Total syntheses of Prelactone V and Prelactone B

Article abstract of DOI:10.1016/j.carres.2017.02.008

The total syntheses of natural products Prelactone-V and Prelactone-B have been accomplished by a novel Chiron approach starting from D-glucose. The synthesis involves isopropylidene acetal formation of D-glucose using Poly(4-vinylpyridine) supported iodine as a catalyst, Tebbe olefination, Grignard reaction, Wittig olefination, selective mono deprotection of acetal using PMA/SiO₂, hydrogenation and anti-1,3-diol formation are as key steps.

Full text of DOI:10.1016/j.carres.2017.02.008

Accepted Manuscript
Total syntheses of Prelactone V and Prelactone B
S. Raghavendra, Krishnaji Tadiparthi, J.S. Yadav
PII:
S0008-6215(16)30597-3
10.1016/j.carres.2017.02.008
CAR 7327
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 27 November 2016
Revised Date: 20 February 2017
Accepted Date: 26 February 2017
Please cite this article as: S. Raghavendra, K. Tadiparthi, J.S. Yadav, Total syntheses of Prelactone V
and Prelactone B, Carbohydrate Research (2017), doi: 10.1016/j.carres.2017.02.008.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Total Syntheses of Prelactone
V and Prelactone B
S. Raghavendra,*, Krishnaji Tadiparthi and J. S. Yadav
1

ACCEPTED MANUSCRIPT
Total Syntheses of Prelactone
V and Prelactone B
S. Raghavendra,*1,2 Krishnaji Tadiparthi1,3 and J. S. Yadav1
1Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-
500007, INDIA
2Dept. of Pharmaceutical Chemistry, School of Pharmacy and health sciences,
International Medical University, Kuala Lumpur 57000, MALAYSIA
3Department of Chemistry, Christ University, Hosur Road, Bangalore – 560029, INDIA
E-mail: srgoud2@gmail.com; Fax: +603-86567229.
Abstract: The total syntheses of natural products Prelactone–V and Prelactone–B have
been accomplished by a novel Chiron approach starting from
involves isopropylidene acetal formation of -glucose using Poly(4-vinylpyridine)
supported iodine as a catalyst Tebbe olefination, Grignard reaction, Wittig olefination,
D–glucose. The synthesis
D
,
selective mono deprotection of acetal using PMA/SiO2, hydrogenation and anti-1,3-diol
formation are as key steps.
Keywords: D
-glucose, P(4-VPI)+I3-, PMA/SiO2, Wittig Olefination, Grignard reaction and
Tebbe reaction and Lactonisation.
1. Introduction
Prelactones 1-4 belong to the family of polyketide macrolides with a δ-lactone,
specifically a β-hydroxy-δ-lactone structure found in components of several drugs and
bioactive natural products [1,2]. In addtion, they also represent useful building blocks for
the synthesis of more complex structures [3-6]. Prelactones 1-5 (Fig. 1) are a subgroup of
this class of natural products isolated in 1993 by Bindseil and Zeeck et al. [7] from the
Streptomyces griseus. Prelactone B represents an early metabolite in the biosynthesis of
polyketide antibiotics.
O
O
O
O
O
O
O
O
OH
OH
OH
OH
Prelactone V
(1)
Prelactone B
(2)
Prelactone E
(3)
Prelactone C
(4)
Corresponding author: E-mail address srgoud2@gmail.com (S. Raghavendra)
2

ACCEPTED MANUSCRIPT
O
O
O
OH
O
OH
Leptomycin B
(5)
Figure 1. Chemical structures of Prelactones
It is well-known that the lactone moiety is responsible for the biological activity
of Compactin and Mevinolin [8,9]. Consequently, a large number of approaches have
been reported for the synthesis of prelactones [10,11,12]. Since δ-lactones are of great
importance in stereo-controlled asymmetric synthesis of natural products [1], the
development of modular strategy for the synthesis of these prelactones would allow the
preparation of natural products as standards during mechanistic studies of polyketide
biosynthesis and also provide a flexible route for the synthesis of di-, tri-, and tetra-
substituted δ-lactones in a highly stereo-controlled manner (Scheme 1).
2. Results and Discussion
In continuation of our efforts towards synthesis of Leptomycin B [16, 17] (5), we
have prepared some intermediates, from which we envisaged that prelactones can be
synthesized in a highly stereo-controlled manner. We put our ideas into practice to
synthesize these important lactones starting from 1,2,5,6-diisopropylidene-
glucofuranose. We have developed a new methodology for the preparation of
isopropylidene acetal from -glucose using Poly(4-vinylpyridine) supported iodine [P(4-
VPI)+I3- ] as a mild, efficient and reusable catalyst [18,19].
D-
D
3

