A carbohydrate approach for the formal total synthesis of (?)-aspergillide C

Article abstract of DOI:10.3762/bjoc.10.329

An enantioselective formal total synthesis of aspergillide C is accomplished using commercially available tri-O-acetyl-D-galactal employing a Ferrier-type C-glycosylation, utilizing a Trost hydrosilylation and protodesilylation as key reactions.

Full text of DOI:10.3762/bjoc.10.329

A carbohydrate approach for the formal total synthesis
of (−)-aspergillide C
Pabbaraja Srihari*1, Namballa Hari Krishna1,2,3, Ydhyam Sridhar1 and Ahmed Kamal2,3
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 3122–3126.
1Division of Natural Products Chemistry, CSIR-Indian Institute of
Chemical Technology, Hyderabad, 500007, India, 2Department of
Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research, Hyderabad, 500037, India and 3Medicinal Chemistry &
Pharmacology, CSIR-Indian Institute of Chemical Technology,
Hyderabad, 500007, India
doi:10.3762/bjoc.10.329
Received: 09 September 2014
Accepted: 09 December 2014
Published: 23 December 2014
Associate Editor: D. Dixon
Email:
Pabbaraja Srihari* - srihari@iict.res.in
© 2014 Srihari et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
alkynylation; chiron approach; Ferrier-type C-glycosylation; macrolide
Abstract
An enantioselective formal total synthesis of aspergillide C is accomplished using commercially available tri-O-acetyl-D-galactal
employing a Ferrier-type C-glycosylation, utilizing a Trost hydrosilylation and protodesilylation as key reactions.
Introduction
Aspergillides A, B and C (Figure 1) (three, novel, bicyclic, and both enantiomers of aspergillide C [21]. The chiron ap-
14-membered macrolides with 2,6-cis or trans-fused di- or proach has been a conventional strategy to achieve the total syn-
tetrahydropyan rings) are unexpected, novel, secondary metabo- thesis of complex, natural products with known handedness.
lites, isolated from the marine-derived fungus Aspergillus
ostianus strain 01F313 in bromine-modified 1/2PD culture
medium [1-4]. Interestingly, these compounds show cytotoxi-
city against mouse lymphocytic leukemia cells (L1210) with
LD50 values of 2.1, 71.0, and 2.0 μg/mL, respectively [5,6]. The
striking structural architecture and interesting biological prop-
erties have attracted significant attention from synthetic
chemists with respect to their total synthesis [7-26] and have
inspired medicinal chemists to synthesize diverse analogues in
search for better potential molecules [27]. We have recently
developed the total synthesis of these 14-membered macrolides
Figure 1: Structures of aspergillides.
and have accomplished the total syntheses of aspergillide B [15]
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Beilstein J. Org. Chem. 2014, 10, 3122–3126.
Herein we disclose our strategy for the formal total synthesis of dihydropyran motif. The side arm fragment 10 was readily
(−)-aspergillide C in a concise manner following the chiron ap- available in large amounts starting from (R)-propylene oxide (9)
proach.
as shown in Scheme 2. We proceeded further by utilizing it for
masking the functionalities. Compound 10 was disilylated using
TMSCl in the presence of n-BuLi and later treated with 1 N
Retrosynthetic Analysis
Through a retrosynthetic analysis, we envisaged that the HCl to get the free secondary alcohol which was further treated
macrolide 3 could be prepared from the seco acid 4 which can with benzoyl chloride in the presence of pyridine to produce the
be easily accessed from 5 in five steps (Scheme 1). Compound corresponding benzoyl ester 7 as a side chain fragment to be
5, in turn, can be synthesized from commercially available tri- utilized for a Ferrier-type C-glycosylation reaction with the
O-acetyl-D-galactal (6) and alkyne 7 through a Ferrier-type sugar tri-O-acetyl-D-galactal (6). Compound 6 was treated with
C-glycosylation reaction followed by the reduction of the triple silylated alkyne 7 in the presence of SnCl4 to afford alkyny-
bond to the trans double bond. Alkyne 7 can be synthesized lated dihydropyran 11 as the only isomer, resulting in an 85%
from alkyne 8 involving an isomerization reaction. Alkyne 8 yield. The resulting dihydropyran ring was found to have a 2,6-
was easily accessible from (R)-propylene oxide (9) through an trans configuration, owing to the attack of the alkyne from the
epoxide opening reaction with 1-butyne.
opposite face of the acetyl-protected carbinol present in C6 pos-
ition [28-31]. The geometry of the compound was also charac-
terized by 2D NMR studies wherein significant NOESY corre-
lations were observed for the C2 proton and the methylene
