Enantioselective Total Synthesis of (+)-Psiguadial B - Journal of the

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Enantioselective Total Synthesis of (+)-Psiguadial B Lauren Marie Chapman, Jordan C Beck, Linglin Wu, and Sarah E. Reisman J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07229 • Publication Date (Web): 24 Jul 2016 Downloaded from http://pubs.acs.org on July 24, 2016

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Journal of the American Chemical Society

Enantioselective Total Synthesis of (+)-Psiguadial B Lauren M. Chapman, Jordan C. Beck, Linglin Wu, and Sarah E. Reisman* The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States

Supporting Information Placeholder ABSTRACT: The first enantioselective total synthesis of the

cytotoxic natural product (+)-psiguadial B is reported. Key features of the synthesis include: 1) enantioselective preparation of a key cyclobutane intermediate by a tandem Wolff rearrangement/asymmetric ketene addition, 2) a directed C(sp3)–H alkenylation reaction to strategically forge the C1–C2 bond, and 3) a ring-closing metathesis to build the bridging bicyclo[4.3.1]decane terpene framework.

has previously been reported5 and elegantly demonstrated in total synthesis,6 however, there was some uncertainty about whether the proximal methyl C–H bonds would intervene unproductively. Me

Me H CHO

H Me

O

From a synthetic standpoint, we reasoned that the primary challenge posed by 1 is construction of the central bicyclo[4.3.1]decane, which is trans-fused to a cyclobutane. Specifically, we identified the C1–C2 bond (Figure 1), which links the A and C rings through vicinal stereogenic centers, as a strategic disconnection. Based on this analysis, we became interested in forming this bond by a Pd-catalyzed C(sp3)–H alkenylation reaction between cyclobutane 5 and vinyl iodide 6. Although the direct product of this reaction would be a ciscyclobutane, we envisioned accessing the thermodynamically more stable trans-cyclobutane through an epimerization process. The C(sp3)–H functionalization of cyclobutanes

Me

CHO

7

1

C

8

O

•

•

OMe

2

D

E

2' CHO 1' H OH Ph key challenges: • synthesis of A-B-C ring system • strategic formation of C1–C2 bond • control of enantioselectivity Me H Me 10

C–O bond formation

+

O

6

OH

• Br

OMe

Me C(sp 3 )–H Me alkenylation

N I

•

ring-closing metathesis, aldol

O

5 prepared by Wolff rearrangement

• •

H Me

MeO 3

OMe

N H

OH

3'

H

H

Me

6

B

O

11

CHO

H Me

Me

5 2

H Me

Ph OH (+)-psiguadial B (1) HepG2 IC 50 = 46 nM

Me

4

A

3

OH

H

(+)-Psiguadial B (1) is a diformyl phloroglucinolcontaining meroterpenoid recently isolated by Shao and coworkers from the leaves of Psidium guajava, a plant that is widely used in traditional Chinese medicine.1 Biological investigations revealed that 1 exhibits potent antiproliferative activity against human hepatoma cells (HepG2 IC50 = 46 nM),1 although detailed mode-of-action studies have not been disclosed. Biosynthetically, the sesquiterpenoid fragment of 1 can be traced to b-caryophyllene;2 indeed, a number of biomimetic approaches to phloroglucinol meroterpenoids starting from b-caryophyllene have been reported.3,4 However, we recognized that an abiotic synthesis of 1 would allow us to develop new chemistry and strategy concepts that would be useful in broader synthetic contexts. Here we report an enantioselective total synthesis of 1, which was enabled by the development of a catalytic asymmetric addition of 8-aminoquinoline to a photolytically generated ketene.

Me H

Me

H

• Me

•

O

4

Figure 1. Retrosynthetic analysis.

