Synthesis of (+)-Disparlure via Enantioselective Iodolactonization

Abstract

The BINOL-amidine organic catalyst 1 was previously shown to promote highly efficient enantioselective halolactonization reactions of olefinic acids. As part of these studies, it was discovered that the enantioenriched iodolactones could be easily converted into enantioenriched cis-1,2-disubstituted epoxides. This halolactonization-epoxidation sequence was applied to the synthesis of (+)-disparlure, which resulted in the shortest catalytic enantioselective synthesis to date, requiring only five steps and proceeding in 33% yield.

Graphical abstract

Electrophilic halocyclizations of olefinic carboxylic acids represent an important class of reactions that has been widely used in organic synthesis.¹ Consequently, the development of asymmetric variants of halolactonization reactions has received considerable attention in recent years, and some significant advances have been made.² We recently reported the discovery of the bifunctional organic catalyst 1 that promotes highly efficient enantioselective halolactonization reactions for a broad array of olefinic acids (Equation 1).³ The BINOL-amidine catalyst 1 was competitive with other catalysts in promoting enantioselective bromolactonizations of 4-and 5-aryl-4-pentenoic acids (2a,b), and at the time of its discovery was unique in its ability to effect bromolactonizations of 5-alkyl-4(Z)-pentenoic acids (2c) via 5-exo cyclizations to generate stereogenic carbonhalogen centers with excellent enantioselectivities.^3a,4 Additionally, we subsequently found that 1 could be used to convert 5-substituted-4(Z)-pentenoic acids into the corresponding iodolactones with a high degree of enantioselectivity.^3b

(1)

As an integral part of developing useful applications of 1 and analogs thereof, we identified several unmet needs in the arena of enantioselective halolactonizations. For example, the enantioselective epoxidation of Z-disubstituted olefins in the absence of directing groups was a significant challenge,⁵ so there was an opportunity to invent efficient methods to generate such epoxides. Toward solving this problem, we discovered that chiral halolactones such as 4, which were easily accessible via enantioselective halolactonizations of 4(Z)-alkenoic acids using 1 (Equation 1), could be readily transformed without erosion of enantiopurity into cis-1,2-disubstituted epoxides such as 5 upon treatment with Cs₂CO₃ in MeOH (Equation 2). We now report the application of this facile iodolactonization-epoxidation sequence to a concise enantioselective synthesis of (+)-disparlure, an important insect pheromone that is broadly used to manage gypsy moth populations.⁶

(2)

The gypsy moth, Lymantria dispar, is an invasive insect that is one of the most destructive exotic organisms in North America.⁷ During outbreaks, the insects cause severe deforestation that can have substantial negative ecological and economic ramifications. Bierl identified disparlure, (Z)-7,8-epoxy-2-methyloctadecane, as the sex attractant emitted by the female gypsy moth in 1970,⁸ and it was later established that (+)-disparlure (6) is the major attractant component.⁹ The management of gypsy moth populations has been successful in part due to the availability of pheromone-containing traps that are highly effective for detecting low density populations.¹⁰ Because of its utility in managing gypsy moth populations and its scarcity from natural sources, disparlure has been the target of a myriad of synthetic investigations. Indeed, since its discovery, there have been more than 50 syntheses of racemic and enantiomerically-enriched disparlure.¹¹ Despite these many successes, there remains opportunity for improvement, so we designed an approach based upon our enantioselective iodolactonization methodology. In particular, we envisaged that (+)-disparlure (6) could be prepared from 7, which would accessible in two steps from the olefinic acid 9 via enantioselective halolactonization followed by reaction of the intermediate iodolactone 8 with methanolic base (Scheme 1).

Scheme 1.

Synthetic strategy towards (+)-disparlure

Our synthesis commenced with the preparation of 9 through a two step procedure from commercially available pentynoic acid (10). In the event, alkylation of the dianion generated from 10 with 1-iododecane, followed by in-situ saponification of any ester byproduct furnished 11 in 82% yield. Partial reduction of the alkyne moiety of 11 was achieved through a P2-Ni hydrogenation to give the Z-alkenoic acid 9 in 85% yield. Gratifyingly, iodolactonization of 9 with N-iodosuccinimide (NIS) in the presence of ent-1 and I₂ gave lactone 8 in 85% yield and 95:5 er. When 8 was processed via a one-pot sequence involving reduction of the lactone moiety followed by Wittig olefination, the requisite epoxide 12 was isolated in 62% yield. Not surprisingly based upon literature precedent,¹² we found that selective reduction of the double bond in 12 by catalytic hydrogenation was problematic because epoxide opening was a significant side reaction. However, after screening a variety of conditions, we ultimately discovered that hydrogenation of 12 using Pt₂O in hexanes delivered (+)-disparlure (6) in 90% yield. This synthesis of (+)-disparlure required only five steps from commercially available starting materials and proceeded in 33% overall yield from 10, making this the shortest catalytic enantioselective synthesis of 6 to date.

In summary, we have demonstrated that enantioselective iodolactonization reactions promoted by the bifunctional BINOL-amidine catalysts 1 and ent-1 can give rapid access to enantioenriched cis-disubstituted epoxides. In order to exemplify the utility of this methodology, it was applied to prepare (+)-disparlure in the shortest catalytic enantioselective synthesis of (+)-disparlure reported to date.¹³ Other applications of 1 and related catalysts in organic synthesis will be reported in due course.

Scheme 2.

Synthesis of (+)-disparlure from pentynoic acid