Enol Acetates: Versatile Substrates for the Enantioselective Intermo

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Enol Acetates: Versatile Substrates for the Enantioselective Intermolecular Tsuji Allyation Ji Liu, Sourabh Mishra, and Aaron Aponick J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08746 • Publication Date (Web): 05 Nov 2018 Downloaded from http://pubs.acs.org on November 5, 2018

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Journal of the American Chemical Society

Enol Acetates: Versatile Substrates for the Enantioselective Intermolecular Tsuji Allyation Ji Liu, Sourabh Mishra, and Aaron Aponick* Florida Center for Heterocyclic Compounds and Department of Chemistry, University of Florida, Gainesville FL 32611 ABSTRACT: A highly versatile enantioselective intermolecular Tsuji allylation that generates alpha-quaternary stereocenters is reported. The methodology utilizes a prochiral enol acetate as a substrate, which is the last class of the original Tsuji substrates to be successfully employed in an enantioselective variant of the venerable reaction. This development enables a highly convergent approach that lends itself to rapid diversification and analog synthesis by facilitating the incorporation of the allyl moiety from an allylic alkoxide, obviating the need for the preparation of allylic enol carbonates. The reaction is operationally simple and employs the readily available PHOX ligand class. More than 30 examples are reported that proceed with ee’s of up to 96% with a scope that tolerates a wide range of functional groups on the allylic component. The enol acetate substrates are readily prepared from both aryl- and aliphatic ketones, where the regioselective preparation has long been known utilizing a variety of methods. The power of this methodology lies in its ability to quickly produce a diverse set of single enantiomer products using different allylic alcohols with a common prochiral enol acetate. This is demonstrated here by two rapid formal syntheses of hamigeran B that utilize a common intermediate to intercept both Clive and Stoltz intermediates, and also to prepare novel intermediate analogs.

INTRODUCTION As the level of complexity continues to increase in preclinical compounds and pharmaceutical agents,1a-c the need for the development of sophisticated new methods that will facilitate the discovery process persists. Of the many challenges in this area,2 one enduring problem is the construction of quaternary stereocenters.3a,b This bond motif is present in a myriad of bioactive compounds4 and continues to inspire developments and innovation at the forefront of contemporary organic chemistry; however, catalytic enantioselective reactions still remain a challenging prospect.5a-f Much progress has been made in this area, and one synthetic method that functions quite well is the Pd-catalyzed Tsuji allylation whereby a prochiral nucleophile is employed to produce α-allyl ketone products (e.g. 3, Scheme 1).6a,b Stoltz described the first enantioselective Tsuji allylation using enol carbonates 1 and silyl enol ethers 4,7 and this was followed by a report from Trost who also employed the carbonates 1.8 Stoltz later reported enantioselective reactions of β-ketoesters 2 9 and Tunge followed these decarboxylative allylation reactions with an enantioselective deacylation reaction employing 1,3-diketones.10 Although many highly successful Tsuji-allylation reactions have been reported on a variety of substrate classes by a number of groups,11a-i challenges still exist. The substrates shown in Scheme 1 comprise both intra- and intermolecular approaches to the α-allyl ketone 3, but in general, the intramolecular substrates furnish the allylation products with the highest enantioselectivities. These substrates can suffer from regiochemistry problems in their preparation,7 and most substrates beyond simple allyls require noncommercial chloroformates that must be prepared locally. These issues could potentially be addressed by an intermolecular reaction such as Tunge's, but the reported examples are limited and the

enantioselectivities are typically good but not excellent (only a single example above 90% ee).10 If a highly enantioselective intermolecular reaction variant could be realized, it would be more convergent, streamline the preparation of the substrates,12 and also facilitate the incorporation of chemical diversity by direct variation of the allylic moiety. Scheme 1. Substrates for Enantioselective Prochiral Enolate Allylation. O

Intramolecular: O

• Generally higher enantioselectivity but less convergent

O Me

O

Me

O O O

2

1 Intermolecular: • Generally lower enantioselectivity but more convergent

OTMS Me

+

R O Tsuji's Conditions: 8, Bu3SnOMe Pd2dba3, dppe allyl carbonate 6 dioxane, reflux (rac, 1983)

O

O

Me

+ MO

OAc

O

L*

5

7

This Work Me +

Me

3

4

6

Pd(0)

