A chemoenzymatic asymmetric synthesis of the hydroxy acid segment of schulzeines B and C

Article abstract of DOI:10.1016/j.tetasy.2009.12.020

A chemoenzymatic asymmetric synthesis of the title compound was developed by a building-block approach. The key steps of the synthesis were (i) an enantioselective lipase-catalyzed acylation of a secondary alcohol, (ii) an efficient diastereoselective add

Full text of DOI:10.1016/j.tetasy.2009.12.020

Tetrahedron: Asymmetry 21 (2010) 27–32
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A chemoenzymatic asymmetric synthesis of the hydroxy acid segment
of schulzeines B and C
*
Sucheta Biswas, Subrata Chattopadhyay, Anubha Sharma
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A chemoenzymatic asymmetric synthesis of the title compound was developed by a building-block
approach. The key steps of the synthesis were (i) an enantioselective lipase-catalyzed acylation of a sec-
ondary alcohol, (ii) an efficient diastereoselective addition of an alkyl-lithium reagent to a glyceraldehyde
derivative, (iii) conversion of an epoxide to a one-carbon homologated allylic alcohol via a sulphorane
addition, and (iv) a cross metathesis between two chiral allylic alcohols and subsequent functionalization
to obtain the ethyl ester of the hydroxy acid unit of the schulzeines.
Received 9 October 2009
Accepted 21 December 2009
Available online 18 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Our interest in the schulzeines was sparked by their biological
activity, especially as potential anti-tumor and immunomodula-
The tetrahydroisoquinoline alkaloids, designated as schulzeines
A–C 1–3 were isolated by a bioassay-guided screening of the
hydrophilic extract of the marine sponge Penares schulzei and
tory agents.7 Although the pharmacophore of the schluzeines has
found to inhibit yeast
48–170 nM and viral neuraminidase (IC50
a
-glucosidase with IC50 values of
OSO3Na
OSO3Na
HO
ꢀ
l
M).1 The constitution
5
9
O
N
R
and the relative stereochemistry of the schluzeines were
elucidated by chemical degradation and extensive 2D-NMR stud-
ies, and the absolute configuration by application of the Mosher
method. The schulzeines encompass the 9,11-tetrahydroisoquino-
line unit and are characterized by a fused d-lactam ring A and a C28
O
OH
N
H
OSO3Na
1: schulzeine A: R = Me, (11bR); 2 schulzeine B: R = H, (11bS);
3: schulzeine C: R = H, (11bR)
sulfated fatty acid side chain
B linked via an amide bond
(Scheme 1).2 Schulzeines B and C differ in the stereochemistry at
the C-11b of the tetrahydroisoquinoline moiety, while schulzeine
A possesses an additional methyl substitution at C-20 of the fatty
acid chain. More recently, the stereochemistry of this stereogenic
center in schulzeine A has been revised.3
OSO3Na
5
HO
Glycosidase inhibitors have become the subject of intense scru-
tiny because of their profound effect on glycoprotein processing,
oligosaccharide metabolism, and cell–cell and cell–virus recogni-
O
OSO3Na
N
O
EtO
9
tion processes.4 The
a-glucosidase inhibitors are potential thera-
OH
NH2
OSO3Na
peutics for the treatment of viral diseases, cancer, and diabetes.5
Their intriguing bioactivity combined with the unique structure
of the schulzeines aroused several synthetic efforts toward these
targets.6 Notably, all the reported syntheses of the tricyclic iso-
quinoline core began with glutamic acid derivatives, while the
fatty acid segment has been synthesized using Sharpless’ asym-
metric dihydroxylation as the key step.
B
A
OH
OH
O
5
EtO
+
9
OH
B1
B2
* Corresponding author. Tel.: +91 22 25590267; fax: +91 22 25505151.
E-mail address: anubhas@barc.gov.in (A. Sharma).
Scheme 1.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.020

28
S. Biswas et al. / Tetrahedron: Asymmetry 21 (2010) 27–32
not been identified so far, their O-sulfated fatty acid segment is
structurally related to other glucosidase inhibitors, including pena-
sulfate8a and the penarolides.8b Hence, we were interested in
developing an efficient asymmetric synthesis of the common
hydroxyalkyl ester unit 20 of the schulzeines B and C. Similar poly-
hydroxy acids and the macrolides derived from them are of wide
occurrence in various natural sources, and several of these show
impressive anti-cancer, antiviral, antifungal as well as vaccine
adjuvant activities.9 Herein, we report the asymmetric synthesis
of 20 that can be easily converted to schulzeines B and C by amida-
tion of the required isoquinoline core and a late stage trisulfation.
ester 20 was conceived using a similar cross metathesis reaction
between the building blocks B1 and B2. We envisaged that the
required building blocks could be individually synthesized by a
biocatalytic route, and using the aldehyde 12, respectively.
