Catalyst-Controlled Formal [4 + 3] Cycloaddition Applied to the Total Synthesis of (+)-Barekoxide and (−)-Barekol

Abstract

The tandem cyclopropanation/Cope rearrangement between bicyclic dienes and siloxyvinyldiazoacetate, catalyzed by the dirhodium catalyst Rh₂(R-PTAD)₄ effectively accomplishes enantiodivergent [4 + 3] cycloadditions. The reaction proceeds by a cyclopropanation followed by a Cope rearrangement of the resulting divinylcyclopropane. This methodology was applied to the synthesis (+)-barekoxide (1) and (−)-barekol (2).

Fused seven-membered carbocycles are present in a wide-variety of terpene natural products.¹ An effective method for the stereoselective synthesis of seven-membered rings is the formal [4 + 3] cycloaddition between vinylcarbenoids and dienes, which gives predictable diastereocontrol, proceeding through a Cope rearrangement of a cis-divinylcyclopropane intermediate.^2,3 Furthermore, chiral dirhodium tetracarboxylate catalysts enable high enantioselectivity to be achieved in these transformations.⁴ Recently, the Sarpong group applied the formal [4 + 3] cycloaddition in a stereodivergent approach to the core of the cyanthane diterpenes.⁵ This paper describes a collaborative study between the Davies and Sarpong groups, resulting in a greatly enhanced level of enantiomeric differentiation for this chemistry and its application to the synthesis of (+)-barekoxide (1) and (−)-barekol (2).⁶

The original studies by Sarpong were conducted on the diene (S)-3 and the unsubstituted vinyldiazoacetate 4a using the enantiomers of Rh₂(DOSP)₄⁷ as catalysts (Table 1, entries 1 and 2).⁵ Each enantiomer of the catalyst gave moderate control of which diastereomer of the tricyclic products (5a or 6a) was formed. Davies has recently demonstrated that siloxyvinyldiazoacetate 4b with Rh₂(PTAD)₄⁸ is a good combination for highly enantioselective [4 + 3] cycloadditions.^3b,c Therefore, the reactions of (S)-3 were re-examined using siloxyvinyldiazoacetate 4b as the carbenoid precursor.

Table 1.

Reaction between enantio-pure diene and diazoacetates

entry	substrate	catalyst	diazo	ratio (5/6)	yield (5+6, %)
1a	(R)-3	Rh2(R-DOSP)4	4a	5:1b	39c
2a	(R)-3	Rh2(S-DOSP)4	4a	1:5b	50c
3d	(S)-3	Rh2(R-DOSP)4	4b	>19:1	76
4d	(S)-3	Rh2(S-DOSP)4	4b	2:1	63
5d	(S)-3	Rh2(R-PTAD)4	4b	>19:1	81
6d	(S)-3	Rh2(S-PTAD)4	4b	<1:19	80

^aReactions were conducted at 8 °C in pentane with 3.0 equivalents of 4a and 1 mol% catalyst;

^bDetermined by ¹H NMR;

^cIsolated yields of the reduced ester protected as a p-nitrobenzoate;

^dReactions were conducted at 0 °C in PhMe with 3.0 equivalents of 4b and 2 mol% catalyst.

The reaction of (S)-3 with 4b catalyzed by Rh₂(R-DOSP)₄ gave exclusively the tricycle 5b, whereas the reaction catalyzed by Rh₂(S-DOSP)₄ still gave a slight preference of 5b over 6b (entries 3 and 4). These results indicate that the substrate control in the reaction between (S)-3 and 4b favors the formation of 5b, which is enhanced in the matched reaction using Rh₂(R-DOSP)₄ as catalyst. The mismatched reaction, however, with Rh₂(S-DOSP)₄ as catalyst gives a mixture of products.

The diastereocontrol of the [4 + 3] cycloaddition is further enhanced when the enantiomers of Rh₂(PTAD)₄ are used as catalysts. Once again in the matched reaction with Rh₂(R-PTAD)₄ as catalyst, 5b is formed with high diastereoselectivity (entry 5). In this case, however, the mismatched reaction with Rh₂(S-PTAD)₄ as catalyst is also highly diastereoselective, generating 6b exclusively (entry 6).