Mapping this strategic bond construction onto a more complete retrosynthesis of (+)-psiguadial B (1), we planned to reserve installation of the two formyl groups and C1’ phenyl substituent until the final steps of the synthesis, thereby simplfiying 1 to 2. Scission of the aryl C–O bond in 2 revealed bromide 3; in the forward sense, the chroman substructure would be constructed via intramolecular Oarylation. Bromide 3 was then further simplified to ketone 4, where the strained 7-membered B-ring would be formed by a potentially challenging7 ring-closing metathesis, while the arene functionality could be installed via aldol condensation. In turn, ketone 4 was expected to be accessible in short order from the product of the directed C(sp3)–H alkenylation reaction, joining fragments 5 and 6.

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Table 1. Optimization of the tandem Wolff rearrangement/catalytic asymmetric ketene addition. O Me

N2

Me

8 hν (254 nm) catalyst THF, rt

Me

•

Me

7

O

O

Me

N (S) H

Me

9

N

5

Entry

mmol

Catalyst (mol %)

Equiv 8

Yield 5 (%)

1

0.10

0

1

55b

1

39

b

46

32

b

–66

58

b

–59

72

b

77

65

b

–15

66

c

81

37

c

79

62

c

80

62

c

79

2

0.10

3

C1 (50)

0.10

4

C2 (50)

0.10

5

C3 (50)

0.10

6

1

C4 (20)

15

10

1

C4 (20)

11

9

1

C5 (50)

0.10

8

1

C4 (50)

0.10

7

1

1

C4 (20)

30

3

C4 (10)

3

ee 5 (%)a 0

a

b Determined by SFC using a chiral stationary phase. Reac1 tions irradiated for 24 h, yield determined by H NMR versus an added internal standard. c Isolated yield. Mes

N N N Me Me

Fe

HO

N BF 4

N

H

HO

N

H

N

Me

Me Me PPY-Me* (C1)

O

N

Indanyl-NHC (C2)

Me

N

(+)-cinchonine (C4)

Me

O

MeO

N

(–)-cinchonidine (C3)

N

O N

(DHQD)2PYR (C5)

N

OMe

N

N

Having identified an approach to 1 that centered on the coupling between 5 and 6, we were left to consider how best to synthesize amide 5 in enantioenriched form. The correScheme 1. C(sp3)–H alkenylation and epimerization strategies.

sponding carboxylic acid had been made previously as a racemate by Wolff rearrangement of diazoketone 7,8 which is readily accessible from commercially available 2,2dimethylcyclopentanone.9 Inspired by several reports of catalytic asymmetric nucleophilic additions to ketenes,10 we hypothesized that enantioenriched 5 could be prepared directly by the photolysis of 7 in the presence of a chiral catalyst and 8-aminoquinoline (8). Thus, we conducted a survey of chiral nucleophilic catalysts known to engage with ketenes (Table 1, C1–C5),10,11 and discovered that 5 could indeed be obtained with promising levels of enantioinduction (15–77% ee, entries 2–6). The enantioselectivity is striking given the substantial rate of background reaction observed in the absence of catalyst (entry 1). Following an investigation of several reaction parameters,12 irradiation of 7 with 254 nm light in the presence of 1 equiv 8 and 20 mol % (+)-cinchonine (C4) in THF was determined to be optimal when conducting the reaction on small scale in a sealed tube (entry 7). Unfortunately, the yield dropped when the reaction was performed on preparative scale in a standard photochemical reaction vessel (entry 8). After detecting the evolution of carbon monoxide, we hypothesized that the decreased yield results from decomposition of ketene 9 by photodecarbonylation.13 In order to drive the product distribution toward nucleophilic trapping, we increased the concentration of 8, which restored the desired reactivity and afforded 5 in 62% yield and 80% ee on 15 mmol scale (entry 9). Moreover, the catalyst loading could be reduced to 10 mol % using this protocol, which reliably produced 5 in 62% yield and 79% ee on a 30 mmol scale (entry 10). Although 5 is obtained in modest ee directly from the reaction, a single recrystallization by layer diffusion provided this key intermediate in enantiomerically pure form. To our knowledge, this is the first example of a tandem Wolff rearrangement/catalytic asymmetric ketene addition. With rapid access to multi-gram quantities of 5, attention turned to its coupling with vinyl iodide 6 (Scheme 1).