As per the synthetic plan (Scheme 2), the commercially avail-
able diol 4 was monoprotected with tert-butyldiphenylsilyl chlo-
ride (TBDPSCl) in the presence of 4-dimethylaminopyridine
(DMAP) to furnish compound 5, which on oxidation with pyridini-
um chlorochromate (PCC) afforded the aldehyde 6. Its reaction
with vinylmagnesium bromide afforded the allylic alcohol 7. For
its resolution, a lipase-catalyzed trans-acetylation appeared prom-
ising. Lipases are widely used in asymmetric organic synthesis
since they do not require any cofactor, operate on a wide range
of substrates, retain good catalytic activity in different media, dis-
play good stereoselectivity, and are commercially available in free
as well as immobilized forms.15a–c We were particularly interested
in the lipase preparation, Novozyme 435Ò that is inexpensive,
robust and effective in resolving racemic carbinol and amines.15d
Although the above-mentioned lipase is generally effective in
resolving linear secondary alcohols, the enantioselectivity is
known to be governed by the reaction conditions such as solvent
used and/or the acyl donor.16a–c In our recent work, we also
observed that Novozyme 435Ò is very effective in resolving
alcohols, possessing methyl14a or vinyl groups14b adjacent to the
carbinol functionality.
2. Results and discussion
For the past several years, we have been interested in formulat-
ing the simple and efficient asymmetric synthesis of various bioac-
tive target compounds, which remains a challenging area, despite
impressive progress in organic synthesis.10a–c To this end, we have
extensively used inexpensive and easily accessible (R)-cyclohexy-
lideneglyceraldehyde 12 as a versatile chiral template11a–h and/or
employed biocatalytic routes12a–d for the asymmetric syntheses
of a diverse array of natural compounds. A chemoenzymatic
approach, combining these methodologies may often provide easy
access to the target compounds, as is illustrated in this paper for
the syntheses of the title compound.
True to our expectation, the alcohol 7 could be efficiently re-
solved using inexpensive vinyl acetate, both as the acyl donor,
and solvent to obtain the (S)-acetate 8 (96% ee) and (R)-7 (91%
ee) at ꢀ50% conversion (5.5 h). For determining the % ees of the
products, a part of the acetate (S)-8 was hydrolyzed with KOH/
Different versions of the olefin metathesis reaction have turned
out to be a promising strategy for the construction of C–C bonds.13
Recently we have successfully utilized cross metathesis of terminal
alkenes to formulate the efficient syntheses of two hydroxy fatty
acids.14 Hence, a convergent strategy toward the C28 fatty acid
i
(CH2)11OTBDPS
iv
iii
HO(CH2)12OH
TBDPSO(CH2)11X
68%
77%
50%
OH
4
5 X = CH2OH
6 X = CHO
7
ii, 92%
(CH2)10
X
v, 93%
vi
(CH2)10
OAc
(CH2)11OTBDPS
CO2Et
77%
(R)-7 +
from 8
OAc
OAc
(91% ee)
9 X = CH2OH
10 X = CHO
11
ii, 88%
8 (96% ee)
OH
O
O
vii
ix
x,xi
O
O
HO
(CH2)9CH3
(CH2)9CH3
O
(CH2)9CH3
81%
75%
67%
CHO
OBn
15
OBn
16
OR
12
13 R = H
viii, 93%
14 R = Bn
OH
HO
xii
xiii
(CH2)9CH3
(CH2)10
OAc
CH3(CH2)9
CO2Et
xiv
80%
61%
OBn
88%
OBn
17
18
HO
HO
OH
xv
(CH2)12CO2Et
(CH2)12CO2Et
OAc
CH3(CH2)9
CH3(CH2)9
91%
OH
OH
20
19
Scheme 2. Reagents and conditions: (i) TBDPSCl/imidazole/DMAP/CH2Cl2/25 °C/8 h (68%), (ii) PCC/NaOAc/CH2Cl2/25 °C/3 h (6: 92%; 10: 88%), (iii) CH2@CHMgBr/THF/25 °C/
6 h (77%), (iv) vinyl acetate/Novozyme 435/25 °C/26 h (50%), (v) Bu4NF/THF/0–25 °C/3 h (93%), (vi) NaH/THF/(EtO)2P(O)CH2CO2Et/0 °C to 25 °C/18 h (77%), (vii) CH3(CH2)9Li/
THF/ꢁ78 °C/3 h (81%), (viii) NaH/THF/BnBr/Bu4NI/ /4 h (93%), (ix) aqueous 2 M HCl/25 °C/6 h (75%), (x) TMSCl/EtOAc/ꢁ20 °C/20 min; MsCl/Et3N/ꢁ20 °C/30 min; aqueous
D
2 M HCl/25 °C/1 h (79%), (xi) K2CO3/MeOH/25 °C/3 h (84%), (xii) Me3SI/BuLi/THF/ꢁ40 °C/1 h, ꢁ40 °C/3 h then 25 °C/12 h (80%), (xiii) 11/Grubbs’ 2nd generation catalyst/
CH2Cl2/25 °C/22 h (61% based on 17), (xiv) H2/10% Pd–C/EtOH/25 °C (88%), (xv) Amberlyst 15Ò/EtOH/25 °C/18 h (91%).

