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Electronic Theses, Treatises and Dissertations The Graduate School
2005 Ring-Closing Metathesis for the Synthesis of Carbocyclic and Heterocyclic Intramolecular Baylis-Hillman Adducts Eunho Song
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COLLEGE OF ARTS AND SCIENCES
RING-CLOSING METATHESIS FOR THE SYNTHESIS OF CARBOCYCLIC AND
HETEROCYCLIC INTRAMOLECULAR BAYLIS-HILLMAN ADDUCTS
By
EUNHO SONG
A Thesis submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Master of Science
Degree awarded: Summer semester, 2005
The members of the Committee approve the thesis of EUNHO SONG defended on April 26, 2005.
Marie E. Krafft Professor Directing Thesis
Armen Zakarian Committee Member
Gregory B. Dudley Committee Member
Joseph B. Schlenoff Committee Member
The Office of Graduate Studies has verified and approved the above named committee members. TABLE OF CONTENTS
List of Tables v
List of Figures vi
List of Schemes xi
List of Abbreviations xii
Abstract xv
I. INTRODUCTION
Baylis-Hillman Reaction 1
Proposed Mechanism 2
Amine-Catalyzed Baylis-Hillman Reaction 3
Intramolecular Baylis-Hillman Reaction 5
Ring-Closing Metathesis Reaction 6
Proposed Mechanism 7
II. RESULTS AND DISCUSSION
Optimization of reaction conditions for Baylis-Hillman Reaction 14
Synthesis of Carbocyclic RCM Products from Baylis-Hillman Adducts 16
Synthesis of Fused ring RCM Products from Baylis-Hillman Adducts 22
Synthesis of 6-Membered Carbocyclic RCM Products from Baylis 25 -Hillman Adducts using substituted hexenal
Synthesis of 6-Membered Heterocyclic RCM Products from Baylis 27 -Hillman Adducts using Chiral-Amino acids 29 Summary
iii III. EXPERIMENTAL 31
REFERENCES 145
BIOGRAPHICAL SKETCH 147
iv LIST OF TABLES
Table 1. Cross-Metathesis Reactions with Esters, Aldehydes and Ketones 10
Table 2. RCM reactions using Protected and Unprotected BH Adducts 11
Table 3. RCM reaction of Baylis-Hillman adducts 12
Table 4. Amine Catalyzed BH Reaction 15
Table 5. BH Reaction with Quinuclidine 16
Table 6. RCM reaction to form IMBH Adducts 18
Table 7. BH and RCM Reaction using electron-deficient alkenes and 21 Grubbs’ catalyst
Table 8. RCM Reaction for the synthesis of Fused ring Products from BH 24 Adducts
Table 9. RCM Reaction from BH Adducts using β-substituted hexenal 27
v LIST OF FIGURES
Figure 1. Proposed Mechanism for the Morita-Baylis-Hillman Reaction 2
Figure 2. Proposed Mechanism for the Cross-Metathesis Reaction 8
Figure 3. A variety of olefin metathesis reactions 9
Figure 4. Oxy-Cope Rearrangement 25
Figure 5. 500 MHz 1H Spectrum of 2a 56
Figure 6. 75 MHz 13C Spectrum of 2a 57
Figure 7. IR Spectrum of 2a 58
Figure 8. 500 MHz 1H Spectrum of 2b 59
Figure 9. 75 MHz 13C Spectrum of 2b 60
Figure 10. IR Spectrum of 2b 61
Figure 11. 500 MHz 1H Spectrum of 2c 62
Figure 12. 75 MHz 13C Spectrum of 2c 63
Figure 13. IR Spectrum of 2c 64
Figure 14. 500 MHz 1H Spectrum of 2d 65
Figure 15. 75 MHz 13C Spectrum of 2d 66
Figure 16. IR Spectrum of 2d 67
Figure 17. 500 MHz 1H Spectrum of 3a 68
Figure 18. 75 MHz 13C Spectrum of 3a 69
Figure 19. IR Spectrum of 3a 70
Figure 20. 500 MHz 1H Spectrum of 3b 71
Figure 21. 75 MHz 13C Spectrum of 3b 72 vi Figure 22 IR Spectrum of 3b 73
Figure 23. 500 MHz 1H Spectrum of 3c 74
Figure 24. 500 MHz 1H Spectrum of 3d 75
Figure 25. 500 MHz 1H Spectrum of 4 76
Figure 26. 75 MHz 13C Spectrum of 4 77
Figure 27. IR Spectrum of 4 78
Figure 28. 500 MHz 1H Spectrum of 8 79
Figure 29. 75 MHz 13C Spectrum of 8 80
Figure 30. IR Spectrum of 8 81
Figure 31. 500 MHz 1H Spectrum of 11 82
Figure 32. 75 MHz 13C Spectrum of 11 83
Figure 33. IR Spectrum of 11 84
Figure 34. 500 MHz 1H Spectrum of 6 85
Figure 35. 75 MHz 13C Spectrum of 6 86
Figure 36. IR Spectrum of 6 87
Figure 37. 500 MHz 1H Spectrum of 10d 98
Figure 38. 75 MHz 13C Spectrum of 10d 89
Figure 39. IR Spectrum of 10d 90
Figure 40. 500 MHz 1H Spectrum of 7 91
Figure 41. 75 MHz 13C Spectrum of 7 92
Figure 42. IR Spectrum of 7 93
Figure 43. 500 MHz 1H Spectrum of 9 94 vii Figure 44. 75 MHz 13C Spectrum of 9 95
Figure 45. IR Spectrum of 9 96
Figure 46. 500 MHz 1H Spectrum of 12 97
Figure 47. 75 MHz 13C Spectrum of 12 98
Figure 48. IR Spectrum of 12 99
Figure 49. 500 MHz 1H Spectrum of 14b 100
Figure 50. 75 MHz 13C Spectrum of 14b 101
Figure 51. IR Spectrum of 14b 102
Figure 52. 500 MHz 1H Spectrum of 14c 103
Figure 53. 75 MHz 13C Spectrum of 14c 104
Figure 54. IR Spectrum of 14c 105
Figure 55. 500 MHz 1H Spectrum of 16 106
Figure 56. 75 MHz 13C Spectrum of 16 107
Figure 57. IR Spectrum of 16 108
Figure 58. 500 MHz 1H Spectrum of 18 109
Figure 59. 75 MHz 13C Spectrum of 18 110
Figure 60. IR Spectrum of 18 111
Figure 61. 500 MHz 1H Spectrum of 17 112
Figure 62. 75 MHz 13C Spectrum of 17 113
Figure 63. IR Spectrum of 17 114
Figure 64. 500 MHz 1H Spectrum of 19 115
Figure 65. 75 MHz 13C Spectrum of 19 116 viii Figure 66. IR Spectrum of 19 117
Figure 67. 500 MHz 1H Spectrum of 24 118
Figure 68. 75 MHz 13C Spectrum of 24 119
Figure 69. IR Spectrum of 24 120
Figure 70. 500 MHz 1H Spectrum of 26 121
Figure 71. 75 MHz 13C Spectrum of 26 122
Figure 72. IR Spectrum of 26 123
Figure 73. 500 MHz 1H Spectrum of 25 124
Figure 74. 75 MHz 13C Spectrum of 25 125
Figure 75. IR Spectrum of 25 126
Figure 76. 500 MHz 1H Spectrum of 27 127
Figure 77. 75 MHz 13C Spectrum of 27 128
Figure 78. IR Spectrum of 27 129
Figure 79. 500 MHz 1H Spectrum of 28b 130
Figure 80. 75 MHz 13C Spectrum of 28b 131
Figure 81. IR Spectrum of 28b 132
Figure 82. 500 MHz 1H Spectrum of 30 133
Figure 83. 75 MHz 13C Spectrum of 30 134
Figure 84. IR Spectrum of 30 135
Figure 85. 500 MHz 1H Spectrum of 31 136
Figure 86. 75 MHz 13C Spectrum of 31 137
Figure 87. IR Spectrum of 31 138 ix Figure 88. 500 MHz 1H Spectrum of 32 139
Figure 89. 75 MHz 13C Spectrum of 32 140
Figure 90. IR Spectrum of 32 141
Figure 91. 500 MHz 1H Spectrum of 33 142
Figure 92. 75 MHz 13C Spectrum of 33 143
Figure 93. IR Spectrum of 33 144
x LIST OF SCHEMES
Scheme 1. BH Reaction for synthesis of densely functionalized molecules 1
Scheme 2. BH Reaction with imidazolium-based ionic liquids 4
Scheme 3. BH reaction cyclic IMBH Adducts using DMAP 6
Scheme 4. RCM reaction using Grubbs catalyst 7
Scheme 5. Possible Products of Olefin Metathesis 13
Scheme 6. Proposed Pathway for the synthesis of intramolecular Baylis- 14 Hillman adducts
Scheme 7. Synthesis of BH Adducts using nonsubstituted alkene aldehydes 17 and methyl acrylate
Scheme 8. Reversible-CM-based macrocycle formation 19
Scheme 9. Synthesis of RCM Products from BH Adducts using 20 monosubstituted alkene aldehydes
Scheme 10. Preparation of 2,3-dimethyl-4-pentenal for the BH reaction 22
Scheme 11. Preparation of Cyclic-BH substrates 23
Scheme 12. Preparation of 3-methyl-5-hexenal for BH reaction 25
Scheme 13. Preparation of 3,3-dimethyl-5-hexenal for BH reaction 26
Scheme 14. Preparation of (allyl-tosyl-amino)-acetaldehyde for BH 28 Reactions
Scheme 15. Synthesis of Heterocyclic-RCM Products from BH Adducts 29
Scheme 16. Proposed combinatorial application for the construction of 29 Hydropyridinol derivatives
xi LIST OF ABBREVATIONS
br broad (spectral)
Bu butyl n-Bu normal butyl oC degrees Celsius
CI chemical ionization (in mass spectrometry)
CM cross metathesis cm centimeters concd concentrated
δ chemical shift in parts million d day(s); doublet (spectral)
DABCO 1,4-Diazabicyclo[2.2.2]octane
DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
DMAP 4-(Dimethylamino)pyridine
DMSO Dimethyl sulfoxide
EI electron impact (in mass spectrometry)
Et ethyl
FT Fourier transform g gram(s) h hour(s)
HQD hydroxy quinuclidine
xii Hz hertz
IMBH Intramolecular Baylis-Hillman Reaction
IR infrared
J coupling constant (in NMR)
LAH lithium aliminium hydride m multiplet (spectral)
Me methyl
MHz megahertz min minute(s) mol mole(s)
MS mass spectrometry m/z mass to charge ratio (in mass spectrometry)
MVK methyl vinyl ketone
NMR nuclear magnetic resonance
Tf trifluoromethanesulfonyl
Ph phenyl ppm parts per million ( in NMR) pr propyl q quartet (spectral)
RCM ring-closing methathesis
RDS rate-determining step
Rf retention factor (in chromatography) xiii ROM ring-opening metathesis
TBS tert-butyldimethylsilyl
THF tetrahydrofuran
Ts toluenesulfonyl
UV untraviolet
xiv ABSTRACT
We have investigated optimum conditions for the Baylis-Hillman and ring-closing metathesis (RCM) reactions. In our experiments, we obtained the best results with quinuclidine (0.25 eq), and MeOH (0.75 eq) for the Baylis-Hillman reaction and 10 mol % of Grubbs #2 with DCM (0.01 M) for the RCM. We performed further reactions based on these optimum conditions. We examined the Baylis-Hillman and RCM reactions the under same conditions in order to extend the ring size from 5-membered to 8-membered and succeeded in the generation of 5-, 6- and 7- membered ring RCM products in 46 %, 67 % and 66 % yields. In the case of longer chains, only cross metathesis products (dimerized products) were detected after the reaction time. From these results, we focused our attention on the construction of 5- or 6-membered cyclic frameworks. At first, we applied optimum conditions for construction of 5- membered rings with α- or α,β-substituted aldehydes. Unfortunately, our attempts to form 5-membered rings with α-substituted aldehydes did not proceed well in the RCM due to steric hindrance. Interestingly, the nitrile-substituted 5-membered ring was readily formed in the RCM in good yield. Second, we performed the synthesis of ring-fused RCM products from Baylis-Hillman adducts using three different aldehydes. The experimental results were shown that only the Baylis-Hillman adduct from benzaldehyde gave a good yield (92 %) in the RCM reaction. Third, we achieved the synthesis of 6-membered carbocyclic RCM products from BH adducts using β-substituted hexenal. We employed 3-methyl and 3,3-dimethyl-5-hexenal in the BH reaction and ultimately obtained desired RCM products in same yield (87 %). It means that steric effects from substituents on the β-position of aldehydes is a not predominant factor influencing the reaction yield. In the end, 6-membered heterocyclic RCM products from BH adducts using chiral amino acids were completed through several well-known steps. These applications have been developed for a combinatorial approach for the construction of heterocyclic xv frameworks.
xvi I INTRODUCTION
Carbon-carbon bond formation is the most fundamental reaction for the construction of a molecular framework in organic chemistry.1 Very recent developments in organic chemistry have clearly established that atom economy, selective transformations and catalytic processes have become the primary and most essential requirement for the development of any efficient synthetic reaction.2 Among many well-known reactions, very recently the Baylis-Hillman reaction3 and olefin metathesis reaction4 have been added to the list of carbon-carbon bond-forming reactions.
