Stereoselective synthesis of 1,6-dioxaspirolactones from spiro-cyclopropanecarboxylated sugars: Total synthesis of dihydro-pyrenolide D

Article abstract of DOI:10.1039/c4ra16753h

An efficient method for the stereoselective construction of 1,6-dioxaspiro[4.n]decan-2-one systems (n = 4, 5) from sugar derived spirocyclopropane carboxylic acids involving a one-pot ring-opening and cyclization reaction is revealed. The generality of th

Full text of DOI:10.1039/c4ra16753h

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Graphical Abstract
A one-pot protocol for the stereoselective construction of γ-spiroketal γ-lactone frameworks from sugar
derived spiro-cyclopropanecarboxylic acids involving a ring enlargement and cyclization reaction is
revealed.

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Stereoselective synthesis of 1,6-
dioxaspirolactones from spiro-
Cite this: DOI: 10.1039/x0xx00000x
cyclopropanecarboxylated sugars: Total
synthesis of dihydro-pyrenolide D
Received 00th January 2012,
Accepted 00th January 2012
Bandi Ramakrishnaa and Perali Ramu Sridhara
DOI: 10.1039/x0xx00000x
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of spirolactones (γ-spiroketal γ
-lactones) are very scarce.13 In
An efficient method for the stereoselective construction of 1,6-
dioxaspiro[4.n]decan-2-one systems (n = 4, 5) from sugar
derived spirocyclopropane carboxylic acids involving a one-
pot ring-opening and cyclization reaction is revealed. The
generality of the methodology and its application in the total
addition, spirolactones are also an excellent synthons for the
preparation of spiroketals14 as well as for further functional
group modifications. Apart from directed protocols,15
photolytic oxidative cyclization of sugar derived nononamides16
and gold phosphate-catalyzed one-pot three component
coupling reaction of alkynols, anilines and glyoxylic acid
towards the preparation of spirolactones17 are noteworthy. In
continuation of our investigation towards the application of
cyclopropanecarboxylated sugars in the stereoselective
synthesis of bicycilc architectures,18 herein we report a general
synthesis of dihydro-pyrenolide
pyrenolide D are reported.
D
and 4-epi-dihydro-
1,6-dioxaspiro system, particularly in the form of spiroketal1 or
spirolactone,2 is one of the intriguing structural unit present in a
number of highly bioactive natural products.3 For example, methodology for the preparation of carbohydrate derived 1,6-
marine toxins like azaspiracids,4 pinnatoxins,5 pteriatoxins,6 dioxa[n,5]-spiroketal butyrolactones (n = 5, 6) involving a one-pot
ring expansion and cyclization reaction of sugar derived donor-
acceptor spiro-cyclopropanecarboxylic acids.19 Further, the
as the core structure. The spiroketal framework provides the
spongistatins7 and spirolides8 etc. possess the spiroketal moiety
essential conformation that is essential to unveil the biological developed methodology was successfully utilized in the total
activity in these molecules. This was evidenced by some of the synthesis of pyrenolide D analogues, 2,3-dihydro-pyrenolide D and
2,3-dihydro-4-epi-pyrenolide D.
The synthesis of carbohydrate derived donor-acceptor
cyclopropanecarboxylic acid was planned starting from the exo-
simplified spiroketal fragments which were found to retain the
biological activity that was exhibited by the parent natural
product.9 Despite their wide occurrence, methods for the
enantioselective construction of these frameworks are very glycals of type 1. Thus, Rh2(OAc)4 catalyzed cyclopropanation of
limited.1 A major challenge in the construction of these exo-glycal20
1 using methyldiazoacetate provided the spiro-
cyclopropanecarboxylate 2 as a mixture of diastereomers.§ In
contrast to the 1,2-cyclopropane carboxylated sugars which have
spirocycles is the stereoselective formation of quaternary ketal
centre. The traditional method for the spiroketal synthesis
involves an acid catalyzed ketalization of a dihydroxy ketone been shown to undergo ring-opening followed by cyclization
precursor, which often produces the thermodynamic product.10 reaction,21 direct exposure of spiro-cyclopropanecarboxylate 2 to a
series of Lewis acids did not provide the expected spirolactone 4.
