Substitution dependent stereoselective construction of bicyclic lactones and its application to the total synthesis of pyranopyran, tetraketide and polyrhacitide A

Article abstract of DOI:10.1039/c6ob01686c

A novel bicyclization strategy has been developed for the stereoselective synthesis of bicyclic lactones, i.e. 7-aryl or alkyl-2,6-dioxabicyclo[3.3.1]nonan-3-ones through a domino cyclization of (R)-3-hydroxyhex-5-enoic acid with an aldehyde in the presen

Full text of DOI:10.1039/c6ob01686c

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Substitution dependent stereoselective construction of bicyclic
lactones and its application to the total synthesis of
Pyranopyran, Tetraketide and Polyrhacitide A
Cite this: DOI: 10.1039/x0xx00000x
B. V. Subba Reddy,a,* Dhanraj O.Biradar,a Y. Vikram Reddy,a J. S. Yadav,a Kiran
Kumar Singarapu,b B. Sridharc
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
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Abstract: A novel bicyclization strategy has been developed for
the stereoselective synthesis of bicyclic lactones, i.e. 7-aryl or
Consequently, several synthetic approaches have been
devised for the synthesis of these natural products
through oxy-Michael, iodo-lactonization, hetero-Diels-
Alder reaction, domino-Aldol reaction and Baylis-
Hillman reaction as key steps.5
alkyl-2,6-dioxabicyclo[3.3.1]nonan-3-ones through
a domino
cyclization of (R)-3-hydroxyhex-5-enoic acid with aldehyde in
the presence of 10 mol% trimethylsilyltriflate under mild
conditions. The salient features of this methodology are high
yields, excellent selectivity, low catalyst loading and faster
reaction times. This method has been successfully applied to the
total synthesis of Pyranopyran, Tetraketide and Polyrhacitide A.
Dioxabicyclo[3.3.1]nonan-3-one skeleton is present
in a large number of natural products such as
cryptocaryolone, tetraketide, leiocarpin A, polyrhacitide
A and B (Figure 1).1 Among them, cryptocaryolone was
isolated from the bark of South African plant,
Cryptocaryalatifolia, which constitutes a 5,6-dihydro-α-
pyranone core and a 1,3-polyol side chain.2 These
natural products are known to exhibit promising
biological activities such as anti-cancer, anti-
inflammatory, and anti-fungal.3 The Chinese ant
Polyrhacis lamellidens is used as folk medicine for the
treatment of pulmonary diseases, rheumatoid arthritis
and hepatitis.4
Figure 1. Examples of bicyclic lactone containing
polyketides
Owing to their fascinating structural features and
inherent biological properties, we were interested to
develop an efficient strategy to produce these bicyclic
compounds, which may be useful for the discovery of
novel anticancer agents. Among various strategies, Prins
cyclization is one of the most useful synthetic strategies
for the stereoselective construction of tetrahydropyran
ring (THP)6 and it has been successfully applied to the
synthesis of THP natural products.7 In particular, its
intramolecular version is a powerful strategy for the
stereoselective construction of fused/bridged oxacycles
b
aCentre for Semiochemicals, Centre for Nuclear Magnetic
Resonance, cLaboratory of X-ray Crystallography, CSIR-
Indian Institute of Chemical Technology, Hyderabad –500
007, India.†Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/c000000x/
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and spirocycles.8,9 However, this strategy has not been
explored in the domino synthesis of bicyclic lactones.
Inspired by the power of cascade cyclizations in
natural products synthesis,10 we herein report a novel
strategy for the stereoselective synthesis of bicyclic
lactones by means of the coupling of aldehyde with (R)-
3-hydroxyhex-5-enoic acid (S)-2, which was prepared
from L-malic acid using a known procedure.11 To test
the feasibility of this cascade, we first investigated the
reaction between benzaldehyde (1a) and (R)-3-
hydroxyhex-5-enoic acid (S)-2 using TMSOTf in
dichloromethane. Interestingly, the expected bicyclic
lactone 3a was obtained in good yield (entry a, Table 1)
when the reaction was performed using 10 mol%
TMSOTf at -15 C to 40 C. A brief screen of solvents
indicated that the reaction was quite solvent dependent.
Among various solvents, DCM proved to be the best. To
evaluate its scope, further reactions were carried out by
a diverse range of aldehydes. As shown in Table 1,
aromatic aldehydes participated well in this reaction.
However, the substituent present on aromatic ring
showed some effect on conversion. Among them, p-
fluoro- and p-chlorobenzaldehydes gave the product
slightly in higher yield than alkyl substituted aromatic
aldehydes (entries i & j, Table 1). This method still
works well with sterically hindered substrates such as 2-
naphthaldehyde, anthracene-9-carboxaldehyde and 9H-
fluorene-3-carbaldehyde (entries b, c & d, Table 1).
The scope of this methodology was further
exemplified with aliphatic aldehydes. However, these
aliphatic substrates gave the products relatively in lower
yields than the corresponding aromatic counterparts
