Gold(I)-Catalyzed Inter- and Intramolecular Additions of Carbonyl Compounds to Allenenes.

The gold(I)-catalyzed intramolecular reaction of allenes with oxoalkenes leads to bicyclo[6.3.0]undecane ring systems, although in the case of terminally disubstituted allenes, seven-membered rings are formed. The related intermolecular addition of aldehydes to allenenes also gives seven-membered rings.

Gold(I)-catalyzed enyne cycloisomerization reactions are powerful tools for the stereoselective construction of complex carbon skeletons.[1] These transformations have been used as the key steps in the total synthesis of diverse natural products.[2,3] We have developed a particularly useful transformation based on the gold(I)-catalyzed [2 + 2 + 2] intramolecular cycloaddition between oxo-1,6-enynes in substrates such as 1, which leads to oxatricyclic derivatives 2a,b by a cascade process in which two C–C and one C–O bonds are formed.[4] This methodology was applied in the total syntheses of (+)-orientalol F[3a] and (−)-englerin A[3b,5] (Scheme ). A mechanistically similar transformation was also developed with oxo-1,5-enynes.[6]

Scheme 1

Gold(I)-Catalyzed [2 + 2 + 2] Intramolecular Cycloaddition between Alkynes and Oxoalkenes

The intermolecular reaction of terminal alkynes with 5-oxoalkenes also gives [3.2.1]oxabicycles.[7] A somewhat analogous intermolecular gold(I)-catalyzed reaction of 5-, 6-, and 7-oxoalkenes with allenamides was developed by the group of Mascareñas to form 7–9-membered rings depending on the length of the tether of the oxoalkenes.[8a] In addition, by use of chiral ligands, this transformation was further developed as an enantioselective process. The same group recently reported the gold(I)-catalyzed [2 + 2 + 2] cycloaddition of allenamides, alkenes, and aldehydes for the synthesis of functionalized tetrahydropyrans.[8b,9] However, similar transformations involving simple oxo-1,7-allenenes have not been described. Herein, as part of a program on the development of new gold(I)-catalyzed cascade reactions for the synthesis of complex sesquiterpenes,[3,10] we report a ready access to the bicyclo[6.3.0]undecane ring system,[11] a motif conspicuously present among sesquiterpenes and higher terpene natural products (Figure ).[12]

Figure 1

Representative natural terpenoids containing eight-membered rings.

We envisioned that in oxo-1,7-allenenes or 1,7-allenenes reacting intermolecularly with carbonyl compounds the attack of the alkene to a gold(I)-activated allene I would generate tertiary carbocation II, which would be rapidly trapped by the carbonyl group to form oxonium cation III (Scheme ). Prins cyclization would then form intermediates IV or V by endo- or exo-pathways, respectively. Gold(I) carbene IV could give rise to eight-membered ring compounds VI or VII when R2 = H, whereas V would lead to seven-membered ring VIII. In addition to the regiochemical uncertainties, control of the final relative configuration was a second matter of concern. It is important to remember that unlike the reaction of the analogous 1,6-enynes 1, where the cyclization proceeds stereospecifically through cyclopropyl gold(I) carbenes as intermediates,[4,13] reactions of allenes with alkenes are fundamentally different since the configuration of the final products is not mechanistically determined. Thus, the initial cyclization could give cis- or trans-five-membered rings II, and furthermore, new stereocenters are generated in the formation of intermediate III from tertiary carbocation II as well as in the Prins cyclization leading to IV.

Scheme 2

Proposed Mechanism for the Gold-Catalyzed Reaction of 11-Oxo-1,7-allenenes

Initially, we investigated the intramolecular reactivity of 11-oxo-1,7-allenenes using allene aldehyde 3a as the substrate in the presence of different catalysts (5 mol %) at room temperature in CH2Cl2 (Table ). In all the cases, we obtained tricyclic derivative 4a as a result of a cascade reaction proceeding selectively through gold(I) carbene IV. The best results were obtained with gold complexes A, A, and D bearing NHC and phosphite ligands (Table , entries 1, 3, and 7). Lower yields were obtained with gold(I) complexes B and C with bulky biphenyl phosphines[14] (Table , entries 4–6). Best results were obtained with IPr–gold(I) cationic complex A with SbF6 as the counteranion, leading to the formation of oxatricyclic derivative 4a in 71% isolated yield as a single diastereomer (Table , entry 1). The reaction could also be carried out with PtCl2, although the yield was poor (Table , entry 8). The relative configuration was confirmed by determining the X-ray crystal structure of diol 4a′,[15] prepared by reduction of 4a with LiAlH4.

Table 1

Catalyst Optimization in the Intramolecular Cycloaddition of 11-Oxo-1,7-allenene 3aa

entry	catalyst	time (h)	yieldb (%)
1	A1	0.25	78 (71)c
2	A2	0.25	45
3	A3 + AgSbF6	0.25	63
4	B	6	37
5	C1	24	25
6	C2 + AgSbF6	24	55
7	D	2 min	67
8	PtCl2	16	10

Conditions: allenene 3a and catalyst (5 mol %) in CH2Cl2 (0.1 M).

Yield of 4a determined by 1H NMR; see the Supporting Information for details.

