (M – 2 H2O)+ (1.6), 113 (16.0), 75 (100). Anal. Calcd for
C9H20O2: C, 67.45; H, 12.58. Found: C, 67.63; H, 12.60.
To a solution of oxalyl chloride in dry CH2Cl2 (2 mL) at
–78 °C, DMSO (0.11 mL, 1.2 mmol) was added. The mixture
was stirred for 15 min, and then the crude diastereomeric
alcohols were added. The reaction mixture was stirred for 2 h
at –78 °C. After this time, Et3N (0.42 mL, 3 mmol) was added
dropwise and the mixture was allowed to warm to room tem-
perature. After 10 min it was diluted with Et2O and a saturated
4.5. Preparation of (3R, 5S)-3-(benzyloxy)-5-methyl-1-
octanol (12)
To a solution of the diol 11 (125 mg, 0.78 mmol) in dry aqueous NH4Cl solution was added. The mixture was ex-
CH2Cl2 (8 mL), a catalytic amount of CSA (19 mg, 0.08 mmol) tracted with Et2O and washed with brine. The combined or-
and benzaldehyde dimethylacetal (0.10 mL, 0.94 mmol) were ganic extracts were dried, filtered, and concentrated. The re-
sequentially added at room temperature. The reaction mixture sulting viscous oil was purified by flash column chromatogra-
was stirred for 1 h, after which TLC showed complete reac- phy to yield 13 (115 mg, 73% overall yield) as a colorless oil:
tion. Then, Et3N was added until pH = 7, stirred for 5 min, and [α]25D= +1.4 (c 2.7, CHCl3); 1H NMR (CDCl3) 0.86 (br s, 3H),
evaporated under reduced pressure. The residue was used 0.87 (br s, 3H), 0.93–1.63 (m, 7H), 2.16 (s, 3H), 2.50 (dd, J =
without further purification.
15.8, 5.3 Hz, 1H), 2.76 (dd, J = 15.8, 6.7 Hz, 1H), 4.00 (m,
To a solution of the crude benzylidene derivative obtained 1H), 4.51 (br s, 2H), 7.28–7.35 (m, 5H); 13C NMR (CDCl3)
in dry CH2Cl2 (5 mL), DIBAL-H (7.5 mL, 1 M solution in 14.3 (q), 19.6 (q), 19.9 (t), 29.0 (d), 31.2 (q), 39.7 (t), 42.6 (t),
cyclohexane, 7.5 mmol) was slowly added at 0 ºC. The reac- 49.1 (t), 71.6 (t), 73.8 (d), 127.5 (d), 127.8 (d), 128.3 (d), 138.5
–~
tion mixture was allowed to warm to rt over a period of (s), 207.7 (s); IR (film) νmax (cm–1) 2956, 1717, 1359, 1096;
15 min. The mixture was diluted with CH2Cl2 and aqueous MS m/z (relative intensity) 262 (M)+ (0.1), 219 (M – C2H3O)+
HCl (5%) was added. The resulting mixture was extracted (0.2), 204 (M – C2H3O – CH3)+ (2.4), 177 (0.3), 138 (15.5), 113
with CH2Cl2. The combined organic layers were washed with (8.0), 91 (100). Anal. Calcd for C17H26O2: C, 77.82; H, 9.99.
saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered, Found: C, 78.10; H, 10.24.
Diaz et al. / Synthesis of (3S,5S,7S)-3,5,7-Trimethyl-1-decyne

302
4.7. Preparation of (3S,5R,7S)-3,7-dimethyl-1-decyn-5-ol (3) thanks the Spanish M.E.C. for a F.P.I. fellowship. Many
The same procedure used above to obtain 9 from 7 was thanks are also given to Dr. J.J. Fernández and to Dr. M.L.
applied to 13 on a 100 mg (0.55 mmol) scale, yielding 3 (73 mg, Souto for assistance.
