Total synthesis of decarestrictine i and botryolide B via RCM protocol

Article abstract of DOI:10.1039/c004556j

A convergent stereoselective total synthesis of decarestrictine I (1) and botryolide B (1a) invoking a common synthetic strategy is reported. The key steps are: ring-closing metathesis of epoxy dienoic esters obtained through the Yamaguchi esterification

Full text of DOI:10.1039/c004556j

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Total synthesis of decarestrictine I and botryolide B via RCM protocol†
Palakodety Radha Krishna* and T. Jagannadha Rao
Received 23rd March 2010, Accepted 27th May 2010
First published as an Advance Article on the web 8th June 2010
DOI: 10.1039/c004556j
A convergent stereoselective total synthesis of decarestrictine
I (1) and botryolide B (1a) invoking a common synthetic
strategy is reported. The key steps are: ring-closing metathesis
of epoxy dienoic esters obtained through the Yamaguchi
esterification of their respective intermediates to furnish
the respective Z-macrocycles (2 and 2a) which were further
extrapolated to their respective targets.
Decarestrictines represent a family of novel 10-membered lactones
produced by different strains of Penicillium.1 So far, six compo-
nents of the family of decarestrictines have been identified. The
identical carbon skeleton that forms a 10-membered lactone ring,
which varies in the oxygen patterns ranging from carbon 3 to 7,
and the presence of one E-configured double bond located either
at C-4 or at C-5 are the salient structural features of this class of
compounds. The decarestrictines show interesting activity in cell
line tests with HEP-G2 liver cells2,3 due to an inhibitory effect
Scheme 1 Retrosynthesis for decarestrictine I and botryolide B.
on cholesterol biosynthesis. Amongst this family, decarestrictine
I (1) has the most unique structural features: a 10-membered
lactone fused with a dihydrofuran framework and a Z-configured
The RCM of substrates possessing diversely protected chiral
centers adjacent to the reacting olefins is still a challenging
proposition, herein substrates 3 and 3a were chosen as RCM
double bond to accommodate the bicyclic structure. Excepting a
precursors. Most often than not, such dienes result in products
patent reference4 no synthesis is reported so far. As a part of our
as Z-isomers either predominantly or exclusively.7 Bearing this in
ongoing program on the total synthesis of bioactive 10-membered
macrolides,5 we accomplished the total synthesis of decarestrictine
D earlier.5a
mind, the synthesis was planned to derive the Z-macrocycles 2
and 2a (Scheme 3 and 4). PMB-deprotection of 2 predictably led
to the dihydrofuran ring (1) via the intramolecular epoxide ring-
opening reaction. However, 2a under the same reaction conditions
afforded 1a. A 6,7-b-epoxide was chosen since all the members of
decarestrictine family followed a common biogenetic pathway and
the C7 mostly bears a b-hydroxy stereogenic center.
Accordingly, the synthesis of 1 starts with the known silyl
derivative of homoallyl alcohol. Thus, the olefin of homoallyl
alcohol derivative was subjected to epoxidation with m-chloro-
perbenzoic acid. Then the racemic epoxide 6 (Scheme 2) was
subjected to Jacobsen’s hydrolytic kinetic resolution to afford
the optically enriched epoxide 7. Epoxide 7 on ring-opening
reaction with n-butyl lithium and TMSI afforded allylic alcohol
88 (70%). The hydroxyl group in 8 was protected as its PMB
ether (PMBBr–NaH–THF/0 ◦C–rt) to afford 9 (84%), the TPS
group in 9 was deprotected with TBAF in THF to afford primary
alcohol 10 (91%) which was converted to acid 4 by a two step
process; firstly to an aldehyde on Swern oxidation and then
on perchlorite oxidation (NaClO2–NaH2PO4·2H2O–t-BuOH–2-
methyl-2-butene) to the acid 4 (80% over two steps).