Isolated yield.

Having the optimal conditions in hands, we sought to evaluate the generality of the reaction, considering the substitution pattern in the allene, the configuration of the alkene, and also the intermolecular reaction between allenenes and aldehydes (Scheme ). By performing the reaction with the monosubstituted allene 3b, we observed the same type of reactivity, leading in this case to a mixture of diastereomers. Catalysts A or A led to a 3:1 mixture of diastereomers 4b in moderate yields (42–46%) after 72 h, whereas more electrophilic catalyst D gave 4b as a 1:1 mixture of diastereomers after just 10 min.[16] Surprisingly, reaction of trisubstituted allene 3c with catalysts A gave seven-membered ring 5 in 78% yield instead of an eight-membered cyclic derivative with a trans configuration at the fusion between the 5- and the 7-membered rings, which was confirmed by X-ray crystallographic analysis.[15] A similar reaction was observed with phosphite gold complex D (88%, 2 min); however, a separable 3:1 mixture of diastereomers was obtained with this catalyst. The lower stereoselectivity observed using catalyst D is probably a consequence of the very high electrophilicity of this gold(I) complex, which favors formation of both intermediates cis- and trans-II through early transition states of closely similar energy. Reaction of substrate 3d with a Z configuration at the alkene led to eight-membered ring 4d in 40–46% yield using catalysts A or D. Compound 4d, which was also observed as a minor product in the cyclization of 3a,[16] could arise by a proton elimination from an intermediate IV with a configuration different from that involved in the formation of 4a.[17] We also investigated the intermolecular version of this reaction using 1,7-allenene 6 and excess aliphatic or aromatic aldehydes (Scheme ). In the presence of phosphite gold(I) catalyst D, fast reactions were observed (5–10 min), yielding hexahydro-1H-cyclopenta[c]oxepines 7a–i in moderate to good yields as mixture of diastereomers as a result of a cyclization/endo-Prins process. The use of complex A moderately increased the diastereoselectivity, although the yields were lower and longer reaction times were required.[16]

Scheme 3

Gold(I)-Catalyzed Intra- and Intermolecular Cycloaddition of 11-Oxo-1,7-allenenes

The cyclization of 11-oxo-1,7-allenenes was extended to ketones instead of aldehydes (Table ). Under the optimized conditions used for aldehyde 3a, we were pleased to observe the formation of the tricyclic compounds 4e–k in 60–87% yields using gold complex A. X-ray crystallographic analysis of 4g unambiguously confirmed its relative configuration.[15] Alkyl ketones, including those with bulky groups, and aryl ketones react similarly. Interestingly, oxoenallenenes with electron-withdrawing groups at the ketone, such as 3j and 3k (Table , entries 6 and 7), reacted smoothly and gave yields similar to those obtained from other ketones, which supports the hypothesis that formation of carbocation II is rate-determining and attack of the carbonyl group is, comparatively, a faster process.

Table 2

Gold(I)-Catalyzed Intramolecular Cycloaddition of 11-Oxo-1,7-allenenes 3e–ka

entry	R	time (h)	product (yield, %)b
1	Me (3e)	6	4e (63)
2	n-Hex (3f)	0.25	4f (64)
3	Cy (3g)	0.15	4g (72)
4	t-Bu (3h)	3	4h (79)
5	Ph (3i)	6	4i (72)
6	3,5-(CF3)2C6H3 (3j)	2	4j (87)
7	CH2Cl (3k)	1	4k (60)

Conditions: allenene 3e–k and A (5 mol %) in CH2Cl2 (0.1 M).

Isolated yields.

Finally, we applied this intramolecular cycloaddition for the enantioselective formation of an oxatricyclic system. The synthesis of the oxoenallene began by alkylation of methyl isobutyrate with geranyl bromide to give ester 8,[18] which was converted into known aldehyde 9(19) in two steps by reduction with LiAlH4 and subsequent oxidation with Dess–Martin periodinone (Scheme ). Enantioselective allenylation of aldehyde 9 was performed by applying Corey’s method[20] using a chiral bromoborane and propadienyltri-n-butylstannane followed by benzylation under standard conditions to yield allene 10. Treatment of 10 with Admix-α and methylsulfonamide followed by oxidative cleavage using NaIO4 on silica[21] led to aldehyde 11. At this point, the excellent enantioselectivity of the allenylation reaction was confirmed by chiral GC (98:2 er). Exposing 11 to cationic gold(I) complex A for 16 h at 25 °C gave 12 in 75% yield as the only isolated tricyclic compound. The intermolecular reaction of 11 occurred with complete retention of the configuration.

Scheme 4

Enantioselective Synthesis of Oxatricyclic Compound 12

In summary, we have found that the intramolecular reaction of 11-oxo-1,7-allenenes gives rise to bicyclo[6.3.0]undecane ring systems, usually in good yields and selectivities, which is remarkable for a reaction that most probably proceeds through an open carbocation. Only in the case of 1,1-dialkyl-substituted alkenes are seven-membered ring systems formed as a consequence of an exo-selective Prins-type cyclization. This reaction can also be carried out intermolecularly between 1,7-allenenes with aliphatic or aromatic aldehydes.