Baylis-Hillman Reaction
Since the Baylis-Hillman reaction, described in 1972 by A. B. Baylis and M. E. D. Hillman, possesses the two features, atom economy and generation of functional groups, it qualifies to be in the list of potentially efficient synthetic reactions.3 This is essentially a three-component reaction involving the coupling of the α-position of activated alkenes with carbon electrophiles, under the catalytic influence of a tertiary amine, providing a simple and convenient method for synthesis of densely functionalized molecules (Scheme 1).
Scheme 1. BH reaction for the synthesis of densely functionalized molecules
XH X EWG tert.amine R' EWG RR' R
tert.amine = DABCO, Quinuclidine, 3-HQD, 3-quinuclidone, indolizine R = aryl, alkyl, heteroaryl; R' = H, COOR, alkyl X = O, NCOOR, NTs, NSO2Ph EWG = COR, CHO, CN, COOR, PO(OEt)2, SO2Ph, SO3Ph, SOPh
1 It was Morita who five years earlier reported the same reaction in the presence of a tertiary phosphine.5 Thus, it is more properly called the Morita-Baylis-Hillman reaction when catalyzed by a tertiary phosphine.
Proposed Mechanism
OH O O R OR OR N
N
N O O H N O R OR OR N N
RCHO Figure 1. Proposed Mechanism for the (Morita)-Baylis-Hillman Reaction
The mechanism of the Baylis-Hillman reaction is believed to proceed through the Michael-initiated addition-elimination sequence. The most generally accepted mechanism of the amine-catalyzed reaction is illustrated in Figure 1.6 The first step in this catalytic cycle involves the Michael-type nucleophilic addition of the tertiary amine to the activated alkene to produce a zwitterionic enolate, which undergoes a nucleophilic attack onto the aldehyde in an aldol fashion to generate a new zwitterion. Subsequent proton migration and release of the catalyst provide the desired multifunctional molecules. Many attempts have been made to increase the rate of the Baylis-Hillman reaction
2 through either physical (temperature control) or chemical (Lewis acid) means. For example, ultrasound7 and microwave irradiation8 have been reported to increase the rate, but require somewhat specialized equipment. Conducting reactions at 40 oC provides an increase in rate of up 2-fold,7 but a recent report that reactions carried out at 0 oC gave rate increase of up to 40-fold which seems the simplest and most effective method for increasing reaction rate.9
Amine Catalyzed Baylis-Hillman Reaction
There are several methods for enhancing the Baylis-Hillman reaction. The first one is amine-catalyzed Baylis-Hillman Reaction. Aggarwal et al.10 examined the application of metals and ligands in accelerating the Baylis-Hillman reaction. They observed an acceleration of the Baylis-Hillman reaction when using combination of DABCO (100 mol%), triethanolamine (50 mol%) and La(OTf)3 (5 mol%). As shown in eq. 1, subsequently DBU and DMAP were also employed for enhancing the rate and yield in the reaction.
OH O EWG condition EWG RH rt R
60 ~ 95 % (depend on R and EWG) (1)
Conditions 1. DABCO (100 mol%), La(OTf)3 (5 mol%), (CH2CH2OH)3N (50 mol%), 12 h 2. DBU (100 mol%), neat, 0.5 ~ 72 h 3. DMAP (10-20 mol%), 15 h ~ 6 days
Recently, Hu and co-workers 11 performed the Baylis-Hillman reaction in the presence of a stoichiometric amount of DABCO in a dioxane-water medium. Fortunately, they observed that these reaction conditions accelerate the rate of reaction and provide the Baylis-Hillman adducts in shorter reaction times (4 – 12h).
3
LiClO (10-70 mol%) 4 OH O O O DABCO (5 mol%) R R' RH R' o -25 C - rt, 20h, Et2O 35-85 % (2) R = Et, Oct, cinnamyl, Ph t R' = H, Me, OCH2Ph, OEt, OBu
CN, CH2CH2CH2
Kawamura and Kobayashi performed more investigations.12 They observed that lithium perchlorate in diethyl ether as an additive (along with a catalytic amount of DABCO) accelerates the Baylis-Hillman reaction, particularly at –20 oC. They also noticed that aliphatic aldehydes require 10 mol % lithium perchlorate, whereas benzaldehyde and cinnamaldehyde require 70 mol % lithium perchlorate for the best results (eq. 2). Ionic liquids13 were found to accelerate (33.6 times faster) the Baylis-Hillman reaction between an aldehyde and an acrylate ester in the presence of DABCO. Later, Aggarwal and co-workers found that when Baylis-Hillman reactions were conducted in the presence of imidazolium-based ionic liquids the products were obtained in low yields (Scheme 2).
Scheme 2. BH reaction with imidazolium-based ionic liquids
ionic liquid (1 mM) OH O O O DABCO (100 mol%)l + R OR' RH OR' rt, 24 h, 14 - 72 %
ionic liquid = [bmim][PF6], [bmim][BF4] R = cinnamyl, Ph, 4-ClPh, 4-(OMe)Ph, 4-MePh,
3,4,5-(OMe)3Ph, fur-2-yl, c-Hex, Bu t R' = Me, Bu
4 Besides these several investigations into the Baylis-Hillman reaction, many research groups have reported interesting results using various amine bases. In addition, focus on the effect of solvent in Baylis-Hillman reaction has been reported. Aggarwal and co- workers 14 examined the role of protic solvents (water, formamide) and hydrogen bonding on the rate acceleration of the Baylis-Hillman reaction. Fortunately, they observed a significant rate acceleration when the reaction was conducted in 5 equiv of formamide. Further acceleration of the reaction is observed in the presence of Yb(OTf)3 (5 mol %) as shown in eq. 3.
CHO EWG OH EWG EWG time (h) yield (%) 3-HQD (1eq) COOMe 6 74 (3) Yb(OTf)3 (5 mol%) COOEt 3.75 80 H NCHO (5eq), rt 2 COOBut 14 96 CN 4 95
Intramolecular Baylis-Hillman Reaction
Although the Baylis-Hillman reaction, in general, has seen a high degree of growth with respect to all three essential components, the intramolecular version of this reaction was not been studied in depth. Murphy and co-workers 15 systematically investigated tandem Michael-aldol intramolecular addition reactions using substrates containing both the activated alkene and electrophile, with various reagents such as amines, phosphines, and thiols. Thiols or thiolates provided the aldol products in the case of five- and six-membered rings. Recently, Keck and Welch16 examined the intramolecular Baylis-Hillman reaction of α,β-unsaturated esters/thioesters containing an enolizable aldehyde group under various conditions. In the case of thiol esters, cyclopentenol products were formed in o high yields when DMAP and DMAP·HCl in EtOH (at 78 C for 1h) or Me3P in CH2Cl2 (at room temperature for 15h) were employed. However, in the case of oxyesters, the 5 desired cyclopentenol adducts were obtained in low yields. Cyclohexenol products were obtained in high yields when Me3P is used as a reagent, wherease DMAP and DMAP·HCl provided products in low yield. One representative example for each case is described in Scheme 3.
Scheme 3. BH reaction cyclic IMBH Adducts using DMAP
n=1 OH X = SEt O DMAP (1 eq) SEt DMAP : 87 % DMAP.HCl Me3P ; 82 % o O EtOH, 78 C, 1h n = 1 OH X = OEt O OHCn X or DMAP : 40 % OEt Me3P : 33 % Me3P (0.1 eq), DCM rt, 15h n = 2 OH O X = SEt SEt DMAP : 29 % Me3P : 75 %
The rate determining step (RDS) of the Baylis-Hillman reaction is the reaction between the ammonium enolate and the aldehyde.6 Thus, increasing the amount of the enolate or activation of the aldehyde will result in increased rates. Long reaction times have been reported using DABCO and in the search for more active catalysts, Drewes found that 3-hydroxyquinuclidine showed considerably faster rates.17 On the basis of the literature reports, quinuclidine is the best catalyst for the Baylis-Hillman reaction.18 In our system, a practical and efficient set of conditions was developed using quinuclidine in an alcoholic medium (MeOH as Lewis acid for hydrogen bonding) to overcome problems commonly associated with the Baylis-Hillman reaction, such as low reaction yields and long reaction time.19
Ring-Closing Metathesis reaction
6 During the studies on the Baylis-Hillman and related chemistry, we envisioned that we could construct some useful ring systems20,21 by ring–closing metathesis (RCM) reaction using the Baylis-Hillman adducts as starting materials.
Scheme 4. RCM reaction using Grubbs catalyst
O Baylis- OH OH R EWG Hillman R EWG RCM R EWG H + R R R PCy MesN N Mes 3 PCy3 Cl Ru Cl Ru Cl Cl Cl Ru O Ph Cl Ph PCy3 PCy3 Grubbs I catalyst Grubbs II catalyst Hoveyda-Grubbs catalyst
Olefin metathesis, termed in 1967 by Calderon and co-workers for the first time,22 has become a powerful and useful method for the formation of carbon-carbon double bonds 23 with enormous synthetic utility, promise and potential. Among several applications of olefin metathesis, ring-closing metathesis (RCM) has been applied in the construction of a variety of cyclic compounds. The first generation Grubbs catalyst was used for enhancing olefin metathesis.24 Subsequent developments produced a second-generation Grubbs catalyst. This catalyst, where one of the PCy3 ligands is replaced by an N-heterocyclic carbene (NHC) ligand with a mesityl group, has been shown to have significantly higher activity than that of the parent Grubbs catalyst.25
Proposed Mechanism
There have been several theoretical and experimental attempts to explain the mechanism and activity of olefin metathesis with the Grubbs catalyst and its derivatives.
7 Most of the theoretical studies have been carried out on simplified model systems. However, the size of ligands, their electronic properties, and conformational flexibility are reported to greatly influence the catalytic reactivity.26
R1 M R1 R1 R1 R2 R1 R2 B C D
[M] [M] A E R2 R1
R R R1 R2 2 2
D R2 M F
R R 2 G 1 Figure 2. Proposed Mechanism for the Cross-Metathesis Reaction
A general mechanistic scheme for the CM of two symmetrically substituted olefins is shown in Figure 2.27 The first step in the catalytic cycle is a [2+2] cycloaddition reaction between B and a transition metal carbene A to give a metallocyclobutane C. The latter undergoes subsequent collapse in a productive fashion to afford a new olefin product D and a new metal carbene E. Similarly, E can react with a molecule of F to yield D, via G, and A, which then re-enters the catalytic cycle. The net result is that D is formed from B and F with A and E as catalytic intermediates. As shown in Figure 3, this transformation has a variety of applications. The illustrated examples include ring-opening metathesis (ROM), ring-closing metathesis (RCM), acyclic diene metathesis (ADMET) and cross metathesis (CM). Through these reactions, olefin metathesis provides a route to unsaturated molecules that are often challenging or impossible to prepare by any other means. Some of the most impressive achievements include the use of ROM to make functionalized polymers, the synthesis of
8 small to large heterocyclic systems by RCM, and the CM of olefins with pendant functional groups.
X X R X ROM + R RCM ADMET
R CM 1 R2 X ROM X R1 + R2 n
Figure 3. A variety of olefin metathesis reactions
Among several applications of olefin metathesis, the generation of olefins with electron-withdrawing functionality, such as α, β-unsaturated aldehydes, ketones, and esters, remains a difficult task in organic chemistry. A practical method to approach this problem would involve olefin metathesis, utilizing well-defined alkylidenes such as
((CF3)2MeCO)2(ArN)Mo=CH(t-Bu) and Grubbs I. However, until several years ago, the generation of olefins with vinylic functionality through the use of cross-metathesis (CM) was met with limited success. In one of few reports of this reaction, Crowe and Goldberg28 demonstrated that acrylonitrile participated in cross-metathesis reactions with a variety of terminal olefins. Now, with the availability of new, more active catalysts, cross metathesis with activated alkenes works well. Other π-conjugated olefins such as enones and enoic esters failed to react with less reactive Grubbs first generation catalyst in cross-metathesis. Recently, Grubbs and co- workers have reported the first successful results on the intramolecular ring-closing metathesis with more reactive ruthenium catalyst (Grubbs second generation catalyst) for the synthesis of α-functionalized olefins.29 Grubbs second generation catalyst displayed unique activity toward previously metathesis-inactive substrates (Table 1).
