Synthesis of Enantioenriched γ-Quaternary Cycloheptenones Using a Combined Allylic Alkylation/Stork–Danheiser Approach: Preparation of Mono-, Bi-, and Tricyclic Systems

Abstract

A general method for the synthesis of β-substituted and unsubstituted cycloheptenones bearing enantioenriched all-carbon γ-quaternary stereocenters is reported. Hydride or organometallic addition to a seven-membered ring vinylogous ester followed by finely tuned quenching parameters achieves elimination to the corresponding cycloheptenone. The resulting enones are elaborated to bi- and tricyclic compounds with potential for the preparation of non-natural analogs and whose structures are embedded in a number of cycloheptanoid natural products.

Introduction

Cycloheptanes bearing all-carbon quaternary stereocenters are incorporated into the polycyclic cores of many natural products including the daphnicyclidins (2),^1a guanacastepenes (3),^1b–d cyathins (4),^1e–i dhilirolide D (5),^1j tricholomalide B (6),^1k–l miniolutelide A (7),^1m and berkeleydione (8)^1m–o (Figure 1A). Due to the biological relevance and structural complexity of these compounds, we sought to develop a stereoselective approach to this quaternary carbon-containing cycloheptane motif. To this end, we envisioned cycloheptenone 1 as a promising synthetic intermediate. Additionally, we viewed enone 1 as an attractive scaffold for annulation strategies toward bi- and tricyclic structures potentially valuable in total synthesis and non-natural analoging. Particularly attractive to us was the homologous structural relationship of the desired [7–n] bicyclic scaffold to the classic [6–5] and [6–6] frameworks used in hundreds of approaches to natural products (Figure 1B). Herein we describe a general enantioselective route to cycloheptenone 1 that allows for facile elaboration to bi- and tricyclic products.

Figure 1.

Potential applications of cycloheptenone 1.

Retrosynthetically, we planned to access cycloheptenone 1 using a Stork–Danheiser type transposition of vinylogous ester 9 (Scheme 1A). In this approach, the quaternary stereocenter of vinylogous ester 9 would be installed by employing our palladium–catalyzed asymmetric allylic alkylation methodology.^2,3 Toward this end, acylation and alkylation of vinylogous ester 10 generates racemic β-ketoester 11, which under our standard decarboxylative alkylation conditions is converted to vinylogous ester 9 (Scheme 1B).^2d

Scheme 1.

Retrosynthesis for cycloheptenone 1 and route to vinylogous ester 9.

As previously reported,^2d initial efforts toward cycloheptenone 1 employing standard transposition conditions⁴ were unsuccessful and led to the discovery of the unusual reactivity of vinylogous ester 9. In contrast to the six-membered ring analog (12), both reduction and organometallic addition to vinylogous ester 9 followed by strong acidic work-up favor formation of the corresponding β-hydroxyketones (14a and 14b) instead of the cycloheptenones (1a and 1b) (Scheme 2A and B). Attempts to convert the β-hydroxyketones to enones resulted in an unexpected retro-aldol/aldol ring contraction that our lab has examined extensively (Scheme 2C).^2d This unexpected reactivity prompted further investigation of the reaction sequence to develop new conditions for the efficient preparation of cycloheptenones.

Scheme 2.

Previous investigation into reactivity of vinylogous ester 9 and β-hydroxyketone 14.

Results and Discussion

After some investigation, alternative reaction conditions enabled access to the elusive β-unsubstituted and substituted cycloheptenones. Gratifyingly, Luche reduction of vinylogous ester 9 followed by strong acidic work-up preferentially generated unsubstituted enone 1a (Scheme 3).⁵ Additionally, quenching the Grignard reaction of vinylogous ester 9 with a sodium phosphate buffer and treating the resulting crude oil with dilute acid in acetonitrile afforded substituted enone 1b. Analysis of the initial crude material suggests that hydroxy enol ether 16 is formed after the sodium phosphate buffer quench.⁶ Subsequent acid treatment likely protonates alcohol 16, which leads to dehydration via generation of the resonance stabilized tertiary carbocation and eventual collapse to enone 1b. Overall, these modified conditions provide divergent routes to γ-quaternary cycloheptenones and acylcyclopentenes in conjunction with our preceding work.

Scheme 3.

Reduction and organometallic addition conditions favoring cycloheptenone formation.