7

L*Pd(0)

O

Me

? 8 3 Potential Advantages: • Intermolecular • Regioselective • Convergent • Enantioselective

The allylation substrates 1,13 2,14,15 and 4 16 represent three of the four original substrates reported by Tsuji and Saegusa, and we surmised that the fourth substrate, enol acetate 8 17 (Scheme 1), could offer a potential entry point to this chemistry. We are unaware of prior attempts to render this transformation enantioselective, perhaps because the conditions utilized by Tsuji require liberation of a

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tin enolate at high temperature (refluxing dioxane).17 Although reports on the utilization of this chemistry are limited, the conditions reported by others for the transformation were unchanged,18a,b further validating the temperature requirement and probability that alternative reaction conditions would need to be developed. We envisioned that enol acetate 8 could rapidly liberate an enol(ate) in high concentration by transesterification with an alcohol or acyl transfer by reaction with an alkoxide such as 7. If successful, this would represent a convergent intermolecular allylation of a substrate that is readily prepared in regioselective fashion;19a,b however, it is likely that the overall reaction would proceed via similar intermediates as other reactions in the intermolecular regime and therefore produce selectivity results typical of the intermolecular reaction manifold. However, if enantioselectivity was a problem, we would work to address this using our Stack-ligands,20a-d as PHOX6a and other P,N-ligands have found broad success in Pd-catalyzed αallylation reactions.21a-f Herein we report our efforts towards these goals, resulting in the development of an enantioselective intermolecular Tsuji allylation using enol acetate substrates.

RESULTS AND DISCUSSION As an initial test, we decided to explore the proposed transformation with enol acetate 11b to establish the reaction conditions and as a substrate benchmarking exercise using a common ligand. Much to our delight, using (S)-t-Bu-PHOX L1,22 the desired transformation was indeed observed, providing 9a in 81% yield but in a mere 78% ee (Scheme 2). This level of selectivity, the lowest of the Tsuji substrates (10a, 11a, & silyl enol ether- 91% ee,7 not shown), was quite unanticipated as achieving a level closer to that of 10b, the Tunge substrate, might be expected. Nevertheless, the reaction did indeed smoothly produce the desired product under mild conditions, but further exploration would be needed.

ity improved to 40% ee, but with the opposite sense of stereochemistry (entry 2). Variation of the ligand backbone further improved the ee, but unfortunately the highest enantioselectivity observed was 50% with aromatic or aliphatic groups of differing steric demand (L3-L6, entries 3-6). The Trost ligand, L7, also afforded the product in similar ee, so our attention turned back to the PHOX ligands. Since the choice of base had a large impact on selectivity, a comparison of Na-, Li-, and K- with L1 was examined and the sodium alkoxide was found to give the product in the highest ee (Scheme 2 vs Table 1, entries 8, 9). In contrast to the other approaches outlined above, these reactions rapidly generate the enolate in high concentration and we surmised that this could be one difference that is negatively impacting the selectivity. Reducing the amount of alkoxide from 2.0 equivalents to 1.0 showed only a very small change, but in the upward direction (entry 10 vs Scheme 2). When the concentration was then reduced to 0.033 M, the ee increased to 88% (entry 11), lending some validity to this notion. Neither further dilution (entry 12) or slow addition of the alkoxide (entry 13) further increased the selectivity. Different PHOX ligands have been demonstrated to be superior to L1 in many cases,23a-d and the more electron deficient trifluoromethylsubstituted PHOX ligand, L8, provided 9a in 83% yield and 90% ee. These conditions were deemed optimal and the scope of the reaction was explored. Table 1. Optimization Studies. OAc Me

R N

Pd2dba3•CHCl3 (2.5 mol %) L1 (6.25 mol %) THF, 0.1 M, rt

Substrate O

Me

Me

N PPh2

L2, R = Ph L3, R = p-F-Ph L4, R = p-OMe-Ph L5, R = Me L6, R = cyclohexyl

N

Ph2P L1

t-Bu

9a

O

O

O NH HN

N

Ar2P

t-Bu Ar = p-CF3Ph

PPh2 Ph2P

L8

Intramolecular

Intermolecular a

R = OAllyl, 10a

R = Me, 10b

97%, 92% ee9

75%, 85% ee 10

Entry

Ligand

Base

Concentration (M)