9 Table 1. Cross-Metathesis Reactions with Esters, Aldehydes and Ketones
Isolated Terminal α-Functionalized Entry Product yield E/Z olefin olefin (equiv.) (%)
TBSO 1 TBSO 62 >20:1 7 CO2Me CO2Me 7 BzO BzO 2 CO Me CO2Me 91 4.5:1 7 2 7
AcO 3 AcO 92 >20:1 3 CHO CHO 3 AcO AcO 4 CHO CHO 62 1.1:1 3 3
AcO Ph AcO Ph 5 3 99 >20:1 3 O O AcO AcO 6 3 95 >20:1 3 O O Reactions with 5 mol % of Grubbs II catalyst.
In particular, ring-closing metathesis (RCM) has been used for the synthesis of a variety of cyclic compounds that include carbocyclic, heterocyclic, and fused ring frameworks.30 Blechert’s group reported the synthesis of 5-membered cyclic skeleton from BH adduct. 31 They compared yields between unprotected hydroxyl groups and TBS- protected hydroxyl groups (Table 2).
10 Table 2. RCM reactions using Protected and Unprotected BH Adducts
OR Grubbs #2 OR EWG EWG + Dimer n DCM, reflux n
EWG = CO2CH3 (a-d) 5 mol% Grubbs #2 CN (e-h) ratio cyclization : dimerization a. n = 0, R = H 2:1 (60%) b. n = 1, R = H 3:2 (42%) c. n = 0, R=TBS >20:1 (97%) d. n = 1, R = TBS >20:1 (89%) e. n = 0, R = H No reaction f. n = 1, R = H >20:1 (46%) g. n = 0, R=TBS 6:1 (90%) h. n = 1, R = TBS >20:1 (86%) Product ratio determined by NMR spectroscopy after complete conversion of the substrate. Conditions: DCM, 40 oC, 0.05 M.
Strikingly, the catalyst shows a much lower reactivity towards acrylate with unprotected hydroxyl group. This difference in reactivity was explained in terms of chelation effect between unprotected hydroxyl group and Ru in catalyst.
11 Recently, Kim’s group synthesized 2,5-dihydrofuran and 2,5-dihydropyrrole skeletal from the Baylis-Hillman adducts of 5,6-dihydro-2H-pyran-2-one via the RCM reaction using Grubbs second generation catalyst (Table 3).32 They also have reported theoretical study for the RCM and CM reaction of selected BH adducts with the second-generation Grubbs catalyst. Prior to theoretical study, they obtained only CM products and no RCM product even at high-dilution conditions (Scheme 5).33 These experimental results are explained by reaction barrier differences for the RCM and CM reactions based on ab intio calculations of the full molecular systems.
Table 3. RCM reaction of Baylis-Hillman adducts
Entry B-H adducts Conditions Products Yields (%)
O O Catalyst (5 mol%), DCM, 1 99 reflux, 15min COOEt COOEt O O Catalyst (5 mol%), DCM, 2 88 reflux, 15min CN CN O O Catalyst (5 mol%), DCM, 3 98 reflux, 15min COMe COMe TsN TsN Catalyst (7 mol%), DCM, 4 98 reflux, 4h COOEt COOEt
TsN TsN Catalyst (5 mol%), DCM, 5 99 reflux, 4h COMe COMe
Catalyst : Grubbs second generation catalyst.
12 Scheme 5. Possible Products of Olefin Metathesis. OH O O
toluene, none OH O Grubbs #2 (14 %) OH O 70-80 oC, 40 h O O
8 %
OH O O O OOH 46 %
The RCM reaction from the Baylis-Hillman adducts is a versatile route to various cyclic frameworks. Although initially the BH reaction was limited by low yields, the need for high concentration and purification problems, modification to the reaction have helped overcome these difficulties to some extent. Our application of the Baylis-Hillman reaction and RCM to the synthesis of various cyclic frameworks will be discussed in the following section and our contribution to this work is expected to be a meaningful development in organic synthesis.
13 II RESULTS AND DISCUSSION
Although earlier reports for intramolecular Baylis-Hillman reaction have been featured in the construction of five- and six-membered rings with activated alkenes and an electrophile, there are alternative pathways for the synthesis of intramolecular Baylis- Hillman adducts. Several research groups have examined the synthesis of intramolecular Baylis- Hillman adducts via RCM reaction. These investigations have demonstrated that the Baylis-Hillman adducts from α-functionalized olefins with terminal olefinic aldehydes can efficiently undergo CM reaction, both inter and intramolecularly. This research project focuses on the development of synthetic methods under organocatalysis and has led to the discovery of an efficient method for the synthesis of carbo- or heterocyclic backbones from the Baylis-Hillman adducts via the RCM reaction. The primary goal of this project is to study the use of various electrophiles in the Baylis- Hillman reaction as well as investigate alternative pathway for the synthesis of intramolecular Baylis-Hillman adducts using the RCM reaction (Scheme 6).
Scheme 6. Proposed pathway for the synthesis of IMBH adducts O O Baylis- OH O OH O R Hillman R Grubbs cat.(5-10 %) R H + OMe OMe OMe R n DCM, reflux R n R n
Optimization of reaction conditions for the Baylis-Hillman reaction
We examined the Baylis-Hillman reaction using both DABCO and quinuclidine as the catalyst in an attempt to find optimum conditions (Table 4).
14 Table 4. Amine Catalyzed BH Reaction
O O Amine-catalyst OH O Ph H + O Ph O solvent
Unsaturated Product Aldehyde Catalyst Solvent Ester (yield %)
a 1eq 2eq DABCO (1eq) Dioxane/H2O (1/1) 49
b 1eq 2eq DABCO (3eq) Dioxane/H2O (2/1) 59
c 1.5eq 1eq PBu3 (0.2eq), PhOH(0.2eq) THF 52 Quinuclidine (0.25eq) 1eq 1.2eq Neat 90d MeOH (0.75eq) a. 6 h, rt; b. 6 h, rt; c. 1 h, rt; d. 20h, rt
In the case of DABCO,34 we tried reactions using different ratios of dioxane/water. Although a 10 % increase in yield was obtained using 2/1(dioxane/water) mixture, it was not a big difference in the Baylis-Hillman reaction. Subsequently, we employed quinuclidine for enhancing the yield as reported by Aggarwal.18 Strikingly, the reaction yield was increased up 90 % using quinuclidine with MeOH as a Lewis acid (Table 4). This remarkable result was explained by hydrogen-bonding interaction MeOH and enolate oxygen of methyl acrylate.19 With 2-pyridine carboxaldehyde and furaldehyde, we examined Baylis-Hillman reactions with methyl acrylate under same conditions in order to test the activity of heterocyclic aldehydes (Table 5).19 These aldehydes also worked well.18
15 Table 5. BH reaction with Quinuclidine
O Quinuclidine (0.25 eq) O OH O O RH + MeOH (0.75 eq) RO
R = O N
Unsaturated Product Aldehyde Conditions Reaction time Ester (yield %)
O H 20 min 94 Quinuclidine N O O (0.25eq) O MeOH (0.75 eq) H 1 hr 76 O
Synthesis of Carbocyclic RCM Products from Baylis-Hillman (BH) Adducts
We have developed a two-step procedure for the synthesis of cyclic Baylis-Hillman adducts.32 The intramolecular Baylis-Hillman reaction of unsubstituted acrylates, followed by RCM using Grubbs catalysts, gives rise to an overall intramolecular BH adduct in which there is a secondary allylic alcohol functionality.35 We finished a synthetic study of the olefin metathesis of BH adducts using the second-generation Grubbs catalyst. We prepared the required starting materials as shown in Scheme 7.
16 Scheme 7. Synthesis of BH Adducts using nonsubstituted alkene aldehydes and methyl acrylate
OH O O O Quinuclidine (0.25 eq) OH Swern MeOH (0.75 eq) H OMe + OMe n N2, rt n n
n = 1 (a), 2 (b) 1 (n = 0), 1a (64 %) 2 (95 %), 2a (84 %) 3 (c), 4 (d) 1b (70 %), 1c (68 %) 2b (89 %), 2c (89 %) 1d (70 %) 2d (80 %)
Alcohols were oxidized to aldehydes (1a-1d) using the Swern oxidation. 36 Subsequent BH reaction with methyl acrylate using quinuclidine led to the Baylis- Hillman adducts (2–2d) in good yields (Scheme 7). We tried to use DABCO22 and several other conditions for the BH reaction, instead of quinuclidine. However, only quinuclidine as a catalyst gave a reasonable yield of desired alcohol for the next RCM reaction step (Table 6).21
17 Table 6. RCM reaction to form IMBH Adducts
OH O OH O Grubbs #2 OH O OMe + MeO DCM, reflux OMe OMe n n n n O OH
Yield Entry S.M. Product (mol % of Grubbs #2 / Molarity)
1 2 n = 0 (3) 46 % (10 mol % / 0.01 M)
2 2a n = 1 (3a) 29 % (5 mol % / 0.1 M) 67 % (10 mol % / 0.01 M)
3 2b n = 2 (3b) < 10 % (5 mol % / 0.1 M) 66 % (10 mol % / 0.01 M)
4 2c n = 3 (3c) Dimer
5 2d n = 4 (3d) Dimer
Conditions: DCM, 40oC, 12h.
With compounds 2-2d in hand, we examined their RCM reactions under high- dilution conditions in order to minimize the intermolecular reactions. Initially, we carried out the reaction of 2a and 2b in DCM (0.1M) with 5 mol % catalyst at 40 oC for 12 h. Unfortunately, however, we generated only 29 % and 10 % respectively of the desired of the RCM products 3a and 3b. When we performed the same reaction in DCM (0.01 M) with 10 mol % catalyst, we could isolate the desired RCM product in 67 % and 66 % yields respectively. Although the synthesis of 5-, 6- and 7-membered rings using the RCM reaction was successful, experiments for 8- and 9-membered rings in our reaction condition failed to produce the desired RCM products. However, the dimerization is reversible, thus we
18 expected that longer reaction times would lead to higher amount of the intramolecular product. For example, Furstner’s group reported the formation of intramolecular RCM macrocyclic product under these conditions (Scheme 8).37
Scheme 8. Reversible-CM-based macrocycle formation.
O O O O O O Grubbs Grubbs
DCM, 17h 28h 45oC 60 % O O 79 %
During the reaction, we monitored the reaction frequently using TLC to detect the formation of any trace of the desired product. Unfortunately, the desired products were not produced under these reaction conditions. Recently, many research groups have studied ring-closing metathesis reactions of α- functionalized olefins extensively.38 In our research, we focused on the application of acetyl, ester and nitrile functionalized olefins to our reaction conditions (Scheme 9).
19 Scheme 9. Synthesis of RCM Products from BH Adducts using monosubstituted alkene aldehydes
Grubbs #2 (10 mol%) O OH OH or Hoveyda-Grubbs R EWG Quinuclidine (0.25eq) R EWG R H + o EWG MeOH (0.75eq) DCM (0.01 M), 40 C R' R' R' (1.2eq) 10hr OH EWG = COMe, CO Me Quinuclidine OH 2 N R EWG R R / R' = H/H, Me/Me R' R' EWG O R H R'
EWG = CO2Me, CN R / R' = H/H, Me/Me
It has been reported that use of MVK instead of acrylate leads to a lower yield due to polymerization of MVK under high pressure conditions.39 Therefore, when we performed BH and RCM reactions with MVK and 5-pentenal, we recovered only 35 % of BH product 4 and 23 % of RCM product 5 (Table 7).
20 Table 7. BH and RCM reaction using electron-deficient alkenes and Grubbs catalyst
Terminal α,β-unsaturated BH adducts RCM product Entry olefin olefin(eq) (yield %) (yield %)
OH O O OH O O 1 H (1.2eq) 4 (35%) 5 (23%)
OH O OH O O O O 2 H OMe (1.2eq) O 6 (22%) 7 (8%)
OH O OH CN CN CN 3 H (1.2eq) 8 (34%) 9 (91%)
O OH O OH O O H O 4 OMe (1.2eq) O 10d 11 12
mixture (mixture of isomers, (mixture of isomers, of isomers 60%) 45%)
Hoveyda-Grubbs catalyst was used for the RCM reaction of 8.
