Asymmetric synthesis of the constitutive C22-carboxylic acid of macroviracin A

Article abstract of DOI:10.1016/j.tet.2015.01.010

An efficient asymmetric synthesis of the C₂₂-trihydroxy fatty acid component of macroviracin A has been developed. The key steps were highly enantioselective (i) lipase-catalyzed acylation, (ii) InCl₃-(S)-BINOL mediated allylation, and (iii) asymmetric dihydroxylation (ADH) reaction. The moderate diastereoselectivity of the ADH reaction was overridden by converting the resultant diol diastereomers to the required epoxide enantiomer.

Full text of DOI:10.1016/j.tet.2015.01.010

Accepted Manuscript
Asymmetric synthesis of the constitutive C -carboxylic acid of macroviracin A
22
Seema V. Kanojia, Sucheta Chatterjee, Sunita Gamre, Subrata Chattopadhyay,
Anubha Sharma
PII:
S0040-4020(15)00041-1
10.1016/j.tet.2015.01.010
TET 26333
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 July 2014
Revised Date: 5 January 2015
Accepted Date: 7 January 2015
Please cite this article as: Kanojia SV, Chatterjee S, Gamre S, Chattopadhyay S, Sharma A, Asymmetric
synthesis of the constitutive C -carboxylic acid of macroviracin A, Tetrahedron (2015), doi: 10.1016/
22
j.tet.2015.01.010.
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ACCEPTED MANUSCRIPT
Asymmetric synthesis of the constitutive C22-carboxylic acid of macroviracin
A
Seema V. Kanojia, Sucheta Chatterjee, Sunita Gamre, Subrata Chattopadhyay,
and Anubha Sharma*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai – 400085, India.
E-mail: anubhas@barc.gov.in
Abstract: An efficient asymmetric synthesis of the C22-trihydroxy fatty acid component of
macroviracin A has been developed. The key steps were highly enantioselective (i) lipase-
catalyzed acylation (ii) InCl3-(S)-BINOL mediated allylation, and (iii) asymmetric
dihydroxylation (ADH) reaction. The moderate diastereoselectivity of the ADH reaction was
overridden by converting the resultant diol diastereomers to the required epoxide enantiomer.
Keywords: asymmetric synthesis • total synthesis • antiviral agent • macroviracin A • lipase
catalyzed reaction
1. Introduction
Impressive progress notwithstanding, design of simple and efficient routes for the
asymmetric synthesis of bioactive target compounds remains a challenging research area.1 For
the past several years, this has been the major focus of our research leading to the asymmetric
syntheses of a diverse array of natural compounds.2 The polyhydroxy 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.3 Some of the
examples of this class of compounds include (i) pinellic acid, responsible for the anti-influenza
activity of Kampo medicine,4a (ii) the pharmacophores of the glycosidase inhibitors such as the
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schulzeines,4b penasulfate4c and the penarolides4d, (iii) oxylipins, used by the AIDS patients as
the immune-boosters etc.4e-g A new family of structurally related glycolipids, isolated from the
mycelium of Streptomyces sp. BA 2836 exhibit a powerful and selective activity against various
human pathogens including herpes simplex-, human immunodeficiency- and varicella-zoster
viruses.5 These compounds, designated as macroviracins are classified into eight types of
congeners (A-D) differing in the length (C22 or C24) of their constitutive fatty acid chains forming
the central lactide ring, and the fatty acid appendages. Their antiviral activity is claimed to be 10
times that of acyclovir. Macroviracin A, a member of this family possesses a 42-membered
macrodiolide core with D-glucose residues, and a long side chain attached to the core. Its
structure resembles that of the sugar-fatty acid lactones, cycloviracins and fattiviracins.
The architectural complexity and therapeutic potential of these compounds make them
synthetically challenging and attractive targets to the organic chemists. Earlier, the total
syntheses of cycloviracin B1,6a-d and cycloviracin D have been reported.6e Till today, the only
synthesis of macroviracin A by Nakata’s group also established the (3R,15S,21R)-configuration
of its constituent fatty acid segment.7 In the only reported synthesis of 2, Nakata et al. used 22-26
steps to synthesize similar compounds like 17 bearing different hydroxyl protecting groups. The
C-3 stereogenic centre was created using Sharpless asymmetric epoxidation followed by
destruction of one of the newly created stereogenic centres. The C-15 stereogenic centre was
installed by the Jacobsen protocol of hydrolytic kinetic resolution of terminal epoxides, while the
C-21 stereogenic centre was inherited from the microbial product, (R)-3-hydroxybutanoate.7b In
another longer synthesis,7a Sharpless asymmetric epoxidation and regioselective epoxide
reduction were used to fix the C-15 stereogenic centre. Hence, the present work was focused on
developing a simple and shorter synthesis of the C22-trihydroxy acid derivative 2. A
2

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retrosynthetic analysis (Figure 1) revealed acid 2 as the precursor of the domain structure 1 of
macroviracin A, because its intermolecular macrodimerization is already reported.7 We paid
particular attention to install an orthogonal protecting group on the C-15 hydroxyl group in 2 as
this needs to be glycosylated later for the synthesis of 1.
OH
OH
O
O
O
OH
OH
OH
O
OH
HO
O
OH
HO
O
4
2
O
HO
HO
O
OH
O
HO
O
HO
OH
4
O
O
2
HO
O
OH
O
O
O
O
2
OH
OH
OH
4
HO
O
HO
HO
OH
Macroviracin A
OR2
BnO
O
OR1
BnO
BnO
4
OR1 OR3 OR2
O
O
O
CO2H
2
5
11
2 R1 - R3 = Orthogonal protecting groups
O
OBn
O
O
O
2
OR1
OBn
OBn
4
OR2
1 R1 / R2 = Protecting groups
Figure 1. Retrosynthesis of compound 1.
3