Yield (%)a

ee (%)

1

L2

NaH

0.1

83

-20

2

L2

BuLi

0.1

81

40

3

L3

BuLi

0.1

73

48

4

L4

BuLi

0.1

69

50

5

L5

BuLi

0.1

80

-13

6

L6

BuLi

0.1

78

45

7

L7

BuLi

0.1

77

53

8

L1

BuLi

0.1

78

70

9

L1

tBuOK

0.1

83

68

10

b

L1

NaH

0.1

81

80

11

b

L1

NaH

0.033

82

88

12b

L1

NaH

0.020

56

87

66

87

83

90

O R Me

CF3

O

10a/b

O

9a

L7

O R

Me

R

F5

Substrate

O

Pd2dba3•CHCl3 (2.5 mol %)

L (6.25 mol %) allyl alcohol (2.0 equiv) base (2.0 equiv), THF, rt

11b

Scheme 2. Substrate Benchmarking. O

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R = OAllyl, 11a

R = Me, 11b

81%, 91% ee7

81%, 78% ee

11a/b a

The same conditions as the intramolecular reactions were employed, but with the addition of 2.0 equiv allyl alcohol and 2.0 equiv NaH.

Several ligands were screened in an attempt to optimize the process and, as we now have a small family of ligands on-hand, initial efforts utilized our StackPhos platform. As can be seen in Table 1, using the sodium alkoxide generated in situ from allyl alcohol and NaH with parent ligand L2, 9a was isolated in 20% ee (entry 1). Interestingly, when the lithium alkoxide was employed, the selectiv-

13

L1

b

L8

14 a

NaH

0.1

NaH b

c

0.033 c

Isolated yield; 1.0 equiv alcohol; NaOC3H5 added over 15 h; final concentration = 0.1 M.


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Journal of the American Chemical Society One of the goals for the development of this intermolecular reaction is to be able to rapidly generate different products from a common precursor. As such, the scope was first explored with respect to allyl incorporation with enol acetate 11b. As can be seen in Table 2, the reaction tolerated a wide variety of substituents to produce the α-quaternary ketone products in good yield and excellent ee by simply using different allylic alcohols 12. Applying these conditions, we were able to produce α-quaternary ketones with substituted allyls including alkyl groups (9b, 9g, 9h), phenyl groups (9c, 9i, 9j) including both electron rich- (9e) and electron-deficient phenyls (9d), and heteroaromatics (9k-m). Interestingly, on allylic alcohols with more bulky 2-alkyl substituents, the reaction with L8 is sluggish, but L1 restores this reactivity and provides the products in high ee. We were particularly excited to find that heteroatoms like the MOM-ether 9n (90% ee) and basic heterocycles such as morpholine 9o and pyrrolidine 9p were smoothly produced under these conditions in high enantiomeric excess, 92% and 93% ee, respectively. It should be noted that, while there are reports of successful enantioselective Tsuji allylation reactions that transfer allyl groups with terminal substitution,8,11c they are not common substrates in these reactions. Consistent with the bulk of the work in this area, after multiple attempts, we found that allyl groups with this substitution pattern did not function well in our reaction either, exhibiting both low reactivity and greatly diminished selectivity.

In addition to examining the reaction with respect to allylic moiety, the reaction scope was studied to probe tolerance for different prochiral enolates, different allyl groups, and combinations thereof. As can be seen in Table 3, substitution at the α-position with groups other than methyl was tolerated, generating a variety of differentially substituted quaternary stereocenters in high enantioselectivity (9q-9s). The tetralone examples incorporate sixmembered cyclic ketones, but the ring-size could also be modified to a seven-membered ring (9t-9u) and contracted to a 5membered ring (9v). Cyclohexanones also perform well in this reaction, but interestingly, these reactions are not as rapid overall as those of tetralones, requiring elevated temperature. The enolate is smoothly formed by acyl transfer, but the allylation does not occur as readily. Additionally, the reactions seem to perform better with respect to yield when NaHMDS is used as base. It is worth noting that alternative side reactions are not a major issue with this methodology, as evidenced by isolation of the ketone and allyl acetate after the reaction. In cases where enolate equilibration would be possible and lead to potential regiochemical problems, only small amounts of regioisomeric product with allylation occurring at the less substituted site have been observed in the crude reaction mixture. Nevertheless, a variety of different types of allyl groups function well in the reaction to provide 9w-9bb. Table 3. Enol Acetate Scope. a ,b