Subsequently, we employed dimethyl pentenal to examine both steric and electronic effects in the BH and RCM reaction. This aldehyde has electron donating methyl groups and is sterically hindered from enolization by two dimethyl groups. The BH reaction of methyl acrylate with 2,2-dimethyl-4-pentenal failed with quinuclidine. Although treatment of 2,2-dimethyl-4-pentenal and methyl acrylate with PBu3 and PhOH in THF led to the formation of the BH product 6, the reaction yield was only 22 % (Table 7).40 As shown in Table 7, RCM product 7 could be obtained in 8 % yield using normal
21 reaction conditions. Reactions with acrylonitrile were also tested and gave higher yields at short reaction times. When we performed the RCM reaction with acrylonitrile and the Hoveyda-Grubbs catalyst,41 the yield of the RCM product 9 was 91 %. Hoveyda and Grubbs have shown that O-chelating benzylidene moieties can be used for providing complexes exhibiting extraordinary stability against water and oxygen. To examine the reactivity of an α,β-substituted aldehyde, we prepared 2,3-dimethyl- 4-pentenal, 10d, for BH reaction via well-known reactions starting with a Claisen rearrangement (Scheme 10).42
Scheme 10. Preparation of 2,3-dimethyl-4-pentenal for the BH reaction
O O Claisen O + OH Pyridine (1.1 eq) LAH (1.1 eq) Cl O HO HO o DCM, 91% 61% THF, 0 C
10c O 10a 10b PCC (2 eq) H DCM, 87% 10d
With 2,3-dimethyl-4-pentenal in hand we examined the BH reaction and obtained a 60 % yield of alcohol 11. Subsequent RCM of alcohol 11 gave enone 12 in 45 % yield (Table 7). Our investigations for BH and RCM reactions with sterically hindered aldehydes have shown that 2,3-dimethyl-4-pentenal and 2,2-dimethyl-4-pentenal led to the formation of BH and RCM product with low yields. These reactions were not nearly as successful as RCM in the synthesis of unsubstituted carbocyclic skeleton from BH adducts. RCM interestingly has found several applications in the synthesis of secondary allylic alcohol frameworks.
22 Synthesis of fused ring RCM products from BH Adducts
We were able to extend the BH and RCM reaction to a different group of aldehydes. Because aldehydes have been the primary source of electrophiles; cyclic, aromatic and heterocyclic aldehydes have been extensively employed in obtaining an interesting class of Baylis-Hillman adducts. In our experiment, applications of electrophiles for the synthesis of fused ring IMBH adducts have been examined to compare reactivity and yield. We prepared the required cyclic aldehydes according to reported methods as shown in Scheme 11.43
Scheme 11. Preparation of Cyclic-BH substrates
O O OH i) iii) ii) iv) O O O OH O 13a O 13 (71 %) 13b (64 %) 13c (81 %) OH O iv) ii) iii) O O OH O
14 14a 14b (60 %) 14c (92 %) O OH O iv) O O ii) O iii) O OH O O O O O O 15 15a 15b (55 %) 15c (60 %) o o + i) NaBH4, THF, 0 C – rt, ii) DIBAL (1.1 eq), Toluene or DCM, -78 C, iii) BrCH3P Ph3, n-BuLi, THF, reflux, iv) PCC, DCM
In subsequent experiments, previous conditions were employed to achieve BH reaction with the new group of aldehydes. It is interesting note that the BH and RCM reaction of the aromatic aldehyde afforded the corresponding BH adduct and RCM product in 83 % and 92 % yields respectively (Table 8).
23 Table 8. RCM reaction for the synthesis of Fused ring Products from BH Adducts
O Quinuclidine OH O Grubbs #2 OH (0.25 eq) (10 mol %) O O + OMe O MeOH (0.75 eq) DCM ( 0.01 M) O 13c 16 reflux 17 OH O OH O O O O 18 19 14c OH OH O O O O O O O O O O O 20 21 15c Unsaturated BH adducts RCM products Entry Terminal Olefin ester (eq) (yield %) (yield %)
OH O O OH O 1 O 16 O 13c 17 (66%) (4:1 mixture of isomers,
22%) O OMe OH O OH O O 2 O (1.2eq) O 14c 18 (83%) 19 (92%)
OH O OH O O O O O 3 O O O O O 21 15c 20 (31%) (No reaction)
Similar results have previously been observed for the Baylis-Hillman reaction by Aggarwal’s group.18 They examined other less reactive electrophiles like benzaldehyde for the Baylis-Hillman reaction and found that the electrophilicity of the aldehyde did not have much effect on reactivity and yield in the reaction. However, there were differences
24 in reaction yields for our attempts. And the aromatic aldehyde was the only substrate that underwent both the Baylis-Hillman and RCM reactions in good yield. (Table 8).
Synthesis of 6-Membered Carbocyclic RCM products from BH Adducts using substituted hexenals
In previous approaches to cyclic carbocyclic products, hexenal was employed for the construction of 6-membered rings. So, we have extended the reaction to include the construction of 6-membered rings using substituted hexenals. 4-Methyl hexenal was prepared from crotonaldehyde through an Oxy-Cope rearrangement as shown in Scheme 12.44
Scheme 12. Preparation of 3-methyl-5-hexenal for BH reaction
O MgBr OH KH, 18-c-6 H CHO Ether, 0 oC THF, reflux then -78 oC 22 (75%) 22a (20%)
A typical experimental procedure for Oxy-Cope rearrangement is described for the reaction of 1,5-heptadien-4-ol with KH. To a solution of 1,5-heptadien-4-ol (22) in THF o was added KH in THF at 20 C under N2 and heated under reflux for 2 h. Quenching was ultimately effected with methanol at –78oC. Oxy-Cope rearrangements proceed at especially low temperature when the alcohol is deprotected (Figure 4).45
- - O < 0oC O negative charge more delocalized in TS and product than in SM
Figure 4. Oxy-Cope Rearrangement
25 4,4-Dimethyl pentenal was employed for the preparation of another BH reaction substrate. Homologation of 2,2-dimethyl pentenal to 3,3-dimethylhex-5-en-1al (23a), via the corresponding vinyl ether (3,3-dimethyl-1-methoxyhexa-1-5-diene), followed by hydrolysis led to the desired β-substituted aldehyde (Scheme 13).46
Scheme 13. Preparation of 3,3-dimethyl-5-hexenal for BH reaction
- Cl Ph O POMe Ph OMe H SO (30 %) O H Ph , n-BuLi 2 4 THF, 0 oC rt rt, 1hr
23 (40 %) 23a (60 %)
With 4-methyl hexenal (22a) and 4,4-dimethyl hexenal (23a) in hand, we studied the BH reaction under previously optimized conditions. Subsequent RCM reaction gave both of the desired RCM products 24 and 26 in 87 % yield (Table 9). Interestingly, we found the methyl or dimethyl groups in the BH adducts had only minor effect on the RCM product yield (Table 9).
26 Table 9. RCM reaction from BH Adducts using β-substituted hexenal
O R OH O OH O CHO Quinuclidine (0.25 eq) Grubbs #2 (10 mol %) R' + O O MeOH (0.75 eq) DCM (0.01 M) O R R = H, R' = Methyl R' R R' R = R' =Methyl 25 (R = H, R = Methyl) 24 (R = H, R = Methyl) 27 (R = R' = Methyl) 26 (R = R' = Methyl)
Terminal Unsaturated BH adducts RCM products Entry Olefin ester (eq) (yield %) (yield %)
OH O OH O O O 1 CHO 25 24 O (1:1 mixture, 82 %) (1:1 mixture, 87 %) OMe (1.2 eq) OH O OH O O O CHO 2
26 (84 %) 27 (87 %)
Synthesis of 6-Membered Heterocyclic RCM products from BH Adducts using Chiral- Amino acids
The Baylis-Hillman and olefin metathesis reactions have quickly consolidated their position as practical and versatile methods for C-C bond formation. In this regard, a combinatorial approach for the construction of heterocyclic structures has received considerable attention in recent years, the main reason being that many derivatives can be synthesized in fewer steps and are applicable to polymer-supported catalysts. To leave 27 functionality in proposed products, we decided to employ an amino acid series as the core structure. These amino acids can provide three different functionalities in one molecule. (Allyl-tosyl-amino)-acetaldehydes 28d and 29d were prepared from glycine and D- alanine through protection, nucleophilic allyl-substitution, LAH-reduction and Swern oxidation reactions (Scheme 14).47
Scheme 14. Preparation of (allyl-tosyl-amino)-acetaldehydes for BH reactions
R R R AcCl (2.5 eq) TsCl (1.1 eq), Et N OH O 3 O H2N H N TsHN MeOH 2 O O DCM O
28 (R=H)47 28a (88 %)59 R= H / Me 29 (R=Me)47 29a (90 %)59 Br K2CO3 Acetone R R R H Swern OH LAH (1.5 eq) O TsN TsN TsN O THF O
61 28d (88 %) 28c 28b (91 %) 60 29c 60 29d (85 %) 29b (90 %)
With these allyl-substituted amide aldehydes 28d and 29d in hand, we accomplished a BH reaction with methyl acrylate and subsequent RCM reaction under typical reaction conditions (Scheme 15). Fortunately, we obtained the corresponding tetrahydropyridinol products 32, 33 originally from glycine and alanine in good yields.
28 Scheme 15. Synthesis of Heterocyclic-RCM Products from BH Adducts
R OH O OH O H O Quinuclidine (0.25 eq) Grubbs #2 (10 mol %) TsN R R O O O + O MeOH (0.75 eq)TsN DCM (0.01 M) TsN
32 (R = H) : 87 % 30 (R = H) 33 (R = Me) : 87 % 31 (R = Me), 8:1
These successful results seem to suggest that the nitrogen atom does not exert much effect on either the Baylis-Hillman reaction or the RCM reaction. From these achievements, other functionality can be introduced on the protected nitrogen after the deprotection process shown in Scheme 16.
Scheme 16. Proposed combinatorial application for the construction of hydropyridinol derivatives OH O OH O OH O Deprotection R' R R R O O O N TsN HN R'
Our approach for constructing hydropyridinol derivatives opened a new strategy for combinatorial methods in the synthesis of heterocyclic derivatives using amino acids through BH and RCM reactions.
Summary
We performed the Baylis-Hillman and RCM reaction under several reaction conditions. Importantly, we synthesized 5- and 6-membered carbocycles, heterocycles and ring-fused frameworks. α-Substituted aldehydes mainly influenced the yield of Baylis-Hillman reaction. On the other hand, no differences in reaction time were not observed in the presence of β-substituted aldehydes.
29 Another application of the Baylis-Hillman and RCM reactions was the construction of 6-membered heterocyclic products from chiral-amino acids. Traditionally, synthesis of heterocyclic frameworks with fewer steps and high yield has been an interesting topic in organic synthesis. Moreover, this application can be used for the synthesis of small molecules for drug discovery. So, our achievement for the synthesis of 6-membered heterocyclic structures through RCM reaction from the Baylis-Hillman adducts opened a new strategy for combinatorial applications.
30 III EXPERIMENTAL
Solvents were reagent grade and in most cases dried prior to use. All other commercially available reagents were used as received unless otherwise noted. The organic extracts were dried over anhydrous MgSO4. Tetrahydrofuran (THF) was distilled from lithium aluminum hydride (LiAlH4) prior to use. Methylene chloride (CH2Cl2), and triethylamine (Et3N) were distilled from calcium hydride. Diethyl ether (Et2O) was distilled from sodium-benzophenone ketyl. Infrared spectra (IR) were obtained on a Perkin Elmer Paragon 1000 FT-IR Spectrophotometer. Elemental Analysis was performed by Atlantic Microlab Inc, Norcrosis, GA. 1H NMR spectra were obtained at 300 MHz on a Varian Gemini spectrometer or at 500 MHz on a Varian VXR500 spectrometer. Carbon spectra were obtained at 75 MHz on a Varian Gemini spectrometer. Mass spectra (MS) were recorded on a Jeol JMS-600. Chemical shifts are reported in parts per million downfield relative to tetramethylsilane (δ 0.00) and coupling constants are reported in Hertz (Hz). The following abbreviations are used for the multiplicities: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; and br = broad.