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2. Results and Discussion
The synthesis commenced by α-alkylation of the ketoester 3 with 6-bromo-1-hexene
followed by Krapcho decarboxylation to furnish the ketone 4, which on reduction with LiAlH4
afforded the alcohol (±)-5. For its resolution, the alcohol (±)-5 was subjected to a lipase-
catalyzed trans-acetylation with vinyl acetate in different solvents. Amongst the tested lipases,
Novozym 435® produced the best result, furnishing the acetate (R)-6 (96% ee) and (S)-5 (91%
ee) after 50% conversion (cf. GC, 2 h) in diisopropyl ether solvent. The resolved alcohol (S)-5
was enantiomerically enriched to 98% ee by a second Novozym 435®-catalyzed acetylation
(10% conversion) as above. Alkaline hydrolysis of the acetate (R)-6 with KOH/MeOH furnished
the alcohol (R)-5. The % ees of the enantiomeric alcohols (R)-5 and (S)-5 were determined from
the relative intensities of the methoxyl resonances of the corresponding α-
methoxytrifluoromethyl phenyl acetates (MTPA), prepared using (R)-MTPA chloride.8 The
configurations of the alcohols were assigned by converting a small aliquot of the respective
alkenol enantiomers into known compounds-(R)- and (S)-nonan-2-ols.9 To offset the limitation
of a resolution-based protocol, the alcohol (S)-5 was converted to its enantiomer (R)-5 under the
Mitsunobu conditions (Ph3P/DEAD/p-nitrobenzoic acid/THF; K2CO3/MeOH/25 oC/8 h, 91%).10
The alcohol (R)-5 was silylated with tert-butyldiphenylsilyl chloride (TBDPSCl) in the
presence of imidazole and 4-dimethylaminopyridine (DMAP) to furnish 7 (Scheme 1.).
Asymmetric dihydroxylation11 of the alkene function in 7 with AD-mix β reagent gave a mixture
of C-2 epimers, 8a and 8b in 91:9 ratio, which could be isolated in pure forms by column
chromatography. Reaction of 8a with para-toluene sulphonyl chloride (p-TsCl)/Bu2SnO/Et3N
proceeded regioselectively at the primary carbinol function to furnish the corresponding
monotosylate. This was converted to the epoxide 9 by treatment with K2CO3/MeOH. To make
4

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the synthesis enantioconvergent, the diol 8b was monosilylated at its primary carbinol site with
trimethylchlorosilane (TMSCl), the adjacent hydroxyl function mesylated with
methanesulphonyl chloride (MsCl) and subsequently desilylated in one pot. The resultant
hydroxymesyl compound was treated with K2CO3/MeOH to furnish the epoxide 9.12 This was
reacted with the Grignard reagent, prepared from 11-bromo-1-undecene in the presence of CuBr
as the catalyst to furnish the alcohol 10. The carbinol function in 10 was protected with 3,4-
dihydropyran (DHP) in the presence of pyridinium p-toluenesulphonate (PPTS) in CH2Cl2 to
furnish 11, which on hydroboration-oxidation with BH3.Me2S afforded compound 12. Its Swern
oxidation proceeded uneventfully to furnish the aldehyde 13. For installing the third stereogenic
center, we preferred an InCl3-mediated allylation of 13 with allyl(Bu)3Sn in the presence of (S)-
BINOL and activated 4Å molecular sieves in CH2Cl2 to obtain the alcohol 14 as a single
enantiomer in good yield.13 Consistent with our previous observation,14 the present result
suggested that the stereochemistry of the allylation reaction was dictated exclusively by the
reagent chirality, without a significant contribution from that present in the substrate. The
alcohol 14 was silylated with tert-butyldimethylsilyl chloride (TBSCl) in the presence of
imidazole and DMAP to furnish 15. Lemieux-Johnson oxidation (OsO4/NMO; NaIO4) of the
olefin function in 15 afforded the aldehyde 16 in 87% yield. Finally, this was subjected to
Pinnick oxidation with NaClO2 to furnish the desired acid 17 (compound 2 equivalent).
The transformation of 17 to 1 would require (i) chemoselective deprotection of the OTHP
group of its ester under neutral conditions to avoid any desilylation; (ii) glycolyzation of the
resultant alcohol; and (iii) macrolactonization after ester hydrolysis and removal of the TBS
group. Hence we converted compound 17 to the hydroxyester 18 by its esterification with CH2N2
and its depranylation with CuCl2.2H2O in MeOH at room temperature.15 The subsequent
5

ACCEPTED MANUSCRIPT
conversion of 18 to 1 can be achieved following Nakata’s protocol7b and some routine synthetic
steps.
3. Conclusion
Overall, we have developed an enantioconvergent synthesis of the C22-trihydroxy acid
segment of macroviracin A in ~4.5% overall yield in 16 steps. A chemoselective protocol for its
conversion the corresponding C-15 hydroxy ester, an advanced precursor of 1 was also
demonstrated. The required stereogenic centres in the target compound were installed using a
lipase-catalyzed acetylation, an asymmetric dihydroxylation and a reagent-controlled asymmetric
allylation. Compared to the reported procedures of 2,7 our synthesis is much shorter, does not
involve destruction of any stereogenic centre, employs highly enantioselective transformations,
and is enantioconvergent. Besides, like the previous reported procedure,7a our synthesis can also
be used to synthesize all the stereoisomers of 17 or 18 by using the suitable enantiomer of 5 and
proper choice of the chiral auxiliaries for asymmetric dihydroxylation and allylation.
6

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OR
OH
O
O
O
iii
ii
i
(S)-5
+
5
5
50%
6: 96% ee
OMe
81%
5
65%
6: R = Ac
(R)-5: R = H
iv
81%
(+)-5
3
4
OR OH
OTBDPS
OR OH
vi
95%
8a:8b = 91:9
v
OH
OH +
83%
5
5
5
8b
7
R = TBDPS
8a
OTBDPS
vii
O
viii
73%
from 8a
5
65%
9
OR1 OR2
OR1 OR2
OR1 OR2
xii
88%
xi
88%
ix
CHO
OH
9
5
11
5
11
5
10
90%
R1 = TBDPS, R2 = THP
R1 = TBDPS, R2 = THP
R1 = TBDPS
10: R2 = H
12
13
x
94%
11: R2 = THP
OR1 OR2 OTBS
OR1 OR2 OR3
OR1 OR2 OTBS
CO2R3
xiii
xv
xvi
CHO
5
11
77%
87%
5
11
63%
5
11
R1 = TBDPS, R2 = THP
R1 = TBDPS, R2 = THP
R1 = TBDPS
17 R2 = THP, R3 = H
18 R2 = H, R3 = Me
>97% ee
14: R3 = H
15: R3 = TBS
16
xiv
81%
xvii
80%
Scheme 1
o
o
i) (a) NaOMe/MeOH/6-bromo-1-hexene/65 C/3.5 h; (b) aqueous NaOH/25 C/2 h; (c) aqueous
o
o
H2SO4/80 C/3 h, ii) LiAlH4/Et2O/25 C/2 h, iii) Vinyl acetate/diisopropyl ether/Novozym
435®/25 oC/1.5 h, iv) KOH/aqueous MeOH/25 oC/3 h, v) TBDPSCl/imidazole/
o
o
DMAP/CH2Cl2/25 C/7 h, vi) AD-mix β/tert-BuOH-H2O (1:1)/0 C/72 h, vii) (a) p-TsCl/
Bu2SnO/Et3N/CH2Cl2/25 oC/3 h; (b) K2CO3/MeOH/25 oC/3 h, viii) (a) TMSCl/ Et3N/EtOAc/-20
oC/30 min; (b) MsCl/Et3N/ -20 oC/30 min; (c) aqueous 2N HCl/25 oC/1 h; (d) K2CO3/MeOH/25
o
o
oC/3 h, ix) CH2=CH(CH2)9MgBr/THF/CuBr/-60 C/1.5 h; 25 C/3 h, x) DHP/PPTS/CH2Cl2/25
oC/3 h, xi) (a) BH3.Me2S/THF/0 to 25 oC/1.5 h; (b) aqueous NaOH/H2O2/0 oC/1 h; 25 oC/3 h, xii)
7