O

Pd2dba3•CHCl3 (2.5 mol %)

+

11b

HO 12 R (1.0 equiv)

O

Me

Me

Me

9r, 75% 83% ee

O Me

O Me

Me

O 9c, 81% 94% ee O

Me

O

Me

9e, 90% 93% ee

9f, 45% 82% ee O

Me

Me

O

Me

9i, 73% 96% ee

O

Me

9k, 81% 94% ee O

O

O Me

9x, 60% 80% ee O

Me

Me

OBn

9j, 65% 84% ee O

Me

Me

9z, 62% 90% ee

CF3

9aa, 61% 87% ee

9y, 68% 94% ee O Me

F

NBnMe 9bb, 70% 92% ee

Me a

S

9l, 80% 96% ee O

Me

9n, 81% 90% ee

Me

9v, 71% 86% ee O

Bn

Me b

9h, 75% 95% ee

Me Me

9u, 75% 85% ee

9w, 70% 92% ee

9g, 92% ee O

Me

Ph

n-Hexyl 61%b

OMe

O

O

Me

Cl

O

O

9t, 65% 92% ee

9d, 83% 92% ee F

O

9s, 90% 90% ee

Ph

Me 9b, 75% 92% ee

Bn Ph

9q, 90% ee

9 O

O

Bn

Me 81%c

R

L8 (6.25 mol %) NaH, THF

O

O

O

Table 2. Allylic Alcohol Scope. a

OMOM

O

O

Me

9o, 71% 92% ee

NMe

9m, 51% 84% ee

N O

Me

9p, 81% 93% ee

N

a Reactions were conducted at room temperature for 12 h at 0.033 M; b L1 employed, reaction time = 48 h.

Reaction conditions: 1.0 equiv enol acetate, 1.0 equiv allylic alcohol, 2.0 equiv NaH, Pd2dba3•CHCl3 (2.5 mol %), L8 (6.25 mol %), 0.033 M in THF, r.t., 12 h. bReaction conditions for cyclohexanones: 1.2 equiv enol acetate, 1.0 equiv allylic alcohol, 1.5 equiv NaHMDS, Pd2dba3•CHCl3 (5.0 mol %), L1 (12.5 mol %), 0.033 M in THF, 50 °C 12 h; c The methallyl group was introduced via methallyl alcohol.

With the successful implementation of the method on a variety of substrates, we sought to employ the intramolecular Tsuji allylation in the context of a convergent natural product synthesis on a target that would also be amenable to analog synthesis in this manner. (+)-Hamigeran B (18) is an antiviral natural product that was isolated from the poecilosclerid sponge Hamigera tarangaensis.24



This compound shows complete inhibition of both herpes and polio virus proliferation with only slight cytotoxicity.24 Interestingly, little is known about the mode of action or the structure activity relationship, despite the successful and elegant synthetic work in this area.23d,25a-k An intermolecular approach would allow for rapid variation of the allyl moiety from a common enol acetate, which could also be varied to introduce further diversity. Substitution of the 2-position of the allylic alcohol would modulate the substituent at C6 on the natural product after condensation (see 18 for numbering24). To this end, we targeted 17, which was previously prepared by Clive in racemic form.25g The enol acetate 13, prepared from the corresponding tetralone,25g was allowed to react with isobutyl-containing allylic alcohol 14 to form 15 in 95% ee (Scheme 3). It is worth noting that this result was obtained with the more common PHOX ligand L1 and the CF3-substituted ligand L8 was not required. Oxidative cleavage of the olefin was achieved under Lemieux-Johnson conditions to afford 16 in 74% yield and subsequent condensation provided the Clive intermediate 17 in 97% yield, completing a formal synthesis.

