Alternative total synthesis of (+)-aspicilin

Article abstract of DOI:10.1080/00397911.2018.1458241

The total synthesis of an 18-membered polyhydroxylated macrolide (+)-Aspicilin was accomplished starting from commercially available enantiopure propylene oxide and D-(+)-gluconolactone by asymmetric synthetic approach. The key reactions involved are Witt

Full text of DOI:10.1080/00397911.2018.1458241

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Alternative total synthesis of (+)-aspicilin
Sridhar Musulla, Bharathi Kumari Y, Mahesh Madala, Srinivasa Rao A &
Vema Venkata Naresh
To cite this article: Sridhar Musulla, Bharathi Kumari Y, Mahesh Madala, Srinivasa Rao A & Vema
Venkata Naresh (2018) Alternative total synthesis of (+)-aspicilin, Synthetic Communications,
48:13, 1657-1662, DOI: 10.1080/00397911.2018.1458241
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SYNTHETIC COMMUNICATIONS®
2018, VOL. 48, NO. 13, 1657–1662
https://doi.org/10.1080/00397911.2018.1458241
Alternative total synthesis of (+)-aspicilin
Sridhar Musullaa,b, Bharathi Kumari Yb, Mahesh Madalaa,b, Srinivasa Rao Aa, and Vema
Venkata Naresha,b
aMedicinal Chemistry Laboratories, GVK Biosciences Private Limited, Hyderabad, Telangana, India;
bDepartment of Chemistry, JNT University, Hyderabad, Telangana, India
ABSTRACT
ARTICLE HISTORY
Received 17 December 2017
The total synthesis of an 18-membered polyhydroxylated macrolide
(þ)-Aspicilin was accomplished starting from commercially
available enantiopure propylene oxide and D-(þ)-gluconolactone by
asymmetric synthetic approach. The key reactions involved are Witttig
reaction, Sharpless asymmetric dihydroxylation, and Yamaguchi
macrolactonization.
KEYWORDS
Aspicilin; S-propylene oxide;
sharpless asymmetric
dihydroxylation and
Yamaguchi
macrolactonization;
witttig olefination
GRAPHICAL ABSTRACT
Introduction
Polyhydroxylated macrolides[1] are interesting synthetic targets to many synthetic chemists
due to their interesting structure and potential biological activities, including inhibition of
cholesterol biosynthesis[2–5] and microfilament formation,[1b] antimalarial and antibacterial
activity,[6,7] and phytotoxicity.[1c]
Aspicilin (1), an 18-membered polyhydroxylated macrolide, was isolated from lichen of
the Lecanoraceae family in 1900 by Hesse.[8] The absolute configuration of Aspicilin (1)
was determined as 4 R,5S,6 R,17S by a combination of various spectroscopic methods,
single-crystal X-ray analysis, and synthetic studies.[9] The impressive structural features
of Aspicilin (1), (four stereocenters in which three contiguous stereocenters (4 R,5S,6 R)
and an 18-membered macrolactone ring) appeared to be an attractive target molecule
for total synthesis. To date, several synthetic approaches have been reported for the total
synthesis of Aspicilin 1 (Fig. 1).[10]
In continuation of our interest on the total synthesis of biologically active natural
products,[11] we herein disclose our successful synthetic approach toward the total
synthesis of 1 utilizing the Witttig reaction, Sharpless asymmetric dihydroxylation, and
Yamaguchi macrolactonization as the key steps.
CONTACT Sridhar Musulla
sm1org@rediffmail.com
GVK Biosciences Private Limited, Nacharam, IDA Mallapur,
Hyderabad, Telangana 500076, India; Department of Chemistry, JNT University, Hyderabad, Telangana 500082, India.
Supplemental data for this article can be accessed on the publisher’s website.
© 2018 Taylor & Francis