ACCEPTED MANUSCRIPT
o
o
(COCl)2/DMSO/Et3N/CH2Cl2/-78 C/0.5 h; 25 C/2 h, xiii) AllylSn(Bu)3/InCl3/4Å molecular
o
o
sieve/(S)-BINOL/CH2Cl2/-78 C/4 h then 25 C/16 h, xiv) TBSCl/imidazole/DMAP/CH2Cl2/25
o
oC/4 days, xv) (a) OsO4/NMO/tert-BuOH/acetone-H2O (8:1)/25 C/12 h; (b) NaIO4/MeCN-
o
o
o
H2O/25 C/2 h, xvi) NaClO2/NaH2PO4/30%H2O2 /MeCN-H2O /0 C/0.5 h; 15 C/6 h, xvii) (a)
CH2N2/Et2O/0 oC/2 h; (b) CuCl2.2H2O/MeOH/25 oC/12 h.
4. Experimental Section
4.1 General Details
All chemicals (Fluka and Lancaster) were used as received. Other reagents were of AR
grade. The anhydrous reactions were carried out under an Ar atmosphere, using freshly dried
solvents. The organic extracts were dried over anhydrous Na2SO4. The IR spectra as thin films
1
13
were scanned with a Jasco model A-202 FT-IR spectrometer. The H NMR (200 MHz) and C
(50 MHz) NMR spectra were recorded with Bruker AC-200 spectrometers in CDCl3. The optical
rotations were recorded with a Jasco DIP 360 digital polarimeter. The CHN analyses were
carried out with a vario Micro cube Elementar analyzer.
4.2 8-Nonen-2-one 4
To a stirred solution of NaOMe [prepared from Na (2.37 g, 10.29 mmol) in MeOH (15
mL)] was dropwise added 3 (10.86 g, 9.35 mmol) at room temperature. After refluxing the
mixture for 0.5 h, 6-bromo-1-hexene (1.83 g, 11.22 mmol) was added into it, and refluxing
continued for an additional 3 h. The mixture was concentrated in vacuo and the residue taken in
EtOAc (50 mL). The organic extract was washed with H2O (3 × 15 mL) and brine (1 × 5 mL),
dried and concentrated in vacuo. The residue was column chromatographed (silica gel, 0-5%
EtOAc/hexane) to afford the α-alkylated ketoester (13.4 g, 72%) as a colorless oil; [Found: C,
66.69; H, 9.27. C11H18O3 requires C, 66.64; H, 9.15%]; Rf (15% EtOAc/hexane) 0.72; ῡ (liquid
8

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film) 1745 cm-1; δH 1.24-1.43 (m, 4H), 1.81-1.86 (m, 2H), 1.98-2.04 (m, 2H), 2.22 (s, 3H), 3.40
(t, J = 7.3 Hz, 1H), 3.72 (s, 3H), 4.90-5.01 (m, 2H) 5.69-5.78 (m, 1H); δC 26.5, 27.7, 28.2, 28.4,
33.0, 51.9, 59.2, 114.2, 138.1, 169.9, 202.5.
A mixture of the above compound (10.4 g, 52.52 mmol) and aqueous 5% NaOH (100
mL) was stirred for 2 h at room temperature, acidified by dropwise addition of aqueous 50%
H2SO4 (50 mL) at 0 oC, and subsequently heated at 80 oC for 3 h. The mixture was extracted with
Et2O (3 × 30 mL), the combined organic extracts washed with H2O (3 × 15 mL) and brine (1 × 5
mL), dried and concentrated in vacuo. The residue was column chromatographed (silica gel, 0-
5% EtOAc/hexane) to furnish pure 4 (6.7 g, 91%) as a colorless liquid; [Found: C, 77.22; H,
11.86. C9H16O requires C, 77.09; H, 11.50%]; Rf (10% Et2O/hexane) 0.81; ῡ (liquid film) 1715,
1641 cm-1; δH 1.28-1.34 (m, 2H), 1.38-1.42 (m, 2H), 1.56-1.61 (m, 2H), 2.02-2.05 (m, 2H), 2.13
(s, 3H), 2.42 (t, J = 7.2 Hz, 2H), 4.92-5.00 (m, 2H), 5.74-5.84 (m, 1H); δC 23.5, 28.4, 28.5, 29.6,
33.4, 43.5, 114.2, 138.6, 208.8.
4.3 (±)-8-Nonen-2-ol 5
To a stirred suspension of LiAlH4 (2.72 g, 71.58 mmol) in Et2O (100 mL) was dropwise
added 4 (6.30 g, 45.00 mmol) in Et2O (100 mL) and the mixture stirred for 2 h at room
temperature till completion of the reaction (cf. TLC). The mixture was treated with aqueous
saturated Na2SO4, filtered through a pad of celite, and the filtrate concentrated in vacuo to obtain
a residue, which on column chromatography (silica gel, 0-5% Et2O/hexane) afforded pure 5 (5.2
g, 81%) as a colorless liquid; [Found: C, 75.78; H, 13.05. C9H18O requires C, 76.00; H, 12.76%];
Rf (15% EtOAc/hexane) 0.56; ῡ (liquid film) 3363, 992 cm-1; δH 1.17 (d, J = 6.6 Hz, 3H), 1.38-
1.48 (m, 7H), 1.58-1.67 (m, 2H), 2.02-2.06 (m, 2H), 3.77-3.81 (m, 1H), 4.92-5.01 (m, 2H), 5.76-
5.83 (m, 1H); δc 23.3, 28.8, 29.0, 33.6, 39.1, 68.1, 114.1, 138.9.
9