O

O

Me

O

Me

5

Pd(OAc) 2 (15 mol %)

Me

N H

N

2

O

Ag2CO 3, TBME, 90 °C

I

10

(75%)

6 (3 equiv)

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N H

Me DBU

O

CH2Cl2, 60 °C (64%)

1. ethylene glycol CH(OMe) 3, p-TsOH PhMe, 80 °C (86%)

N

2. Cp2Zr(H)Cl, THF; then, Ph 3P CH2; then, 5M HCl

11

(58%, 2 steps)

O

Me Me O (–)-12

undesired enantiomer

Me N H

Me

N

5

O

Me

5 2

Pd(OAc) 2 (15 mol %) Ag2CO 3, TBME, 90 °C

I 13 (2 equiv)

O

O Me

O

(72%)

14

Me

N H

N O O

Me 1. Cp2Zr(H)Cl, THF

Me Ph 3P

O

2. KOH, MeOH, rt (70%, 2 steps)

Me

H

15


O

CH2;

O

then, 5M HCl (88%)

(+)-12

desired enantiomer

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Scheme 2. Completion of the synthesis of (+)-psiguadial B (1). Me

CuTC (15 mol %) L1 (30 mol %) Me 3Al, Et 2O, –35 °C

Me O

Me

Me

Ph O

L1:

O

Me Br

H

(94%, 19:1 dr)

(+)-12

Me

Me Me O

KOH

+ H

1

H

Li

O

MeOH, 80 °C

THF, –78 °C (80%, 2:1 dr, 54% single diastereomer)

Me

(92%)

O 16 OMe

4

Me

Me

OMe

17

P N

Ar

Me Ph

Me

H

Me

H

Me

Me

H

Me Me

H Me

O

CuI, 2,2'-bipy H (20 mol %) Me

OMe

9

KOt-Bu, DMF 120 °C H 2 DDQ EtO(CH 2)2OH MeCN/CH 2Cl2 0 °C to rt (60%, 4.8:1 dr, 2 cycles)

MeO

(75%)

OMe

Crabtree's cat. (5 mol %)

OH

H

H Me

H 2 (500 psi) CH2Cl2, rt

Br

Me

MeO

(90%)

Br

MeO

(93%)

3 OMe

H

Me

Me

OH

Me

1,4-BQ PhH, 80 °C

19

Me

H

HG-II (10 mol %)

OH

18 OMe

H

Br

Me

Me

OMe

H

CHO H Me

O

OMe

BF 3•OEt 2, Et 2O –78 °C to –45 °C

1'

H EtO

Ph 2Cu(CN)Li2

H Me

O

OMe 20

(90%, 2:1 dr)

To our delight, subjection of a mixture of 5 and 6 to Pd(OAc)2 and Ag2CO3 at 90 °C provided cis-cyclobutane 10 in 75% yield. The requisite trans-cyclobutane was obtained by selective epimerization14 at C2, as determined by deuterium-labeling studies. Ketalization of 11 enabled clean reductive cleavage of the directing group, and the corresponding aldehyde was telescoped through Wittig olefination and hydrolysis to afford vinyl enone (–)-12 in 58% yield, over the two steps. It was at this stage that we were able to obtain single crystals of trans-cyclobutane 11 suitable for X-ray diffraction. Unfortunately, 11 was found to be in the incorrect enantiomeric series for elaboration to natural (+)-psiguadial B (1). To our dismay, we could not circumvent this problem by simply employing (–)-cinchonidine (C3) in the tandem Wolff rearrangement/asymmetric ketene addition, as this pseudoenantiomeric catalyst afforded ent-5 in lower yield and only 59% ee (Table 1, entry 4). We recognized that the correct enantiomer of 12 could potentially be generated from 5 through an alternate sequence involving epimerization at C5 instead of C2. To this end, iodide 13 (isolated as an 8:1 mixture of olefin isomers) was prepared and subjected to the cross-coupling conditions, furnishing 14 in 72% yield on gram-scale. Reduction of the amide provided the cis-aldehyde (not shown), which was epimerized at C5 by treatment with KOH in methanol to give 15. Gratifyingly, methylenation and hydrolysis under the previously developed conditions provided (+)-12, the desired enantiomer. Thus, utilization of 13 as a coupling partner eliminated a linear protection step and substantially improved material throughput. Moreover, it is notable that either enantiomer of 12 can be prepared using a single enantiomer of organocatalyst.