Page 4 of 8

Scheme 4. Divergent synthesis of intermediate analogs. OAc Me

O

HO Me

R

12

OMe 13 O Me

OMe

Me

O Me

OMe

85% (2 steps)

O

Et

Me

Me 93% 93% ee 21

H

Et CH2OMOM 65% 93% ee 22

85% (2 steps)

O

Me

MOMO

O

Me

Me OMe 23

OMe

65% (2 steps)

O

Me

76% 88% ee 19

OMe

Et 72% 90% ee 20

Me

Me

Me

Et OMe 24

Et OMe 25

Scheme 3. Formal synthesis of (+)-hamigeran B. OAc Me

O Me

a.

Me

HO

OMe 13

Me b.

OMe

14

15 95% ee

O 6

Me Br

5 4 1

H

O Me

9

Me

O ref 25d 11 OH O 18 (+)-hamigeran B

Me OMe 17

Conditions: a. Pd2dba3•CHCl3 (2.5 mol %), (S)-tBuPhox (6.25 mol %), NaH (2 equiv), THF, rt, 12 h; b. OsO4, NMO, NaIO4, dioxane/H2O (1:1), rt, 12 h; c. NaOH, EtOH/H2O (5:1), reflux, 12 h.

Me c.

O Me

OMe 16

Conditions: a. Pd2dba3•CHCl3 (2.5 mol %), (S)-tBuPhox (6.25 mol %), NaH (2 equiv), THF, rt, 12 h, 67%, 95% ee; b. OsO4, NMO, NaIO4, dioxane/H2O (1:1), rt, 12 h, 73%; c. NaOH, EtOH/H2O (5:1), reflux, 12 h, 97%.

The power of this methodology lies in the potential ability to quickly diversify the products using the same prochiral enol acetate. To test this notion, 13 was instead treated with the parent allyl alcohol to form 19, which is an intermediate prepared by Stoltz23d and consequently represents another formal synthesis (Scheme 4). Additionally, new previously unknown intermediate analogs are easily accessed. Instead of the iso-propyl group in 17, a methyl was readily installed by using the 2-ethyl allyl alcohol to afford 20 in 90% ee and 23 after oxidative cleavage and condensation. The angular group at C9 is also straightforward to modify by augmenting the enol acetate. To illustrate this, an ethyl group was instead included and 21 was prepared in 93% ee, leading to the C6unsubstituted analogue 24. Additionally, the oxidation state at C6 could easily be increased by using a mono-protected diol, to give 22 and then 25 in 93% ee. In principle, a large variety of modifications could be made to these positions and also to the aromatic moiety in efforts to produce single enantiomer libraries on natural product-like compounds containing the α-quaternary stereocenter.

These studies demonstrate that the intermolecular Tsuji allylation can be highly enantioselective with a diverse reaction scope. During our optimization studies, it was found that these reactions had a strong dependence on concentration and we postulated that this could be applicable to the related Tunge substrates also. To study this we employed the starting materials, 10b-d to make the appropriate comparisons. As can be seen in Table 4, simply diluting the reaction enhances the ee. Although the magnitude of the change is substrate dependent, introducing both the simple allyl to 10b and 10c and methyallyl to 10c, the selectivity improves (entries 110 vs 2; 310 vs 4; 510 vs 6).26 These experiments employed L1 but the deacylative allylation at the higher concentrations could be improved with alternative ligands (selectivity for ent-9q was improved to 81% ee).10 Here, with low concentration, using L8 also further increases the ee (entry 7). Although the source of the dilution effects are not clear, one potential explanation is that with high enolate concentration, the ostensible inner-sphere process27 may show leakage to an outer-sphere mechanism. Taken as a whole, the results demonstrate that both types of intermolecular Tsujiallylations can be high yielding and enantioselective. This development should provide a nice complement to the existing work in the area and allow for expansion of these reactions in many new directions.


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Journal of the American Chemical Society Table 4. Concentration effect on deacylative allylation. a O

R1

O

O

L, Pd2dba3•CHCl3

10b, R1= Me 10c, R1 = methallyl 10d, R1 = allyl

allyl or methallyl alcohol

AUTHOR INFORMATION

R1

Corresponding Author

R2

NaH, THF, rt, 12 h

The Supporting Information is available free of charge on the ACS Publications website.