S. Biswas et al. / Tetrahedron: Asymmetry 21 (2010) 27–32
29
MeOH to furnish the alcohol (S)-7. The % ees of the enantiomeric
alcohols (R)- and (S)-7 were determined from the relative intensi-
ties of the methoxyl resonances of the corresponding MTPA esters,
were recorded with a Bruker AC-200 spectrometer. The optical
rotations were recorded with a Jasco DIP 360 digital polarimeter.
prepared using (R)-a-methoxytrifluoromethyl phenylacetyl
3.2. 12-tert-Butyldiphenylsilyloxydodecan-1-ol 5
(MTPA) chloride.17 The acetate (S)-8 was desilylated with Bu4NF
to furnish the primary alcohol 9, which was used for the synthesis
of the building block 11 (B1 equivalent). For assigning the configu-
ration of 8, a part of the alcohol 9 was mesylated and subsequently
reduced with LiAlH4 to furnish (S)-tetradec-1-en-3-ol. Comparison
of its specific rotation with the reported value established its con-
figuration.18 For the synthesis of the intermediate 11, the alcohol 9
was oxidized with PCC to furnish the aldehyde 10. This on Wittig–
Horner reaction with triethyl phosphonoacetate furnished the con-
jugated ester 11. The E-geometry of the olefin function was ascer-
tained from the 1H NMR spectrum.
A mixture of 4 (7.0 g, 34.65 mmol), TBDPSCl (10.0 g, 36.42
mmol), imidazole (2.82 g, 41.48 mmol), and DMAP (cat.) in CH2Cl2
(50 mL) was stirred at room temperature for 8 h. The mixture was
poured into H2O (50 mL), the organic layer separated and the aque-
ous portion extracted with CHCl3 (2 ꢂ 15 mL). The combined or-
ganic extracts were washed with H2O (2 ꢂ 10 mL), aqueous 10%
HCl (1 ꢂ 10 mL), H2O (2 ꢂ 10 mL) and brine (1 ꢂ 5 mL), and dried.
Solvent removal followed by column chromatography (silica gel,
0–15% EtOAc/hexane) of the residue furnished 5. Yield: 10.37 g
(68%); colorless oil; IR: 3348, 3071, 3049 cmꢁ1 1H NMR: d 1.04
;
For the other building block 17 (B2 equivalent), following our
own methodology, the known aldehyde 12 was reacted with
CH3(CH2)9Li to furnish the anti-triol derivative 13 almost exclu-
sively (dr: = 96:4). Use of the corresponding Grignard reagent pro-
duced a 22:78 mixture of syn/anti triol derivatives. The anti-
compound 1319 could be easily obtained in stereochemically pure
form by column chromatography. The anti-stereochemistry of 13
was confirmed from the 1H NMR resonances of the carbinol pro-
tons that appeared at d 3.63 (t, 1H) and d 3.87–3.97 (m, 3H). For
the corresponding syn-isomer, these appear at d 3.46–3.48, d
3.68–72 and d 3.94–4.02 as 1:1:2 multiplets.19 Benzylation of 13
with benzyl bromide (BnBr) and Bu4NI in the presence of NaH as
the base produced compound 14. This on treatment with aqueous
HCl furnished the diol 15. Its reaction with trimethylsilyl chloride
(TMSCl) in the presence of Et3N in EtOAc followed by mesylation of
the resultant product with mesyl chloride (MsCl), and subsequent
desilylation with HCl furnished the C-2 mesylated intermediate.
After isolation, this was treated with K2CO3 to furnish the
(2S,3S)-epoxide 16. This was reacted with the sulphorane, gener-
ated by a base (n-BuLi)-catalyzed deprotonation of trimethylsulfo-
nium iodide (Me3SI) to afford the allylic alcohol 17.
(s, 9H), 1.17–1.40 (m, 16H), 1.44 (br s, 1H), 1.53–1.65 (m, 4H),
3.58–3.67 (m, 4H), 7.25–7.41 (m, 6H), 7.64–7.69 (m, 4H); 13C
NMR: d 19.2, 25.7, 26.8, 29.4, 29.6, 32.6, 32.7, 63.1, 63.9, 127.5,
129.4, 134.1, 135.5. Anal. Calcd for C28H44O2Si: C, 76.30; H, 10.06.
Found: C, 76.14; H, 9.88.
3.3. 12-tert-Butyldiphenylsilyloxydodecanal 6
To a cooled (0 °C) and stirred suspension of PCC (4.71 g,
21.83 mmol) and NaOAc (10 mol %) in CH2Cl2 (30 mL) was added
the alcohol 5 (6.4 g, 14.55 mmol) in one portion. After stirring for
3 h, the reaction mixture was diluted with Et2O (30 mL) and the
supernatant passed through a pad of silica gel (200 ꢂ 100). Removal
of solvent in vacuo followed by column chromatography of the res-
idue (silica gel, 0–10% EtOAc/hexane) furnished pure 6. Yield:
5.86 g (92%); colorless oil; IR: 2712, 1726 cmꢁ1 1H NMR: d 1.04
;
(s, 9H), 1.25–1.42 (m, 14H), 1.44–1.62 (m, 4H), 2.37–2.45 (m,
2H), 3.64 (t, J = 6.4 Hz, 2H), 7.34–7.42 (m, 6H), 7.64–7.69 (m, 4H),
9.75 (t, J = 1.2 Hz, 1H); 13C NMR: d 19.2, 22.1, 25.7, 26.9, 29.1,
29.4, 29.5, 32.6, 43.9, 64.0, 127.5, 129.5, 134.1, 135.6, 203.0. Anal.