73% overall yield) as a colorless oil: [α]25D= +18.0 (c 0.15,
CHCl3); 1H NMR (CDCl3) 0.89 (br s, 3H), 0.91 (br s, 3H), 1.22
REFERENCES AND NOTES
(d, J = 6.7 Hz m, 3H), 1.22–1.71 (m, 8H), 2.11 (br s, 1H), 2.59
(m, 1H), 3.88 (m, 1H); 13C NMR (CDCl3) 13.7 (q), 19.1 (q),
20.0 (t), 21.1 (q), 23.1 (d), 28.8 (d), 39.6 (t), 40.0 (t), 68.4 (d),
(1) (a) Manker, D.C.; Faulkner, D.J.; Stout, T.J.; Clardy, J.
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(suppl. 1), 233–240.
~
69.1 (d), 89.0 (s); IR (film) νmax (cm–1) 2929, 2360, 2341, 1730;
MS m/z (relative intensity) 183 (M + 1)+ (8.0), 182 (M)+ (1.7),
149 (100), 125 (6.7), 105 (13.9), 91 (52.0). Anal. Calcd for
C12H22O: C, 79.06; H, 12.16. Found: C, 79.32; H, 12.47.
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4.8. Preparation of (3S,5S,7S)-3,5,7-trimethyl-1-decyne (2)
To a stirred solution of 3 (50 mg, 0.23 mmol) in dry
pyridine (3 mL) was added TsCl (105 mg, 0.55 mmol) at 0 ºC.
The reaction mixture was allowed to warm to 45 ºC and stirred
for 6 h, after which TLC showed complete reaction. The
mixture was then diluted with H2O and the aqueous layer was
extracted with Et2O. The ethereal extracts were washed with
H2O, saturated CuSO4 solution, and brine, dried, and concen-
trated. The tosylate was used without further purification.
To a stirred slurry of copper(I) iodide (262 mg, 1.38 mmol)
in dry THF (3 mL) under nitrogen at –20 ºC, methyllithium
(2.2 M in Et2O, 1.3 mL, 1.3 mmol) was added. The solution
became clear and was stirred for 0.5 h. A solution of the crude
tosylate in dry THF was added dropwise, and the mixture
stirred overnight with warming to 50 ºC. The reaction was
quenched with ammonium hydroxide-saturated aqueous
NH4Cl solution. The solution was stirred until the copper salts
were completely dissolved in the aqueous layer. The aqueous
layer was extracted with ether, and the combined extracts were
dried over MgSO4 and concentrated under reduced pressure.
The resulting residue was purified by flash column chroma-
tography to yield 2 (31 mg, 63% yield overall) as a colorless
oil: [α]25D= + 6.5 (c 0.83, CHCl3); 1H NMR (CDCl3) 0.83–1.03
(m, 9H), 1.11–1.26 (m, 8H), 1.36 (br s, 3H), 1.65 (m, 2H), 1.78
(br s, 1H), 2.57 (m, 1H); 13C NMR (CDCl3) 14.3 (q), 17.4 (q),
19.1 (t), 19.8 (q), 20.4 (q), 20.6 (t), 23.1 (d), 28.8 (d), 29.2 (d),
39.7 (t), 45.0 (t), 43.5 (t), 66.0 (d), 68.6 (s), 89.1 (s); IR (film)
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(12) For details about the determination of relative stere-
ochemistry of the newly created stereocenter, see ref. 9.
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ratory Chemicals, 4th ed.; Butterworth-Heinemann:
Oxford, 1996.
~
νmax (cm–1) 2360, 2341, 1730, 1096; MS m/z (relative intensity)
180 (M)+ (10), 165 (M – CH3)+ (17), 152 (34), 136 (100).
HMRS calcd for C13H24 (M)+ :180.1878. Found: 180.1883.
Acknowledgments. We thank the Ministerio de Ciencia y
Tecnología (PB98-0443-C02-01) of Spain and FEDER
(1FD97-0747-C04-01) for supporting this research. D.D.
Israel Journal of Chemistry
41
2001