OMe 1. pyr•HCl, 200 °C (62% single diast.)

O

H

Ph

OMe

21

2. MeOCHCl 2,TiCl4 CH2Cl2, –78 °C to rt (50%)

H Me

O

H

OH CHO

Ph

OH

(+)-psiguadial B (1) 15 steps from diazoketone

With the correct enantiomer of vinyl enone 12 in hand, attention turned to installation of the methyl group at the C1 quaternary center (Scheme 2). Reaction of 12 with Gilman’s reagent furnished ketone 4 in only moderate yield and 3:1 dr. Fortunately, the yield and diastereoselectivity of the conjugate addition was enhanced by employing the coppercatalyzed asymmetric method developed by Alexakis and coworkers,15 which provided 4 in 94% yield and 19:1 dr. Subsequent aldol condensation between 4 and aldehyde 16 afforded exo-enone 17 in excellent yield. However, 1,2addition into this hindered ketone proved challenging. Allylic alcohol 18 was obtained in good yield and serviceable dr by employing vinyllithium in THF at –78 °C; extensive experimentation aimed at improving the dr proved unfruitful. Finally, the key ring-closing metathesis proceeded with excellent efficiency using the second generation Hoveyda– Grubbs catalyst (HG-II), delivering the fully assembled A-BC ring system in 93% yield. With the strained sesquiterpene framework secured, both the di- and trisubstituted olefins in 3 were hydrogenated in the presence of Crabtree’s catalyst, thus establishing the C9 stereogenic center with 16:1 dr and providing 19 in 90% isolated yield. The final ring of the psiguadial framework was constructed by a Cu-catalyzed intramolecular Oarylation reaction, which furnished pentacycle 2 in 75% yield.16 Completion of the synthesis required installation of the phenyl group at C1’ and formylation of the E-ring. To this end, treatment of 2 with DDQ in the presence of ethoxyethanol17 effected benzylic oxidation to give 20 in 60% yield over 2 cycles. Addition of BF3•OEt2 to a mixture of 20 and diphenylcyanocuprate18 delivered 21 in 90% yield as an inseparable 2:1 mixture of diastereomers, favoring the desired