protons of the carbinol moiety present on C6. Also, the NOESY
correlation was absent between the C2 proton and the C6 proton
(Figure 2).
Scheme 2: Synthesis of 11. Reaction conditions: (a) n-BuLi, THF/
HMPA (5:1), −78 °C to rt, 12 h, 95%; (b) Li, t-BuOK, H2N(CH2)3NH2, rt,
4 h, 92%; (c) i. n-BuLi, TMSCl, THF, −78 °C, 92%. ii. pyridine,
C6H5COCl, CH2Cl2, 0 °C to rt, 1 h, 98%; (d) SnCl4, CH2Cl2, 0 °C to rt,
1 h, 85%.
Scheme 1: Retrosynthetic analysis for (−)-aspergillide C.
Results and Discussion
In recent work on aspergillides, Achmatowicz adducts were
utilized as the key source for the construction of the dihy-
dropyran moiety and the side arm was synthesized using a
Zipper rearrangement as a key reaction after an epoxide ring
opening reaction of (R)-propylene oxide/(S)-propylene oxide
with n-BuLi. In the present context, we have focused on a
chiron approach for the synthesis of aspergillide C and thus
chose commercially available tri-O-acetyl-D-galactal as the raw
material, which can be directly utilized for the synthesis of the
Figure 2: Key NOESY correlations observed in compound 11.
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Beilstein J. Org. Chem. 2014, 10, 3122–3126.
After the alkynylation reaction, the stage was set to proceed
further for the partial reduction of the alkyne moiety to obtain
the trans-configured olefin. Based on our previous experience
with this transformation, we proceeded directly with Trost’s
hydrosilylation–protodesilylation protocol [32], where alkyne
11 was treated with excess triethoxysilane in the presence of a
catalytic amount of [Cp*Ru(MeCN)3]PF6 to afford vinyl
triethoxysilane 12 (Scheme 3). Compound 12 was then
protodesilylated upon exposure to HF/pyridine to yield the
desired trans-olefin 5. Compound 5 possessed the required
stereochemical configuration including the desired trans-olefin
geometry, but required a one-carbon homologation to access the
matched seco acid 4. To achieve the one-carbon homologation
with appropriate functionality, it was necessary to perform
sequential chemoselective transformations. In this regard, we
proceeded by selectively deprotecting the acetyl groups
(without affecting the benzoate functionality) by employing
acetyl chloride in anhydrous methanol to afford diol 13 [33]. A
two-fold silylation and selective mono desilylation afforded pri-
mary alcohol 14 which was converted to its corresponding
nitrile via the triflate. The nitrile functionality was hydrolysed
with 8 N NaOH in ethanol to yield the seco acid 4. The seco
acid 4 was already utilized for the total synthesis of (−)-
aspergillide C through macrolactonization and TBS deprotec-
tion as reported earlier by Kuwahara (Table 1) [23]. Thus, by
Scheme 3: Synthesis of 4 and formal total synthesis of (−)-aspergillide
C (3). Reaction conditions: (a) [Cp*(MeCN)3Ru]PF6, (EtO)3SiH,
CH2Cl2, 0 °C to rt, 1 h, 95%; (b) HF/pyridine, pyridine, THF, 0 °C, 5
min, 90%; (c) cat. AcCl, MeOH, rt, 12 h, 90%; (d) (i) TBSCl, imidazole,
DMAP, CH2Cl2, rt, 12 h, 95%; (ii) 70% HF in pyridine, THF, 0 °C, 12 h,
90%; (e) (i) Tf2O, 2,6-lutidine, −78 °C, 10 min; (ii) NaCN, DMF/DMSO,
18-crown-6, 90 °C, 30 min 88% overall for two steps; (f) 8 N NaOH,
EtOH, 90 °C, 3 h, 75%.
Table 1: Comparision of 1H and 13C NMR data of seco acid 4 with earlier data.
Kuwahara data [23]
Our data
Position
δ mult [J (Hz)]
13C NMR CDCl3,125 MHz δ mult [J (Hz)]
13C NMR
CDCl3, 500 MHz
CDCl3, 300 MHz
CDCl3, 75 MHz
1
2
174.9 (COOH)
37.7 (CH2)
175.0
37.8
2.72 (dd, J = 16.1, 8.8, 1H)
2.53 (dd, J = 16.1, 3.9, 1H)
2.71 (dd, J = 15.9, 9.1)
2.53 dd (15.9, 3.8)
3
4
5
6
7
8
9
3.93–3.96 (m, 1H)
68.1 (CH)
69.5 (CH)
126.7 (CH)
127.5 (CH)
72.5 (CH)
130.7 (CH)
134.8 (CH)
3.93–3.98 (m)
68.1
4.18 (dt, J = 8.8, 3.2, 1H)
5.85–5.91 (m, 2H)
4.18 (dt J = 9.0, 3.2)
5.84–5.91 (m)
69.6
126.7
127.5
72.4
4.69 (d, J = 5.9, 1H)
4.68 (d, J = 5.3)
5.51 (dd, J = 15.6, 5.9, 1H)
5.66 (dt, J = 15.6, 6.6, 1H)
5.51 (dd, J = 15.8, 6.0)
5.77–5.60 (m)
130.7
134.6
2.00–2.08 (m, 1H)
2.08–2.16 (m, 1H)
10
36.0 (CH2)
1.96–2.20 (m)
1.34–1.52 (m)
35.9
11
12
13
14
15
16
17
18
OH
1.34–1.52 (m, 3H)
1.55–1.63 (m, 1H)
24.4 (CH2)
31.7 (CH2)
64.4 (CH)
22.8 (CH3)
−4.6 (Si-CH3)
−4.1 (Si-CH3)
18.2 (C)
24.5
31.7
64.4
22.9
−4.6
−4.1
18.2
25.9
–
3.82 (sex, J = 6.3, 1H)
1.18 (d, J = 6.3, 3H)
0.093 (s, 3H)
0.086 (s, 3H)
–
3.82 (sex, J = 6.0)
1.18 (d J = 6.0)
0.09 (s)
0.08–0.10 (m)
–
0.90 (s, 9H)
25.9 (C(CH3)3)
–
0.90 (s)
1.25 (s, 1H)
1.25 (s)
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Beilstein J. Org. Chem. 2014, 10, 3122–3126.
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the known key intermediate 4 in 8 steps with an overall yield of
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