Calcd for C28H42O2Si: C, 76.66; H, 9.65. Found: C, 76.48; H, 9.81.
In the last sequence of reactions, the alcohol 17 was subjected to
a cross-metathesis reaction with the allylic acetate 11 in the pres-
ence of Grubbs’ 2nd generation catalyst to furnish the desired alco-
hol 18 (61%, based on conversion of 17) along with the unreacted
alcohols 11 and 17. The homo-dimerized products of 11 and 17 were
obtained in trace amounts. We used the alcohol 17 in excess in view
of its easy availability and also the fact that its dimerized product (if
any) would produce a highly polar product, which can be separated
easily from the alcohol 18. Generally, increasing steric bulk through
the addition of hydroxyl protection reduces the cross-metathesis
reactivity of the alkenols.13f Hence we used the unprotected alcohol
17 directly for the metathesis. The 1H NMR resonances of the newly
generated olefinic protons and that at the C-2 position appeared to-
gether as complex multiplets, precluding the assignment of the
geometry of the newly generated olefin function. However, this
was not important for the present synthesis. Catalytic hydrogena-
tion of 18 gave the acetoxy ester 19, which was converted to the
target hydroxy ester 20 by an acid (Amberlyst 15Ò)-catalyzed
trans-esterification with ethanol.
3.4. ( )-14-tert-Butyldiphenylsilyloxytetradec-1-en-3-ol 7
To a stirred solution of 6 (5.60 g, 12.78 mmol) in THF (25 mL)
was slowly added CH2@CHMgBr (36.5 mL, 25.57 mmol, 0.7 M in
THF), and the mixture stirred for 6 h. The reaction was quenched
with aqueous 10% NH4Cl, the mixture filtered and concentrated
in vacuo. The residue was dissolved in Et2O (30 mL), the organic
layer washed with water (2 ꢂ 10 mL) and brine (1 ꢂ 5 mL), and
dried. Solvent removal in vacuo and column chromatography (sil-
ica gel, 0–10% Et2O/hexane) of the residue afforded ( )-7. Yield:
4.59 g (77%); colorless oil; IR: 3357, 997 cmꢁ1 1H NMR: d 1.04 (s,
;
9H), 1.26–1.42 (m, 16H), 1.45–1.60 (m, 5H), 3.64 (t, J = 6.4 Hz,
2H), 4.07–4.17 (m, 1H), 5.06–5.26 (m, 2H), 5.78–5.98 (m, 1H),
7.31–7.44 (m, 6H), 7.64–7.69 (m, 4H); 13C NMR: d 19.2, 25.3,
25.7, 26.8, 29.4, 29.6, 32.6, 37.0, 64.0, 73.3, 114.5, 127.5, 129.4,
134.1, 135.5, 141.3. Anal. Calcd for C30H46O2Si: C, 77.19; H, 9.93.
Found: C, 77.34; H, 9.78.
3.5. (S)-3-Acetoxy-14-tert-butyldiphenylsilyloxytetradec-1-ene 8
3. Experimental
A mixture of ( )-7 (2.0 g, 4.29 mmol), vinyl acetate (5 mL) and
Novozyme 435Ò (0.250 g) was agitated on an orbital shaker at
110 rpm for 5.5 h. The reaction mixture was filtered, and the solu-
tion was concentrated in vacuo to give a residue, which on column
chromatography (silica gel, 0–10% EtOAc/hexane) gave pure (R)-7
3.1. General experimental details
The chemicals (Fluka and Lancaster) were used as received.
Other reagents were of AR grade. All anhydrous reactions were car-
ried out under an Ar atmosphere, using freshly dried solvents. The
organic extracts were dried over anhydrous Na2SO4. The IR spectra
as thin films were scanned with a Jasco model A-202 FT-IR spec-
trometer. The 1H NMR (200 MHz) and 13C NMR (50 MHz) spectra
and (S)-8. (R)-7: Yield: 0.780 g (39%); colorless oil; ½a D22
¼ ꢁ3:0 (c
ꢃ
1.07, CHCl3); (S)-8: Yield: 0.960 g (44%); colorless oil; ½a D22
¼
ꢃ
ꢁ4:4 (c 1.11, CHCl3); IR: 1740, 1033, 930 cmꢁ1
;
1H NMR: d 1.04
(s, 9H), 1.15–1.42 (m, 16H), 1.43–1.65 (m, 4H), 2.04 (s, 3H), 3.65

30
S. Biswas et al. / Tetrahedron: Asymmetry 21 (2010) 27–32
(t, J = 6.4 Hz, 2H), 5.12–5.26 (m, 3H), 5.69–5.80 (m, 1H), 7.31–7.46
(m, 6H), 7.64–7.69 (m, 4H); 13C NMR: d 19.2, 21.2, 25.1, 25.8, 26.9,
29.4, 29.6, 32.6, 34.2, 64.0, 74.8, 116.5, 127.6, 129.5, 134.1, 135.6,
136.7, 170.2. Anal. Calcd for C32H48O3Si: C, 75.54; H, 9.51. Found:
C, 75.39; H, 9.37.