This might be attributed due to the higher stability and lower strain
On the other hand, oxidative radical cyclization is
contemporary approach that offers an access to the kinetically
a
controlled preparation of spiroketals.11 Recently, IBX/Yb(OTf)3 of spiro-cyclopropanecarboxylate, when compared to linearly fused
mediated ring enlargement of donor-acceptor cyclopropanes to systems.
give [n,5]-spiroketals in moderate yield has been reported.12
We assumed that, converting the cyclopropanecarboxylate to the
corresponding carboxylic acid will increase the electrophilicity of
Although several methods have been reported for the synthesis
of spiroketals, the stereoselective protocols for the preparation the carbonyl group and facilitate the cyclopropane ring opening.
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Thus, ester 2 was hydrolyzed to give spiro-cyclopropanecarboxylic cyclopropanecarboxylic acids. Thus, a series of pyranose fused
acid 3 and reacted with catalytic BF3.Et2O. Under these conditions, 3 cyclopropanecarboxylated sugar derivatives 5, 8 and 11 were
underwent a facile one-pot ring-opening and cyclization reaction to subjected to the base hydrolysis to obtain the corresponding spiro-
provide the expected spirolactone 4 as a single diastereomer. The cyclopropanecarboxylic acids 6, 9 and 12, respectively, in excellent
formation of a single diastereomer clearly indicates the existence of yield. Subjecting these acid derivatives to the BF3.Et2O mediated
oxonium ion intermediate that is trapped by the carboxylic acid, ring-opening cyclization reaction provided the sugar derived 1,6,-
minimizing the anomeric effect of both the rings, which leads to the dioxaspirolactones 7, 10 and 13, respectively, in good yield. In the
formation of thermodynamically more stable spirocyclic system. The all ring-opening and cyclization reactions we observed the formation
stereochemistry at the spirocentre was unambiguously assigned by of thermodynamically more stable spirolactone as the only product,
2D NOESY experiment.
except in the case of spirolactone 13 in which a 55:45 ratio of
thermodynamic vs kinetic product formation was observed (Table 1,
entry 1-3). Towards the application of this methodology to fully
substituted hexose derived spirocyclic systems, glucose based donor-
acceptor cyclopropanecarboxylated compounds 14 and 17 were
hydrolyzed to obtain the corresponding acids 15 and 18 which were
upon exposure to BF3.Et2O lead to the formation of 1,6-
dioxaspiro[4.5]decan-2-one systems 16 and 19 as single
diastereomers, respectively.
The methodology was further evaluated in the case of furanose fused
spiro-cyclopropanecarboxylic
acids.
Thus,
spiro-
cyclopropanecarboxylates 20, 23, 26 and 29 were hydrolyzed to
obtain furanose fused spiro-cyclopropanecarboxylic aicds 21, 24, 27
and 30, respectively. Reaction of these acids with BF3.Et2O provided
the 1,6-dioxaspiro[4.4]nonan-2-one motifs 22, 25, 28 and 31 as
Scheme 1 Synthesis of 1,6-dioxaspiro[4.5]decan-2-one by a single diastereomers in good yield. Interestingly, it was observed
one-pot ring-opening and cyclization reaction.
that in all the spirolactones that were synthesized, the oxygen of the
lactone prefer to have a 1,2-syn relationship. These observations
indicate that the stereochemistry at spirocentre is a cumulative
outcome based on the stability of the chair-like oxonium ion
intermediate and the anomeric effect, which will be substantially
influenced by the stereocentre adjacent to the spirocentre.22
Table 1. Stereoselective synthesis of pyranose derived 1,6-dioxaspiro[4.5]
decan-2-one systems.
Table 2. Stereoselective synthesis of furanose derived 1,6-dioxaspiro[4.4]
nonan-2-one systems.
a Mixture of diastereomers. b Yield refers to pure and isolated products.
a Mixture of diastereomers. b Yield refers to pure and isolated products. c
Major diastereomer is represented.
