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Ruthenium Catalyzed Alkene-Alkyne Coupling of Di-substituted Olefins: Application to the Stereoselective Synthesis of Trisubstituted Enecarbamates. Barry M. Trost, and James J. Cregg J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja511911b • Publication Date (Web): 30 Dec 2014 Downloaded from http://pubs.acs.org on January 3, 2015
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Ruthenium Catalyzed Alkene-Alkyne Coupling of Disubstituted Olefins: Application to the Stereoselective Synthesis of Trisubstituted Enecarbamates. Barry M. Trost, James J. Cregg Department of Chemistry, Stanford University, Stanford, California, 94305-5080, United States
Supporting Information Placeholder ABSTRACT: The Ru-catalyzed alkene-alkyne coupling reaction has been demonstrated to be an enabling methodology for the synthesis of complex molecules. However, to date, it has been limited to monosubstituted olefins. Herein we report the first general utilization of disubstituted olefins in the Ru-catalyzed alkene-alkyne coupling reaction by employing carbamate directing groups. The products are stereodefined trisusbstituted enecarbamates. The elaboration of these structures towards the asymmetric synthesis of complex aminocyclopentitols, and 1,2-amino alcohols are discussed.
Disubstituted Olefins: R3
R1
+
OR
R4
S
R3
R1 Ru
+ R
cat. CpRu(CH3CN)3PF 6 R
rt, Acetone or DMF
R R
However, to date, the intermolecular reaction has been limited to monosubstituded olefins.3 Thus given the success of the reaction as a powerful tool for the rapid construction of molecular complexity we became interested in finding a way to facilitate the reaction using disubstituted olefins. Considering that the mechanism of the reaction is believed to proceed through a ruthenacyclopentene intermediate,1 we postulated that when using disubstituted olefins this intermediate was destabilized due to detrimental steric interactions (Figure 1).
R3
R4
R4
NR
Ru
R3
R1 R 2 R5
R4
Ru
H 2 R1 R
R5
This work: Use Directing Group to Increase Stability of Ruthenacyclopentene Intermediate
R3
X R1 NHBoc
R5
R
S
R2
R5
Ru
Key Step in the total synthesis of: Amphidinolide A Amphidinolide P (eq 1) R Callipeltoside A Lasonolide A Bryostatin 16
cat. CpRu(CH3CN)3PF 6
R2
Rationale: Increased Steric Strain
R4
The alkene-alkyne coupling reaction between olefins and alkynes catalyzed by ruthenium (+2) complexes has been demonstrated to be a highly atom-economic reaction for the regio-, diastereo-, and chemoselective synthesis of 1,4-dienes (eq 1).1 The reaction represents the ideal addition reaction, forming one C-C bond, and two stereodefined olefins, without the need of any premetalated reagents. The utility of the reaction has been demonstrated by its use as a key step in a number of total syntheses (eq 1).2
R5
R2
R1
1-6% CpRu(CH3CN)3PF 6
+
R3
R4
Acetone, rt 1-8h
R3 R4
R1 NHBoc
X=Directing Group
First general application of disubstituted olefins as reactive partners. Good reactivity at rt using low catalyst loadings (1-6% Ru). Completly Selective for alpha-amino C-H. Single enecarbamate geometry. Dienes can be chemoselectivly functionalized.
Figure 1: Utilization of carbamate directing groups to facilitate the Ru-catalyzed alkene-alkyne coupling reaction of disubstituted olefins. To alleviate this problem we hoped that a Lewis basic directing group could coordinate the cationic ruthenium center and increase the stability of the complex. Herein we report the success of such a strategy; employing carbamates as directing groups we were able to facilitate the coupling of branched disubstituted olefins under extremely mild conditions. This methodology represents the first general example of disubstituted olefins being used as substrates in the Rucatalyzed alkene-alkyne coupling reaction. The resultant trisubstituted enecarbamates are formed with complete stereoselectivity, require no stoichiometric metals and are synthesized from readily available alkenes and alkynes. Enecarbamates are excellent substrates for a diverse range of synthetic transformations; including hydrogenation,4 dihydroxylation,5 halogenation,6 cyclopropanation,7 amination,8 aminoxylation,9 in Diels-Alder reactions,10 as imine surrogates,11 as nucleophiles in stereoselective C-C bond forming reactions,12 and as amino acid precursors via
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hydroformylation.13 In addition, they represent key structural motifs in a variety of bioactive natural products.14 However, the available methods for the stereoselective synthesis of more highly susbstituted enecarbamates remains a challenge. The synthesis of β,β’-trisubstituted enecarbamates are limited to the carbometalation of ynamides,15 or the cross coupling of carbamates with preformed stereodefined vinyl halides and triflates.16 In addition, for the carbometalation of ynamides, the directing groups required to obtain good regioselectivities are difficult to remove. Thus during our initial screening of carbamate directing groups we were interested in finding a more synthetically versatile group. Gratifyingly the tert-Butyl carbamates (Boc) proved to be optimal for the reaction; providing excellent reactivity, selectivity, and product stability (Table 1). Methallyl Boc amine 1a could be coupled with alkyne 2 using either 3% or 1% catalyst to give enecarbamate 3a in excellent yield. Carboxybenzyl (Cbz) (1b) was also effective, however, it was less reactive, presumably due to the sensitivity of the ruthenium catalyst to aromatic rings.