extracts were washed with aqueous saturated NH4Cl (1 ꢂ 10 mL),
dried and concentrated in vacuo to give a residue, which on col-
umn chromatography (silica gel, 0–15% EtOAc/hexane) furnished
13. Yield: 8.90 g (81%); colorless oil; ½a D22
¼ þ5:1 (c 1.14, CHCl3),
ꢃ
{lit.19
½
a 2D2
ꢃ
¼ þ4:2 (c 0.83, CHCl3)}; IR: 3418 cmꢁ1
;
1H NMR: d
0.86 (dist. t, J = 6.8 Hz, 3H), 1.20–1.40 (m, 20H), 1.56–1.62 (m,
8H), 1.94 (br s, 1H), 3.63 (t, J = 6.4 Hz, 1H), 3.87–3.97 (m, 3H);
13C NMR: d 13.9, 22.4, 23.5, 23.7, 24.9, 25.5, 29.1, 29.4, 31.7, 32.4,
34.6, 35.9, 63.9, 70.4, 78.1, 109.2. Anal. Calcd for C19H36O3: C,
73.03; H, 11.61. Found: C, 73.17; H, 11.47.
3.6. (S)-12-Acetoxytetradec-13-en-1-ol 9
To a cooled (0 °C) and stirred solution of 8 (0.950 g, 1.87 mmol)
in THF (5 mL) was added Bu4NF (1.87 mL, 1 M in THF, 1.87 mmol).
The reaction mixture was brought to room temperature and stirred
until the reaction was complete (cf. TLC, 3 h). The mixture was
poured into ice cold water (15 mL) and extracted with EtOAc
(2 ꢂ 10 mL). The organic extract was washed with water
(2 ꢂ 10 mL) and brine (1 ꢂ 5 mL), and dried. Removal of solvent
followed by column chromatography of the residue (silica gel, 0–
15% EtOAc/hexane) furnished 9. Yield: 0.470 g (93%); colorless
3.10. (2R,3S)-3-Benzyloxy-l,2-cyclohexylidenedioxytridecane 14
To a stirred suspension of NaH (1.44 g, 50% suspension in oil,
29.97 mmol) in THF (30 mL) was added 13 (8.5 g, 27.24 mmol))
in THF (30 mL) under Ar. After the evolution of H2 had subsided,
the mixture was refluxed for 1 h, brought to room temperature,
Bu4NI (10 mol %) and BnBr (5.59 g, 32.69 mmol) in THF (30 mL)
was added dropwise. The mixture was refluxed until consumption
of 13 (cf. TLC, ꢀ4 h), brought to room temperature, and treated
with ice-cold H2O (30 mL). The organic layer was separated, the
aqueous portion extracted with Et2O (2 ꢂ 25 mL). The combined
organic extracts were washed with H2O (2 ꢂ 10 mL) and brine
(1 ꢂ 5 mL), and dried. Solvent removal followed by column chro-
matography (silica gel, 0–10% EtOAc/hexane) of the residue fur-
oil; ½a 2D2
ꢃ
¼ ꢁ6:1 (c 1.08, CHCl3); IR: 3421, 1738 cmꢁ1
;
1H NMR: d
1.22–1.39 (m, 16H), 1.52–1.61 (m, 4H), 2.05 (s, 3H), 3.62 (t,
J = 6.6 Hz, 2H), 5.16–5.25 (m, 3H), 5.68–5.84 (m, 1H); 13C NMR: d
21.2, 25.0, 25.7, 29.3, 29.4, 32.6, 34.1, 62.9, 74.8, 116.4, 136.5,
170.4. Anal. Calcd for C16H30O3: C, 71.07; H, 11.18. Found: C,
70.88; H, 11.07.