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S. MUSULLA ET AL.
Figure 1. Structure of (þ)-Aspicilin (1).
Results and discussion
Our retrosynthetic approach for the synthesis of Aspicilin is outlined in Scheme 1. The
target molecule 1 could be made from hydroxy acid 2 by intramolecular Yamaguchi
macrolactonization, whereas 2 could be synthesized from the coupling reaction of two
key fragments aldehyde 3 and phosphonium salt 4. Aldehyde 3 could be obtained from
cheap and commercially available D-(þ)-gluconolactone 5 and 4 was achieved from known
chiral epoxide 6.
Thus, the synthesis of (þ)-Aspicilin 1 mainly involved the synthesis of two key fragments
aldehyde 3 and phosphonium salt 4 followed by their coupling into the target molecule. First,
our synthesis begins with the preparation of key fragment phosphonium salt 4, which was
shown in Scheme 1. Accordingly, opening of known chiral epoxide 6 with oct-7-enylmagne-
sium bromide (prepared from 1-bromooctene and Mg in THF) in the presence of CuCN in
THF at −15 °C to rt furnished allyl alcohol 7 in 81% of yield. Subsequent Silyl ether forma-
tion of resulting alcohol 7 using TBSCl in the presence of Imidazole in CH2Cl2 at 0 °C to rt
for 6 h provided silyl ether 8 in 89% of yield. Next, Silyl ether 8 was subjected to hydrobora-
tion with 9-BBN-H followed by treatment with sodium hydroxide and H2O2 to give alcohol 9
in 81% yield. Treatment of alcohol 9 with CBr4 and PPh3 in CH2Cl2 at 0 °C to rt for 4 h gave
Scheme 1. Retroanalysis of (þ)-Aspicilin (1).

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Scheme 2. Synthesis of fragment 4. Reagents and conditions: (a) 1-bromooctene, Mg, CuCN, THF, reflux
to −15 °C, 7 h; (b) TBSCl, imidazole, CH2Cl2, 0 °C to rt, 6 h; (c) i) 9-BBN, THF, reflux, 3 h ii) NaOH, H2O2, rt,
12 h; (d) CBr4, PPh3, CH2Cl2, 0 °C to rt, 12 h; (e) PPh3, CH3CN, 90 °C, 24 h, quantitative.
bromide 10 in 88% yield, which was later converted into corresponding phosphonium salt 4
using PPh3 in CH3CN at 90 °C for 24 h in quantitative yield (Scheme 2).
After successful synthesis of phosphonium salt 4, we next focused on another key fragment
aldehyde 3 followed by its coupling with phosphonium salt 4 lead to the target molecule.
Accordingly, commercially available D-(þ)-gluconolactone 5 was converted into trans-ester
11 according to a known procedure.[12] Consequently, ester 11 was subjected to Sharpless
asymmetric dihydroxylation[13] with AD-mix-β in t-BuOH-H2O (1:1) at 0 °C for 22 h to give
corresponding diol 12 in 83% yield as a single diastereomer. In the next step, the newly
formed hydroxy groups in the resulting diol 12 were protected as its benzyl ethers using BnBr
in the presence of NaH in THF at 0 °C to rt for 8 h to give tri-benzyl ether 13 in 84% yield.
Treatment of the methyl ester in 13 using DIBAL-H gave an aldehyde 3 in 82% yield, which
upon Wittig reaction with phosphonium salt 4 using NaHMDS in THF at 0 to −78 °C furn-
ished isomeric mixture of olefin 14 in 81% of yield. Next, the olefin mixture 14 was subjected
to partial hydrogenation with 5% Pd-C in ethyl acetate to afford saturated compound 15 in
91% yield, which on treatment with H5IO6 in Et2O at rt followed by a Wittig olefination of
resulting aldehyde afforded the exclusively trans ester 16 in 81% yield (Scheme 3).
Later, Ester 16 was subjected to base (LiOH) hydrolysis in THF:MeOH:H2O (3:1:1) to
afford the corresponding acid 17, which on desilylation with TBAF in THF at 0 °C to room
temperature for 3 h afforded hydroxy acid 2 in 89% yield. After successful synthesis of
hydroxyl acid fragment 2, it was then focused at macrolactonization and further
transformations to complete the synthesis of Aspicilin 1. Accordingly, hydroxy-acid 2
was subjected to macrolactonization under Yamaguchi high dilution conditions[14] ((i)
2,4,6-trichlorobenzoyl chloride, Et3N, dry THF, rt, 2 h; ii) DMAP, toluene, 90 °C) to
provide the lactone 18 in 69% yield. In the final step, deprotection of three benzyl ethers
in lactone 18 was removed successfully in a single step using TiCl4 at 0 °C to r.t to afford
25
Aspicilin 1 [m.p. 151–153 °C. [α]D ¼ þ 36.8 (c 0.6, CHCl3) in 76% yield. The characteriza-
tion (1H and 13C NMR spectroscopy and optical rotation) of our synthetic sample was ident-
ical to the literature data.
Experimental section
(5R,6S,7R,18S,E)-5,6,7-tris(benzyloxy)-18-methyloxacyclooctadec-3-en-2-one (18)
To a stirred solution of 2 (0.38 g, 0.61 mmol) and Et3N (0.26 mL, 1.83 mmol) in dry
THF (3 mL), a solution of 2, 4, 6-trichlorobenzoyl chloride (0.22 mL, 0.91 mmol) in