ACCEPTED MANUSCRIPT
O
O
O
O
O
a
c
O
b
O
O
D-Glucose
O
O
HO
O
7
8
O
O
HO
O
O
O
O
O
e, f
O
d
HO
O
HO
O
O
O
9
10
11
O
O
O
g
HO
h
i
TsO
O
O
12
13
O
O
O
O
OH OH
OH
OH
j
l,m
k
O
OH
O
OH
14
16
Prelactone V (1)
15
-
o
Scheme 1. Reagents and conditions: a) P(4-VPI)+I3 , dry acetone, 3 Ao MS, 50 C, 8 h, 65%; b)
PDC, Ac2O, 3Ao MS, CH2Cl2, r.t., 2 h, 85%; c) CH3PPh3I, n-BuLi, THF, -78 oC to r.t., 2 h, 95%;
d) 1 mol% PMA/SiO2, CH3CN, r.t., 5 min, 95%; e) NaIO4, aq. NaHCO3, CH2Cl2, 1 h; f) NaBH4,
o
MeOH, 0 C to r.t., 30 min, 94%; g) H2, 10% Pd(OH)2/C, ethyl acetate, r.t., 2 h, 95%; h) TsCl,
o
Et3N, DMAP, CH2Cl2, r.t., 4 h, 95%; i) LiAlH4, THF, 0 C to reflux, 3 h, 88%; j) 30% AcOH,
heat, 2 h, 72%; k) LiAlH4, THF, 0 - 60 oC, 3 h, 85%; l) NaIO4, cat. NaHCO3 solution, CH2Cl2, 1
h; m) Ethyl acetate, LiHMDS, THF, -78 oC, 2 h, 62%.
Accordingly, we commenced the synthesis of prelactones from commercially
available
D
-glucose as
a
starting material. Initially, 3-hydroxy-1,2,5,6-di–O-
isopropylidene-α-
D
-glucofuranose 7 was prepared from D-glucose by using a new
-
method which was developed by us [18] using P(4-VPI)+I3 a mild, efficient and reusable
catalyst [19]. Oxidation of compound 7 with PDC [20,21,22] followed by one carbon
o
Wittig olefination with PPh3CH3I in THF using n–BuLi at –78 C afforded diacetonide
olefin 9 in 95% yield. Selective mono deprotection of 5,6–isopropylidene acetal 9 was
achieved by using 1 mole% phosphomolibdic acid supported on silica gel (PMA/SiO2) in
acetonitrile to furnish the diol 10 in 95% yield [23]. Oxidative cleavage of 10 using
sodium periodate and aq. NaHCO3 (cat.) afforded the corresponding aldehyde which in
situ reduction with NaBH4 in methanol at 0 oC provided the alcohol 11 in 94% yield. The
stereoselective hydrogenation of 11 in the presence of 10% Pd(OH)2/C in ethyl acetate at
60 psi resulted the compound 12 in 95% yield.
4

ACCEPTED MANUSCRIPT
Tosylation of compound 12 with tosyl chloride in the presence of Et3N in CH2Cl2
resulted the tosylate 13 in 95% yield. The compound 13 was subjected for reduction with
LiAlH4 under refluxing in THF to give the compound 14 in 88% yield. Cleavage of the
1,2-isopropylidene acetal 14 upon heating with 30% aq. AcOH provided the lactol 15,
which on subsequent treatment with LiAlH4 in THF afforded the triol 16. Oxidative
cleavage of triol 16 with sodium periodate in the presence of aq. NaHCO3 in CH2Cl2 gave
the aldehyde which was immediately treated with organo lithium reagent which is
generated in-situ from ethyl acetate and LiHMDS in THF at –78 oC to afford the anti-1,3-
diol [24-30] containing β-hydroxy-ethylester in 62% yield as a major isomer, which was
simultaneously underwent lactonisation to afford a six-membered (-)-Prelactone V (1)
(Scheme 1).
Furthermore we focused our attention on the synthesis of Prelactone B (2). Thus,
the synthesis of Prelactone B commenced from the key intermediate 10 which was used
for the synthesis of Prelactone V (1) (Scheme 1).
Scheme 2. Reagents and conditions: a) i. NaIO4, aq. NaHCO3, CH2Cl2, 1 h; ii. MeMgI, dry ether,
o
0 C to r.t., 2 h, 95%; b) PCC, NaOAc, CH2Cl2, r.t., 6 h, 89%; c) Tebbe’s reagent
[Cp2TiCH2AlCl(CH3)2], THF, 0 oC to r.t., 15 min, 90%; d) H2, 10% Pd(OH)2/C, ethyl acetate, r.t.,
o
4 h, 98%; e) 30% AcOH, heat, 2 h, 72%; f) LiAlH4, THF, 0 C to r.t., 4 h, 85%; g) NaIO4, aq.
NaHCO3, CH2Cl2, 1 h; h) Ethyl acetate, LiHMDS, THF, -78 oC to r.t., 62%.
Oxidative cleavage of the diol 10 using sodium periodate in the presence of aq.
NaHCO3 in CH2Cl2 provided the corresponding aldehyde, which was further subjected to
o
the Grignard reaction i.e. with methylmagnesium iodide in dry ether at 0 C. The
diastereomeric mixture of alcohol 17 thus obtained was oxidized using PCC in the
presence of NaOAc in CH2Cl2 to give the ketone 18 in 89% yield. Methylenation of the
5