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branching at the allyl position (1d), and additional Lewis basic sites (1g) all gave good reactivity and only one olefin isomer. Of particular interest was the reaction of boronic ester 1c to give 3c in excellent yield. I
O
TMS
+
B
TMS
O
5% Pd(dppf)Cl 2, NaHCO 3 NHBoc
NHBoc
DME:H 2O (2:1), 85 oC, 16h
3c 1 equiv
(eq 2)
7 75% yield
Under standard Suzuki coupling conditions the coupling of iodobenzene and enecarbamate 3c proceeded smoothly to give compound 7 (eq 2). In addition to TMS propyne more highly functionalized TMS alkynes and alkynoates17 proved to be excellent substrates in the reaction (Table 2). Table 2. Screening of Alkyne Partners.a R1 NHBoc
+
1a, 1k, 1m
Table 1. Substrate Scope for Alkene Partnera
Ru%
Alkene
1
3%
R=Me 1a
R2
Acetone, 0.5 M, 1-6h, rt
2b-2f
Entry
R3
1-6% CpRu(CH 3CN) 3PF 6
R2
R3
Alkyne
Product
R1 NHBoc
3i-3n Yieldb
TMS
NHR R
+
TMS
1a-1i 1 equiv
TMS
1-6% CpRu(CH 3CN) 3PF 6
NHR
0.5 M Acetone, 1-8h, rt
2
TMS
2b
HO
3
1 equiv
NHBoc
93%
NHBoc
72%
3i
OH TMS
Entry
Ru%
Alkene
Product
Yieldb
2
6%
TMS
1
3% 1%
NHBoc
OH TMS
TMS CO2Me
3
TMS NHCbz
6%
3j
2c
3a 2
NHCbz
1b
3%
R=Et 1k
TMS
2d
61%
3
6%
4
O
B
TMS
O
O
B
NHBoc
6%
83%
R=Me 1a 5 equiv
MeO 2C
C 4H 9 BDMS
NHBoc
3k
CO2Me
3b O
HO
95 % 98 %
NHBoc
1a
R=Me 1a 2 equiv
BDMS NHBoc
2e C6H13
3c
NHBoc
O
TMS
6% NHBoc
NHBoc
1d TMS
NHBoc
O NHBoc
TMS
S
55%(90%c)
NHBoc
3g TMS
3%
TMS
TMS
82%
NHBoc
1h
70%(94%c)
CO2Me CO2Me
TMS
1g
8
2f
O
69% 3:1 3m:3n
+ NHBoc
MeO
NHBoc
C6H13
One olefin isomer detected by NMR. Heating to 80 °C required to eliminate rotamers. bYields are of isolated material.