31 Hex-5-enal (1a) A solution of oxalyl chloride (1.3 mL, 15 mmol) in DCM (13 mL) at –78 oC was treated with dimethyl sulfoxide (2.1 mL, 30 mmol). The resulting solution was stirred for 5 min, treated with 5-hexen-1-ol (1.2 mL, 10 mmol) in DCM (10 mL), and further stirred at –78 oC for 15 min. Following the addition of triethylamine (8.4 mL, 60 mmol), the reaction mixture was stirred for 5 min (–78 oC) and the cooling bath was removed. The solution was allowed to warm to room temperature over a period of 20 min. The reaction mixture was quenched by the addition of 10 % aqueous hydrochloric acid, diluted with water, and extracted with ether. The combined ether extracts were dried (MgSO4) and concentrated in vacuo. Flash chromatography affords aldehyde 1a (635 mg, 65 %).48
Hep-6-enal (1b) A solution of oxalyl chloride (1.2 mL, 13.2 mmol) in DCM (13 mL) at –78 oC was treated with dimethyl sulfoxide (1.9 mL, 26.4 mmol). The resulting solution was stirred for 5 min, treated with 6-hepten-1-ol (1.2 mL, 8.8 mmol) in DCM (10 mL), and further stirred at –78 oC for 15 min. Following the addition of triethylamine (7.4 mL, 52.8 mmol), the reaction mixture was stirred for 5 min (–78 oC) and the cooling bath was removed. The solution was allowed to warm to room temperature over a period of 20 min. The reaction mixture was quenched by the addition of 10 % aqueous hydrochloric acid, diluted with water, and extracted with ether. The combined ether extracts were dried
(MgSO4) and concentrated in vacuo. Flash chromatography affords aldehyde 1b (680 mg, 70 %).49
Oct-7-enal (1c) A solution of oxalyl chloride (1.0 mL, 11 mmol) in DCM (10 mL) at –78 oC was treated with dimethyl sulfoxide (1.6 mL, 23 mmol). The resulting solution was stirred for 5 min, treated with 7-octen-1-ol (1.2 mL, 7.5 mmol) in DCM (10 mL), and further stirred at –78 oC for 15 min. Following the addition of triethylamine (6.3 mL, 45 mmol), the reaction mixture was stirred for 5 min (–78 oC) and the cooling bath was removed. The
32 solution was allowed to warm to room temperature over a period of 20 min. The reaction mixture was quenched by the addition of 10 % aqueous hydrochloric acid, diluted with water, and extracted with ether. The combined ether extracts were dried (MgSO4) and concentrated in vacuo. Flash chromatography affords aldehyde 1c (583 mg, 62 %).50
Non-8-enal (1d) A solution of oxalyl chloride (0.9 mL, 10.2 mmol) in DCM (13 mL) at –78 oC was treated with dimethyl sulfoxide (1.5 mL, 20 mmol). The resulting solution was stirred for 5 min, treated with 5-hexen-1-ol (1.2 mL, 6.8 mmol) in DCM (10 mL), and further stirred at –78 oC for 15 min. Following the addition of triethylamine (6.7 mL, 41 mmol), the reaction mixture was stirred for 5 min (–78 oC) and the cooling bath was removed. The solution was allowed to warm to room temperature over a period of 20 min. The reaction mixture was quenched by the addition of 10 % aqueous hydrochloric acid, diluted with water, and extracted with ether. The combined ether extracts were dried
(MgSO4) and concentrated in vacuo. Flash chromatography affords aldehyde 1d (70 mg, 70 %).51
BH adduct (2) To a stirred mixture of pent-4-enal (0.2 g, 2.4 mmol) and methyl acrylate (0.2 mL, 2.9 mmol) was added quinuclidine (67 mg, 0.6 mmol) and methanol (0.08 mL, 1.8 mmol). The homogeneous reaction mixture was stirred at room temperature for 8 h, and the reaction progress was monitored by TLC. The reaction mixture was purified by flash column chromatography to give 2 in good yield (407 mg, 95 %).31
BH adduct (2a) To a stirred mixture of hex-5-enal (0.1 g, 1 mmol) and methyl acrylate (0.1 mL, 1.2 mmol) was added quinuclidine (28 mg, 0.25 mmol) and methanol (0.03 mL, 0.75 mmol). The homogeneous reaction mixture was stirred at room temperature for 8 h, and the reaction progress was monitored by TLC. The reaction mixture was purified by flash
33 column chromatography to give 2a in good yield (155 mg, 84 %). 500 MHz 1H NMR: δ
1.44 (m, 1H, CH2CHHCH2), 1.58 (m, 1H, CH2CHHCH2), 1.68 (m, 2H, CH2CH2CHOH),
2.10 (dt, 2H, J = 6.8, 6.8, CH2CH2CH=C), 3.80 (s, 3H, OCH3), 4.40 (broad t, 1H, J = 6
CH2CHOHC=C), 4.97 (dm, 1H, J = 10.3, CH=CHH), 5.02 (dd, 1H, J = 17.1, 1.5,
CH=CHH), 5.81 (ddt, 1H, J = 17.1, 10.3, 6.8, CH2CH=CH2), 5.82 (partly obscured s, 1H, C=CHH), 6.25 (s, 1H, C=CHH). 75 MHz 13C NMR: δ 25.05, 33.43, 35.60, 51.86, 71.63, 114.66, 124.99, 138.50, 142.37, 166.97. IR (cm-1): 1639, 1718, 2948, 3448. Mass + spectrum m/z (CI ): 185. Anal.Calcd for C10H16O3: C, 65.19; H, 8.75. Found: C, 64.90; H, 8.72.
BH adduct (2b) To a stirred mixture of hep-6-enal (200 mg, 1.8 mmol) and methyl acrylate (0.2 mL, 2.2 mmol) was added quinuclidine (50 mg, 0.4 mmol)) and methanol (0.06 mL, 1.4 mmol). The homogeneous reaction mixture was stirred at room temperature, and the reaction progress was monitored by TLC. The reaction mixture was purified by flash column chromatography to give 2b in good yield (317 mg, 89 %). 500 MHz 1H NMR: δ
1.35-1.49 (m, 4H, CHOHCH2CH2CH2, CH2CH2CH2CH=C), 1.64-1.69 (m, 2H,
CH2CH2CHOH), 2.07 (dt, 2H, J = 6.8, 6.8, CH2CH2CH=C), 3.80 (s, 3H, OCH3), 4.39 (dt,
1H, J = 6.4, 6.8, CH2CHOHC=C), 4.95 (dm, 1H, J = 10.3, CH=CHH), 5.01 (ddt, 1H, J =
17.0, 1.4, 1.4, CH=CHH), 5.81 (ddt, 1H, J = 17.1, 10.3, 6.8, CH2CH=CH2), 5.82 (partly obscured s, 1H, C=CHH), 6.25 (s, 1H, C=CHH). 75 MHz 13C NMR: δ 25.52, 28.88, 33.88, 36.25, 52.10, 72.00, 114.63, 125.20, 139.04, 142.64, 167.24. IR (cm-1): 1439, + 1639, 1718, 2857, 2928, 3447. Mass spectrum m/z (CI ): 199. Anal.Calcd for C11H18O3: C, 66.64; H, 9.15. Found: C, 66.37; H, 9.13.
BH adduct (2c) To a stirred mixture of oct-7-enal (200 mg, 1.6 mmol) and methyl acrylate (0.2 mL, 2.0 mmol) was added quinuclidine (45 mg, 0.4 mmol)) and methanol (0.05 mL, 1.2 mmol). The homogeneous reaction mixture was stirred at room temperature, and the
34 reaction progress was monitored by TLC. The reaction mixture was purified by flash column chromatography to give 2c in good yield (303 mg, 89 %). 500 MHz 1H NMR: δ
1.33-1.49 (m, 6H, CHOHCH2CH2CH2, CHOHCH2CH2CH2CH2, CH2CH2CH2CH=C),
1.64-1.69 (m, 2H, CH2CH2CHOH), 2.06 (dt, 2H, J = 6.8, 6.8, CH2CH2CH=C), 3.80 (s,
3H, OCH3), 4.40 (broad t, 1H, J = 6.4, CH2CHOHC=C), 4.95 (d, 1H, J = 10.3, CH=CHH), 5.02 (dd, 1H, J = 17.1, 1.5, CH=CHH), 5.80 (partly obscured s, 1H,
C=CHH), 5.81 (ddt, 1H, J = 17.1, 10.3, 6.8, CH2CH=CH2), 6.24 (s, 1H, C=CHH). 75 MHz 13C NMR: δ 26.06, 29.20, 29.26, 34.08, 36.55, 52.26, 72.16, 114.64, 125.32, 139.41, 167.43. IR (cm-1): 1639, 1719, 2928, 3448.
BH adduct (2d) To a stirred mixture of non-6-enal (200 mg, 1.4 mmol) and methyl acrylate (0.2 mL, 1.7 mmol) was added quinuclidine (39 mg, 0.4 mmol)) and methanol (0.05 mL, 1.1 mmol). The homogeneous reaction mixture was stirred at room temperature, and the reaction progress was monitored by TLC. The reaction mixture was purified by flash column chromatography to give 2d in good yield (283 mg, 89 %). 500 MHz 1H NMR: δ
1.33-1.41 (m, 8H, CHOHCH2CH2CH2, CHOHCH2CH2CH2CH2, CH2CH2CH2CH2CH=C,
CH2CH2CH2CH=C), 1.63-1.71 (m, 2H, CH2CH2CHOH), 2.05 (dt, 2H, J = 6.8, 6.8,
CH2CH2CH=C), 3.80 (s, 3H, OCH3), 4.40 (broad t, 1H, J = 6.4, CH2CHOHC=C), 4.94 (d, 1H, J = 10.3, CH=CHH), 5.00 (dd, 1H, J = 17.1, 1.5, CH=CHH), 5.80 (partly obscured s,
1H, C=CHH), 5.82 (ddt, 1H, J = 17.1, 10.3, 6.8, CH2CH=CH2), 6.23 (s, 1H, C=CHH). 75 MHz 13C NMR: δ 25.97, 29.04, 29.23, 29.46, 33.95, 36.42, 52.06, 71.91, 114.39, 125.13, 139.33, 142.77, 167.26. IR (cm-1): 1639, 1719, 2927, 3442.
5-Hydroxycyclopent-1-ene carboxylic acid methyl ester (3) A solution of BH adduct 2 (50 mg, 0.3 mmol) was added to a stirring solution of Grubbs #2 catalyst (23 mg, 10 mol %) in DCM (30 mL, 0.01 M). The flask was fitted with a condenser and refluxed under nitrogen for 12 hours. The reaction mixture was then reduced in volume to 0.5 mL and purified directly through flash column
35 chromatography. The desired product was obtained (19 mg, 46 %).31
6-Hydroxycyclohex-1-ene carboxylic acid methyl ester (3a) A solution of BH adduct 2a (50 mg, 0.3 mmol) was added to a stirring solution of Grubbs #2 catalyst (23 mg, 10 mol %) in DCM (30 mL, 0.01 M). The flask was fitted with a condenser and refluxed under nitrogen for 12 hours. The reaction mixture was then reduced in volume to 0.5 mL and purified directly through flash column chromatography. The desired product was obtained (28 mg, 67 %). 500 MHz 1H NMR: δ
1.60-1.65 (m, 1H, CH2CHHCH2), 1.75-1.86 (m, 3H, CH2CHHCH2, CHCH2CH2), 2.14-
2.19 (m, 1H, CH2CHHCH=C), 2.28 (ddt, 1H, J = 20, 4.9, 4.9, CH2CHHCH=C), 3.79 (s,
3H, OCH3), 4.56 (broad t, 1H, J = 5, CH2CHOHC=C), 7.13 (t, 1H, J = 4, CH2CH=C). 75 MHz 13C NMR: δ 17.44, 26.12, 29.88, 51.72, 63.47, 132.40, 143.19, 165.01. IR (cm-1): 1266, 1751, 1939, 2926. Mass spectrum m/z (CI+): 157.
7-Hydroxycyclohep-1-enecarboxylic acid methyl ester (3b) A solution of BH adduct 2b (50 mg, 0.3 mmol) was added to a stirring solution of Grubbs #2 catalyst (21 mg, 10 mol %) in DCM (30 mL, 0.01 M). The flask was fitted with a condenser and refluxed under nitrogen for 12 hours. The reaction mixture was then reduced in volume to 0.5 mL and purified directly through flash column chromatography. The desired product was obtained (28 mg, 66 %). 500 MHz 1H NMR: δ
1.54-1.64 (m, 2H, CHOHCH2CH2CH2), 1.70-1.88 (m, 4H, CH2CH2CH2CH=C,
CHOHCH2CH2), 2.03-2.16 (m, 1H, CH2CHHCH=C), 2.26 (ddt, 1H, J = 20.4, 4.2, 4.2,
CH2CHHCH=C), 3.75 (s, 3H, OCH3), 4.53 (m, 1H, CH2CHOHC), 7.09 (t, 1H, J = 3.6, 13 CH2CH=C). 75 MHz C NMR: δ 17.64, 26.35, 30.11, 51.96, 59.58, 63.66, 132.40, 143.45, 168.01. IR (cm-1): 1262, 1714, 2945, 3467. Mass spectrum m/z (CI+): 171.
Dimer RCM product (3c) A solution of BH adduct 2b (50 mg, 0.24 mmol) was added to a stirring solution of Grubbs #2 catalyst (20 mg, 10 mol %) in DCM (24 mL, 0.01 M). The flask was fitted
36 with a condenser and refluxed under nitrogen for 12 hours. The reaction mixture was then reduced in volume to 0.5 mL and purified directly through flash column chromatography. The desired product was obtained (28 mg, 63 %). 500 MHz 1H NMR: δ
1.34-1.38 (m, 12H, CHOHCH2CH2CH2, CHOHCH2CH2CH2, CHOHCH2CH2CH2CH2,
CHOHCH2CH2CH2CH2, CH2CH2CH2CH=C, CH2CH2CH2CH=C), 1.63-1.68 (m, 4H,
CH2CH2CHOH, CH2CH2CHOH), 1.97-1.98 (m, 4H, CH2CH2CH=C, CH2CH2CH=C),
3.80 (s, 6H, OCH3, OCH3), 4.40 (broad t, 2H, J = 6.3, CH2CHOHC, CH2CHOHC), 5.37
(t, 2H, J = 3.4, CH2CH=CH, CH2CH=CH), 5.81 (s, 2H, C=CHH, C=CHH), 6.24 (s, 2H, C=CHH, C=CHH).