* e-mail: [email protected]

9a, R1 = Me, R2 = H 9q, R1 = methallyl, R2 = H ent-9q, R1 = allyl, R2 = Me

ORCID

Entry

Substrate

L

Concentration (M)

Product

Yield (%)b

ee (%)

1

10b

L1

0.1

9a

75

8510

2

10b

L1

0.033

9a

75

87 10

3

10c

L1

0.075

9q

88

72

4

10c

L1

0.033

9q

75

80 10

5

10d

L1

0.075

ent-9q

57

77

6

10d

L1

0.033

ent-9q

80

82

7

10d

L8

0.033

ent-9q

85

88

a

Reaction conditions: Pd2dba3•CHCl3 (2.0 mol %), ligand (4.5 mol %), NaH (2.0 equiv), rt, 12 h; bIsolated yield.

Ji Liu: 0000-0003-0096-3352 Sourabh Mishra: 0000-0001-6737-9949 Aaron Aponick: 0000-0002-4576-638X

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT The authors thank the University of Florida and The National Science Foundation (CHE-1362498) for their generous support of our programs.

REFERENCES 1

CONCLUSION In summary, we have developed an efficient, highly selective, intermolecular Tsuji-allylation. The method utilizes enol acetates, the remaining Tsuji substrate for which an enantioselective variant has yet to be realized. This substrate class is advantageous because it is readily prepared as the desired thermodynamic enolate precursor by a variety of methods. The intermolecular allylation of enol acetates demonstrated here facilitates the rapid diversification of the products. For these reasons, this is predicted to be an important advance, enabling the method to quickly generate structural variants of α-quaternary stereocenter-containing compounds, demonstrated here by work on the hamigeran B scaffold where both formal syntheses and analoging were readily accomplished. It is also demonstrated that selectivity has a strong dependence on concentration in intermolecular acyl-transfer reactions. At lower concentrations, the products are obtained in higher enantioselectivity. This was applicable to both the present reaction with enol acetates and the Tunge-type 1,3-diketone substrates. With respect to substrate scope, the enantioselective decarboxylative allylation methodologies developed by Stoltz and Trost work exceedingly well. Considering the success of these methods and the commercial availability of allylchloroformate, their methods would likely be the methods of choice to obtain unsubstituted allyl products. Using the present method, the simple allyl is not as highly enantioselective, but a wide variety of 2-substituted α-allyl products are readily obtained in high ee. This offers a nice complement to the existing methods and should find use in the preparation of a variety of types of bioactive compounds. Further studies into the scope and application of the method are underway and will be reported in due course.

2 3

4 5

6

7 8

ASSOCIATED CONTENT 9

Supporting Information Experimental procedures and compound characterization data

(a) Lovering, F. Escape from Flatland 2: Complexity and Promiscuity. Medchemcomm 2013, 4, 515–519; (b) Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752–6756; (c) Shioiri, T.; Izawa, K.; Konoike, T. Pharmaceutical Process Chemistry; Shioiri, T., Izawa, K., Konoike, T., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2010. Wender, P. A.; Miller, B. L. Synthesis at the Molecular Frontier. Nature 2009, 460, 197–201. (a) Fuji, K. Asymmetric Creation of Quaternary Carbon Centers. Chem. Rev. 1993, 93, 2037–2066; (b) Christoffers, J.; Baro, A. Quaternary Stereocenters; Christoffers, J., Baro, A., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, FRG, 2005. Newman, D. J.; Cragg, G. M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod. 2016, 79, 629–661. (a) Corey, E. J.; Guzman-Perez, A. The Catalytic Enantioselective Construction of Molecules with Quaternary Carbon Stereocenters. Angew. Chem., Int. Ed. 1998, 37, 388–401; (b)Trost, B. M.; Jiang, C. Catalytic Enantioselective Construction of All-Carbon Quaternary Stereocenters. Synthesis 2006, No. 3, 369–396; (c) Quasdorf, K. W.; Overman, L. E. Catalytic Enantioselective Synthesis of Quaternary Carbon Stereocentres. Nature 2014, 516, 181–191; (d) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules. Acc. Chem. Res. 2015, 48, 740–751; (e) Feng, J.; Holmes, M.; Krische, M. J. Acyclic Quaternary Carbon Stereocenters via Enantioselective Transition Metal Catalysis. Chem. Rev. 2017, 117, 12564–12580; (f) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Enantioselective Catalytic Formation of Quaternary Stereogenic Centers. Eur. J. Org. Chem. 2007, 5969–5994. (a) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novák, Z.; Krout, M. R.; et al. Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies. Chem. Eur. J. 2011, 17, 14199–14223; (b) Hong, A. Y.; Stoltz, B. M. The Construction of All-Carbon Quaternary Stereocenters by Use of Pd-Catalyzed Asymmetric Allylic Alkylation Reactions in Total Synthesis. Eur. J. Org. Chem. 2013, 2745–2759. Behenna, D. C.; Stoltz, B. M. The Enantioselective Tsuji Allylation. J. Am. Chem. Soc. 2004, 126, 15044–15045. Trost, B. M.; Xu, J. Regio- and Enantioselective Pd-Catalyzed Allylic Alkylation of Ketones through Allyl Enol Carbonates. J. Am. Chem. Soc. 2005, 127, 2846–2847. Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Deracemization of Quaternary Stereocenters by Pd-Catalyzed Enantioconvergent Decarboxylative Allylation of Racemic β-Ketoesters. Angew. Chem., Int. Ed. 2005, 44, 6924–6927.