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4.4 (R)-8-Acetoxynon-1-ene 6
A mixture of (±)-5 (4.6 g, 32.39 mmol) and Novozym 435® (1.0 g) in vinyl acetate (10.0
mL) was agitated on an orbital shaker at 110 rpm for 1.5 h. The reaction mixture was diluted
with Et2O (15 mL), filtered, and the filtrate concentrated in vacuo to get a residue, which on
column chromatography (silica gel, 0-10% Et2O/hexane) gave pure (R)-6 (2.6 g, 44%) and (S)-5
23
(1.9 g, 41%) as colorless liquids. (S)-5: [α]D +5.4 (c 1.36, CHCl3); (R)-6: [Found: C, 71.81; H,
23
11.05. C11H20O2 requires C, 71.70; H, 10.94%]; Rf (10% Et2O/hexane) 0.80; [α]D -0.8 (c 1.7,
CHCl3); ῡ (liquid film) 1738, 911 cm-1; δH 1.19 (d, J = 6.0 Hz, 3H), 1.27-1.38 (m, 5H), 1.40-
1.48 (m, 1H), 1.55-1.64 (m, 2H), 2.02-2.06 (m containing a s at δ 2.04, 5H), 4.87-5.01 (m, 3H),
5.77-5.82 (m, 1H); δC 19.9, 21.3, 25.2, 28.8, 33.6, 35.8, 70.9, 114.2, 138.9, 170.7.
4.5 (R)-8-Nonen-2-ol 5
A mixture of (R)-6 (2.00 g, 10.87 mmol) and KOH (0.700 g, 12.50 mmol) in MeOH (25
mL) was stirred at room temperature for 3 h. The mixture was filtered, concentrated in vacuo,
diluted with H2O (30 mL) and extracted with Et2O (2 × 20 mL). The organic extracts were
washed with H2O (2 × 10 mL) and brine (1 × 5 mL), and dried. Removal of solvent in vacuo
followed by column chromatography of the residue (silica gel, 0-10% Et2O/hexane) afforded
pure (R)-5 (1.3 g, 81%) as a colorless liquid; [Found: C, 75.78; H, 12.72. C9H18O requires C,
25
76.00; H, 12.76%]; Rf (15% EtOAc/hexane) 0.56; [α]D -6.7 (c 1.35, CHCl3); ῡ (liquid film)
3363, 992, 909 cm-1; δH 1.17 (d, J = 6.2 Hz, 3H), 1.22-1.46 (m, 9H), 2.00-2.10 (m, 2H), 3.75-
3.89 (m, 1H), 4.89-5.00 (m, 2H), 5.70-5.84 (m, 1H); δC 23.4, 28.4, 28.9, 33.5, 38.9, 67.8, 114.1,
138.8.
4.6 (R)-8-tert-Butyldiphenylsilyloxynon-1-ene 7
10

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A solution of (R)-5 (1.12 g, 7.88 mmol), TBDPSCl (2.60 g, 9.46 mmol), imidazole (0.805
g, 11.83 mmol) and DMAP (catalytic) in CH2Cl2 (20 mL) was stirred for 7 h at room
temperature. The mixture was poured into ice-cold H2O (20 mL), the organic layer separated,
and the aqueous portion extracted with CHCl3 (3 × 10 mL). The combined organic extracts were
washed with water (2 × 10 mL), and brine (1 × 5 mL), and dried. Removal of solvent in vacuo
followed by column chromatography (silica gel, 0-5% EtOAc/hexane) of the residue afforded
25
pure 7 (2.5 g, 83%) as a colorless liquid; [α]D +16.0 (c 1.10, CHCl3); [Found: C, 78.52; H,
9.73. C25H36OSi requires C, 78.89; H, 9.53%]; Rf (10% Et2O/hexane) 0.90; [α]D25 +16.0 (c 1.10,
CHCl3); ῡ (liquid film) 1641, 997 cm-1; δH 1.09 (merged s and d, J = 6.0 Hz, 12H), 1.25-1.36 (m,
8H), 1.98-2.09 (m, 2H), 3.83-3.92 (m, 1H), 4.94-5.07 (m, 2H), 5.77-5.90 (m, 1H), 7.38-7.47 (m,
6H), 7.71-7.75 (m, 4H); δC 19.4, 23.3, 25.2, 27.1, 28.9, 29.2, 29.8, 33.8, 39.5, 69.7, 114.2, 127.5,
129.5, 134.7, 135.1, 136.0, 139.3. Anal. Calcd. for C25H36OSi: C, 78.89; H, 9.53%. Found: C,
78.52; H, 9.73%.
4.7 (2R,8R)/(2S,8R)-8-tert-Butyldiphenylsilyloxynonane-1,2-diol 8a/8b
To a cooled (0 °C) and stirred solution of 7 (2.40 g, 6.32 mmol) in aqueous 50% tert-
BuOH (100 mL) was added AD-mix β (8.84 g, 1.4 g/mmol), and the mixture stirred till
completion of the reaction (cf. TLC, ~ 72 h). Aqueous saturated Na2SO3 was added to the
mixture, the organic layer separated and the aqueous portion extracted with CHCl3 (3 × 10 mL).
The combined organic extracts were washed with H2O (3 × 10 mL) and brine (1 × 5 mL), dried
and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-
10% Et2O/hexane) to afford pure 8a (2.23 g, 85%) and 8b (0.24 g, 9%) as colorless liquids. 8a:
[Found: C, 72.67; H, 9.54. C25H38O3Si requires C, 72.41; H, 9.24%]; Rf (5% MeOH/CHCl3)
0.40; [α]D23 +11.3 (c 1.04, CHCl3); ῡ (liquid film) 3428, 3071 cm-1; δH 1.06 (merged s and d, J =
11