3.7. (S)-12-Acetoxytetradecan-13-enal 10
nished 14. Yield: 10.19 g (93%); colorless oil; ½a D22
¼ þ5:0 (c 1.16,
ꢃ
As described for 6, oxidation of the alcohol
9
(0.800 g,
CHCl3); IR: 3060, 1644 cmꢁ1 1H NMR: d 0.87 (dist. t, J = 6.4 Hz,
;
2.96 mmol) with PCC (0.958 g, 4.44 mmol) and NaOAc (10 mol %)
3H), 1.15–1.39 (m, 20H), 1.51–1.61 (m, 8H), 3.48–3.56 (m, 1H),
3.86–3.90 (m, 1H), 3.95–4.04 (m, 2H), 4.51–4.73 (m, 2H), 7.29–
7.34 (m, 5H); 13C NMR: d 14.1, 22.7, 23.8, 24.0, 25.0, 25.2, 29.3,
29.6, 29.7, 31.4, 31.9, 34.9, 36.2, 65.8, 72.9, 77.6, 79.0, 109.4,
127.5, 127.8, 128.3, 138.7. Anal. Calcd for C26H42O3: C, 77.56; H,
10.51. Found: C, 77.71; H, 10.47.
in CH2Cl2 (25 mL), followed by work up gave 10. Yield: 0.700 g
(88%); colorless oil;
½
a 2D2
ꢃ
¼ ꢁ4:6 (c 1.04, CHCl3); IR: 2716,
1737 cmꢁ1 1H NMR: d 1.19–1.32 (m, 14H), 1.56–1.65 (m, 4H),
;
2.02 (s, 3H), 2.36–2.41 (m, 2H), 5.09–5.21 (m, 3H), 5.67–5.78 (m,
1H), 9.72 (t, J = 1.5 Hz, 1H); 13C NMR: d 21.1, 21.9, 24.9, 29.0,
29.2, 29.3, 34.0, 43.8, 74.7, 116.4, 136.5, 170.3, 202.1. Anal. Calcd
for C16H28O3: C, 71.60; H, 10.52. Found: C, 71.68; H, 10.67.
3.11. (2R,3S)-3-Benzyloxytridecane-l,2-diol 15
3.8. Ethyl (S)-14-acetoxyhexadeca-2E,15-dienoate 11
A mixture of 14 (5.0 g, 12.44 mmol) and aqueous HCl (6 mL, 2 M)
was stirred at 25 °C until completion of the reaction (cf. TLC, 6 h).
Most of the solvent was removed in vacuo, the residue diluted with
H2O (30 mL) and extracted with EtOAc (3 ꢂ 20 mL). The combined
organic extracts were washed successively with H2O (3 ꢂ 10 mL),
10% aqueous NaHCO3 (2 ꢂ 10 mL), H2O (2 ꢂ 10 mL) and brine
(1 ꢂ 5 mL), and dried. Solvent removal followed by column chroma-
tography (silica gel, 0–5% MeOH–CHCl3) of the residue gave pure 15.
To a cooled (0 °C) and stirred suspension of pentane-washed
NaH (0.140 g, 2.91 mmol, 50% suspension in oil) in THF (5 mL)
was added triethyl phosphonoacetate (0.652 g, 2.91 mmol) in
THF (5 mL). After 15 min, when the solution became clear, the
aldehyde 10 (0.650 g, 2.42 mmol) in THF (5 mL) was injected into
it. After stirring at room temperature for 18 h, the mixture was
poured into ice-water and extracted with Et2O (3 ꢂ 10 mL). The
ether layer was washed with water (2 ꢂ 10 mL) and brine (1 ꢂ 5
mL), dried, and concentrated in vacuo to give a residue, which on
column chromatography (silica gel, 0–10% Et2O/hexane) furnished
Yield: 3.0 g (75%); colorless oil; ½a D22
ꢃ
¼ þ7:3 (c 1.12, CHCl3), (lit.20
½
aꢃD
¼ þ6:4 (c 1.07, CH2Cl2)); IR: 3398, 1620, 1063 cmꢁ1; 1H NMR d
0.87 (dist. t, J = 6.8 Hz, 3H), 1.21–1.59 (m, 18H), 2.72 (br s, 2H),
3.56–3.69 (m, 1H), 3.72–3.78 (m, 3H), 4.51–4.65 (m, 2H), 7.27–
7.36 (m, 5H); 13C NMR: d 14.0, 22.6, 25.2, 29.5, 29.7, 30.3, 31.8,
63.3, 72.5, 72.7, 80.8, 127.7, 127.8, 128.3, 138.1. Anal. Calcd for
C20H34O3: C, 74.49; H, 10.63. Found: C, 74.35; H, 10.80.
pure 11. Yield: 0.630 g (77%); colorless oil; ½a D22
¼ ꢁ5:4 (c 1.03,
ꢃ
CHCl3); IR: 1739, 1722, 982 cmꢁ1 1H NMR: d 1.05–1.31 (m, 17H),
;