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A.; Aponick, A. Incorporation of Axial Chirality into PhosphinoImidazoline Ligands for Enantioselective Catalysis. ACS Catal. 2017, 7, 2133–2138; (d) Mishra, S.; Liu, J.; Aponick, A. Enantioselective Alkyne Conjugate Addition Enabled by Readily Tuned Atropisomeric P , N Ligands. J. Am. Chem. Soc. 2017, 139, 3352–3355. (a) Burger, E.; Barron, B.; Tunge, J. Catalytic Asymmetric Synthesis of Cyclic α-Allylated α-Fluoroketones. Synlett 2006, 2824–2826; (b) Mino, T.; Wakui, K.; Oishi, S.; Hattori, Y.; Sakamoto, M.; Fujita, T. Kinetic Resolution of Allylic Esters in Palladium-Catalyzed Asymmetric Allylic Alkylations Using C–N Bond Axially Chiral Aminophosphine Ligands. Tetrahedron: Asymmetry 2008, 19, 2711–2716; (c) Noël, T.; Bert, K.; Van der Eycken, E.; Van der Eycken, J. Imidate-Phosphanes as Highly Versatile N,P Ligands and Their Application in Palladium-Catalyzed Asymmetric Allylic Alkylation Reactions. Eur. J. Org. Chem. 2010, 2010, 4056–4061; (d) Hu, Z.; Li, Y.; Liu, K.; Shen, Q. Bis(Perfluoroalkyl) Phosphino-Oxazoline: A Modular, Stable, Strongly π-Accepting Ligand for Asymmetric Catalysis. J. Org. Chem. 2012, 77, 7957–7967; (e) Shen, C.; Xia, H.; Zheng, H.; Zhang, P.; Chen, X. Synthesis of Novel CarbohydrateBased Iminophosphinite Ligands in Pd-Catalyzed Asymmetric Allylic Alkylations. Tetrahedron: Asymmetry 2010, 21, 1936–1941; (f) Mazuela, J.; Pàmies, O.; Diéguez, M. A New Modular Phosphite-Pyridine Ligand Library for Asymmetric Pd-Catalyzed Allylic Substitution Reactions: A Study of the Key Pd-π-Allyl Intermediates. Chem. Eur. J. 2013, 19, 2416– 2432. It should be noted that other ligands have been successfully employed in these transformations. See Ref 8. (a) Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Enantioselective Construction of Quaternary N-Heterocycles by Palladium-Catalysed Decarboxylative Allylic Alkylation of Lactams. Nat. Chem. 2012, 4, 130–133; (b) Reeves, C. M.; Eidamshaus, C.; Kim, J.; Stoltz, B. M. Enantioselective Construction of α-Quaternary Cyclobutanones by Catalytic Asymmetric Allylic Alkylation. Angew. Chem., Int. Ed. 2013, 52, 6718–6721; (c) Craig, R. A.; Loskot, S. A.; Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. PalladiumCatalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones. Org. Lett. 2015, 17, 5160–5163; (d) Mukherjee, H.; McDougal, N. T.; Virgil, S. C.; Stoltz, B. M. A Catalytic, Asymmetric Formal Synthesis of (+)-Hamigeran B. Org. Lett. 2011, 13, 825–827. Wellington, K. D.; Cambie, R. C.; Rutledge, P. S.; Bergquist, P. R. Chemistry of Sponges. 