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S. MUSULLA ET AL.
Scheme 3. Synthesis of (þ)-Aspicilin (1). Reagents and conditions: (a) AD-mix-β, MeSO2NH2, t-BuOH-
H2O, 0 °C, 22 h; (b) BnBr, NaH, THF, 0 °C to rt, 8 h; (c) DiBAL-H, -78 °C, CH2Cl2, 2 h; (d) 4, NaHMDS,
THF, 0 °C, then −78 °C, 6 h; (e) H2, Pd/C, EtOAc, rt, 3 h; (f) i) H5IO6, Et2O, 0 °C to rt, 5 h. Ii) Ph3P=CHCOOMe,
Benzene, reflux, 2 h; (g) LiOH, THF:MeOH:H2O (3:1:1), rt, 4 h; (h) TBAF, THF, 0 °C to rt, 3 h; (i) i) 2,4,6-
trichlorobenzoyl chloride, Et3N, dry THF, rt, 2 h, ii) DMAP, toluene, 90 °C, 10 h; (j) TiCl4, 0 °C to rt, 2 h.
dry THF (1 mL) was added. The resulting mixture was stirred for 2 h at room temperature
under nitrogen atmosphere and evaporated to afford the mixed anhydride. It was diluted
with toluene (10 mL) and filtered quickly through celite. The filtrate was added dropwise to
a stirred solution of DMAP (0.07 g, 0.61 mmol) in toluene (490 mL) (total volume used for
this operation was 500 mL) at 90 °C over a period of 8 h. After the complete addition, the
reaction mixture was stirred at same temperature for 2 h. It was cooled; washed with 7% aq
NaHCO3 (40 mL), 2 M aqueous HCl (40 mL), brine (40 mL); and dried (Na2SO4). The
organic layer was evaporated and the obtained residue was purified by column chromato-
graphy (silica gel, 60–120 mesh, 15% EtOAc in pet. ether) to give 18 (0.24 g, 69%) as a
25
syrup. [α]D1 -10.6 (c 0.56, CH2Cl2); IR (neat): 2931, 2851, 1719, 1649, 1455, 1366, 1166,
1067 cm−1; H NMR (300 MHz, CDCl3) δ: 7.34–7.21 (m, 15H, ArH), 7.12 (dd, 1H, J ¼ 8.3,
16.1 Hz, olefinic), 6.01 (d, 1H, J ¼ 16.1 Hz, olefinic), 4.99 (m, 1H, benzylic), 4.88 (d, 1H,
J ¼ 14.49 Hz, benzylic), 4.66 (d, 1H, J ¼ 14.49 Hz, benzylic), 4.64 (d, 1H, J ¼ 11.25 Hz,
benzylic), 4.57 (d, 1H, J ¼ 11.91 Hz, benzylic), 4.39 (d, 1H, J ¼ 11.25 Hz, benzylic), 4.32