ACCEPTED MANUSCRIPT
ketone 18 using Tebbe’s reagent [31] afforded the olefin 19 in 97% yield, which in turn
was subjected to hydrogenation in the presence of 10% Pd(OH)2/C in ethyl acetate at 60
psi to give the compound 20 in 98% yield. Cleavage of the 1,2-isopropylidene acetal 20
by heating with 30% aq. AcOH gave the lactal 21, which upon reduction with LiAlH4
o
in THF at 0 C afforded the triol 22. Oxidative cleavage of compound 22 using sodium
periodate in the presence of aq. NaHCO3 in CH2Cl2 gave the corresponding aldehyde,
which on subsequent treatment with organolithium reagent generated from anhydrous
ethyl acetate using LiHMDS in THF at –78 oC to afford anti-1,3-diol [11] as a β hydroxy
ethyl ester which was simultaneously underwent smooth lactonization to afford
prelactone B (2) in 60% yield as a major isomer (Scheme 2). The synthesized Prelactone
V (1) and Prelactone B (2) have been confirmed by the spectral studies. The spectral and
physical data (melting point, specific optical rotation) of 1 and 2 were very closely
matching with the reported data in the literature [32-35].
3. Conclusion
In conclusion, we have successfully demonstrated a modular strategy for the
synthesis of Prelactone V and Prelactone B from 1,2,5,6-diisopropylidene-
D-
glucofuranose using Poly(4-vinylpyridine) supported iodine [P(4-VPI)+I3-] as a mild,
efficient and reusable catalyst for the protection of 1,2 and 5,6 hydroxy groups of-
glucose.
D-
Financial interest
The authors declare no competing financial interest.
Acknowledgements
S. R. and K. T. thank CSIR, New Delhi for the award of a research fellowship.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
6