ACCEPTED MANUSCRIPT
6.2 Hz, 12H), 1.17-1.39 (m, 10H), 1.78 (broad s, 2H), 3.42-3.45 (m, 1H), 3.64-3.67 (m, 2H),
3.80-3.84 (m, 1H), 7.37-7.41 (m, 6H), 7.67-7.70 (m, 4H); δC 19.3, 19.5, 23.3, 25.5, 27.1, 29.7,
25
33.1, 39.4, 66.8, 69.5, 72.3, 127.5, 129.4, 135.9. 8b: [α]D +17.6 (c 1.06, CHCl3); [Found: C,
25
72.55; H, 9.04. C25H38O3Si requires C, 72.41; H, 9.24%]; Rf (5% MeOH/CHCl3) 0.42; [α]D
+17.6 (c 1.06, CHCl3); ῡ (liquid film) 3401, 3071 cm-1; δH 1.08 (merged s and d, J = 6.2 Hz,
12H), 1.18-1.43 (m, 10H), 1.80 (broad s, 2H), 3.25-3.28 (m, 1H), 3.47-3.85 (m, 3H), 7.31-7.40
(m, 6H), 7.63-7.68 (m, 4H); δC 19.2, 19.4, 23.1, 25.2, 25.5, 27.0, 33.1, 39.2, 69.4, 70.7, 76.0,
127.3, 127.4, 129.3, 129.4, 134.4, 134.7, 135.8.
4.8 (2R,8R)-8-tert-Butyldiphenylsilyloxy-1,2-epoxynonane 9 (from 8a)
To a stirred solution of 8a (2.23 g, 5.39 mmol) in CH2Cl2 (50 mL) were added Bu2SnO
(0.040 g, 0.16 mmol), Et3N (0.93 mL, 6.68 mmol) and p-TsCl (1.08 g, 5.66 mmol). After stirring
for 3 h at room temperature, brine (10 mL) was added and the mixture extracted with CHCl3 (2 ×
20 mL). The combined organic extracts were washed with H2O (1 × 10 mL), and brine (1 × 5
mL), and dried. Solvent removal followed by column chromatography (silica gel, 0-15% EtOAc-
hexane) of the residue furnished the corresponding monotosylate (2.5 g, 83%) as a colorless
liquid; [Found: C, 67.55; H, 7.84. C32H44O5SSi requires C, 67.57; H, 7.80%]; Rf (20%
22
EtOAc/hexane) 0.45; [α]D +8.6 (c 1.00, CHCl3); ῡ (liquid film) 3500, 1362, 1177 cm-1; δH
1.03-1.06 (merged s and d, 12H), 1.15-1.34 (m, 10H), 1.81 (broad s, 1H), 2.44 (s, 3H), 3.76-3.89
(m, 3H), 3.98-4.04 (m, 1H), 7.33-7.41 (m, 8H), 7.64-7.67 (m, 4H), 7.78-7.82 (m, 2H); δC 19.2,
21.6, 23.2, 25.0, 27.0, 29.3, 32.5, 39.2, 69.3, 69.4, 73.9, 127.3, 127.4, 127.9, 129.3, 129.4, 129.9,
132.6, 134.5, 134.8, 135.8, 144.9.
A mixture of the above compound (2.50 g, 4.40 mmol) and anhydrous K2CO3 (1.22 g, 8.80
mmol) in MeOH (10 mL) was stirred for 3 h at room temperature. The supernatant was decanted,
12

ACCEPTED MANUSCRIPT
concentrated in vacuo, diluted with H2O (20 mL) and extracted with EtOAc (3 × 10 mL). The
organic extract was washed with H2O (3 × 10 mL), and brine (1 × 5 mL), and dried. Solvent
removal followed by column chromatography (silica gel, 0-15% EtOAc/hexane) of the residue
gave pure 9 (1.53 g, 88%) as a colorless liquid; [Found: C, 75.91; H, 9.09. C25H36O2Si requires
C, 75.70; H, 9.15%]; Rf (10% EtOAc/hexane) 0.84; [α]D22 +13.8 (c 1.05, CHCl3); ῡ (liquid film)
1241, 822 cm-1; δH 1.03 (merged s and d, J = 6.0 Hz, 12H), 1.29-1.48 (m, 10H), 2.41-2.45 (m,
1H), 2.71-2.75 (m, 1H), 2.82-2.91 (m, 1H), 3.77-3.86 (m, 1H), 7.32-7.41 (m, 6H), 7.64-7.70 (m,
4H); δC 19.0, 23.0, 24.9, 25.6, 26.8, 29.1, 32.1, 39.0, 46.6, 51.9, 63.2, 127.2, 129.2, 134.2, 134.5,
135.3, 135.6.
4.9 (2R,8R)-8-tert-Butyldiphenylsilyloxy-1,2-epoxynonane 9 (from 8b)
o
To a cooled (-20 C) and stirred solution of 8b (0.240 g, 0.58 mmol) and Et3N (0.3 mL,
2.03 mmol) in EtOAc (2 mL) was added TMSCl (0.074 mL, 0.58 mmol). After stirring for 0.5 h,
Et3N (0.13 mL, 0.93 mmol) and MsCl (0.05 mL, 0.69 mmol) were successively added into the
mixture. After stirring for another 0.5 h, the mixture was brought to 25 °C, aqueous 2M HCl (2
mL) was added and stirring continued for 1 h. The organic layer was separated, the aqueous
portion extracted with EtOAc (3 × 10 mL) and the combined organic extracts washed
successively with H2O (3 × 10 mL), aqueous 2M HCl (2 × 10 mL), H2O (2 × 10 mL) and brine
(1 × 5 mL), and dried. Solvent removal afforded the corresponding 1-hydroxy-2-mesylate, which
was used as such for the next step.
A mixture of the above compound (0.238 g, 0.50 mmol) and anhydrous K2CO3 (0.139 g,
1.01 mmol) in MeOH (5 mL), was stirred for 3 h at room temperature. The supernatant was
decanted, the solid residue washed with EtOAc (20 mL) and the combined organic extracts
concentrated in vacuo. The residue was taken in EtOAc (20 mL) washed with water (2 × 10 mL)
13

ACCEPTED MANUSCRIPT
and brine (1 × 5 mL), and dried. Removal of solvent in vacuo followed by column
chromatography (silica gel, 0-10% EtOAc/hexane) of the residue afforded pure 9 (0.149 g, 65%)
24
as a colorless oil. [α]D +13.6 (c 1.01, CHCl3). Rf (10% EtOAc/hexane) 0.83. Its IR and NMR
spectral data were similar to that synthesized from 8a.
4.10 (2R,8S)-2-tert-Butyldiphenylsilyloxy-19-eicosen-8-ol 10
To a cooled (-60 °C) and stirred solution of the Grignard reagent prepared from 11-
bromoundec-1-ene (1.80 g, 7.73 mmol) and Mg (0.222 g, 9.27 mmol) in THF (80 mL) was
added CuBr (catalytic) followed by 9 (1.53 g, 3.86 mmol) in THF (20 mL) after 0.5 h. Stirring
was continued for 1 h at -60 °C and 3 h at room temperature. The mixture was treated with
aqueous saturated NH4Cl, the organic layer separated and the aqueous portion extracted with
Et2O (3 × 20 mL). The combined organic extracts were washed with water (2 × 10 mL) and brine
(1 × 5 mL), dried, concentrated in vacuo, and the residue column chromatographed (silica gel, 0-
10% Et2O/hexane) to obtain pure 10 (1.9 g, 90%) as a colorless liquid; [Found: C, 78.11; H,
10.90. C36H58O2Si requires C, 78.48; H, 10.61%]; Rf (10% EtOAc/hexane) 0.54; [α]D23 +10.7 (c
1.03, CHCl3); ῡ (liquid film) 3358, 909 cm-1; δH 1.03 (merged s and d, J = 6.0 Hz, 12H), 1.26-
1.49 (m, 29H), 1.97-2.07 (m, 2H), 3.47-3.67 (s, 1H), 3.74-3.85 (m, 1H), 4.88-5.03 (m, 2H), 5.70-
5.90 (m, 1H), 7.34-7.39 (m, 6H), 7.64-7.68 (m, 4H); δC 19.1, 23.2, 25.1, 25.5, 25.6, 26.9, 28.8,
29.1, 29.4, 29.5, 29.6, 29.7, 33.7, 37.3, 37.4, 39.3, 69.4, 71.7, 114.1, 127.3, 129.2, 129.3, 134.5,
134.8, 135.8, 139.0.
4.11 (13S,19R)-19-tert-Butyldiphenylsilyloxy-13-tetrahydropyranyloxyeicosene 11
A solution of 10 (1.20 g, 2.18 mmol), DHP (0.275 g, 3.27 mmol) and PPTS (catalytic) in
CH2Cl2 (20 mL) was stirred for 3 h at room temperature. The mixture was poured into aqueous
5% NaHCO3 (20 mL), the organic layer separated and the aqueous portion extracted with CHCl3
14