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configuration. Double demethylation was achieved with pyridine hydrochloride at 200 °C; at this stage the diastereomeric resorcinols were readily separable by column chromatography. Finally, both aryl aldehydes were installed simultaneously by subjection to Rieche formylation conditions,19 delivering (+)-psiguadial B (1) in 50% yield. Synthetic 1 was found to be spectroscopically identical in all respects to the natural sample reported by Shao et al.1,10 In summary, the total synthesis of the cytotoxic natural product (+)-psiguadial B (1) was completed in 15 steps from diazoketone 7. The synthetic strategy was enabled by the de novo construction of the trans-fused cyclobutane ring via a tandem Wolff rearrangement/asymmetric ketene addition, followed by a Pd-catalyzed C(sp3)–H alkenylation reaction. Notably, both enantiomers of the natural product are accessible from a single enantiomer of organocatalyst. Efforts to expand the scope of these key transformations and apply this sequence in the synthesis of other trans-cyclobutanecontaining natural products are ongoing in our laboratory. ASSOCIATED CONTENT Supporting Information. Experimental procedures, characterization and spectral data for all compounds, and crystallographic data (CIF). This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author [email protected] ACKNOWLEDGMENT Prof. Greg Fu is gratefully acknowledged for insightful discussions. We thank Dr. Allen Oliver and Dr. Nathan Schley for X-ray crystallographic structure determination and Dr. David VanderVelde for assistance with NMR structure determination. We thank Dr. Scott Virgil and the Caltech Center for Catalysis and Chemical Synthesis for access to analytical equipment, and Materia, Inc. for a donation of HG-II catalyst. Fellowship support was provided by the NSF (L. M. C., Grant No. DGE-1144469) and SNF (L. W., Grant No. PBZHP2-147311). S.E.R. is an American Cancer Society Research Scholar and a Heritage Medical Research Foundation Investigator. Financial support from the California Institute of Technology, the NIH (NIGMS RGM097582A), the American Cancer Society, the Research Corporation Cottrell Scholars program, and DuPont is gratefully acknowledged. REFERENCES 1 Psiguadial A, B: Shao, M.; Wang, Y.; Liu, Z.; Zhang, D.-M.; Cao, H.-H.; Jiang, R.-W.; Fan, C.-L.; Zhang, X.-Q.; Chen, H.-R.; Yao, X.-S.; Ye, W.-C. Org. Lett. 2010, 12, 5040.