Dimer RCM product (3d) A solution of BH adduct 2b (50 mg, 0.22 mmol) was added to a stirring solution of Grubbs #2 catalyst (19 mg, 10 mol %) in DCM (22 mL, 0.01 M). The flask was fitted with a condenser and refluxed under nitrogen for 12 hours. The reaction mixture was then reduced in volume to 0.5 mL and purified directly through flash column chromatography. The desired product was obtained (29 mg, 67 %). 500 MHz 1H NMR: δ
1.32-1.35 (m, 16H, CHOHCH2CH2CH2, CHOHCH2CH2CH2, CHOHCH2CH2CH2CH2,
CHOHCH2CH2CH2CH2, CH2CH2CH2CH2CH=C, CH2CH2CH2CH2CH=C, CH2CH2CH2
CH=C, CH2CH2CH2CH=C), 1.63-1.67 (m, 4H, CH2CH2CHOH, CH2CH2CHOH), 1.97-
1.98 (m, 4H, CH2CH2CH=C, CH2CH2CH=C), 3.80 (s, 6H, OCH3, OCH3), 4.40 (broad t,
2H, J = 6.3, CH2CHOHC, CH2CHOHC), 5.37 (t, 2H, J = 3.4, CH2CH=CH, CH2CH=CH), 5.81 (s, 2H, C=CHH, C=CHH), 6.24 (s, 2H, C=CHH, C=CHH).
BH adduct (4) To a stirred mixture of pentenal (0.24 mL, 2.4 mmol) and methyl acrylate (0.24 mL, 2.9 mmol) were added quinuclidine (67 mg, 0.6 mmol) and methanol (0.08 mL, 1.8 mmol). The homogeneous reaction mixture was stirred at room temperature for 8 h and the reaction progress was monitored by TLC. The reaction mixture was purified by flash column chromatography to give 4 in good yield (132 mg, 35 %). 500 MHz 1H NMR: δ
37 1.65-1.72 (m, 2H, CHCH2CH2), 2.16 (m, 2H, CH2CH2CH=C), 2.36 (s, 3H, CCH3), 4.45
(t, 1H, J = 7, 6, CH2CHC=C), 4.97 (d, 1H, J = 10, CH=CHH), 5.04 (d, 1H, J = 17,
CH=CHH), 5.82 (ddt, 1H, J = 17.1, 9.3, 6.4, CH2CH=CH2), 6.02 (s, 1H, C=CHH), 6.11 (s, 1H, C=CHH). 75 MHz 13C NMR: δ 26.70, 30.31, 35.58, 71.00, 115.21, 125.97, 138.33, 150.43, 200.91. IR (cm-1): 1366, 1672, 2925, 3445. Mass spectrum m/z (CI+): 155.
BH adduct (8) To a stirred mixture of 2,2-dimethyl-4-pentenal (0.22 mL, 1.6 mmol) and acrylonitrile (0.13 mL, 1.9 mmol) were added quinuclidine (45 mg, 0.4 mmol) and methanol (0.05 mL, 1.2 mmol). The homogeneous reaction mixture was stirred at room temperature and the reaction progress was monitored by TLC. The reaction mixture was purified by flash column chromatography to give 8 in good yield (90 mg, 34 %). 500 1 MHz H NMR: δ 0.99 (s, 3H, CCH3), 1.00 (s, 3H, CCH3), 2.06 (dd, 1H, J = 13.7, 7.3,
CCH2CH=C), 2.24 (dd, 1H, J = 13.7, 7.8, CCH2CH=C), 4.06 (s, 1H, CCHC=C), 5.12 (d, 1H, J = 17.7, CH=CHH), 5.13 (d, 1H, J = 10.8, CH=CHH), 5.87 (ddt, 1H, J = 16.1, 10.7, 13 7.3, CH2CH=CH2), 5.99 (s, 1H, C=CHH), 6.14 (s, 1H, C=CHH). 75 MHz C NMR: δ 22.29, 23.56, 38.88, 43.69, 78.71, 118.55, 124.69, 133.00, 134.58. IR (cm-1): 1391, 2228, 2966, 3467. Mass spectrum m/z (CI+): 166.
BH adduct (11) To a stirred mixture of 2,3-methyl-4-pentenal (0.1 g, 0.9 mmol) and methyl acrylate (0.1 ml, 1,1 mmol) were added quinuclidine (25 mg, 0.3 mmol) and methanol (0.03 mL, 0.75 eq). The homogeneous reaction mixture was stirred at room temperature for 6h and the reaction progress was monitored by TLC. The reaction mixture was purified by flash column chromatography to give 11 in good yield (105 mg, 60 %, isomer mixtures = 1:1). 75 MHz 13C NMR: δ 20.82, 22.92, 31.70, 49.45, 54.23, 74.20, 111.31, 125.26, 140.29, 145.70, 154.13. IR (cm-1): 1721, 2969, 2516. Mass spectrum m/z (CI+): 198.
38 BH adduct (6) Under an argon atmosphere, to a stirred solution of phenol (15 mg, 20 mmol) in THF was added methyl acrylate (0.17 mL, 0.8 mmol), 2,2-dimethyl-4-pentenal (0.25 mL, 1.6 mmol), phenol (15 mg, 1.6 mmol) and tributylphosphine (0.04 mL, 20 mol %) successively, which was stirred for 6 h at room temperature. After completion of the reaction, the mixture was purified by flash column chromatography to give 6 (35 mg, 1 22 % yield). 500 MHz H NMR: δ 0.83 (s, 3H, CH3C), 0.87 (s, 3H, CH3C), 2.02 (dd, 1H, J = 13.7, 7.3, CCHHCH=C), 2.16 (dd, 1H, J = 13.7, 7.8, CCHHCH=C), 3.79 (s, 3H,
OCH3), 4.38 (s, 1H, CCHOHC=C), 5.07 (d, 1H, J = 18.1, CH=CHH), 5.08 (d, 1H, J =
10.3, CH=CHH), 5.80 (s, 1H, C=CHH), 5.88 (ddt, 1H, J = 17.1, 10.3, 7.3, CH2CH=CH2), 6.32 (s, 1H, C=CHH). 75 MHz 13C NMR: δ 28.89, 37.23, 46.38, 48.73, 55.92, 56.22, 122.45, 130.32, 138.25, 139.46, 143.09, 177.50. IR (cm-1): 1713, 2959, 3450. Mass spectrum m/z (CI+): 198.
Crotyl Propanoate (10a) A solution of crotyl alcohol (2.4 mL, 28 mmol) in DCM (10mL) was stirred in the presence of pyridine (2.5 mL, 30.1 mmol) as 0.3 M solution in DCM. The solution was cooled to 0 oC and propionyl chloride (1.9 mL, 28 mmol) was added dropwise over 2-3 min. The cooling bath was then removed and the reaction mixture was allowed to warm to 25 oC. Stirring was continued at 25 oC for 2 h. Following this the reaction mixture was washed by the addition of 10 % aqueous hydrochloric acid, diluted with water, and extracted with DCM. The combined DCM extracts were dried (MgSO4) and concentrated in vacuo. Flash chromatography afford 10a in 3.3 g (91 %).42
Claisen Rearrangement of Ester (10b: 2,3-Dimethyl-4-pentenoic Acid) A stirred solution of dry N-isopropylcyclohexylamine (1.57 mL, 9.4 mmol) in THF was cooled to 0 oC and treated with n-butyllithium (5.36 mL, 8.6 mmol) in hexane solution over several minutes. After the mixture was stirred for an additional 10 min following the addition, the solution was cooled to –78 oC and crotyl propanoate 10a (1 g,
39 7.8 mmol) was added dropwise over 2 - 3 min. Within 5 min after the addition of the ester was complete, Me3SiCl (1.1 mL, 8.6 mmol) was added in one batch. The cooling bath was then removed and the reaction mixture was allowed to warm to 25 oC over 30 min. Stirring at 67 oC for 30 min. Following this, 2 mL of methanol was added and the reaction mixture was stirred for 10 min at 25 oC to effect hydrolysis of the silyl ester. The reaction mixture was then added to 20 mL of 5 % aqueous sodium hydroxide solution. The aqueous solution was washed with two 15 mL portions of ether (washings discarded) and acidified with concentrated hydrochloric acid, and then the product acid was isolated by DCM extraction. Distillation at reduced pressure afforded 10b in 610 mg (61 % yield).42
2,3-Dimethyl-4-pentenol (10c) A solution of 2,3-dimethyl-4-pentenoic acid 10b (1g, 7.9 mmol) was added to a stirred solution of LAH (0.34 mg, 8.7 mmol) in THF (30 mL). A stirring solution was cooled to 0 oC for 2 h. After completion of the reaction it was quenched with water and sodium hydroxide. The desired product was extracted with DCM. The crude product 10c was relatively unstable and sensitive to heat and used directly in the next step.
2,3-Dimethyl-4-pentenal (10d) A solution of 2,3-dimethyl-4-pentenol 10c (1g, 8.8 mmol) in DCM (10 mL) was added to a stirred solution of PCC (3.85 g, 17.6 mmol) with Celite in DCM (20 mL). The mixture solution was stirred in room temperature for 3 h. After completion of the reaction, the solution was poured into fritted glass filter funnel and then purified by flash column chromatography to give 10d (860 mg, 87 % yield, cis:trans mixture = 1:1). 75 MHz 13C NMR: δ 10.81, 17.95, 38.59, 51.36, 115.56, 140.28, 205.29. IR (cm-1): 1707, 2360, 2964. Mass spectrum m/z (CI+): 113.
2-Acetyl-cyclopenten-1-ol (5) A solution of BH adduct 4 (50 mg, 0.32 mmol) was added to a stirring solution of
40 Grubbs #2 catalyst (27 mg, 10 mol %) in DCM (0.01 M). The flask was fitted with a condenser and refluxed under nitrogen for 12 hr. The reaction mixture was then reduced in volume to 0.5 mL and purified directly through flash column chromatography. The desired product was obtained (9 mg, 23 %).52
2-Carboxylic methyl ester-5,5-dimethyl-cyclopenten-1-ol (7) A solution of BH adduct 6 (68 mg, 0.35 mmol) was added to a stirring solution of Grubbs #2 catalyst (30 mg, 10 mol %) in DCM (0.01 M). The flask was fitted with a condenser and refluxed under nitrogen for 12 h. The reaction mixture was then reduced in volume to 0.5 mL and purified directly through flash column chromatography. The desired product was obtained in 8 % yield (5 mg). 500 MHz 1H NMR: δ 1.10 (s, 6H,
(CH3)2C), 2.24 (ddd, 1H, J = 18.6, 2.3, 1.2, CCHHCH=C), 2.43 (ddd, 1H, J = 18.5, 2.4,
2.4, CCHHCH=C), 3.77 (s, 3H, OCH3), 4.46 (s, 1H, CCHOHC=C), 6.88 (t, 1H, J = 2.4, 13 CH2CH=C). 75 MHz C NMR: δ 17.88, 23.54, 37.66, 41.14, 46.94, 77.45, 95.48, 171.41. IR (cm-1): 1259, 1717, 2954, 3437. Mass spectrum m/z (CI+): 120.
2-Cyano-5,5-dimethyl-cyclopenten-1-ol (9) A solution of BH adduct 6 (65 mg, 0.4 mmol) was added to a stirring solution of Grubbs #2 catalyst (25 mg, 10 mol %) in DCM (0.01 M). The flask was fitted with a condenser and refluxed under nitrogen for 12 h. The reaction mixture was then reduced in volume to 0.5 mL and purified directly through flash column chromatography. The desired product was obtained in 91 % yield (43 mg). 500 MHz 1H NMR: δ 1.08 (s, 3H,
CH3C), 1.11 (s, 3H, CH3C), 2.28 (ddd, 2H, J = 18.6, 3.0, 1.2, CCHHCH=C), 2.44 (dd, J = 18.6, 2.4, 2.4, CCHHCH=C), 4.38 (broad s, 1H, CCHOHC=), 6.77 (t, 1H, J = 4, 13 CH2CH=C). 75 MHz C NMR: δ 21.83, 27.49, 42.46, 46.47, 83.92, 116.13, 117.74, 150.70. IR (cm-1): 1433, 2959, 3278. Mass spectrum m/z (EI+): 137. Anal.Calcd for
C8H11NO: C, 70.04; H, 8.08; N, 10.21. Found: C, 69.79; H, 7.96; N, 10.03.