ACCEPTED MANUSCRIPT
(3 × 10 mL). The combined organic extracts were washed with water (2 × 10 mL) and brine (1 ×
5 mL), and dried. Removal of solvent in vacuo followed by column chromatography (silica gel,
0-10% EtOAc/hexane) of the residue afforded pure 11 (1.3 g, 94%) as a colorless liquid; [Found:
C, 77.31; H, 10.35. C41H66O3Si requires C, 77.54; H, 10.48%]; Rf (10% EtOAc/hexane) 0.84;
[α]D22 +9.4 (c 1.13, CHCl3); ῡ (liquid film) 1375, 999 cm-1; δH 1.05 (merged s and d, 12H), 1.26-
1.63 (m, 34H), 1.97-2.08 (m, 2H), 3.43-3.59 (m, 2H), 3.77-3.93 (m, 2H), 4.63 (broad s, 1H),
4.89-5.03 (m, 2H), 5.70-5.91 (m, 1H), 7.34-7.41 (m, 6H), 7.64-7.68 (m, 4H); δC 19.2, 19.9, 23.2,
24.9, 25.0, 25.2, 25.6, 27.0, 28.9, 29.1, 29.5, 29.6, 29.8, 31.2, 33.4, 33.5, 33.8, 34.9, 35.0, 39.4,
62.6, 69.6, 76.6, 97.4, 114.1, 127.4, 127.5, 129.3, 129.4, 134.6, 134.9, 135.5, 135.8, 139.1.
4.12 (13S,19R)-19-tert-Butyldiphenylsilyloxy-13-tetrahydropyranyloxyeicosan-1-ol 12
To a cooled (0 °C) and stirred solution of 11 (1.10 g, 1.74 mmol) in THF (25 mL) was
injected BH3.Me2S (0.58 mL, 2M in THF, 1.16 mmol). After 0.5 h, the solution was brought to
room temperature, stirred for 1 h at room temperature and treated with aqueous 3N NaOH (1
mL). After cooling to 0 °C, H2O2 (1 mL) was added slowly, stirring continued for 1 h at 0 °C and
for 3 h at room temperature. The mixture was poured into H2O (20 mL), the organic layer
separated and the aqueous portion extracted with EtOAc (3 × 10 mL). The combined organic
extracts were washed with water (2 × 10 mL) and brine (1 × 5 mL), and dried. Removal of
solvent in vacuo followed by column chromatography (silica gel, 0-10% EtOAc/hexane) of the
residue afforded pure 12 (1.0 g, 88%) as a colorless liquid; [Found: C, 75.23; H, 10.62.
27
C41H68O4Si requires C, 75.40; H, 10.50%]; Rf (15% EtOAc/hexane) 0.45; [α]D +7.9 (c 1.10,
CHCl3); ῡ (liquid film) 3409, 1023 cm-1; δH 1.05 (merged s and d, 12H), 1.24-1.60 (m, 39H),
3.49-3.65 (m, 4H), 3.76-3.89 (m, 2H), 4.61 (broad s, 1H), 7.31-7.46 (m, 6H), 7.62-7.74 (m, 4H);
15

ACCEPTED MANUSCRIPT
δC 19.2, 19.9, 21.0, 23.2, 25.0, 25.5, 25.6, 25.7, 27.0, 29.4, 29.6, 29.8, 31.2, 32.8, 33.4, 35.0,
39.4, 60.4, 62.6, 63.0, 69.5, 76.7, 97.4, 127.3, 127.4, 129.3, 129.4, 134.6, 134.9, 135.8.
4.13 (13S,19R)-19-tert-Butyldiphenylsilyloxy-13-tetrahydropyranyloxyeicosanal 13
To a cooled (-78 °C) and stirred solution of oxalyl chloride (0.119 g, 0.94 mmol) in
CH2Cl2 (20 mL) was added DMSO (0.15 mL, 2.15 mmol). After stirring for 10 min, 12 (0.560 g,
0.86 mmol) was added, followed by Et3N (0.60 mL, 4.29 mmol) after 20 min. After stirring for 2
h at room temperature, the reaction mixture was poured into H2O (20 mL), the organic layer
separated and the aqueous portion extracted with CHCl3 (3 × 10 mL). The combined organic
extracts were washed with water (2 × 10 mL) and brine (1 × 5 mL), and dried. Removal of
solvent in vacuo followed by column chromatography (silica gel, 0-10% EtOAc/hexane) of the
residue afforded pure 13 (0.490 g, 88%) as a colorless oil; [Found: C, 75.91; H, 10.12.
22
C41H66O4Si requires C, 75.64; H, 10.22%]; Rf (10% EtOAc/hexane) 0.75; [α]D +9.8 (c 1.00,
CHCl3); ῡ (liquid film) 2719, 1720 cm-1; δH 1.04 (merged s and d, 12H), 1.24-1.81 (m, 36H),
2.36-2.45 (m, 2H), 3.44-3.64 (m, 2H), 3.77-3.90 (m, 2H), 4.62 (broad s, 1H), 7.32-7.41 (m, 6H),
7.64-7.68 (m, 4H), 9.75 (t, J = 1.8 Hz, 1H); δC 19.1, 19.9, 21.9, 23.1, 23.7, 24.9, 25.1, 25.5, 26.8,
26.9, 29.0, 29.2, 29.3, 29.4, 29.5, 29.7, 31.1, 33.3, 33.4, 34.8, 34.9, 39.2, 39.3, 43.6, 43.8, 62.7,
69.4, 76.5, 97.3, 127.3, 129.2, 134.5, 134.8, 135.4, 135.7, 202.6, 209.1.
4.14 (4R,16S,22R)-22-tert-Butyldiphenylsilyloxy-16-tetrahydropyranyloxytricos-1-en-4-ol
14
A mixture of azeotropically dried InCl3 (0.037 g, 0.16 mmol), (S)-BINOL (0.047 g, 0.16
mmol) and molecular sieve 4Å (0.04 g) in CH2Cl2 (20 mL) was stirred for 2 h followed by slow
addition of allylBu3Sn (0.46 mL, 1.51 mmol). After 10 min, the reaction mixture was cooled to -
78 °C and 13 (0.490 g, 0.75 mmol) added dropwise. After stirring at -78 °C for 4 h and at room
16