Having discovered that the siloxyvinyldiazoacetate 4b gives much better stereodifferentiation than 4a, the next series of reactions explored whether a resolution would be possible using (±)−3. The reaction of 4b catalyzed by Rh₂(R-DOSP)₄ was highly diastereoselective, but the major diastereomer 5b was produced in only 53% ee. In contrast, the reaction catalyzed by Rh₂(R-PTAD)₄ had excellent reagent control, in which 5b was produced in 90% ee and the other diastereomer (ent-6b) was produced in 99% ee.

This transformation can also be effectively extended to a more sterically hindered diene (S)-7, using TIPS as the protecting group. The Rh₂(R-PTAD)₄-catalyzed reaction of (S)-7 and the siloxydiazoacetate 4b generated product 8 as a single diastereomer (entry 1, Table 3), whereas the reaction initiated by Rh₂(S-PTAD)₄ afforded the other isomer 9 with excellent diastereoselectivity (entry 2, Table 3). Extension of the study from a bicyclo[4.3.0]nonane to a bicyclo[4.4.0]decane system revealed the subtle controlling influences assocciated with this selectivity. The Rh₂(R-PTAD)₄-catalyzed reaction of diene (S)-10 with siloxydiazoacetate 4b generated two diastereomers of the formal [4 + 3] cycloadducts, 11 and 12 in a 9:1 ratio (entry 3, Table 2). The same reaction catalyzed by Rh₂(S-PTAD)₄ switched the diastereoselectvity, favoring 12 with a 4: 1 dr. These results indicate that the chiral catalyst has a conrolling influence on the diastereoselectvity in the bicyclo[4.4.0]decane system but the effect is not as overwhelming as it is in the bicyclo[4.3.0]nonane system.

Table 3.

Reaction scope between enantio-pure diene and diazoacetate 4b

entry	catalyst	ratio (8/9)	yield (major isomer only, %)
1	Rh2(R-PTAD)4	>19:1	82
2	Rh2(S-PTAD)4	<1:19	76
entry	catalyst	ratio (11/12)	yield (major isomer only, %)
3	Rh2(R-PTAD)4	9:1	77
4	Rh2(S-PTAD)4	1:5	66
entry	catalyst	ratio (14/15)	yield (major isomer only, %)
5	Rh2(R-PTAD)4	4:1	63
6	Rh2(S-PTAD)4	1:7	69
entry	catalyst	ratio (17/18)	yield (major isomer only, %)
7	Rh2(R-PTAD)4	2:1	55
8	Rh2(S-PTAD)4	1:16	81

Table 2.

Reaction between racemic 3 and diazoacetate 4b

catalyst	ratio (5 b/ent-6b)	yield (5b, %)	yield (ent-6b, %)	ee (5b, %)	ee (ent-6b, %)
Rh2(R-DOSP)4	10:1	48	NDa	53	NDa
Rh2(R-PTAD)4	1.7:1	39	25	90	99

^aNot determined.

With access to a range of diasteromeric bicyclo[4.4.0]decane-derived dienes, studies were then conducted to determine if the catalyst control could be extended to generate different pairs of diastereomeric products. Substrate (S)-13 is epimeric to (S)-10 at the siloxy carbon, which is closely positioned next to the diene. However, the catalyst effect is not greatly influenced by this change. The reaction of (S)-13 with the siloxydiazoacetate 4b catalyzed by Rh₂(R-PTAD)₄ afforded the formal [4 + 3] cycloadducts, 11 and 12 in a 4:1 dr (entry 5) whereas the Rh₂(S-PTAD)₄-catalyzed reaction favored 12 by a 7:1 dr (entry 6). The next series of experiments examined the influence of the ring fusion configuration on the selectivity. All the compounds to date have been cis-fused, but diene (S)-16 is trans-fused. The Rh₂(R-PTAD)₄-catalyzed reaction of (S)-16 with 4b showed poor diastereoselectvity as the formal cycloadducts 17 and 18 were produced in only a 2: 1 dr (entry 7). However, the Rh₂(S-PTAD)₄-catalyzed reaction was much more diastereoselective, favoring 18 (16: 1 dr, entry 8). Even though these reactions do not display perfect catalyst control, they are still effective for the diastereoselective synthesis of the tricyclic product because six distinct diastereomers wre generated in isolated yields rnaging from 55–81%.