3f CO2Me CO2Me NHBoc
6%
C6H13 MeO
3m
a
O NHBoc
1f
R=CH 2NHBoc 1m
NHBoc OMe
O
3n
O
S
6%
6%
52%
3e
O
7
5
OTBS
NHBoc
3% 1e
6
58%(91%c)
3d
TBSO
5
77%
3l
NHBoc
1c
4
82%
CO2Me
3h
NHBoc
One olefin isomer detected by NMR. Heating to 80 °C required to eliminate rotamers. bYields are of isolated material. cYield is based on recovered alkene (brsm). a
Varying the R group on the alkene was possible, as a number of different functional groups were tolerated (1c1h)(Table 1). Heteroatoms, including oxygen (1e), sulfur (1f), and silicon (1h), electron deficient aromatic rings (1f),
Free alcohols (2b and 2c) were tolerated without the need for any protecting groups. Our group has previously shown that benzyldimethylsilyl (BDMS) alkynes are also effective substrates for the ruthenium catalyzed alkene-alkyne coupling reaction,18 and this proved to be true in our case as well (2e). The vinyl BDMS functional group represents an excellent substrate for Hiyama couplings and TamaoFleming oxidations, and is more stable than most activated silicon cross coupling reagents. Satisfied that the method allowed for the synthesis of a diverse range of highly functionalized trisubstituted enecarbamates, we turned our attention to the functionalization of the products. We envisioned chemoselective activation of the enecarbamate being possible and were pleased to
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find that we could reduce the enecarbamate selectively by employing TFA, and TES-H at low temperatures (Scheme 1). Compound 4 is a gamma amino olefin, which are useful substrates for intramolecular electrophilic cyclization19 and hydroamination reactions.20 Additionally the product contains the substructure found in a number of α2δ-ligands known to modulate voltage-gated calcium channels, with the best-known example being the drug pregabalin.21 Scheme 1. Chemoselective Reduction TMS
R1 N
R2
Rh
NHBoc
NHR1
R3
Pregabalin
R4 R3
Pd, Rh, Ir, Fe, Au
R1 N
or X+
R2
R3
NH 2
4 84% yield
-15 oC, 16h, DCM
3a
R4
CO2H
3 equiv TFA, 5 eq TES-H NHBoc
Amino olefins represent useful substrates for hydroamination and electophilic cyclizations.
R2
Given the stereoselectivity of the coupling reaction we were also interested in employing the enecarbamates as substrates for asymmetric transformations. Lam has shown that enecarbamates can be asymmetrically dihydroxylated with excellent ee’s to form α-hydroxy aldehydes.5 Inspired by this we attempted the Sharpless dihydroxylation of 3a. The enecarbamate was dihydroxylated selectively to give 5 in good yield and enantioselectivity (Scheme 2).
composition. Looking to take advantage of the aminal we reduced it to give the 1,2 amino alcohol 6. 1,2 Amino alcohols are common in a number of bioactive molecules, including the drugs vinblastine and nicergoline, and have led to a number of synthetic methodologies.22 In addition to reducing the aminal we hoped that we could use it as an imine surrogate. We hypothesized that the pendant vinyl silane of 5 could be used as a tethered nucleophile to attack the imine generated by addition of a Lewis acid. After some optimization it was shown that TMSOTf was the most effective Lewis acid. The reaction gave compound 8 as a single diastereomer in excellent yield. The method allows for the synthesis of highly substituted aminocyclopentitols. Aminocyclopentitols are structures of significant synthetic and biological interest,23 with examples including the antibiotic pactamycin and insecticide trehazolin. Our proposed mechanism for the alkene-alkyne coupling is depicted in Scheme 3. Assuming that the reaction proceeds through a ruthenacyclopentene intermediate we believe that the observed stereo- and chemoselectivity can be accounted for based on 2 discriminating events in the mechanistic cycle. Scheme 3. Mechanistic Rationale.
R3 R3
Scheme 2. Asymmetric Synthesis of Cylopentanols and 1,2 Amino Alcohols.
H
R1
+
R NHBoc
R2
R2
VIII
S
Observed Product
Ru S
NHBoc
Hb
Ha
S
3S 3S OtBu TMS
TMS
HO
(DHQ) 2PHAL, K 2OsO4(OH) 4, K 2CO 3,
NHBoc
NHBoc
K 2Fe(CN) 6, KHCO 3, MsNH 2, 4 oC, 70h
3a
5
R3
Ru
H VII
OH
73% yield, 83% brsm, 88% ee
or
R3
HO
VI
R
NHBoc
R3
R2
OH
O Ru
or Ha
R1
R3
NH
Hb II
Ru
R2 BocHN
8 80% yield
R=CH 2R1
H H
endo face disfavored
R3
TMS NHBoc
5
1.2 equiv TMSOTf, TES-H
HO