SYNTHETIC COMMUNICATIONS®
1661
(d, 1H, 11.91 Hz, –OCH), 4.12 (d, 1H, J ¼ 8.61 Hz, –OCH), 3.84 (dd, 1H, J ¼ 1.05, 8.61 Hz,
–OCH), 3.31 (m, 1H, –OCH), 1.62–0.99 (m, 23H, 10 x –CH2, –CH3); 13C NMR (75 MHz,
CDCl3) δ: 165.5, 144.0, 138.8, 138.7, 138.1, 128.5, 128.4, 128.1, 128.0, 127.9, 127.7, 127.53,
127.1, 125.4, 84.3, 79.6, 78.8, 74.3, 74.2, 71.1, 70.6, 35.4, 31.0, 29.2, 28.2, 28.0, 27.4, 26.7,
26.5, 25.8, 23.2, 20.1; HRMS (ESI): m/z calculated for C39H50O5Na [MþNa]þ 621.3556,
found 621.3559.
(+)-Aspicilin (1)
To a stirred solution of 18 (0.2 g, 0.33 mmol) in CH2Cl2 (1 mL), TiCl4 (0.15 mL,
1.33 mmol) in CH2Cl2 (1 mL) was added at 0 °C and stirred at room temperature for
2 h. The reaction mixture was treated with saturated NaHCO3 solution (5 mL) and
extracted with CHCl3 (3 � 10 mL). The combined organic layers were washed with water
(10 mL), brine (10 mL) and dried (Na2SO4) and concentrated. The residue was purified by
column chromatography (silica gel, 60–120 mesh, 30% EtOAc in pet. ether) to afford 1
25
(82 mg, 76%) as a colorless syrup, [α]D þ 35.8 (c 0.9, CH2Cl2); m.p.: 151–153 °C; IR
1
(neat): 3444, 3277, 2928, 2854, 1709, 1649, 1455, 1366, 1245, 1163, 1075 cm−1; H NMR
(400 MHz, CDCl3): δ 6.91 (dd, 1H, J ¼ 5.3, 16.0 Hz, olefinic), 6.13 (d, 1H, J ¼ 16.0 Hz,
olefinic), 5.08–5.02 (m, 1H, –OCH), 4.63–4.57 (m, 1H, –OCH), 3.79–3.73 (m, 1H,
–OCH), 3.62–3.54 (m, 1H, –OCH), 3.31 (brs, 1H, –OH), 3.14 (brs, 1H, –OH), 2.88 (brs,
1H, –OH), 1.59–1.54 (m, 4H, 2 x –CH2), 1.49–1.26 (m, 19H, 8 x –CH2, –CH3);
13C NMR (75 MHz, CDCl3): δ 165.5, 144.6, 123.1, 74.8, 73.3, 71.2, 69.9, 35.8, 32.0, 28.1,
27.7, 27.5, 27.2, 27.1, 26.4, 24.2, 23.7, 20.5; HRMS (ESI): m/z calculated for C18H32O5Na
[MþNa]þ 351.2147, found 351.2154.
Conclusion
Thus, in summary, an efficient stereoselective total synthesis of Aspicilin (1) has been
achieved from commercially available D-(þ)-gluconolactone. The key steps involved
in this synthesis are Wittig olefination, Sharpless asymmetric dihydroxylation, and
Yamaguchi macrolatonization.
Acknowledgments
The autohrs are thankful to GVK Bio sciences, JNT University, Hyderabad for constant
encouragement in providing laboratory facilities and analytical data.
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