Tetrahedron Letters 55 (2014) 7068–7071

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Tetrahedron Letters

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A model approach towards the polycyclic framework presentin cembranoid natural products dissectolide A, plumarellideand mandapamate

http://dx.doi.org/10.1016/j.tetlet.2014.10.1410040-4039/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding authors. Tel.: +91 40 23016084 (F.A.K.); tel.: +91 40 23134848;fax: +91 40 23010785 (G.M.).

E-mail addresses: faiz@iith.ac.in (F.A. Khan), gmehta43@gmail.com (G. Mehta).

sarcofuranocembrenolide Bcembrene A

O

O

HH

HO

O

OHCO2MeH H

H

rameswaralide

O H

H

O

O

HHO

O

HO

CO2Me

havellockate

OOH

OO

H

O H

OO

OH

H

H HH

verrillin

OO

OOH

intricarene

OMeO

CO2Me

OHO

O

Figure 1. Polycyclic cembranoid and nor-cembranoid natural produ

Laxmaiah Vasamsetty a, Faiz Ahmed Khan a,⇑, Goverdhan Mehta b,⇑a Department of Chemistry, Indian Institute of Technology, Hyderabad 502 205, Indiab School of Chemistry, University of Hyderabad, Hyderabad 500 046, India

a r t i c l e i n f o a b s t r a c t

Article history:Received 12 October 2014Revised 25 October 2014Accepted 28 October 2014Available online 1 November 2014

Keywords:Cembranoid diterpenesFuranobutenolidesStille couplingCross metathesis/RCMTransannular Diels–Alder reaction

A macrocyclic furanobutenolide was crafted from readily available furan building-blocks to set-up atransannular Diels–Alder reaction which delivered the carbocyclic core present in a class of cembranoidditerpene natural products.

� 2014 Elsevier Ltd. All rights reserved.

Discovered nearly half a century ago, cembranoid diterpenefamily has steadily grown.1 Numbering over three hundred strongpresently and widely distributed over different geographical loca-tions around the world, cembranoids have been encounteredamong diverse terrestrial plants, insects and marine sources thatinclude tobacco leaves, termites, soft corals and even paracloacalglands of male alligators (Alligator sinensis).2 Primarily based on a14-membered ring system precursor like cembrene A (Fig. 1),3 bio-synthetically derived from the initial macrocyclization of geranylg-eraniol pyrophosphate, this macrocyclic framework transmutesinto a range of highly oxygenated, polycyclic frameworks throughelegant orchestration of diverse cyclase and oxidase phases.4 Theresulting cembranoids are a cornucopia of complex, polycyclic,functionally embellished and stereochemically endowed group ofnatural products2,5 and a few prototypical examples are displayedin Figure 1.6 In addition to their alluring biosynthetic origin andoccurrence, cembranoids also exhibit broad ranging bioactivityprofile that includes pheromonal, immunomodulatory, anti-inflammatory, anti-apoptotic and neuroprotective to name afew.5 Given these structural and functional attributes, cembranoidshave been attractive and widely pursued targets of syntheticcampaigns which have led to development of several innovative

strategies and culminated in the total synthesis of a few prominentmembers of this family.7,8

cts.

O

HO

H

H

O

OOH

OHH

H

2. plumarellide

O

O

OHO

H

OH

5

(4+2)

cycloaddition

OH

Scheme 1. Plausible biomimetic pathway to plumarellide (2) from furanobuteno-lide 5.

4

11

O

O

OO

O

O O

oxidation

10

Diels-Alder

Scheme 3. Retrosythetic delineation of model tetracyclic framework 4.

L. Vasamsetty et al. / Tetrahedron Letters 55 (2014) 7068–7071 7069

As part of our continuing interest in the synthesis of complex,bioactive polycyclic cembranoids like havellockate9a and ramesw-aralide9b (Fig. 1) from the Indian Ocean and neighbouring regions,we were drawn to exploratory studies toward the synthesis of cem-branoids like mandapamate 1, plumarellide 2 and norcembranoiddissectolide A 3, embodying a common polycyclic core.10 In thatvein, it is contextual to recall an elegantly conceptualized recentapproach of Pattenden co-workers.11a toward cembranoids 1–3,particularly toward plumarellide 2, along a speculative biomimeticpathway advanced by them.7c,d,11a This involved a transannularDiels–Alder reaction (IMDA) in a preformed furanobutenolidebased macrocycle 5 to deliver 2 as the pivotal step, Scheme 1(Fig. 2).