DCM, -78 to -20 oC, 40 min
OH
6 79% yield
N H Vi
H CO2Me
Vinblastine
H 2N
H
O
OR
N H
N
Nicergoline
OH O
RHN OH
OH
Ar O
O
R2
Ha 2 NHBoc Ha1
NHBoc
Never Observed V
H H
exo face favored N OH OH
HO OH
Pactamycin
Ru R
R2
RHN
NHAr
OH
R3
NHBoc
Bioactive Targets: N
R1 III
HO
R1 I
B-Hydride elimination of Hb
Ha1 Ha 2 NHBoc IV
Hb
Ru
Favored due to chelation
R
R
DCM, -78 to -20 oC, 25 min
OH
R2
NHBoc
1.2 equiv TMSOTf NHBoc
5
H
R2
R2
NHBoc
TMS
Ru
R3
Trehazolin
Surprisingly the product did not fragment to the aldehyde as seen by Lam. Lam used 2-oxazolidone as the nitrogen protecting group, and this difference may account for the difference in stability of the N-acyl aminal products. The resulting N-acyl aminal 5 was stable to column chromatography and could be stored in the freezer without noticeable de-
The first is chelation, which leads to preferential formation of intermediate II vs. intermediate I. Compound III, formed by β-hydride elimination from intermediate I was never observed. Additionally, intermediate II places the C-Ha bond available for β-hydride elimination following bond rotation, but places the C-Hb bond unable to acquire the necessary geometry to undergo β-hydride elimination. The second discriminating event occurs from intermediate II, where there are then 2 possible diastereotopic agostic interactions (IV or V), leading to either intermediate VI or intermediate VII after β-hydride elimination. Intermediate V experiences
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less detrimental steric interactions by placing the Boc-amido group on the convex-like face of the bicycle[3.2.0] heptanelike system compared to intermediate IV where this group is on the concave-like face. Such differences account for formation of intermediate VII in preference to intermediate VI. After reductive elimination intermediate VII leads to the observed product VIII. In summary we report the first general application of disubstituted olefins in the ruthenium catalyzed alkenealkyne coupling, and its application to the synthesis of β,βtrisusbstituted enecarbamates with complete control of geometry. The application of such substrates to the synthesis of highly complex biologically relevant structural motifs has been illustrated. Mechanistic understanding from this endeavor should enable the continued expansion of the ruthenium catalyzed alkene-alkyne coupling reaction to additional disubstituted olefins.
ASSOCIATED CONTENT Supporting Information. Experimental details, compound characterization data, and spectra. This material is available free of charge via http://pubs.acs.org
AUTHOR INFORMATION Corresponding Author
[email protected] Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT We thank the NSF for their generous support of our programs (NSF CHE-1360634).
REFERENCES (1) (a) Trost, B. M.; Pinkerton, A. B.; Toste, F. D.; Sperrle, M. J. Am. Chem. Soc. 2001, 123, 12504. (b) Trost, B. M.; Surivet, J.-P. Angew. Chem. Int. Ed. 2001, 40, 1468. (c) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. Rev. 2001, 101, 2067. (d) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Angew. Chem. Int. Ed. 2005, 44, 6630. (e) Trost, B. M.; Machacek, M. R.; Faulk, B. D. J. Am. Chem. Soc. 2006, 128, 6745. (2) (a) Trost, B. M.; Wrobleski, S. T.; Chisholm, J. D.; Harrington, P. E.; Jung, M. J. Am. Chem. Soc. 2005, 127, 13589. (b) Trost, B. M.; Papillon, J. P. N.; Nussbaumer, T. J. Am. Chem. Soc. 2005, 127, 17921. (c) Trost, B. M.; Gunzner, J. L.; Dirat, O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 10396. (d) Trost, B. M.; Stivala, C. E.; Hull, K. L.; Huang, A.; Fandrick, D. R. J. Am. Chem. Soc. 2014, 136, 88. (e) Trost, B. M.; Dong, G. Nature 2008, 456, 485. (3) Three examples of cyclic disubstituted olefins have been reported. However extension of these substrates has been unsuccessful. See: Trost, B. M., Dean Toste, F. Tetrahedron Lett. 1999, 40, 7739. (4) Gopalaiah, K.; Kagan, H. B. Chem. Rev. 2011, 111, 4599. (5) Gourdet, B.; Lam, H. W. Angew. Chem. Int. Ed. 2010, 49, 8733. (6) (a) Phipps, R. J.; Hiramatsu, K.; Toste, F. D. J. Am. Chem. Soc. 2012, 134, 8376. (7) Song, Z.; Lu, T.; Hsung, R. P.; Al-Rashid, Z. F.; Ko, C.; Tang, Y. Angew. Chem. Int. Ed. 2007, 46, 4069. (8) Matsubara, R.; Kobayashi, S. Angew. Chem. Int. Ed. 2006, 45, 7993.