In continuation, we became interested in the synthesis of 1
primarily due to its impressive structural features and report the
same herein through a tandem RCM/intramolecular epoxide-ring
opening reaction sequence to access the bicyclic framework en
route to 1. Alongside, a related stratagem involving Yamaguchi
esterification followed by the RCM/deprotection set furnished yet
another target 1a. Interestingly, botryolides are biosynthetically
related new decarestrictine analogs isolated from Botryotrichum
sp. (NRRL).6
We envisioned a convergent strategy via the assembly of late-
stage intermediates 4 and 5 (4a and 5, Scheme 1) that are
conveniently accessed from the inexpensive starting materials like
1,4-butanediol and propylene oxide. While the application of
Jacobsen hydrolytic kinetic resolution and Sharpless asymmetric
epoxidation helped us garner the stereogenic centers of the target
molecules; Yamaguchi esterification, RCM and intramolecular
epoxide ring-opening reaction are the other key steps adopted to
accomplish the total synthesis of 1. A similar strategy was planned
for the first total synthesis of 1a.
Another intermediate, epoxy alkene 5 (Scheme 2) was synthe-
sized from the known propargylic alcohol 11.9 Compound 11 was
converted to cis-allylic alcohol 12 (67%) via partial reduction with
Ni(OAc)2·4H2O–NaBH4 in ethanol10 under H2 atmosphere. Allylic
alcohol 12 on Sharpless asymmetri◦c epoxidation [(-)-DIPT–
Ti(OiPr)4–cumenehydroperoxide/-20 C] afforded epoxy alcohol
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian
Institute of Chemical Technology, Hyderabad 500 607, India. E-mail:
prkgenius@iict.res.in; Fax: +91-40-27160387
† Electronic supplementary information (ESI) available: Experimental
procedures and spectral data. See DOI: 10.1039/c004556j
3130 | Org. Biomol. Chem., 2010, 8, 3130–3132
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dihydrofuran ring containing decarestrictine I13 (1, 69%), evidently
through the intramolecular epoxide ring-opening reaction. The
spectral data of synthetic 1 was matched with the reported data
and found in agreement.4
To check whether only anti-configured 6,7-epoxide and 3-
OPMB functional groups are conveniently positioned to undergo
the dihydrofuran formation during the deprotection step and not
otherwise, an independent study was undertaken. Accordingly,
enantiomeric acid 4a was synthesized using a related strategy
(Scheme 4). Acid 4a on Yamaguchi esterification with epoxy
alcohol 5 gave ester 3a in comparable yields. Later 3a on RCM
under similar reaction conditions furnished 2a in comparable
yields. Subsequently, following an analogous PMB-deprotection
2a (DDQ–CH2Cl2–H2O/rt) however did not result in the bicyclic
system but rather furnished botryolide B (1a). Thus, the logic
that spatial proximity plays an important role in facilitating an
intramolecular epoxide ring-opening reaction holds good for 2
and a simple PMB-deprotection occurred in the case of lactone 2a
to afford botryolide B (1a, 75%) as the lone product. Compound
2a was identified from its spectral analysis.14
Scheme 2 Reagents and conditions: a) (S,S)-(salen) CoIII(OAC), 0.55 eq.
H2O, rt, 18 h; (b) n-BuLi, Me3S+I-, THF, -20 ◦C–rt, 3 h, 70%;
c) PMBBr, NaH, THF, 0 ◦C–rt, 12 h (84%), d) TBAF, THF, 0 ◦C–rt,
2 h (91%); e) i) (COCl)2, DMSO, Et3N, CH2Cl2, -78 ◦C, 1 h, ii) NaClO2,
NaH2PO4·2H2O, t-BuOH–2-methyl-2-butene (3 : 1), 0 ◦C–rt, 12 h (80%
over two steps); f) ref. 9; g) Ni(OAc)2·4H2O, NaBH4, H2, EtOH, rt, 2 h
(67%); h) (-)-DIPT, Ti(OiPr)4, cumenehydroperoxide, CH2Cl2, -20 ◦C, 12 h
(93%); i) i) (COCl2), DMSO, Et3N, CH2Cl2, -78 ◦C, 1 h, ii) Ph3PCH3+I-,
KOtBu, THF, 0 ◦C, 8 h (62%); j) DDQ, CH2Cl2–H2O (19 : 1), rt, 1 h, (90%).