ACCEPTED MANUSCRIPT
temperature for 16 h, the reaction mixture was treated with aqueous saturated NH4Cl. The
organic layer was separated and the aqueous portion extracted with CHCl3 (2 × 10 mL). The
combined organic extracts were washed with water (2 × 10 mL) and brine (1 × 5 mL), dried and
concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-10%
Et2O/hexane) to afford pure 14 (0.400 g, 77%) as a colorless oil; [Found: C, 76.39; H, 10.68.
25
C44H72O4Si requires C, 76.24; H, 10.47%]; Rf (10% EtOAc/hexane) 0.67; [α]D +9.4 (c 1.20,
CHCl3); ῡ (liquid film) 3457, 998 cm-1; δH 1.02 (merged s and d, J = 6.0 Hz, 12H), 1.25-1.79
(m, 39H), 2.07-2.32 (m, 2H), 3.49-3.66 (m, 3H), 3.76-3.85 (m, 2H), 4.61 (broad s, 1H), 5.08-
5.15 (m, 2H), 5.71-5.85 (m, 1H), 7.33-7.40 (m, 6H), 7.63-7.67 (m, 4H); δC 19.2, 19.9, 23.2, 24.9,
25.2, 25.5, 25.6, 27.0, 29.6, 29.8, 31.1, 33.3, 35.0, 36.7, 37.3, 39.3, 41.9, 62.5, 69.5, 70.6, 76.4,
97.3, 117.9, 127.3, 129.3, 134.5, 134.9, 135.5, 135.8.
4.15
(4R,16S,22R)-4-tert-Butyldimethylsilyloxy-22-tert-butyldiphenylsilyloxy-16-
tetrahydropyranyloxytricos-1-ene 15
A mixture of 14 (0.300 g, 0.43 mmol), TBSCl (0.098 g, 0.65 mmol), imidazole (0.044 g,
0.65 mmol) and DMAP (catalytic) in CH2Cl2 (20 mL) was stirred at room temperature for 4
days. It was poured into ice-cold water (20 mL), the organic layer was separated and the aqueous
portion extracted with CHCl3 (3 × 10 mL). The combined organic extracts were washed with
water (2 × 10 mL) and brine (1 × 5 mL), and dried. Removal of solvent in vacuo followed by
column chromatography (silica gel, 0-5% EtOAc/hexane) of the residue afforded pure 15 (0.283
g, 81%) as a colorless liquid; [Found: C, 74.20; H, 10.89. C50H86O4Si2 requires C, 74.38; H,
24
10.74%]; Rf (10% EtOAc/hexane) 0.81; [α]D +8.5 (c 1.17, CHCl3); ῡ (liquid film) 1640, 912
cm-1; δH 0.03 and 0.05 (two s, 6H), 0.87 (s, 9H), 1.03 (merged s and d, 12H), 1.25-1.83 (m, 38H),
2.15-2.33 (m, 2H), 3.44-3.69 (m, 3H), 3.76-3.92 (m, 2H), 4.63-4.65 (m, 1H), 4.97-5.09 (m, 2H),
17

ACCEPTED MANUSCRIPT
5.73-5.81 (m, 1H), 7.31-7.40 (m, 6H), 7.64-7.68 (m, 4H); δC -4.6, -4.4, 18.1, 19.2, 19.8, 19.9,
23.2, 25.0, 25.2, 25.3, 25.5, 25.6, 25.9, 27.0, 29.6, 29.7, 29.8, 31.2, 33.3, 34.7, 35.0, 36.8, 37.9,
39.4, 39.8, 41.9, 62.6, 69.6, 72.0, 75.3, 96.8, 97.4, 116.5, 116.9, 127.3, 127.4, 129.3, 134.6,
134.9, 135.5, 135.8.
4.16
(3R,15S,21R)-3-tert-Butyldimethylsilyloxy-21-tert-butyldiphenylsilyloxy-15-
tetrahydropyranyloxydocosanal 16
To a stirred solution of 15 (0.200 g, 0.25 mmol) in acetone:water (8:1, 20 mL) were
added NMO (0.067 g, 0.50 mmol) and OsO4 (0.004 g, 0.012 mmol) in tert-BuOH (1 mL). After
stirring overnight, the mixture was treated with aqueous saturated Na2SO3, the organic layer
separated and the aqueous portion extracted with Et2O (3 × 10 mL). The combined organic
extracts were washed with water (2 × 10 mL) and brine (1 × 5 mL), and dried. Removal of
solvent in vacuo followed by preparative thin layer chromatography (silica gel, 10%
EtOAc/hexane) of the residue afforded the pure diol (0.200 g, 99%) as a colorless thick oil;
[Found: C, 71.62; H, 10.86. C50H88O6Si2 requires C, 71.37; H, 10.54%]; Rf (5% MeOH/CHCl3)
0.55; [α]D24 +1.4 (c 1.02, CHCl3); ῡ (liquid film) 3413, 1463 cm-1; δH 0.08 and 0.1 (two s, 6H),
0.89 (s, 9H), 1.04 (merged s and d, 12H), 1.26-1.75 (m, 40H), 2.84 (broad, 2H), 3.38-3.65 (m,
4H), 3.77-4.12 (m, 4H), 4.63 (broad s, 1H), 7.31-7.43 (m, 6H), 7.64-7.68 (m, 4H); δC -3.8, -3.4,
-3.2, 18.6, 20.0, 20.8, 24.0, 25.5, 26.0, 27.5, 27.8, 30.7, 31.9, 34.2, 35.7, 37.1, 38.2, 38.4, 39.8,
40.1, 63.3, 67.6, 67.9, 69.7, 70.4, 71.9, 73.4, 98.1, 128.1, 130.1, 135.3, 135.6, 136.6.
o
To a cooled (10 C) and stirred solution of the above diol (0.170 g, 0.20 mmol) in
aqueous 60% CH3CN (20 mL) was added NaIO4 (0.052 g, 0.24 mmol) in portions. After stirring
for 2 h, the mixture was filtered, the filtrate treated with aqueous 10% NaHSO3 and thoroughly
extracted with CHCl3 (2 × 10 mL). The organic layer was washed with water (2 × 10 mL) and
18