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(9) Lu, M.; Lu, Y.; Zhu, D.; Zeng, X.; Li, X.; Zhong, G. Angew. Chem. Int. Ed. 2010, 49, 8588. (10) Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2000, 122, 7843. (11) (a) Kobayashi, S.; Gustafsson, T.; Shimizu, Y.; Kiyohara, H.; Matsubara, R. Org. Lett. 2006, 8, 4923. (b) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292. (c) Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2008, 130, 14452. (12)(a) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41, 292. (b) Terada, M.; Soga, K.; Momiyama, N. Angew. Chem. Int. Ed. 2008, 47, 4122. (13) Klaus, S.; Neumann, H.; Jacobi von Wangelin, A.;Goerdes,D.; Struebing, D.; Huebner, S.; Hateley, M.; Weckbecker, C.; Huthmacher, K.; Riermeier, T.; Beller, M. J. Organomet. Chem. 2004, 689, 3685. (14) (a) Yet, L. Chem. Rev. 2003, 103, 4283. (b) Shen, R.; Lin, C. T.; Bowman, E. J.; Bowman, B. J.; Porco, J. A. J. Am. Chem. Soc. 2003, 125, 7889. (c) Pandey, A. K.; Sharma, R.; Shivahare, R.; Arora, A.; Rastogi, N.; Gupta, S.; Chauhan, P. M. S. J. Org. Chem. 2013, 78, 1534. (15) (a) Gourdet, B.; Lam, H. W. J. Am. Chem. Soc. 2009, 131, 3802. (b) Gourdet, B.; Rudkin, M. E.; Watts, C. A.; Lam, H. W. J. Org. Chem. 2009, 74, 7849. (c) Gourdet, B.; Smith, D. L.; Lam, H. W. Tetrahedron 2010, 66, 6026 (16) (a) Wallace, D. J.; Klauber, D. J.; Chen, C.; Volante, R. P. Org. Lett. 2003, 5, 4749. (b) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809. (c) Bolshan, Y.; Batey, R. A. Angew. Chem. 2008, 120, 2139. (d) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 6338. (17) Trost, B. M.; Mueller, T. J. J.; Martinez, J. J. Am. Chem. Soc. 1995, 117, 1888. (18) Trost, B. M.; Machacek, M. R.; Ball, Z. T. Org. Lett. 2003, 5, 1895. (19) Zhou, L.; Chen, J.; Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc. 2011, 133, 9164. (20) (a) Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1998, 63, 8983. (b) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070. (c)Komeyama, K.; Morimoto, T.; Takaki, K. Angew. Chem. Int. Ed. 2006, 45, 2938. (d) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 6042. (e) Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614. (f) Cochran, B. M.; Michael, F. E. J. Am. Chem. Soc. 2008, 130, 2786. (g) Liu, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 1570. (h) Ohmiya, H.; Moriya, T.; Sawamura, M. Org. Lett. 2009, 11, 2145. (i) Hesp, K. D.; Tobisch, S.; Stradiotto, M. J. Am. Chem. Soc. 2010, 132, 413. (21) Murtagh, L.; Dunne, C.; Gabellone, G.; Panesar, N.J.; Field, S.; Reeder, L. M.; Saenz, J.; Smith, G. P.; Kissick, K.; Martinez, C.; Van Alsten, J. G.; Evans, M. C.; Franklin, L. C.; Nanninga, T. N.; Wong, J. Org. Process Res. Dev. 2011, 15, 1315. (22) Bergmeier, S. C. Tetrahedron 2000, 56, 2561. (b) Kang, T.; Kim, H.; Kim, J. G.; Chang, S. Chem. Commun. 2014, 50, 12073. (c) Karjalainen, O. K.; Koskinen, A. M. P. Org. Biomol. Chem. 2012, 10, 4311. (d) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338. (e) Trost, B. M.; Miege, F. J. Am. Chem. Soc. 2014, 136, 3016. (23) (a) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. Rev. 1999, 99, 779. (b) Boyce, G. R.; Johnson, J. S. Angew. Chem. Int. Ed Engl. 2010, 49, 8930. (c) Sharpe, R. J.; Malinowski, J. T.; Johnson, J. S. J. Am. Chem. Soc. 2013, 135, 17990.
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Insert Table of Contents artwork here: NHBoc
R2
+ R1
R2
2 steps
TMS
1-6% CpRu(CH3CN)3PF 6 NHBoc
Acetone, rt 1-8h
TMS R1
R1
R2
OH
NHBoc HO R 2
2 steps
First general application of disubstituted olefins as reactive partners. Complete control of enecarbamate geometry.
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R1
NHBoc
5