1.42–1.61 (m, 4H), 2.05 (s, 3H), 2.12–2.22 (m, 2H), 4.17 (q,
J = 7.2 Hz, 2H), 5.11–5.25 (m, 3H), 5.63–5.84 (m containing a d at
d 5.79, J = 15.8 Hz, 2H), 6.88–7.02 (m, 1H); 13C NMR: d 14.2, 21.2,
24.9, 27.9, 29.0, 29.3, 29.4, 32.0, 34.1, 60.0, 74.8, 116.4, 121.1,
136.5, 149.4, 166.7, 170.3. Anal. Calcd for C20H34O4: C, 70.97; H,
10.12. Found: C, 71.16; H, 10.16.
3.12. (2S,3S)-3-Benzyloxy-l,2-epoxytridecane 16
To
a
cooled (ꢁ20 °C) and stirred solution of 15 (1.16 g,
3.60 mmol) and Et3N (1.76 mL, 12.6 mmol) in EtOAc (12 mL) was
added TMSCl (0.46 mL, 3.6 mmol). After stirring for 20 min, Et3N
(0.8 mL, 5.76 mmol) and MsCl (0.334 mL, 4.32 mmol) were added
successively into the mixture. After stirring for another 30 min, the
mixture was brought to 25 °C, aqueous 2 M aqueous HCl (7.0 mL)
was added and stirring continued for 1 h. The organic layer was sep-
arated, the aqueous portion extracted with EtOAc (2 ꢂ 15 mL) and
the combined organic extracts were washed successively with H2O
(3 ꢂ 10 mL), aqueous 2 M HCl (2 ꢂ 10 mL), H2O (2 ꢂ 10 mL) and
brine (1 ꢂ 5 mL), and dried. Solvent removal afforded the corre-
3.9. (2R,3S)-l,2-Cyclohexylidenedioxytridecan-3-ol 13
To a cooled (ꢁ78 °C) and stirred solution of 1-decyl-Li [prepared
from 1-bromodecane (15.60 g, 70.59 mmol) and Li (1.1 g,
155.29 mmol)] in THF (70 mL) was added 12 (6.0 g, 35.29 mmol)
in THF (30 mL). After stirring the mixture for 3 h at ꢁ78 °C, it
was gradually brought to room temperature and treated with
aqueous saturated NH4Cl, the supernatant was decanted and the
residue washed with Et2O (2 ꢂ 20 mL). The combined organic
sponding 1-hydroxy-2-mesylate. IR: 1456, 1350 cmꢁ1
.

S. Biswas et al. / Tetrahedron: Asymmetry 21 (2010) 27–32
31
A mixture of the above compound (1.14 g, 2.83 mmol) and
anhydrous K2CO3 (1.17 g, 8.48 mmol) in MeOH (20 mL), was stirred
for 3 h at room temperature. The supernatant was decanted, the
solid residue washed with EtOAc (20 mL) and the combined organ-
ic extracts concentrated in vacuo. The residue was taken in EtOAc
(30 mL) washed with H2O (3 ꢂ 15 mL) and brine (1 ꢂ 5 mL), dried
and concentrated in vacuo. Column chromatography (silica gel, 0–
5% EtOAc/hexane) of the residue gave pure 16. Yield: 0.722 g (84%);
gel, 0–15% EtOAc/hexane) furnished pure 19. Yield: 0.095 g (88%);
colorless oil;
½
a 2D2
ꢃ
¼ þ13:2 (c 1.14, CHCl3); IR: 3457, 1740,
1730 cmꢁ1; 1H NMR: d 0.86 (dist. t, J = 6.4 Hz, 3H), 1.23–1.60 (con-
taining a s at d 1.32, 47H), 2.03 (s, 3H), 2.26 (t, J = 7.2 Hz, 2H), 2.69
(br s, 2H), 3.47–3.58 (m, 2H), 4.08 (q, J = 7.0 Hz, 2H), 4.28–4.36 (m,
1H); 13C NMR: d 14.1, 14.2, 21.3, 22.7, 25.0, 25.6, 26.0, 29.1, 29.2,
29.3, 29.6, 30.5, 31.9, 33.6, 34.1, 60.2, 74.3, 74.5, 74.7, 171.3,
174.0. Anal. Calcd for C32H62O6: C, 70.80; H, 11.51. Found: C,
70.54; H, 11.72.
colorless oil; ½a D22
ꢃ
¼ ꢁ22:5 (c 1.28, CHCl3), (lit.20
[
a
]