2

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Psiguadial C, D and proposed biosynthesis: Shao, M.; Wang, Y.; Jian, Y.Q.; Huang, X.-J.; Zhang, D.-M.; Tang, Q.-F.; Jiang, R.-W.; Sun, X.-G.; Lv, Z.-P.; Zhang, X.-Q.; Ye, W.-C. Org. Lett. 2012, 14, 5262. 3 (a) Tran, D. N. Rhodium-Catalyzed Imine-Directed C-H Bond Activation and Biomimetic Synthesis of Sesquiterpenoids. PhD Thesis, ETH Zürich 2014. (b) Semi-syntheses of guajadial & psidial A: Lawrence, A. L.; Adlington, R. M.; Baldwin, J. E.; Lee, V.; Kershaw, J. A.; Thompson, A. L. Org. Lett. 2010, 12, 1676. (c) Semi-synthesis of caryolanemagnolol: Cheng, X.; Harzdorf, N. L.; Shaw, T.; Siegel, D. Org. Lett. 2010, 12, 1304. 4 Biomimetic syntheses of several related meroterpenoids from bicyclogermacrene has also been reported: Tran, D. N.; Cramer, N. Chem. Eur. J. 2014, 20, 10654. 5 (a) Zhang, S.-Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2013, 135, 12135. (b) Wang, B.; Lu, C.; Zhang, S. -Y.; He, G.; Nack, W. A.; Chen, G. Org. Lett. 2014, 16, 6260. (c) Xiao, K. -J.; Lin, D. W.; Miura, M.; Zhu, R. -Y.; Gong, W.; Wasa, M.; Yu, J. -Q. J. Am. Chem. Soc. 2014, 136, 8138. For seminal studies, see: (d) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965. (e) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154. For a review, see: (f) Yamaguchi, J.; Itami, K.; Yamaguchi, A. D. Angew. Chem. Int. Ed., 2012, 51, 8960. 6 (a) Gutekunst, W. R.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 19076. (b) Gutekunst, W. R.; Gianatassio, R.; Baran, P. S. Angew. Chem. Int. Ed. 2012, 51, 7507. (c) Gutekunst, W. R.; Baran, P. S. J. Org. Chem. 2014, 79, 2430. (d) Panish, R. A.; Chintala, S. R.; Fox, J. M. Angew. Chem. Int. Ed. 2016, 55, 4983. For other relevant examples in synthesis see: (e) Feng, Y.; Chen, G. Angew. Chem. Int. Ed. 2009, 49, 958. (f) Ting, C. P.; Maimone, T. J. Angew. Chem. Int. Ed. 2014, 53, 3115. 7 We were aware of unsuccessful efforts to prepare b-caryophyllene by ringclosing metathesis. See: Dowling, M. S.; Vanderwal, C. D. J. Org. Chem. 2010, 75, 6908. 8 Ghosh, A.; Banerjee, U. K.; Venkateswaran, R. V. Tetrahedron 1990, 46, 3077. 9 This starting material can also be prepared according to the procedure by: Caille, S.; Crockett, R.; Ranganathan, K.; Wang, X.; Woo, J. C. S.; Walker, S. D. J. Org. Chem. 2011, 76, 5198. 10 (a) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 10006. (b) Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 6176. 11 (a) Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634, 9. (b) Zhang, Y. R.; He, L.; Wu, X.; Shao, P. -L.; Ye, S. Org. Lett. 2008, 10, 277. For a review on catalytic, asymmetric additions to ketenes, see: (c) Paull, D. H.; Weatherwax, A.; Lectka, T. Tetrahedron 2009, 65, 6771. 12 See Supporting Information. 13 Tidwell, T. T. Ketenes, 2nd Edition; John Wiley & Sons: Hoboken, New Jersey, 2006; pp 443-447. 14 The major side product in this reaction is spirocyclic lactam S1 (see Supporting Information), which presumably arises via aza-Michael addition of the amide to the pendant enone. This material could be partially converted to 11 by resubjection to the epimerization conditions. For related examples, see: (a) Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3680. (b) Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 6541. 15 (a) d’Augustin, M.; Palais, L. T.; Alexakis, A. Angew. Chem. Int. Ed. 2005, 44, 1376. (b) Vuagnoux-d'Augustin, M.; Alexakis, A. Chem. Eur. J. 2007, 13, 9647. 16 Suchand, B.; Krishna, J.; Mritunjoy, K.; Satyanarayana, G. RSC Adv. 2014, 4 (27), 13941. 17 (a) Saito, A.; Nakajima, N.; Tanaka, A.; Ubukata, M. Tetrahedron 2002, 58, 7829. (b) Dennis, E. G.; Jeffery, D. W.; Johnston, M. R.; Perkins, M. V. Tetrahedron 2012, 68, 340. 18 (a) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A. J. Org. Chem. 1984, 49, 3938. (b) Lipshutz, B. H.; Parker, D. A.; Kozlowski, J. A.; Nguyen, S. M. Tetrahedron Lett. 1984, 25, 5959. 19 (a) Rieche, A.; Gross, H.; Höft, E. Chem. Ber. 1960, 93, 88. (b) Aukrust, I. R.; Skattebol, L. Acta Chem. Scand. 1996, 50, 132. (c) Kraus, G. A.; Mengwasser, J.; Maury, W.; Oh, C. Bioorg. Med. Chem. Lett. 2011, 21, 1399.


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TOC graphic: Me

Me

H

O Me Me

CHO N H

prepared by tandem Wolff rearrangement/ asymmetric ketene addition

+

H Me

N I

O

O

H

OH CHO

Ph

OH

(+)-psiguadial B



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 1. Retrosynthetic analysis.

92x103mm (600 x 600 DPI)


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Table of Contents graphic 32x12mm (600 x 600 DPI)



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Scheme 1. C(sp3)–H alkenylation and epimerization strategies. 61x21mm (600 x 600 DPI)


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Scheme 2. Completion of the synthesis of (+)-psiguadial B (1).

85x43mm (600 x 600 DPI)



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Table 1. Optimization of the tandem Wolff rearrangement/catalytic asymmetric ketene addition. 19x4mm (600 x 600 DPI)


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catalyst structures to accompany table 1 48x28mm (600 x 600 DPI)


Enantioselective Total Synthesis of (+)-Psiguadial B - Journal of the

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