In actuality, however, in situ generated enol ether/cyclic hemi-ketal 6 (a model for 5) from a preassembled macrocyclic precursor,underwent tautomerization to 8 prior to the contemplated

HOMeO2C

HO

H

H

OOH

OHH

H

O

HO

H

H

O

OOH

OHH

H

2. plumarellide1. mandapamate

O

HO

HH

H

O

O

OH

HO H

3. dissectolide A 4

O

O

O O

Figure 2. Structures of mandapamate (1), plumarellide (2) and dissectolide A (3).

O

OH

H

O

OOH

CO2Me

6

(4+2)

cyclization

O

O

HO

H

OO

R

×

O

O

OOR

H

H

H H

R= CO2Me

7

8 9

O

O

OHO

H

OHR

Scheme 2. Formation of deviant product 9 from furanobutenolide 6.

transannular Diels–Alder reaction to eventuate in a deviant prod-uct 9 rather than the expected product 7 Scheme 2.11a This out-come, though grounded in a plausible conceptual foundation,thwarted further progress toward the synthesis of natural producttargets 1–3. A very recent tactical modification of the syntheticscheme by Pattenden’s co-workers11b to rectify the observed devi-ation did not fructify.

In this backdrop, we decided to explore a variant of the pro-posed7c,d,11 transannular Diels–Alder reaction (vide supra) employ-ing a readily accessible and functionally less encumbered substrateto access the common tetracyclic segment 4 harboured by cembra-noids 1–3.

From a retrosynthetic perspective, tetracyclic structure 4 couldbe accessed by setting-up a transannular Diels–Alder reaction 10 inwhich the dienophilic ene-dione moiety can be generated throughan appropriate oxidation manoeuvre on the furan moiety of a fur-anobutenolide 11, Scheme 3. It was therefore decided to imple-ment this protocol on a model substrate in a concise sequenceand the preliminary results are disclosed here.

Commercially available 5-bromo-2-furfural 12 on Pd-mediatedNegishi-type coupling12 with hexenylzinc chloride 13 readilyfurnished 5-alkenylated furan 14, Scheme 4. Vinylogous Mukaiy-ama aldol reaction between 14 and 2-(tert-butyldimethylsiloxy)-3-bromofuran 15, promoted by bismuth triflate,13 led tofuranobutenolide 16 in modest yield. Exposure of 16 to borontriflu-oride–triethysilane milieu effected both TBS-deprotection andhydrogenolysis to furnish methano-furanobutenolide 17, Scheme 4.Stille coupling14 between 17 and vinyltributyl stannane in thepresence of tetrakis (triphenylphosphine)palladium(0) installedthe desired vinyl-butenolide moiety and delivered 18.

Vinyl substituted furanobutenolide 18 had been crafted toimplement RCM between the vinyl and the hexenyl arms on thebutenolide and furan moieties, respectively, to generate the macro-cyclic ring. After some optimization efforts, it was observed thatexposure of 18 to Grubbs-2 catalyst led to two readily separableproducts 11 and 19 formed through straightforward RCM andsequential cross-metathesis (CM)/ring-closing metathesis(RCM),15 respectively. Structure of the RCM derived macrocycle11, particularly the cis-disposition of the newly formed doublebond was secured through single crystal X-ray structure determi-nation16 and the crystal structure is displayed in Scheme 4. Simi-larly, the formulation of dimeric macrocycle 19 formed throughtandem CM/RCM process was confirmed through single crystalX-ray structure determination16 and the crystal structure is shownin Scheme 4. Interestingly, framework of 11, encountered in thepresent sequence, is reminiscent of the basic skeleton present innatural product sarcofuranocembrenolide B.6a

Furanobutenolide based macrocycle 11, bearing a 1,3-dienemoiety, was now poised for setting-up a transannular Diels–Alderreaction through unraveling of ene-dione moiety through furanoxidation. In the event, 11 was subjected to controlled sodiumchlorite oxidation17 of the furan moiety to furnish ene-dione 10with cis-disposition of the double bond (Jcis = 11.2 Hz), Scheme 5.Thermal activation (90 �C) of 10 led to the desired transannularDA reaction and resulted in the formation of a single productwhose stereostructure 21 was elucidated through single crystal

O OTBS

OO

BrO

O

OTBSO

Br

Br

H

ZnCl

OO

H

OO

O OO

O

+OO

OO

a b

c d e

12 14 16

17 18

11

Br

OO

19

13 15

X-ray structure of 11 X-ray structure of 19

O

O O

Scheme 4. Reagents and conditions: (a) 1.3 equiv hexenylzinc chloride, 3 mol % Pd(PPh3)4, THF, rt, 8 h, 64% (b) 1.3 equiv TBSOF, 10 mol % Bi(OTf)3, Et2O, 0 �C–rt, 1 h, 40% (c)2.0 equiv BF3�Et2O, 10 equiv Et3SiH, CH2Cl2,�30 �C, 1.5 h, 70% (d) 1.2 equiv vinyl tributyltin, 10 mol % Pd(PPh3)4, 65 �C, 12 h, 71% (e) Grubbs 2nd generation (20 mol %), CH2Cl2,40 �C, 16 h, 11 (29%), 19 (30%).