ACCEPTED MANUSCRIPT
brine (1 × 5 mL), and concentrated in vacuo to get a residue, which on preparative thin layer
chromatography (silica gel, 7% EtOAc/hexane) furnished pure 16 (0.144 g, 88%) as a colorless
oil; [Found: C, 72.55; H, 10.64. C49H84O5Si2 requires C, 72.71; H, 10.46%]; Rf (10%
24
EtOAc/hexane) 0.64; [α]D +7.6 (c 1.00, CHCl3); ῡ (liquid film) 2712, 1727 cm-1; δH 0.04 and
0.08 (two s, 6H), 0.84 (s, 9H), 1.02 (broad s, 12H), 1.24-1.74 (m, 38H), 2.47-2.50 (m, 2H), 3.48-
3.55 (m, 2H), 3.75-3.84 (m, 2H), 4.12-4.17 (m, 1H), 4.61 (broad s, 1H), 7.30-7.36 (m, 6H), 7.64-
7.66 (m, 4H), 9.78 (broad d, J = 2.2 Hz, 1H); δC -4.9, -4.6, 18.0, 19.2, 19.9, 23.2, 25.1, 25.2,
25.5, 25.7, 27.0, 29.6, 29.9, 31.2, 34.9, 37.8, 39.4, 50.8, 62.6, 68.2, 69.5, 76.7, 97.4, 127.3, 127.4,
129.4, 134.6, 134.9, 135.8, 202.5
4.17
(3R,15S,21R)-3-tert-Butyldimethylsilyloxy-21-tert-butyldiphenylsilyloxy-15-
tetrahydropyranyloxydocosanoic acid 17
To a stirred solution of 16 (0.120 g, 0.15 mmol) in CH3CN (0.5 mL) was added NaH2PO4
(6.2 mg, 0.04 mmol) in water (0.5 mL) and 30% H2O2 (185 µL, 0.16 mmol). The mixture was
cooled to 0 ºC, and NaClO2 (21.5 mg, 0.24 mmol) in water (1 mL) was added dropwise over 0.5
h. The reaction mixture was stirred at 15 ºC till completion of the reaction (~6 h, monitored by
gas evolution), Na2SO4 (0.25 g) added, and the mixture extracted with EtOAc (3 × 10 mL). The
organic layer was washed with water (2 × 5 mL) and brine (1 × 2 mL), and concentrated in vacuo
to get a residue, which on preparative thin layer chromatography (silica gel, 10% EtOAc/hexane)
furnished pure 17 (0.077 g, 63%) as a colorless thick oil; [Found: C, 71.20; H, 10.39.
24
C49H84O6Si2 requires C, 71.31; H, 10.26%]; Rf (5% MeOH/CHCl3) 0.25; [α]D +6.6 (c 1.00,
CHCl3); ῡ (liquid film) 3500-2500, 1712 cm-1; δH 0.08 and 0.09 (two s, 6H), 0.88 (s, 9H), 1.04
(s, 12H), 1.20-1.69 (m, 38H), 2.48-2.51 (m, 2H), 3.65-3.95 (m, 4H), 4.06-4.11 (m, 1H), 4.64
(broad s, 1H), 7.35-7.41 (m, 6H), 7.65-7.68 (m, 4H); δC -4.9, -4.6, 14.1, 17.9, 19.2, 19.9, 22.7,
19

ACCEPTED MANUSCRIPT
23.2, 25.1, 25.2, 25.5, 25.7, 27.0, 29.7, 29.8, 31.2, 31.9, 33.4, 34.9, 37.3, 39.4, 41.9, 50.7, 62.6,
69.5, 69.6, 76.8, 97.3, 127.3, 127.4, 129.4, 134.6, 135.8, 139.2, 175.5.
4.18 Methyl (3R,15S,21R)-3-tert-Butyldimethylsilyloxy-21-tert-butyldiphenylsilyloxy-15-
hydroxydocosanoate 18
o
To a cooled (0 C) solution of 17 (0.120 g, 0.15 mmol) in Et2O (10 mL) was added
CH2N2 in Et2O in portions till the starting material was consumed (2 h). The reaction mixture
was purged with N2 (g) to remove the solvent. The residue was dissolved in MeOH (10 mL),
CuCl2.2H2O (10 mol%) added, and the mixture stirred at room temperature till completion of the
reaction (cf. TLC, ~12 h). The mixture was diluted with Et2O (20 mL), filtered, and concentrated
in vacuum. The residue was purified by column chromatography (silica gel, 0-15%
EtOAc/hexane) to get 18 (0.087 g, 80%) as a colorless oil; [Found: C, 71.45; H, 10.48.
24
C45H78O5Si2 requires C, 71.56; H, 10.41%]; Rf (5% MeOH/CHCl3) 0.59; [α]D +6.1 (c 0.814,
CHCl3); ῡ (liquid film) 3448, 1731 cm-1; δH 0.08 (s, 6H), 0.89 (s, 9H), 1.04 (s, 12H), 1.25-1.53
(m, 33H), 2.40-2.44 (m, 1H), 2.50-2.55 (m, 1H), 3.54-3.57 (m, 1H), 3.71 (s, 3H), 3.79-3.83 (m,
1H), 3.98-4.02 (m, 1H), 7.35-7.42 (m, 6H), 7.67-7.69 (m, 4H); δC -4.6, 14.4, 19.3, 19.5, 22.9,
23.4, 25.4, 25.7, 27.2, 29.3, 29.6, 29.8, 30.4, 31.6, 32.1, 36.7, 37.6, 39.6, 41.3, 51.9, 68.2, 69.8,
72.2, 127.5, 127.6, 129.5, 129.6, 134.8, 135.8, 136.1, 173.7.
20

ACCEPTED MANUSCRIPT
References
1.
(a) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P.S. Angew. Chem., Int. Ed.
2000, 39, 44–122; (b) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37,
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Graphical abstract
Asymmetric synthesis of the constitutive C22-carboxylic acid of macroviracin A
Seema V. Kanojia, Sucheta Chatterjee, Sunita Gamre, Subrata Chattopadhyay, and Anubha
Sharma
An enantioconvergent synthesis of the advanced intermediate of macroviracin A has been
developed, using enantioselective lipase-catalyzed acylation, asymmetric allylation, and
asymmetric dihydroxylation reaction to install the required stereogenic centres. The key
reactions proceeded with good to excellent stereoselectivity.
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