To examine the application of this methodology in bicyclic systems,
exo-olefin 32 was cyclopropanated to give a diastereomeric mixture
of tricyclic cyclopropanecarboxylate 33 which upon base hydrolysis
provided the corresponding carboxylic acid 34. BF3.Et2O mediated
Encouraged with this result the generality of the reaction was
investigated by applying it to a number of sugar derived spiro-
2 | J. Name., 2012, 00, 1-3
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ring-opening and cyclization of 34 provided the tricyclic pyrenolide D. Similarly hydrogenolysis of compound 44 provided
spirolactone 35 as a 1:1 diastereomeric mixture (Scheme 2).
the fused tricyclic lactone 47 (Scheme 3).
Scheme 2 Synthesis of tricyclic spiro systems possessing
spirolactone moiety.
Application of the similar protocol on spiro-cyclopropane carboxylic
acids 37 and 40, synthesized from esters 36 and 39, provided the
spiro-lactones 38a and 38b (8:7) and 41a and 41b (3:2), respectively
(Table 3, entry 1 and 2). The lower diastereoselectivity in these
reactions might be due to the lack of stereocentre adjacent to the
spirocenter. The methodology is also equally applicable to the
synthesis of fused lactones that has been shown by synthesizing the
cyclopropanecarboxylic acid 43, prepared from 42,23 and treating
with BF3.Et2O to give linearly fused tricyclic lactone 44 as a single
diastereomer (Table 3, entry 3).24
Scheme 3 Synthesis of pyrenolide D analogues and linearly fused
tricyclic lactone.
Conclusions
Table 3. Synthesis of tricyclic spirosystems.
In conclusion, a stereoselective protocol for the construction of
spiro[6.5] and spiro[5.5]lactone using a diastereomeric mixture
of carbohydrate derived spiro-cyclopropanecarboxylates was
revealed. The generality of the reaction was investigated by
applying the methodology to synthesize a variety of spirocyclic
systems. In all the spiro-lactones that were synthesized it was
observed that there is a pronounced effect of the stereocentre
adjacent to the anomeric position which directs the chirality of
emerging spirocentre. This methodology was also further
applied to synthesize a series of tricyclic spiro[furan-2,2'-
spiro-cyclopropane
carboxylic acida (%)b
spiro-lactone (%)b
spiro-cyclopropa-
-ne carboxylatea
entry
OBn
OBn
O
OBn
O
O
OMe
OH
1
O
O
O
O
O
O
O
BnO
BnO
BnO
36
37 (92)
38a:38b (8:7), (75)c
O
O
O
OMe
OH
2
3
O
O
O
O
O
O
O
BnO
BnO
BnO
furo[3,2-b]furan] ring systems. A successful application of the
39
40 (74)
41a:41b (3:2), (77)c
developed methodology was shown by synthesizing dihydro-
pyrenolide D and dihydro-4-epi-pyrenolide D. Exploitation of
this protocol in the total synthesis of bioactive natural products
and the investigation of controlling the stereochemistry at the
spirocentre are in progress.
OMe
OH
O
O
O
O
O
O
O
O
O
O
BnO
BnO
BnO
42
43 (95)
44 (83)
a Mixture of diastereomers. b Yield refers to pure and isolated products. c
Major diastereomer is represented.
We thank Council of Scientific and Industrial Research (CSIR),
New Delhi (Grant No: 01(2408)/10/EMR-II) for support.
Notes and references
a School of Chemistry, University of Hyderabad, Hyderabad – 500 046.
To demonstrate the significance of the developed methodology we
planned to synthesize the analogues of a bio-active spirolactone
containing natural product pyrenolide D25 (IC50 = 4 ꢀg/mL against
HL-60). Thus, purified spirolactones 41a and 41b were treated with
10% Pd/C under hydrogen atmosphere to give the 2,3-dihydro-
§
To the best of our knowledge highly diastereoselective
cyclopropanation of exocyclic enol ethers has not yet been demonstrated.
Electronic Supplementary Information (ESI) available: Experimental
1
pyrenolide
D
45, and 2,3-dihydro-4-epi-pyrenolide
D
46.
procedures, characterization data and copies of H and 13C spectra of all
Surprisingly to the best of our knowledge, the synthesis of dihydro-
pyrenolides 45 and 46 has not been reported to date. We assume that
the biological activity of these compounds would reveal the
importance of the unsaturated lactone moiety in the natural product
new compounds, copies of DEPT, COSY and NOESY spectra of all
spirocyclic lactones. See DOI: 10.1039/c000000x/
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1
(a) F. Perron and K. F. Albizati, Chem. Rev. 1989, 89, 1617–1661; 14 P. DeShong and P. J. Rybczynski, J. Org. Chem. 1991, 56, 3207-
(b) J. E. Aho, P. M. Pihko and T. K. Rissa, Chem. Rev. 2005, 105
,
3210.