a

O

O

OO

O O

OO

O OH

O OH

H

H

H

11 20

4 21

b

X-raystructure of 21

O

O

OO

O

O O

10

H

H

H

H

H

Scheme 5. Reagents and conditions: (a) 2.25 equiv NaH2PO4, 4 equiv NaClO2,tBuOH/H2O, 0 �C–rt, 1 h, 94% (b) Toluene, 90 �C, 7 h, 67%.

7070 L. Vasamsetty et al. / Tetrahedron Letters 55 (2014) 7068–7071

X-ray structure determination16 (see crystal structure in Scheme 5).Stereostructure of 21 while validating our basic premise(Scheme 3), indicated that the overall process from 10 to 21 wasmore eventful than what had been contemplated. Thus, thetrans-disposition of ring junction hydrogens (marked red) in 21was indicative of the fact that the cis-ene-dione moiety in 10 hadisomerized to its trans form 20 prior to the transannular Diels–Alder reaction. Furthermore, structure of 21 indicated that the but-enolide moiety in the initially formed tetracyclic product 4 hadopened-up during the reaction regime to eventuate in 21,Scheme 5. Nevertheless, an access to the 5–6–7 fused tricyclic corehas been realized. We hasten to add that we are cognizant of thefact that stereochemical issues and implementation of this themein more functionally rich substrates remains a challenge. Theseare being addressed.

In conclusion, we have outlined a short approach to the tricar-bocyclic core present in a select group of complex cembranoids

employing a biomimetically inspired transannular Diels–Alderreaction as the key step. It is expected that learnings from thismodel study will enable its adaptation to more functionally embel-lished environment to target the cembranoid natural products.

Acknowledgments

L.V. and F.A.K. wish to thank the Council of Scientific and Indus-trial Research in India for the award of a Research Fellowship andresearch support, respectively. G.M. acknowledges the researchsupport from Eli Lilly and Jubilant-Bhartia Foundations and theaward of National Research Professorship by the Government ofIndia.

Supplementary data

Supplementary data (experimental procedures, characteriza-tion data, copies of 1H and 13C NMR and X-ray crystallographic datafor 11, 19 and 21) associated with this article can be found, in theonline version, at http://dx.doi.org/10.1016/j.tetlet.2014.10.141.

References and notes

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16. Single crystal X-ray data for 11, 19 and 21 was collected at 293 K on aCrysAlisPro, Oxford Diffraction Ltd, Version 1.171.35.19, equipped with Cu–Karadiation (k = 1.5418 Å) source. The crystal structure were solved by directmethods using SIR92 and refined by full-matrix least-squares methods on F2

using SHELXL97. Crystal data of 11: (CCDC 1025523), C15H16O3, M = 212.20,monoclinic, P21/c, a = 11.1445(5) Å, b = 26.6286(12) Å, c = 8.5188(4) Å,V = 2527.9(2) Å3, Z = 8, qcalcd = 1.284 g/cm3, 13,922 reflections measured,4566 unique (Rint = 0.0315), R1 = 0.0311and wR2 = 0.1674. Crystal data of 19:(CCDC 1025524), C30H32O6, M = 212.20, triclinic, P�1, a = 6.1643(4) Å,b = 8.1611(8) Å, c = 13.5043(17) Å, V = 662.49(11) Å3, Z = 1, qcalcd = 1.225g/cm3, 3988 reflections measured, 2342 unique (Rint = 0.0310), R1 = 0.0870and wR2 = 0.2463. Crystal data of 21: (CCDC 1025525), C15H16O4, M = 260.28,monoclinic, P21/c, a = 10.9603(14) Å, b = 6.0930(6) Å, c = 20.001(3) Å,V = 1325.6(3) Å3, Z = 4, qcalcd = 1.304 g/cm3, 4870 reflections measured, 2485unique (Rint = 0.0264), R1 = 0.0785 and wR2 = 0.1790. Crystallographic data(excluding structure factors) for the structures in this letter have beendeposited with the Cambridge Crystallographic Data Centre.

17. Annangudi, S. P.; Sun, M.; Salomon, R. G. Synlett 2005, 1468.