Based on these initial results, we examined the scope of β-substituted enones available from nucleophilic attack on vinylogous ester 9. The buffer and dilute acid conditions described above (Table 1, method A) accommodate β-substituent groups initiating in sp³ hybridization, producing allyl, homoallyl, and pentenyl substituted enones in moderate to excellent yield (entries 1–5). Attempts to apply this quenching sequence to reactions involving sp and sp² hybridized carbon nucleophiles resulted in complex reaction mixtures. Selectivity for the cycloheptenone was restored by quenching such reactions with a concentrated strong acid (i.e., hydrochloric or sulfuric acid) and heating the resulting solutions at elevated temperature (Table 1, methods B and C). These conditions initially produce a mixture of β-hydroxyketone and enone that converges to the desired product over time.⁷ In this manner, the synthesis of vinyl, alkynyl, aryl, and heteroaryl substituted enones is accomplished (entries 6–10). Of particular note is entry 8, in which an ortho-substituted aryl Grignard reagent can be incorporated to generate enone 1j.⁸ In general, application of the appropriate work-up conditions allows access to a variety of β-substituted γ-quaternary cycloheptenones.

Table 1.

Scope of organometallic addition to vinylogous ester 9.^a

entry	R	work-upb	product (1)	yield (%)c
1		A	1c	73
2		A	1d	93
3		A	1e	90
4		A	1f	82
5		A	1g	92
6d		B	1h	84
7		C	1i	97
8e		C	1j	66
9		B	1k	72
10		B	1l	84

^aConditions: vinylogous ester 9 (1.0 equiv), CeCl₃ (2.5 equiv), RMgX or RLi (3.0 equiv) in THF, 23 °C then work-up by methods A, B, or C.

^bMethod A: a) pH 6.5 Na₃PO₄ buffer b) 6 mM HCl, CH₃CN; Method B: 10% w/w aq HCl, 60 °C; Method C: 2 M H₂SO₄, 60 °C.

^cYield of isolated product.

^dSee Supporting Information for slightly different reaction parameters.

^eProduct is 1.9 : 1 mixture of atropisomers.

With various cycloheptenones in hand, we sought to elaborate these compounds to bi- and tricyclic structures (Table 2). We first examined olefin metathesis reactions between the β-substituent and quaternary center allyl fragment to generate a number of [7–5], [7–6], [7–7], and [7–8] fused ring systems. Substrates possessing two terminal olefins lead to bicyclic products with high efficiency (entries 1, 3, 5, and 8). This process also accommodates the production of trisubstituted olefin products (i.e., 17b, 17d, and 17f) through ring-forming enyne metathesis (entry 2) or ring closing metathesis (entries 4 and 6). In addition, cycloheptenone 1j is converted to the [7–7–6] tricyclic enone (17g) under the reaction conditions (entry 7). The ketone transposition/ring closing metathesis sequence is also amenable to trans-propenyl analog 18,⁹ producing the [7–6] system (17i) with the alkene adjacent to the quaternary center (Scheme 4A).

Table 2.

Ring closing metathesis on cycloheptenones to generate bi- and tricyclic products.^a

entry	substrate (1)	R1	product (17)		yield (%)b
1c	1h		17a 17b	R2 = H	93
2	1i			R2 =	99
3d	1c		17c 17d	R2 = H	91
4d	1d			R2 = Me	90
5	1e		17e 17f	R2 = H	90
6	1f			R2= Me	98
7e	1j		17g		96
8	1g		17h		99

^aConditions: cycloheptenone 1 (1.0 equiv) and Grubbs–Hoveyda 2^nd generation catalyst (5.0 mol %) in benzene, 50 °C.

^bYield of isolated product.

^cSee Supporting Information for alternative reaction parameters.

^d1,4-benzoquinone (10 mol %) added.

^ePerformed in toluene.

Scheme 4.

Synthetic applications.

Having produced two [7–6] structures with variable olefin positions, we next investigated conditions to generate the conjugated dienone system. Interestingly, treatment of skipped diene 17c with base at ambient temperature migrated both olefins into the six-membered ring, producing diene 17j (Scheme 4B). Alternatively, the alkenes can be migrated into conjugation with the carbonyl by microwave irradiation, affording diene 17k (Scheme 4B).

Lastly, we envisioned enone 1i as an ideal substrate for a Pauson–Khand reaction given the proximal enyne functionality. Treatment of 1i with dicobalt octacarbonyl employing dimethylsulfoxide as an activating agent¹⁰ produced the [7–5–5] tricyle in excellent yield with a 3:1 diastereomeric ratio of 19a:19b (Scheme 4C).

Conclusions

In summary, we have developed a method to access β-functionalized cycloheptenones (1) possessing a γ-quaternary stereocenter through a sequence involving asymmetric alkylation followed by addition of an organometallic reagent and acid-mediated ketone transposition. Subsequent manipulation of the newly incorporated β-substitutents provides a number of bi- and tricyclic compounds with potential for the preparation of non-natural analogs and whose structure is present in cycloheptanoid natural products. Further efforts toward the total synthesis of such targets will be reported in due course.