4406–4440.
15 (a) M. Yamamoto, M. Yoshitake and K. Yamada, J. Chem. Soc.,
Chem. Commun. 1983, 991-992; (b) E. Pavlakos, T. Georgiou, M.
2
(a) W.-L. Xiao, H.-J. Zhu, Y.-H. Shen, R.-T. Li, S.-H. Li, H.-D. Sun,
Y.-T. Zheng, R.-R. Wang, Y. Lu, C. Wang and Q.-T. Zheng, Org.
Tofi, T. Montagnon and G. Vassilikogiannakis, Org. Lett. 2009, 11,
Lett. 2005,
7
, 2145-2148; (b) J. Robertson, P. T. Chovatia, T. G.
4556-4559.
Fowler, J. M. Withey and D. J. Woollaston, Org. Biomol. Chem. 16 A. Martín, I. Pérez-Martín and E. Suárez, Org. Lett. 2005,
2010, , 226–233. 2030.
For reviews on chemistry of spiroketals and their synthesis: (a) M. 17 L. Cala, A. Mendoza, F. J. Fañanás and F. Rodríguez, Chem.
A. Brimble and F. A. Farès, Tetrahedron 1999, 55, 7661-7706; (b) T. Commun. 2013, 49, 2715-2717.
K. Mead and B. N. Brewer, Curr. Org. Chem. 2003, , 227–256; (c) 18 (a) B. Ramakrishna and P. R. Sridhar, Org. Lett. 2013, 15, 4474-
M. A. Brimble, D. P. Furkert and Curr. Org. Chem. 2003,
1484; (d) L. Cala, F. J. Fañanás and F. Rodríguez, Org. Bimol. Chem.
7, 2027-
8
3
7
7
,
1461–
4477; (b) P. R. Sridhar, K. Seshadri and G. M. Reddy, Chem.
Commun. 2012, 48, 756-758.
2014, 12, 5324-5330; (e) S. V. Ley, R. M. Myers, L.-G. Milroy in 19 For reviews on carbohydrate fused donor-acceptor cyclopropanes: (a)
Science of Synthesis
,
2007, Vol 29, pp: 613-689. Ed. S. Warriner.
H.-U. Reissig, Top. Curr. Chem. 1988, 144, 73-135; (b) H.-U.
Reissig and R. Zimmer, Chem. Rev. 2003, 103, 1151–1196; (c) M.
Yu and B. L. Pagenkopf, Tetrahedron 2005, 61, 321–347; (d) F. De
Simone and J. Waser, Synthesis 2009, 3353-3374; (e) E. Wenkert,
Acc. Chem. Res. 1980, 13, 27-31; (f) T. F. Schneider, J. Kaschel and
D. B. Werz, Angew. Chem. Int. Ed. 2014, 53, 5504 – 5523.
Houben-Weyl, Thieme-Verlag, Stuttgart, Germany.
4
5
M. Satake, K. Ofuji, H. Naoki, K. J. James, A. Furey, T. McMahon,
J. Silke and T. Yasumoto, J. Am. Chem. Soc. 1998, 120, 9967-9968.
(a) D. Uemura, T. Chou, T. Haino, A. Nagatsu, S. Fukuzawa, S.-Z.
Zeng and H.-S. Chen, J. Am. Chem. Soc. 1995, 117, 1155-1156; (b)
T. Chou, O. Kamo and D. Uemura, Tetrahedron Lett. 1996, 37, 4023- 20 All the exo-glycals were synthesized by elimination of HI from the
4026; (c) T. Chou, T. Haino, M. Kuramoto and D. Uemura,
Tetrahedron Lett. 1996, 37, 4027-4030; (d) N. Takada, N. Umemura,
K. Suenaga, T. Chou, A. Nagatsu, T. Haino, K. Yamada and D.
Uemura, Tetrahedron Lett. 2001, 42, 3491-3494.
corresponding iodomethyl pyranose/furanose or by methylenation of
the corresponding protected lactone with Petasis reagent. For more
exo-glycals and spirocyclopropanes please see Ref. 18a.
