Enantiospecific synthesis of (-)-4-thiocyanatoneopupukeanane †

Enantiospecific total synthesis of the natural enantiomer of the marine sesquiterpene (-)-4- thiocyanatoneopupukeanane ( 6 ) is described. The bicyclo[2.2.2]octanonecarboxylate 11 , obtained from ( R )-carvone and methyl methacrylate via Michael-Michael reaction, was transformed into bicyclo[2.2.2]octenecarboxylic acid 8 . Intramolecular cyclopropanation reaction of the diazo ketone 7 , derived from the acid 8 , followed by regioselective reductive cyclopropane ring cleavage generated neopupukeanol 20 , which was transformed into (-)-4-thiocyanatoneopupukeanane 6 .


Introduction
In variety of marine organisms, chemical defense via secretion of toxic and/or strong smelling organic compounds from their skin glands is a common phenomenon as part of the self-defense mechanism to protect themselves from higher animals.Based on the observation that the nudibranch Phyllidia varicosa Lamarck secretes a toxic substance lethal to fish and crustaceans, Scheuer and coworkers investigated on the chemical constituents of the skin extracts of P. varicosa and also from its prey, a sponge Ciocalypta sp.These investigations led to the isolation 1 of two isotwistane (1) based sesquiterpenes, 9-and 2-isocyanopupukeananes 2 and 3. Subsequently, during their biosynthetic experiments directed towards discovering the origin of the isocyano group in marine sponges, Scheuer and co-workers 2 isolated a new sesquiterpene 4 from the sponge Ciocalypta sp.containing a new carbon framework neopupukeanane.Later the research groups of Scheuer and Higa reported 3 the isolation of two thiocyanate containing sesquiterpenes, and assigned the structures as 2-and 4-thiocyanatoneopupukeananes 5a and 6, from the sponge Phycopsis terpnis (from Okinawa) and from an unidentified species from Pohnpei.Subsequently, Faulkner and co-workers reported 4 the isolation of 2-thiocyanatoneo-pupukeanane 5b from Axinyssa aplysinoides from Palau, which was found to be identical to that isolated by Scheuer and Higa, and corrected the stereochemistry of the thiocyanate group as endo, on the basis of the 2D NMR spectra in C 6 D 6 .Biosynthetically, origin of pupukeananes and neopupukeananes can be explained by a common pathway via cyclization and rearrangement of cadinanes. 2It is interesting to note that very few (<10) natural products have been reported to contain a thiocyanate group.Even though significant amount of synthetic activity 5 was reported on the synthesis of pupukeananes, there was no report on the synthesis of neopupukeananes prior to 1998. 6,7In continuation of our interest in the enantiospecific synthesis of natural products, 8 herein we describe the details 6 of the enantiospecific total synthesis of 4-thiocyanatoneopupukeanane 6 starting from (R)-carvone employing an intramolecular cyclopropanation reaction based approach.

Results and Discussion
It was envisaged (Scheme 1) that the intramolecular cyclopropanation reaction of the diazo ketone 7, derived from bicyclo[2.2.2]octenecarboxylic acid 8, followed by cyclopropane ring cleavage would generate the isotwistanone 9 in a regioselective manner.Whereas, Michael-Michael reaction of (R)-carvone (10) with methyl methacrylate could be exploited for the generation of the bicyclo[2.2.2]octenecarboxylic acid 8.
The synthetic sequence is depicted in Scheme 2. Thus, reaction of (R)-carvone 10 with lithium hexamethyldisilazide (LiHMDS) in hexane at -78 °C followed by reaction of the resultant kinetic dienolate with one equivalent of methyl methacrylate furnished the bicyclic keto ester 11, m.p. 59-61 °C (lit. 960-61 °C) via the Michael-Michael reaction in a highly regio-and stereoselective manner, which on catalytic hydrogenation generated the keto-ester 12.For the conversion of the keto group into olefin, reduction-methanesulfonylation-elimination protocol was contemplated.Thus, regioselective reduction of the keto ester 12 with sodium borohydride in methanol at 0 °C furnished the alcohol 13, m.p. 68-70 °C.Methanesulfonylation reaction of the alcohol 13 with methanesulfonyl chloride in pyridine in the presence of a catalytic amount of DMAP followed by purification over a silica gel column furnished the mesylate 14, m.p. 67-69 °C, in 60% yield. 10 Treatment of the mesylate 14 with sodium ethoxide in refluxing THF-ethanol furnished the bicyclo[2.2.2]octenecarboxylic acid 8 in moderate yield.In another direction, in an attempt to reductively remove the methanesulfonate group to generate the alcohol 15, the methanesulfonate 14 was treated with an excess of lithium aluminium hydride (LAH) in refluxing THF, which resulted in the formation of the olefinic alcohol 16 in 80% yield, contrary to the expected alcohol 15.The structure of the alcohol 16 was derived from its spectral data.