2-Carboxylic methyl ester-3,4-methyl-cyclopentenol (12)
41 A solution of BH adduct 11 (50 mg, 0.25 mmol) was added to a stirring solution of Grubbs #2 catalyst (21 mg, 10 mol %) in DCM (0.01 M). The flask was fitted with a condenser and refluxed under nitrogen for 12 hours. The reaction mixture was then reduced in volume to 0.5 mL and purified directly through flash column chromatography. The desired product was obtained in 45 % yield (19 mg, cis:trans mixture = 1:1). 75 MHz 13C NMR: δ 20.89, 22.98, 31.71, 49.50, 54.28, 74.22, 125.24, 140.23, 154.14. IR (cm-1): 1718, 3956, 3482. Mass spectrum m/z (CI+): 170.
cis-Cyclohexane-1,2-dicarboxylic lactone (13)
A mixture of NaBH4 (475 mg, 12.3 mmol) in THF (5 mL) was stirred and cooled in an ice bath while cis-1,2-cyclohexanedicarboxylic anhydride (2 g, 12.3 mmol) in THF (7 mL) was added over 5 min. The ice bath was removed and stirring was continued for 1h. 10 % hydrochloric acid was added and the mixture diluted with water. Subsequent extraction with EtOAc gave desired 13 in 71 % yield (1.85 g).43
cis-Cyclohexane-1-hydroxy lactone (13a) To a solution of cis-cyclohexane-1,2-dicarboxylic lactone 13 (230 mg, 1.65 mmol) in DCM at –78 oC was added a DIBAL 1.0 M solution (3.2 mL, 3.3 mmol). The reaction was stirred for 4 hr and quenched by the addition of MeOH and H2O. The solution was diluted with EtOAc and the pH was carefully adjusted to 3 by the addition of dilute sulfuric acid. The organic fraction was concentrated and used for next step without further purification.53
cis-Cyclohexene-1-hydroxy lactone (14a) To a solution of phthalide 14 (1.1 g, 7.9 mmol) in DCM at –78 oC was added a DIBAL 1.0 M solution (9.5 mL, 9.1 mmol). The reaction was stirred for 4 h and quenched by the addition of MeOH and H2O. The solution was diluted with EtOAc and the pH was carefully adjusted to 3 by addition of dilute sulfuric acid. The organic fraction was concentrated and used for next step without further purification.
42
2,3-O-Isopropylidene-erythrose (15a) To a solution of phthalide 15 (500 mg, 3.1 mmol) in DCM at –78 oC was added a DIBAL 1.0 M solution (3.7 mL, 3.5 mmol). The reaction was stirred for 4 h and quenched by the addition of MeOH and H2O. The solution was diluted with EtOAc and the pH was carefully adjusted to 3 by addition of dilute sulfuric acid. The organic 54 fraction was concentrated and used for next step without further purification.
(2-Vinyl cyclohexyl)-methanol (13b) A 50 mL flask under argon was charged with methyl triphenylphosphonium bromide (5.85 g, 16.1 mmol) and dry THF. The flask was placed in an ice-water bath and n-BuLi (10 mL, 16.1 mmol) was added dropwise with stirring. After the addition of n- BuLi was complete, the orange reaction mixture was stirred for 15 min at 0 oC and then warmed to room temperature. Cis-cyclohexane-1-hydroxy lactone 13a (456 mg, 3.2 mmol) was added dropwise and the solution was stirred for an additional 5 min. The reaction mixture was stirred under reflux for 1 h. After completion of the reaction, the mixture quenched with water and then extracted with EtOAc. Following purification with flash column chromatography produced the desired product in 64 % yield (287 mg).43, 55
(2-Vinyl-phenyl)-methanol (14b) A 50 mL flask under argon was charged with methyl triphenylphosphonium bromide (2.3 g, 6.4 mmol) and dry THF. The flask was placed in an ice-water bath and n- BuLi (6.4 mL, 6.4 mmol) was added dropwise with stirring. After the addition of n-BuLi was complete, the orange reaction mixture was stirred for 15 min at 0 oC and then warmed to room temperature. Cis-cyclohexene-1-hydroxy lactone 14a (220 mg, 1.6 mmol) was added dropwise and stirred for an additional 5 min. The reaction mixture was stirred under reflux for 1 h. After completion of the reaction, the mixture quenched with water and then extracted with EtOAc. Following purification with flash column chromatography produced 14b in 60 % yield (129 mg). 500 MHz 1H NMR: δ 4.78 (s, 2H,
43 ArCH2OH), 5.39 (d, 1H, J = 11, ArCH=CHH), 5.74 (d, 1H, J = 17.5, ArCH=CHH), 7.07
(dd, 1H, J = 17.3, 11.2, ArCH=CH2), 7.30 (m, 1H, Ar), 7.34 (m, 1H, Ar), 7.38 (d, 1H, J = 7, Ar), 7.58 (d, 1H, J = 7.5, Ar). 75 MHz 13C NMR: δ 63.56, 116.71, 126.19, 128.15, 128.40, 128.54, 134.02, 136.86, 137.77. IR (cm-1): 1482, 1624, 3337. Mass spectrum m/z (CI+): 134.
5,6-Dideoxy-2,3-O-isopropylidene-erythro-pent-5-enitol (15b) A 50 mL flask under argon was charged with methyl triphenylphosphonium bromide (4.6 g, 12.9 mmol) and dry THF. The flask was placed in an ice-water bath and n-BuLi (8.1 mL, 9.6 mmol) was added dropwise with stirring. After the addition of n- BuLi was complete, the orange reaction mixture was stirred for 15 min at 0 oC and then warmed to room temperature. Cis-cyclohexene-1-hydroxy lactone 15a (220 mg, 1.6 mmol) was added dropwise and stirred for an additional 5 min. The reaction mixture was stirred under reflux for 1 h. After completion of the reaction, the mixture quenched with water and then extracted with EtOAc. Following purification with flash column chromatography produced 15b in 78 % yield (530 mg).56
2-Vinyl cyclohexane carbaldehyde (13c) A solution of (2-vinyl cyclohexyl)-methanol 13b (395 mg, 2.8 mmol) in DCM was added to a stirred solution of PCC (1.2 g, 5.6 mmol) with Celite in DCM. The mixture solution was stirred at room temperature for 3 h. After completion of the reaction, the solution poured into fritted glass filter funnel and then purified by flash column chromatography to give 13c (318 mg, 81 % yield).57
2-Vinyl benzaldehyde (14c) A solution of (2-vinyl-phenyl)-methanol 14b (150 mg, 1.1 mmol) in DCM was added to a stirred solution of PCC (527 mg, 2.2 mmol) with Celite in DCM. The mixture solution was stirred at room temperature for 3 h. After completion of the reaction, the solution poured into fritted glass filter and then purified by flash column chromatography
44 to give 14c (140 mg, 92 %). 500 MHz 1H NMR: δ 5.54 (d, 1H, J = 10.5, CH=CHH), 5.74 (d, 1H, J = 16.5, CH=CHH), 7.47 (ddd, 1H, J = 7.8, 3.9, 4.4, aromatics), 7.56 (dd, 1H, J
= 17.6, 10.8, ArCH=CH2), 7.60 (dd, 1H, J = 3.4, 3.9, aromatics), 7.86 (d, 1H, J = 7.5, aromatics), 10.31 (s, 1H, CHO). 75 MHz 13C NMR: δ 119.65, 127.67, 128.14, 131.44, 133.10, 133.59, 134.03, 140.75, 192.64. IR (cm-1): 1693, 2735, 2846, 3062. Mass spectrum m/z (CI+): 133.
5,6-Dideoxy-2,3-O-isopropylidene-erythro-pent-5-enital (15c) A solution of 15b (525 mg, 3.3 mmol) in DCM was added to a stirred solution of PCC (1.5 mg, 6.6 mmol) with Celite in DCM. The mixture solution was stirred at room temperature for 3 h. After completion of the reaction, the solution poured into fritted glass filter and then purified by flash column chromatography to give 15c (430 g, 82 %).56
BH adduct (16) To a stirred mixture of 2-vinyl cyclohexane carbaldehyde 13c (97 mg, 0.7 mmol) and methyl acrylate (0.08 mL, 0.8 mmol) were added quinuclidine (20 mg, 0.18 mmol) and methanol (0.02 mL, 0.53 mmol). The homogeneous reaction mixture was stirred at room temperature for 8 h and the reaction progress was monitored by TLC. The reaction mixture was purified by flash column chromatography to give 16 (35mg, 22 %, 4:1 1 mixture of isomers). 500 MHz H NMR: δ 1.13-1.75 (m, 9H, CH2CH2CH2, CH2CH2CH2,
CH2CH2CH2, CH2CH2CH2, CH2CHCHCH) 2.14 (m, 1H, CH2CHCHCH=), 3.78 (s, 3H,
OCH3), 4.81 (d, 1H, J = 1, CHCHC=), 5.06 (dd, 1H, J = 10.3, 2.0, CH=CHH), 5.14 (dd, 1H, J = 17.1, 1.5, CH=CHH), 5.76 (ddd, 1H, J = 16.6, 9.5, 9.8, CHCH=CH), 5.88 (dd, 1H, J = 1.5, 1.5, C=CHH), 6.35 (dd, 1H, J = 1.5, 1.5, C=CHH). 75 MHz 13C NMR: δ 23.17, 26.06, 26.18, 34.06, 44.73, 45.28, 51.95, 70.43, 114.90, 125.18, 143.22. IR (cm-1): 1719, 2851, 2928, 3512. Mass spectrum m/z (CI+): 225.
BH adduct (18)
45 To a stirred mixture of 2-vinyl benzaldehyde 14c (84 mg, 0.6 mmol) and methyl acrylate (0.07mL, 0.72 mmol) were added quinuclidine (17 mg, 0.2 mmol)) and methanol (0.02 mL, 0.5 mmol). The homogeneous reaction mixture was stirred at room temperature for 8 h and the reaction progress was monitored by TLC. The reaction mixture was purified by flash column chromatography to give 18 (111 mg, 83 %). 500 1 MHz H NMR: δ 3.79 (s, 3H, OCH3), 5.33 (dd, 1H, J = 10.8, 1.5, CH=CHH), 5.60 (t, 1H, J = 1, ArCHC), 5.66 (dd, J = 17.3, 1.5, CH=CHH), 5.92 (s, 1H, C=CHH), 6.37 (s, 1H,
C=CHH), 6.94 (dd, 1H, J = 17.3, 11.2, ArCH=CH2), 7.33 (dd, 2H, J = 4.6, 4.9, aromatics), 7.47 (dd, 1H, J = 4.6, 4.4, aromatics), 7.52 (dd, 1H, J = 4.7, 4.9, aromatics). 75 MHz 13C NMR: δ 52.30, 69.45, 116.95, 126.47, 126.87, 127.10, 128.22, 128.33, 134.37, 136.75, 137.75, 141.83, 159.98, 167.31. IR (cm-1): 1715, 2950, 3443. Mass spectrum m/z (CI+): 218.
BH adduct (20) To a stirred mixture of 15c (121 mg, 0.8 mmol) and methyl acrylate (0.1mL, 1.2 mmol) were added quinuclidine (23 mg, 0.3 mmol)) and methanol (0.03 mL, 0.5 mmol). The homogeneous reaction mixture was stirred at room temperature for 8 h and the reaction progress was monitored by TLC. The reaction mixture was purified by flash column chromatography to give 20 (1:2 mixture isomers, 75 mg, 31 %).
2-Carboxylic acid methyl ester hexahydroinden-1-ol (17) A solution of the major BH adduct 16 (68 mg, 0.3 mmol) was added to a stirring solution of Grubbs #2 catalyst (26 mg, 10 mol %) in DCM (0.01 M). The flask was fitted with a condenser and refluxed under nitrogen for 12 h. The reaction mixture was then reduced in volume to 0.5 mL and purified directly through flash column chromatography. The desired product was obtained in 66 % yield (38 mg). (1 isomer) 500 MHz 1H NMR:
δ 1.25-1.36 (m, 4H, CHOHCHCH2CH2, CHOHCHCH2CH2CH2), 1.59-1.60 (m, 1H,
CHOHCHCH2CH2), 1.81-1.84 (m, 2H, CH2CH2CH2CHCH=C), 1.99-2.04 (m, 2H,
CH2CH2CHCH=C), 2.11-2.13 (m, 1H, CH2CHCH=C), 3.78 (s, 3H, OCH3), 4.60 (d, 1H,
46 J = 8.5, CHCHC=C), 6.85 (broad s, 1H, CHCH=C). 75 MHz 13C NMR: δ 26.08, 26.35, 27.82, 29.79, 46.90, 51.48, 56.17, 78.28, 137.68, 148.16, 165.90. IR (cm-1): 1706, 2927, 3524. Mass spectrum m/z (CI+): 197
2-Carbocylic acid methyl ester inden-1-ol (19) A solution of BH adduct 18 (50 mg, 0.23 mmol) was added to a stirring solution of Grubbs #2 catalyst (20 mg, 10 mol %) in DCM (0.01 M). The flask was fitted with a condenser and refluxed under nitrogen for 12 h. The reaction mixture was then reduced in volume to 0.5 mL and purified directly through flash column chromatography. The desired product was obtained in 92 % yield (40 mg). (1 isomer) 500 MHz 1H NMR: δ
3.90 (s, 3H, O=COCH3), 5.45 (s, 1H, ArCHOHC), 7.53-7.46 (m, 3H, aromatics), 7.59 (s, 1H, ArCH=C), 7.63 (d, 1H, J = 6.3, aromatics). 75 MHz 13C NMR: δ 52.03, 75.88, 124.14, 124.58, 129.19, 129.26, 141.88. IR (cm-1): 1573, 1707, 2949, 3439. Mass spectrum m/z (CI+): 190.