D = ꢁ17 (c 1.16,
CH2Cl2) for (2R,3S)-16); IR: 1254, 850 cmꢁ1; 1H NMR: d 0.87 (dist. t,
J = 6.8 Hz, 3H), 1.26 (br s, 18H), 2.48–2.52 (dd, t, J = 1.8 Hz, 3.0 Hz,
1H), 2.79 (t, J = 3.0 Hz, 1H), 2.99–3.06 (m, 2H), 4.58 (d, J = 11.7 Hz,
1H), 4.84 (d, J = 11.7 Hz, 1H), 7.26–7.40 (m, 5H); 13C NMR: d 14.1,
22.7, 25.5, 29.3, 29.5, 29.6, 31.9, 32.3, 43.1, 55.1, 71.6, 80.5,
127.4, 127.8, 128.3, 138.7. Anal. Calcd for C20H32O2: C, 78.90; H,
10.59. Found: C, 78.75; H, 10.43.
3.16. Ethyl (14S,17S,18S)-14,17-18-trihydroxyoctacosanoate 20
A mixture of 19 (0.09 g, 0.17 mmol) and Amberlyst 15Ò (0.05 g)
in EtOH (5 mL) was magnetically stirred at 25 °C for 18 h. After fil-
tering the mixture, it was concentrated in vacuo, and the residue
subjected to preparative chromatography (silica gel, 15% EtOAc/
hexane) to obtain pure 20. Yield: 0.077 g (91%); colorless oil;
3.13. (3S,4S)-4-Benzyloxytetradec-1-en-3-ol 17
½
a 2D2
ꢃ
¼ ꢁ11:7 (c 0.912, CHCl3); IR: 3446, 1742 cmꢁ1
;
1H NMR: d
0.87 (dist. t, J = 6.4 Hz, 3H), 1.27–1.56 (containing a s at d 1.30,
47H), 2.32 (t, J = 6.8 Hz, 2H), 2.44 (br s, 2H), 2.82 (br s, 1H), 3.44–
3.65 (m, 3H), 4.10 (q, J = 7.2 Hz, 2H); 13C NMR: d 14.2, 21.2, 22.5,
25.0, 25.3, 25.5, 27.3, 27.7, 29.2, 29.3, 29.8, 30.2, 31.2, 31.9, 32.1,
34.4, 60.7, 72.4, 74.4, 74.7, 169.2. Anal. Calcd for C30H60O5: C,
71.95; H, 12.08. Found: C, 70.54; H, 11.72.
To a cooled (ꢁ40 °C) and stirred suspension of Me3SI (1.57 g,
7.73 mmol) in THF (20 mL) was added n-BuLi (4.31 mL, 1.5 M in
hexane, 6.46 mmol). After stirring for 1 h, compound 16 (0.470 g,
1.55 mmol) in THF (5.0 mL) was injected into the mixture and stir-
ring continued at ꢁ40 °C for 3 h and at room temperature for 12 h.
H2O (15 mL) was added to the mixture, the organic layer separated,
and the aqueous layer extracted with EtOAc (2 ꢂ 10 mL). The com-
bined organic extracts were washed with H2O (1 ꢂ 10 mL), and
brine (1 ꢂ 5 mL), and dried. Solvent removal followed by column
chromatography (silica gel, 0–15% EtOAc/hexane) of the residue
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gave pure 17. Yield: 0.393 g (80%); colorless oil; ½a D22
¼ þ3:1 (c
ꢃ
0.980, CHCl3); IR: 3444, 992, 922 cmꢁ1 1H NMR: d 0.89 (dist. t,
;
J = 6.4 Hz, 3H), 1.27 (br, s, 16H), 1.57–1.63 (m, 2H), 2.55 (br s,
1H), 3.32–3.39 (m, 1H), 4.08–4.17 (m, 1H), 4.55 (d, J = 11.4 Hz,
1H), 4.65 (d, J = 11.4 Hz, 1H), 5.21–5.41 (m, 2H), 5.84–5.95 (m,
1H), 7.34–7.38 (m, 5H); 13C NMR: d 14.1, 22.7, 25.1, 29.4, 29.6,
29.7, 29.9, 30.4, 31.9, 72.6, 74.4, 82.3, 116.8, 127.8, 127.9, 128.5,
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79.05; H, 10.59.
3.14. Ethyl (14S,17S,18S)-14-acetoxy-17-hydroxy-18-benzyloxy-
octacosa-2E,15E/Z-dienoate 18
A mixture of 11 (0.130 g, 0.38 mmol), 17 (0.180 g, 0.56 mmol)
and Grubbs’ 2nd generation catalyst (4 mol %) in CH2Cl2 (15 mL)
was stirred for 22 h. After concentrating the mixture in vacuo,
the residue was subjected to column chromatography (silica gel,
0–15% EtOAc/hexane) to give pure 18. Yield: 0.146 g (61% based
on conversion of 17); colorless oil; ½a D22
ꢃ
¼ ꢁ9:3 (c 1.03, CHCl3);
IR: 3461, 1735, 1722, 972 cmꢁ1
; d 0.85 (dist. t,
1H NMR:
J = 6.2 Hz, 3H), 1.24–1.58 (m containing a s at d 1.30, 39H), 2.03
(s, 3H), 2.15–2.24 (m, 3H), 3.27–3.35 (m, 1H), 4.07–4.28 (m, 4H),
4.47–4.65 (m, 2H), 5.22–5.25 (m, 1H), 5.70–5.83 (m, 2H), 6.98 (d,
J = 16.2 Hz, 1H), 7.35–7.39 (m, 5H); 13C NMR: d 14.0, 21.2, 22.6,
24.9, 25.0, 27.9, 29.0, 29.3, 29.4, 29.5, 29.8, 30.3, 31.8, 32.1, 34.3,
60.0, 72.4, 73.2, 74.1, 82.3, 121.1, 127.7, 128.3, 130.5, 132.3,
138.1, 149.4, 166.7, 170.2. Anal. Calcd for C39H64O6: C, 74.48; H,
10.26. Found: C, 74.72; H, 10.45.
3.15. Ethyl (14S,17S,18S)-14-acetoxy-17,18-dihydroxyoctacosa-
noate 19
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sitive pressure of H2. The mixture was diluted with Et2O (30 mL)
and passed through a small pad of silica gel. Removal of solvent
in vacuo followed by column chromatography of the residue (silica
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