21 C. Kim, T. Brady, S. H. Kim and E. A. Theodorakis, Syn. Comm.
2004, 34, 1951-1965.
6
7
N. Takada, N. Umemura, K. Suenaga and D. Uemura, Tetrahedron
Lett. 2001, 42, 3495-3497.
22 The influence of the stereocentre adjacent to the spirocentre in
spirolctone stereochemistry is under investigation.
(a) G. R. Pettit, Z. A. Cichacz, F. Gao, C. L. Herald, M. R. Boyd, J.
M. Schmidt and J. N. A. Hooper, J. Org. Chem. 1993, 58, 1302-1304; 23 Compound 42 was obtained by cyclopropanation of the
(b) J. Pietruszka, Angew. Chem. Int. Ed. 1998, 37, 2629-2636; (c) G.
R. Pettit, J. Nat. Prod. 1996, 59, 812-821.
corresponding endo-glycal, which was obtained by the isomerization
of exo-glycal precursor for the synthesis of 39 under chromatographic
purification over neutral alumina. Please see the supporting
information.
8
9
(a) T. Hu, J. M. Curtis, Y. Oshima, M. A. Quilliam, J. A. Walter, W.
M. Watson-Wright and J. L. C. Wright, J. Chem. Soc., Chem.
Commun. 1995, 2159-2161; (b) T. Hu, I. W. Burton, A. D. Cembella, 24 Although formation of spirolactones and linearly fused bicyclic
J. M. Curtis, M. A. Quilliam, J. A. Walter and J. L. C. Wright, J. Nat.
Prod. 2001, 64, 308-312.
lactones goes through oxonium ion intermediate, it should be noted
that, unlike the formation of spiro-lactones, the stereochemistry of
linearly fused bicyclic ketal/acetal centre is fully governed by the
stereochemistry of cyclopropane carboxylate starting material.
(a) B. A. Kulkarni, G. P. Roth, E. Lobkovsky and J. A. Porco, Jr., J.
Comb. Chem. 2002, 4, 56–72; (b) H. Huang, C. Mao, S.-T. Jan and F.
M. Uckun, Tetrahedron Lett. 2000, 41, 1699–1702; (c) F. M. Uckun, 25 For isolation: (a) M. Nukina and H. Hirota, Biosci. Biotech. Biochem.
C. Mao, A. O. Vassilev, H. Huang and S.-T. Jan, Bioorg. Med. Chem.
Lett. 2000, 10, 541–545; (d) S. Mitsuhashi, H. Shima, T. Kawamura,
K. Kikuchi, M. Oikawa, A. Ichihara and H. Oikawa, Bioorg. Med.
1992, 56, 1158-1159. For total synthesis: (b) K. M. Engstrom, M. R.
Mendoza, M. Navarro-Villalobos and D. Y. Gin, Angew. Chem. Int.
Ed. 2001, 40, 1128-1130. For synthesis of analogues, see: (c) J.
Robertson, K. Stevens and S. Naud, Synlett. 2008, 2083-2086.
Chem. Lett. 1999,
9, 2007–2012; (e) G. Zinzalla, L.-G. Milroy and S.
V. Ley, Org. Biomol. Chem. 2006,
4
, 1977-2002.
10 P. Deslongchamps, D. D. Rowan, N. Pothier, G. Sauvé, J. K.
Saunders, Can. J. Chem. 1981, 59, 1105-1121.
11 J. Sperry, Y.-C. Liu and M. A. Brimble, Org. Biomol. Chem. 2010, 8,
29-38.
12 C. Brand, G. Rauch, M. Zanoni, B. Dittrich and D. B. Werz, J. Org.
Chem. 2009, 74, 8779–8786.
13 (a) J. M. Mellor and S. Mohammed, Tetrahedron 1993, 49, 7547-
7556; (b) G. L. Bundy, C. H. Lin and J. C. Sih, Tetrahedron 1981,
37, 4419- 4429; (c) A. P. Rauter, J. Figueiredo, M. Ismael, T. Canda,
J. Font and M. Figueredo, Tetrahedron: Asymmetry 2001, 12, 1131–
1146.
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