1311 (93%), which on Swern oxidation followed by 1C Wittig
olefination (Ph3PCH3 I-–KOtBu–THF) afforded epoxy alkene 14
+
(80% over two steps). The PMB group in 14 was deprotected with
DDQ in CH2Cl2–H2O to obtain alcohol intermediate 5 (90%).
The acid 4 (Scheme 3) on coupling with 5 under Yam-
aguchi conditions (2,4,6-trichlorobenzoyl chloride–Et3N–THF
then DMAP–toluene) afforded the dienoic ester 312 (82%). Com-
pound 3 underwent RCM smoothly upon using 10 mol% of
Grubbs’ II generation catalyst at reflux in CH2Cl2 to provide the
desired macrolactone (Z)-27 (~63%) as the major product. Next,
lactone 2 on treatment with DDQ in CH2Cl2 underwent PMB-
deprotection and a spontaneous second ring-closure to afford the
Scheme 4 Reagents and conditions: a) (R,R)-(salen) CoIII(OAc), 0.55 eq.
H2O, rt, 18 h; (b) n-BuLi, Me3S+I-, THF, -20 ◦C–rt, 3 h, 85%; c) PMBBr,
NaH, THF, 0 ◦C–rt, 12 h (70%), d) TBAF, THF, 0 ◦C–rt, 2 h (80%); e) i)
(COCl)2, DMSO, Et3N, CH2Cl2, -78 ◦C, 1 h, ii) NaClO2, NaH2PO4·2H2O,
t-BuOH–2-methyl-2-butene (3 : 1), 0 ◦C–rt, 12 h (80% over two steps); f)
2,4,6-trichlorobenzoyl chloride, Et3N, THF, 0 ◦C–rt, 4 h, then DMAP, 4,
toluene, 0 ◦C–rt, 12 h (85%); g) Grubbs’ II generation catalyst, CH2Cl2,
reflux, 12 h (75%); h) DDQ, CH2Cl2–H2O, 0 ◦C-rt, 1 h, (72%).
Both the products (1 and 1a) were characterized by their spectral
data. For instance, the Z-geometry of the double bond(s) was
assigned based on the coupling constants of the olefinic protons
(J = 1.8, 8.3, 11.7, and 1.5, 7.8, 10.9 Hz). Further, the structures of
1 and 1a and their absolute stereochemistry were unambiguously
established by comparing the spectral analysis.14
Scheme 3 Reagents and conditions: a) 2,4,6-trichlorobenzoyl chloride,
Et3N, THF, 0 ◦C–rt, 4 h, then DMAP, 4, toluene, 0 ◦C–rt, 12 h (82%);
b) Grubbs’ II generation catalyst, CH2Cl2, reflux, 12 h (63%); c) DDQ,
CH2Cl2–H2O, 0 ◦C–rt, 1 h, (69%).
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Incidentally, some of the other decarestrictines synthesized
involving RCM are listed,15 though the strategy to access the
respective intermediates differ.
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In conclusion, we described the stereoselective total synthesis
of decarestrictine I (1) and botryolide B (1a) via an RCM of
the respective dienoic esters possessing sensitive chiral functional
groups on either side of the bisolefins. While macrolide 2 en-
dowed with harmoniously positioned epoxide and –OPMB groups
underwent a facile second cyclization to furnish 1 during the
deprotection step via an intramolecular ring-opening reaction; the
syn-diastereomer 2a afforded 1a under similar reaction conditions.
The syntheses reported herein established the relative and absolute
stereochemistry of both the targets.
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Acknowledgements
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3132 | Org. Biomol. Chem., 2010, 8, 3130–3132
This journal is
The Royal Society of Chemistry 2010
©