19. Novel Bioactive Metabolites from Hamigera Tarangaensis. J. Nat. Prod. 2000, 63, 79–85. (a) Nicolaou, K. C.; Gray, D.; Tae, J. Total Synthesis of Hamigerans: Part 1. Development of Synthetic Technology for the Construction of Benzannulated Polycyclic Systems by the Intramolecular Trapping of Photogenerated Hydroxy-o-Quinodimethanes and Synthesis of Key Building Blocks. Angew. Chem., Int. Ed. 2001, 40, 3675–3678; (b) Nicolaou, K. C.; Gray, D.; Tae, J. Total Synthesis of Hamigerans: Part 2. Implementation of the Intramolecular Diels–Alder Trapping of Photochemically Generated Hydroxy-o-Quinodimethanes; Strategy and Completion of the Synthesis. Angew. Chem., Int. Ed. 2001, 40, 3679; (c) Lau, S. Y. W. Concise and Protective Group-Free Syntheses of (±)Hamigeran B and (±)-4-Bromohamigeran B. Org. Lett. 2011, 13, 347– 349; (d) Clive, D. L. J.; Wang, J. Stereospecific Total Synthesis of the Antiviral Agent Hamigeran B - Use of Large Silyl Groups to Enforce Facial Selectivity and to Suppress Hydrogenolysis. Angew. Chem., Int. Ed. 2003, 42, 3406–3409; (e) Nicolaou, K. C.; Gray, D. L. F.; Tae, J. Total Synthesis of Hamigerans and Analogues Thereof. Photochemical Generation and Diels-Alder Trapping of Hydroxy-o-Quinodimethanes. J. Am. Chem. Soc. 2004, 126, 613–627; (f) Trost, B. M.; Pissot-Soldermann, C.; Chen, I.; Schroeder, G. M. An Asymmetric Synthesis of Hamigeran B via a Pd Asymmetric Allylic Alkylation for Enantiodiscrimination. J. Am. Chem. Soc. 2004, 126, 4480–4481; (g) Clive, D. L. J.; Wang, J. Synthesis of (±)Hamigeran B, (−)-Hamigeran B, and (±)-1 -Epi -Hamigeran B: Use of Bulky Silyl Groups to Protect a Benzylic Carbon−Oxygen Bond from Hydrogenolysis. J. Org. Chem. 2004, 69, 2773–2784; (h) Madu, C. E.; Lovely, C. J. A Pauson-Khand Approach to the Hamigerans. Org. Lett. 2007, 9, 4697–4700; (i) Taber, D. F.; Tian, W. Synthesis of (-)-Hamigeran B. J. Org. Chem. 2008, 73, 7560–7564; (j) Miesch, L.; Welsch, T.; Rietsch, V.; Miesch, M. Intramolecular Alkynylogous Mukaiyama Aldol Reaction Starting from Bicyclic Alkanones Tethered to Alkynyl Esters: Formal Total Synthesis of (±)-Hamigeran B. Chem. Eur. J. 2009, 15, 4394–4401; (k) Cai, Z.; Harmata, M. Studies Directed toward the Synthesis of Hamigeran


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Journal of the American Chemical Society B: A Catalytic Oxidative Cyclization. Org. Lett. 2010, 12, 5668–5670. 26 At the suggestion of a reviewer, for a control, we repeated and verified that the results reported in Table 4 (taken from reference 10) were reproducible in our hands. 27 Keith, J. A.; Behenna, D. C.; Sherden, N.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Nielsen, R. J.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. The Reaction Mechanism of the Enantioselective Tsuji Allylation: Inner-Sphere and Outer-Sphere Pathways, Internal Rearrangements, and Asymmetric C-C Bond Formation. J. Am. Chem. Soc. 2012, 134, 19050–19060.



Convergent Enantioselective Intermolecular Tsuji Allylation

R' O

OAc R

L*, Pd2dba3•CHCl3 NaO

Tsuji's Final Substrate

CF3

L*

R

O

R'

Readily Diversified

Page 8 of 8

Ar2P

>30 examples ee up to 97%


N

t-Bu Ar = p-CF3Ph

Enol Acetates: Versatile Substrates for the Enantioselective Intermo

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