(entries l, m & nl, Table 1). The reaction conditions are
compatible with TBDPS ethers (entry n, Table 1). To
our delight, this method provides a direct access to a
naturally occuring bicyclic lactones like pyranopyran
and tetraketide (entry a & l, Table 1). It is a highly
diastereoselective process providing
diastereomer, which was confirmed by H NMR of
unpurified products.
a
single
1
As shown in Table 2, the stereochemistry of
products derived from 2-halo- and 2-nitrosubstituted
aryl aldehydes differs at C8 position, which may be
due to electronic effect of substituent on aromatic
ring (Table 2). In contrary, 2-methylbenzaldehyde
gave the trans-product (entry i, Table 1) instead of
the expected cis-product, which was confirmed by
Table 1. Synthesis of trans-bicyclic lactones
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nOe studies. This result clearly indicates that the
substituent present at 2-position of the aldehyde plays
a key role in stereochemical outcome of the reaction.
Table 2. Synthesis of cis-bicyclic lactones
Figure 2. Characteristic nOe cross peaks of products
For compounds shown in Table 2 (4, R = 2-haloaryl),
3
the scalar couplings for H8 (3JH8-H7=5.0Hz, JH8-
H7'=11.5Hz), along with the nOe cross peaks between
H8/H5, H5'/H3(ax) support the first ring of the
5
bicyclononane in C2 chair conformation where the
second ring adopts a boat conformation with H5 and H8
being flagpole hydrogens as shown in Figure 2. NMR
experiments were conducted on selected products 4a,
3k, 4b (supporting information). The stereochemistry of
other products was assigned by analogy. The relative
configuration of the product 4b (Table 2) was
unambiguously determined by single crystal X-ray
diffraction analysis (Figure 3).12
The relative stereochemistry of the above compounds
was determined by using 1D and 2D NMR experiments.
For compounds depicted in Table 1 (3, R= aryl or
3
alkyl), the scalar couplings for H8 (3JH8-H7=3.0Hz, JH8-
H7'=11.5Hz), H3(3JH3-H4=5.4Hz), H3'(3JH3'-H4=1.5Hz) and
H4 (all small couplings), H6(small couplings) along
with the presence of nOe cross correlations between
H7(ax)/H5, H8/H3(eq), H5'/H3(ax) suggest the structure
adopts a bicyclononane conformation with both rings in
5C2 and 5C8 chair conformation (Figure 2).
Figure 3. A view of 4b, showing the atom-labelling
scheme. Displacement ellipsoids are drawn at the 30%
probability level and H atoms are represented by circles
of arbitrary radii.
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We proposed a plausible reaction mechanism in
Scheme 1. Acid catalyzed Prins reaction of an aldehyde
(1) and a homoallylic alcohol ((S)-2) leads to the
formation of (E)-oxocarbenium ion (A). Alder et al15
explained that the (E)-oxocarbenium ion occupies
a chair transition state leads to the generation of
tetrahydropyranyl cation, which is highly stable
due to delocalization. The optimal geometry for
delocalization tends to keep the hydrogen at C-4 in
a pseudo-axial position, which facilitates the
equatorial attack of an appended nucleophile to avoid
unfavourable 1,3-diaxial interactions resulting in the
formation of bicyclic lactone (3).16
Scheme 2. Stereoselective synthesis of polyrhacitide A
To demonstrate its synthetic versatility, the present
protocol was applied to the synthesis of polyrhacitide A.
The required (S)-3-hydroxyhex-5-enoic acid (5f) was
prepared from L-aspartic acid using
a
known
procedure.13 The chiral aldehyde (1x) was synthesized
by following a multi-step sequence.14 Accordingly, the
condensation of (S)-3-hydroxyhex-5-enoic acid (5f)
with (3R,5R)-3,5-dihydroxydodecanal (1x) in the
presence of 10% TMSOTf gave the bicyclic lactone (7)
in 50% yield. A subsequent deprotection of TBDPS
ethers using HF/Pyridine afforded the required
polyrhacitide A (8) in 60% yield (Scheme 2). The
structure of
polyrhacitide A was confirmed by
comparison of its spectral data and optical rotation with
a reported data in literature.5 Thus this method was
successfully applied to the total synthesis of
polyrhacitide A.
Scheme 1. Stereochemical outcome of the reaction
In conclusion, a novel cascade process has been
developed
for
the
synthesis
of
dioxabicyclo[3.3.1]nonan-3-one scaffolds, which are
found as key structural components of many natural
products. It was successfully applied to the total
synthesis of polyrhacitide A. This approach is very
attractive for the synthesis of bicyclic lactone containing
natural products like pyranopyran, tetraketide and
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V. Swathi, M. Swain, M. Pal Bhadra, B. Sridhar, D.
Satyanarayana, B. Jagadeesh, Organic Lett., 2014, 16, 6267.
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polyrhacitide A. Therefore, this method provides a
direct access to bicyclic lactones with diverse
substitution pattern.
BDO and YVR thank CSIR, New Delhi for the award of
fellowships. BVS thanks CSIR, New Delhi for financial support as
part of XII Five Year plan programme under title ORIGIN (CSC-
0108).
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