ACCEPTED MANUSCRIPT
References
[1] J. Cortes, K. E. H. Wiesman, G. A. Roberts, M. J. B. Brown, J. Staunton, P. F.
Leadlay, Science 268 (1995) 1487-1489.
[2] C. M. Kao, G. Luo, L. Katz, D. E. Cane, C. Khosla, J. Am. Chem. Soc. 116 (1994)
11612-11613.
[3] S. Hanessian, J. Ma, W. Wang, J. Am. Chem. Soc. 123 (2001) 10200-10206.
[4] J. A. Marshall, G. M. Schaaf, J. Org. Chem. 68 (2003) 7428-7432.
[5] S. Sudek, N. B. Lopanic, L. E. Waggoner, M. Hildebrand, C. Anderson, H. Liu, A.
Patel, D. H. Sherman, M. G. Haygood, J. Nat. Prod. 70 (2007) 67-74.
[6] A. B. III. Smith, B. S. Freeze, M. Xian, T. Hirose, Org. Lett. 7 (2005) 1825-1828.
[7] M. Gerlitz, P. Hammann, R. Thiericker, J. Rohr, J. Org. Chem. 57 (1992) 4030-
4033
.
[8] J. A. Endo, J. Med. Chem. 28 (1985) 401-405.
[9] D. L. J. Clive, K. S. K. Murthy, A. G. H. Wee, J. S. Prasad, G. V. J. D. Silva, M.
Majewski, P. C. Anderson, C. F. Evans, R. D. Haugen, J. Am. Chem. Soc. 112
(1990) 3018-3028.
[10] For the synthesis of prelactone B, see L. Lili, K. Yulong, L. Xiaohua, and F.
Xiaoming Org. Lett., 13 (2011) 3868–3871.
[11] P. Jennifer, P. D. Ignacio, R. D. Iwan, Ch. Matt, E. T. James, G, Kociok-Köhn,
and D. B. Steven Org. Lett., 13 (2011) 3592–3595.
[12] J. E. Claudia, L. Sylvain, P. Florent, T. Maris, and V. Pierre J. Org. Chem., 76
(2011) 840–845 (references cited therein).
[13] For the synthesis of prelactone C, see Y. Yamashita, S. Saito, H. Ishitani, S.
Kobayashi, J. Am. Chem. Soc. 125 (2003) 3793-3798.
[14] T. K. Chakraborty, S. Tapadar, Tetrahedron Lett. 42 (2001) 1375-1377.
[15] T. Esumi, H. Fukuyama, R. Oribe, K. Kawazoe, Y. Iwabuchi, H. Irie, S.
Hatakeyama, Tetrahedron Lett. 38 (1997) 4823-4826.
[16] M. Kobayashi, W. Wang, Y. Tsutsui, M. Sugimoto, N. Murakami, Tetrahedron Lett.
39 (1998) 8291-8294.
[17] J. A. Marshall, G. M. Schaaf, J. Org. Chem. 68 (2003) 7428-7432.
[18] Manuscript is under preparation.
7

ACCEPTED MANUSCRIPT
[19] N. G. Khalig, RSC Adv. 2 (2012) 3321-3327.
[20] D. H. Hollenberg, R. S. Klein, Fox, J. Carbohydr. Res. 67 (1978) 491-494.
[21] D. C. Baker, D. Horton, C. G. Tindall, J. Carbohydr. Res. 24 (1972) 192-197.
[22] S. Czernecki, C. Georgoulis, C. L. Stevens, K. Vijayakumaran, Tetrahedron Lett.
26 (1985) 1699-1702.
[23] J. S. Yadav, S. Raghavendra, M. Satyanarayana, E. Balanarsaiah, Synlett 16
(2005) 2461-2464.
[24] J. Yuan, K. Lindner, H. J. Frauenrath, Org. Chem. 71 (2006) 5457-5467.
[25] J. W. Burton, J. S. Clark., S. Derrer, T. C. Stork, J. G. Bendall, A. B. Holmes, J.
Am. Chem. Soc. 119 (1997) 7483-7498.
[26] D. Seyferth, J. K. Heeren, G. Singh, S. O. Grim, W. B. Hughes, J. Organomet.
Chem. 5 (1966) 267-274.
[27] S. H. Pine, G. S. Shen, H. Hoang, Synthesis 2 (1991) 165-167.
[28] P. Yu, Y. Yang, Y, Z. Y. Zhang, T. C. W. Mak, H. N. C. Wong, J. Org. Chem.
62 (1997) 6359-6366.
[29] A. Mengel, O. Reiser, Chem. Rev. 99 (1999) 1191-1224.
[30] P. Radhakrishna, P. V. N. Reddy, Tetrahedron Lett. 47 (2006) 4627-4630.
[31] F. N. Tebbe, G. W. Parshall, G. S. Reddy, J. Am. Chem. Soc. 100 (1978) 3611-
3613.
[32] D. Enders, M. Hass, Synlett 14 (2003) 2182-2184.
[33] V. K. Aggarwal, I. Bae, H.-Y. Lee, Tetrahedron 60 (2004) 9725-9733.
[34] J. S. Yadav, M. S. Reddy, A. R. Prasad, Tetrahedron Lett. 46 (2005) 2133-2136.
[35] J. S. Yadav, K. B. Reddy, G. Sabitha, Tetrahedron Lett. 45 (2004) 6475-6476.
8

ACCEPTED MANUSCRIPT
The main highlights of this article are
•
•
The total syntheses of natural products Prelactone–V and prelactone–B using a chiron approach
starting from commercially available D–glucose.
The synthesis involves isopropylidene acetal formation of D-glucose using Poly(4-vinylpyridine)
supported iodine as a novel catalyst.
•
•
The synthesis also involves the selective mono deprotection using PMA/SiO2 catalyst.
The synthesis also involves Tebbe olefination, Grignard addition and Wittig homologation in
reasonable yields.