Scheme 3
Formation of the alcohol 16 can be explained as shown in Scheme 3. First reduction of the ester group generates the alkoxide 17a, which acts as an intramolecular base and brings out the E 2 -elimination of the mesylate.This was further established by carrying out the reaction in two distinct steps.Thus, reduction of the ester group in the mesylate 14 with LAH at low temperature furnished the hydroxy mesylate 17 in 82% yield.Treatment of the alcohol 17 with one equivalent of n-butyllithium in THF furnished the alcohol 16.It is worth noting that the steric crowding plays an important role in this elimination reaction.For example, elimination of the mesylate was found to be a minor pathway when the isopropyl group in 14 was replaced by the isopropenyl group.Since the olefinic alcohol 16 was readily available, it was transformed into the acid 8. Thus, oxidation of the alcohol 16 with PCC and sodium acetate in dichloromethane furnished the aldehyde 18 in 80% yield, which on further oxidation with 1.6 M Jones' reagent in acetone furnished the acid 8 in 98% yield, which was characterized as its methyl ester 8a.The acid 8 was then transformed into the tetracyclic ketone 19 via intramolecular cyclopropanation reaction 11 of the diazo ketone 7. Thus, reaction of the acid 8 with oxalyl chloride furnished the acid chloride, which upon treatment with an excess of ethereal diazomethane furnished the diazo ketone 7 in 88% yield.Anhydrous copper sulfate catalyzed decomposition of the diazo ketone 7 in refluxing cyclohexane led to the formation of the tetracyclic ketone 19, m.p. 61-63 °C, via stereospecific insertion of the intermediate keto carbenoid, in 60% yield, whose structure was established from its spectral data.It was anticipated that regioselective cyclopropane ring cleavage of the tetracyclic ketone 19 would generate neopupukean-4-one 9, since it is well established 12 that in the reaction of cyclopropyl ketones using lithium in liquid ammonia reduction conditions, the cyclopropane bond which has better overlap with the carbonyl π-orbital will be cleaved.Thus, reaction with an excess of lithium in liquid ammonia transformed the tetracyclic ketone 19 directly into the endo neopupukean-4-ol 20, m.p. 57-59 °C, instead of the ketone 9, in a regio and stereoselective manner.Oxidation of the alcohol 20 with PCC and silica gel in methylene chloride furnished neopupukean-4-one 9, which exhibited spectral data (IR, 1 H and 13 C NMR) identical to that of the sample 7e obtained earlier.
Stereoselective reduction of the ketone group in 9 with sodium borohydride in methanol at ice temperature furnished the alcohol 20, establishing unambiguously the endo stereochemistry of the hydroxy group in the alcohol 20.Reaction of the alcohol 20 with methanesulfonyl chloride in pyridine in the presence of a catalytic amount of DMAP furnished the methanesulfonate 21, m.p. 52-54 °C, in 84% yield, which on reaction with potassium thiocyanate in acetone in a sealed tube furnished 4-thiocyanatoneopupukeanane 6 in 68% yield [α] 28 D : -117.6 (c 1.08, CHCl 3 ), which exhibited optical rotation and spectral data identical to those of the natural product. 3 O PCC NaBH 4 20 9 In conclusion, we have developed an enantiospecific approach to the natural enantiomer of the marine sesquiterpene, 4-thiocyanatoneopupukeanane starting from the readily available monoterpene (R)-carvone, employing Michael-Michael addition, intramolecular alkoxide mediated E 2 -elimination of a mesylate, intramolecular diazo ketone cyclopropanation and regiospecific cyclopropane ring cleavage as key reactions.

Experimental Section
General Procedures.Melting points are recorded using Tempo and Mettler FP1 melting point apparatus and are uncorrected.IR spectra were recorded on Perkin Elmer 781 and Jasco FTIR 410 spectrophotometers. 1 H (300 MHz) and 13 C (75 and 22.5 MHz) NMR spectra were recorded on Jeol JNM λ-300 and FX-90Q spectrometers.The chemical shifts ( ppm) and coupling constants (Hz) are reported in standard fashion with reference to either internal tetramethylsilane (for 1 H) or the central line (77.1 ppm) of CDCl 3 (for 13 C).In the 13 C NMR spectra, the nature of the carbons (C, CH, CH 2 or CH 3 ) was determined by the DEPT-135 experiment, and are given in parentheses.Mass spectra were recorded using Jeol JMS-DX 303 GCMS instrument and relative intensities are given in parentheses.Elemental analyses were carried out using Carlo Erba 1106 CHN analyser.Optical rotations were measured using a Jasco DIP-370 digital polarimeter and [α] D values are given in units of 10 -1 deg cm 2 g -1 .Acme's silica gel (100-200 mesh) was used for column chromatography.All small-scale dry reactions were carried out using standard syringe septum technique.Low temperature reactions were conducted in a bath made of alcohol and liquid nitrogen.Dry THF was obtained by distillation over sodium-benzophenone ketyl.Dry ether and hexane were obtained by distillation over sodium and stored over sodium wire.Dry dichloromethane was prepared by distilling over calcium hydride.Copper sulfate was dried by irradiation in a microwave oven prior to use.Liquid ammonia was obtained in cylinders from Mysore Ammonia Ltd. and distilled over sodium prior to use.