The stereochemistry of the [4 + 3] cycloaddition is controlled in the initial cyclopropanation. Theoretical calculations have shown that the alkene approaches in essentially an end-on mode,⁹ whereas the Cope rearrangement of the divinylcyclopropane proceeds through a boat transition state.² Several studies have demonstrated that the same sense of asymmetry is obtained in the reaction catalyzed by either Rh₂(R-DOSP)₄ or Rh₂(R-PTAD)₄.^3b,c These catalysts will cause the diene to approach from the front face as illustrated in Figure 1.^3b,c This results in a matched double stereoselection because the siloxy group of the diene (S)-3 is pointing away from the carbenoid during the cyclopropanation. The Cope rearrangement of the divinylcyclopropane would generate 5b. The reaction of (S)-3 catalyzed by Rh₂(S-DOSP)₄ or Rh₂(S-PTAD)₄ are mismatched reactions, but the stereodirecting influence of Rh₂(S-PTAD)₄ is sufficiently strong to overwhelm the inherent stereodirecting influence of (S)-3, leading to the clean formation of 6b.

Figure 1.

Stereochemical analysis of the matched reactions of (S)-3

With an understanding of the factors influencing optimal stereocontrol in hand, we then applied it to the synthesis of (+)-barekoxide and (−)-barekol. The requisite diene was prepared in three steps from commercially available scalerolide (see the Supporting Information for details). Due to the more sterically crowded nature of the double bond in the diene 19, a higher temperature (70 °C) and 3–5 equivalents of 4b were required for an efficient reaction. The Rh₂(R-PTAD)₄ catalyzed reaction gave a 6: 1 mixture of diastereomers favoring 20, whereas the Rh₂(S-PTAD)₄ catalyzed reaction gave a 9: 1 mixture of diastereomers favoring 21. The mixture of 20 and 21 was only slightly separable by chromatography on silica gel impregnated with 5% AgNO₃, but fortunately 20 could be selectively crystallized. In the Rh₂(R-PTAD)₄ catalyzed reaction, the pure desired diastereomer 20 was isolated in 47% yield after recrystallization. In this way, the configuration of a demanding quaternary stereocenter at the B–C ring fusion was effectively controlled.

The synthesis of (+)-barekoxide (1) and (−)-barekol (2) from the tricycle 20 was readily achieved as illustrated in Scheme 1. Palladium catalyzed hydrogenation of 20 generated 22 in essentially quantitative yield. Reduction of the ester in 22 followed by acidic hydrolysis of the silyl enol ether generated the enone 23 in 64% overall yield for the two steps. DIBAL-H reduction of the enone 23 generated the allylic alcohol 24, an epimer of (−)-barekol (2), in 95% yield. Deoxygenation of 24 with double bond isomerization using the Gevorgyan procedure¹⁰ followed by epoxidation with m-CPBA generated (+)-barekoxide (1) in 58% yield over two steps. Acid-catalyzed isomerization of (+)-barekoxide (1) to (−)-barekol (2)¹¹ was achieved in 73% yield using the reported literature procedure.^6a

Scheme 1.

In summary, these studies demonstrate that the combination of the siloxyvinyldiazoacetate and Rh₂(R-PTAD)₄ is very effective in enantiodivergent [4 + 3] cycloadditions. The chiral catalyst controls the diastereoselectivity of the [4 + 3] cycloaddition and can overwhelm the inherent selectivity of the chiral substrate. Even in the system used for the synthesis of (+)-barekoxide (1) and (−)-barekol (2), which required elevated temperatures for an effective reaction, good levels of diastereocontrol was possible, enabling the stereoselective synthesis of an all-carbon quaternary center.

Table 4.

Stereodivergent [4 + 3] cycloaddition

catalyst	ratio (4b/19)	dr (20/21)	yield (20 + 21, %)
Rh2(R-PTAD)4	5:1	6:1	65 (47a)
Rh2(S-PTAD)4	3:1	1:9	63

^aIsolated yield of pure 20.