Allylmagnesium bromide In a typical preparation, allyl bromide (1.4 mL, 17 mmol) in 20 mL of ether was added dropwise to magnesium turnings (830 mg, 34 mmol) stirred initially in 10 mL of ether. The reaction initiated promptly, and the addition of allyl bromide was extended over a period of 2 h. In most preparations, the volatiles were distilled to a cold trap under vacuum, nitrogen was admitted, and fresh ether was added to produce a solution of about 1 M.
1-Methyl-1,5-hexadien-3-ol (22) Crotonaldehyde (1 g, 14 mmol) in ether was added dropwise to allylmagnesium bromide (15.7 mmol) in ether at 0 oC. The reaction mixture was stirred for 2 h at 0 oC. After completion of the reaction, purification with flash column chromatography produced 22 in 75 % yield (1 g).58
47 3-Methyl-5-hexenal (22a) Excess KH (1.44 g, 36 mmol) in a mineral oil suspension (30 wt. %) was washed with dry THF. 1-Methyl-1,5-hexadien-3-ol 22 (0.5 g, 4.5 mmol) in 10 mL of THF was added dropwise. 18-Crown-6 (0.6 g, 2.3 mmol) in 1 mL of THF was added. The mixture was heated under reflux for 2 h, cooled to –78 oC, and quenched by rapid injection of 0.6 mL of MeOH. The resulting slurry was immediately poured into a mixture of 30 mL of ether and 5 mL of saturated NH4Cl solution. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product 22a was relatively unstable and sensitive to heat and directly used in the next step.58
3,3-Dimethyl-1-methoxyhexa-1, 5-diene (23)
A flask was charged with MeOCH2Ph3PCl (3 g, 8.8 mmol) and dry THF under argon gas. 2,2-Dimethyl-4-pentenal (1 g, 8 mmol) in THF was placed in a dropping funnel. The flask was placed in an ice-water bath and n-BuLi (5.3 mL, 8.5 mmol) was added dropwise by syringe with stirring. After the addition of n-BuLi was complete, the orange reaction mixture was brought to room temperature and stirred for an additional 20 min. The reaction flask was again cooled in an ice-water bath and the 2,2-dimethyl-4- pentenal in THF was added dropwise. The reaction mixture was stirred overnight at reflux. After completion of the reaction, the THF solution was concentrated under vacuum. The crude product, which contained Ph3PO, was used without purification in the subsequent hydrolysis step.46
3,3-Dimethylhex-5-en-1-al (23a) 30 % Sulfuric acid (1.5 mL) was added to a stirred solution of 3,3-dimethyl-1- methoxyhexa-1, 5-diene 23 (0.4 g, 2.9 mmol) in THF (5 mL). After the mixture had been stirred for 1h, it was brought pH 9 using saturated sodium bicarbonate solution, and then extracted with ether. The combined extracts were washed with brine, then dried and filtered. A small portion was evaporated to yield aldehyde 23a. The crude product was purified directly through flash column chromatography to give 23a (360 mg, 60 %). 46
48 BH adduct from β-methyl substituted hexenal (24) To a stirred mixture of 3-methyl-5-hexenal 22a (90 mg, 0.8 mmol)) and methyl acrylate (0.9 mL, 0.96mmol) were added quinuclidine (23 mg, 0.2 mmol) and methanol (0.03 mL, 0.6 mmol). The homogeneous reaction mixture was stirred at room temperature for 8h and the reaction progress was monitored by TLC. The reaction mixture was purified by flash column chromatography to give 24 (130 mg, 82 %, 1:1 mixture of isomers). 75 MHz 13C NMR: δ 25.25, 28.60, 33.61, 35.98, 51.83, 71.65, 114.36, 124.95, 138.78, 142.41, 166.98. IR (cm-1): 1719, 2953, 3450. Mass spectrum m/z (CI+): 199.
BH adduct from β-dimethyl substituted hexenal (26) To a stirred solution of 3,3-dimethylhex-5-en-1-al (50 mg, 0.4 mmol) and methyl acrylate (0.04 mL, 0.5 mmol) were added quinuclidine (11 mg, 0.1 mmol)) and methanol (0.02 mL, 0.3 mmol). The homogeneous reaction mixture was stirred at room temperature for 8h and the reaction progress was monitored by TLC. The reaction mixture was purified by flash column chromatography to give 26 (71 mg, 84 %). 500 1 MHz H NMR: δ 0.98 (s, 3H, CCH3), 1.00 (s, 3H, CCH3), 1.51 (dd, 1H, J = 14.8, 2.8, CCHHCHOH), 1.57 (dd, 1H, J = 14.6, 8.7, CCHHCHOH), 2.05 (dd, 1H, J = 13.1, 6.3,
CCHHCH=CH2), 2.10 (dd, 1H, J = 13.1, 6.3, CCHHCH=CH2), 3.78 (s, 3H, OCH3), 4.59
(dd, 1H, J = 8.4, 2.8, CH2CHC=C), 5.02 (dm, 1H, J = 16.7, CH=CHH), 5.03 (dm, 1H, J = 10.1, CH=CHH), 5.80 (obscured s, 1H, C=CHH), 5.84 (ddt, 1H, J = 16.7, 10.4, 7.3, 13 CH2CH=CH2), 6.18 (s, 1H, C=CHH). 75 MHz C NMR: δ 27.34, 27.41, 33.19, 47.08, 48.02, 51.71, 69.17, 116.94, 124.16, 135.52, 144.08, 166.88. IR (cm-1): 1198, 1439, 1722, 2954, 3495. Mass spectrum m/z (CI+): 212.
2-Carboxylic methyl ester-5-methyl-cyclohex-2-enol (25) A solution of BH adduct 24 (50 mg, 0.25 mmol) was added to a stirring solution of Grubbs #2 catalyst (11 mg, 10 mol %) in DCM (0.01 M). The flask was fitted with a condenser and refluxed under nitrogen for 12 h. The reaction mixture was then reduced
49 in volume to 0.5 mL and purified directly through flash column chromatography. The desired products were obtained in 87 % yield (37 mg). 500 MHz 1H NMR: δ 1.00 (d, 3H,
J = 6.6, CHCH3), 1.35 (ddd, 1H, J = 14.6, 4.2, 12.6, CHCHHCHOH), 1.74 (dddd, 1H, J
= 19, 10.2, 2.4, 1.2, CHCHHCH=C), 1.91-2.03 (m, 2H, CH2CHCH3CH2, CHCHHCHOH), 2.36 (dddd, 1H, J = 19.2, 6.0, 5.4, 1.2, CHCHHCH=C), 3.77 (s, 3H,
OCH3), 4.56 (broad m, 1H, CH2CHOHC=C), 7.09 (dd, 1H, J = 5.4, 2.4, CH2CH=C). 75 MHz 13C NMR: δ 21.19, 22.74, 34.54, 38.08, 51.73, 63.39, 131.71, 143.09, 167.75. IR -1 + (cm ): 1717, 2951, 3463. Mass spectrum m/z (CI ): 170. Anal.Calcd for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.33; H, 8.28.
2-Carboxylic methyl ester-5,5-dimethyl-cyclohex-2-enol (27) A solution of BH adduct 26 (71 mg, 0.34 mmol) was added to a stirring solution of Grubbs #2 catalyst (28 mg, 10 mol %) in DCM (0.01 M). The flask was fitted with a condenser and refluxed under nitrogen for 12 h. The reaction mixture was then reduced in volume to 0.5 mL and purified directly through flash column chromatography. The desired products were obtained in 87 % yield (55 mg). 500 MHz 1H NMR: δ 0.91 (s, 3H,
CH3C), 1.04 (s, 3H, CH3C), 1.51 (dd, 1H, J = 13.2, 8.4, CCHHCHOH), 1.83 (ddd, 1H, J = 13.2, 6.3, 2.1, CCHHCHOH), 2.0 (dddd, 1H, J = 19.2, 4.9, 1.7, 1.7, CCHHCH=C),
2.11 (ddd, 1H, J = 19.5, 3.0, 3.1, CCHHCH=C), 3.78 (s. 3H, OCH3), 4.57 (m, 1H, 13 CH2CHOHC=C), 7.00 (ddd, 1H, J = 4.9, 3.8, 1.1, CH2CH=C). 75 MHz C NMR: δ 26.63, 30.05, 30.34, 39.93, 42.87, 51.67, 64.45, 131.01, 141.39, 167.62. IR (cm-1): 1045, 1234, 1719, 1751, 2955. Mass spectrum m/z (CI+): 184.
Glycine methyl ester (28: Glycine) Acetyl chloride (4.8 mL, 68 mmol) was added dropwise to methanol (27 mL) over 8 min under nitrogen atmosphere. The solution was stirred for 5 min at room temperature and glycine (2 g, 27 mmol) was added in one portion at room temperature. The reaction mixture was refluxed for 2h. Solvent was removed in vacuo to yield the corresponding methyl ester.47
50 Alanine methyl ester (29: Alanine). Acetyl chloride (4 mL, 56 mmol) was added dropwise to methanol (23 mL) over 8 min under nitrogen atmosphere. The solution was stirred for 5 min at room temperature and D-alanine (2 g, 23 mmol) was added in one portion at room temperature. The reaction mixture was refluxed for 2hr. Solvent was removed in vacuo to yield the corresponding methyl ester.47
N-Tosylglycine methyl ester (28a) Triethylamine (1.24 mL, 8.9 mmol) was added to a stirred solution of glycine methyl ester 28 (1 g, 8.1 mmol). The solution was stirred for 5 min at room temperature and TsCl (1.7 g, 8.9 mmol) in DCM was added. The reaction mixture was stirred for 5 h at room temperature. Subsequent flash column chromatography gave 28a (1.73 g, 88 %).59
N-Tosylalanine methyl ester (29a) Triethylamine (1.1 mL, 8 mmol) was added to a stirred solution of alanine methyl ester 29 (1 g, 7.2 mmol). The solution was stirred for 5 min at room temperature and TsCl (1.5 g, 8.8 mmol) in DCM was added. The reaction mixture was stirred for 5hr at room temperature. Subsequent flash column chromatography gave 29a (1.73 g, 90 %).59
(N,N-Allyl-tosyl)-glycine methyl ester (28b)
K2CO3 (0.6 g, 4.4 mmol) was added to the solution of N-tosylglycine methyl ester (1 g, 4.1 mmol) in acetone a room temperature. The solution was stirred for an additional 10 min and allyl bromide (0.4 mL, 4.4 mmol) was added slowly. The reaction mixture was stirred for 6 h under reflux. The desired product was obtained by flash column 1 chromatography to give 28b (1 g, 91 %). 500 MHz H NMR: δ 2.44 (s, 3H, ArCH3), 3.65
(s, 3H, OCH3), 3.91 (d, 2H, J = 6, TsNCH2CH=C), 4.04 (s, 2H, TsNCH2C=O), 5.19 (dd, 1H, J = 17.1, 1.5, CH=CHH), 5.21 (dd, 1H, J = 10.3, 1.0, CH=CHH), 5.70 (ddt, 1H, J =
18.1, 10.3, 6.4, CH2CH=CH2), 7.33 (d, 2H, J = 8.5, aromatics), 7.76 (d, 2H, J = 8,
51 aromatics). 75 MHz 13C NMR: δ 21.76, 47.05, 51.00, 52.30, 120.10, 127.62, 129.80, 132.45, 137.02, 143.73, 169.60. IR (cm-1): 1159, 1753, 2953. Mass spectrum m/z (CI+): 284.
(N,N-Allyl-tosyl)-alanine methyl ester (29b)
K2CO3 (0.6 g, 4.4 mmol)) was added to the solution of N-tosylalanine methyl ester (1 g, 3.9 mmol) in acetone a room temperature. The solution was stirred for an additional 10 min and allyl bromide (0.37 mL, 4.4 mmol) was added slowly. The reaction mixture was stirred for 6h under reflux. The desired product was obtained by flash column chromatography to give 29b (1.1 g, 90 %).60
2-(Allyl-tosyl-amino)-ethanol (28c) A solution of (N,N-allyl-tosyl)-glycine methyl ester 28b (0.5 g, 1.9 mmol) was added to a stirred solution of LAH (0.1 g, 3 mmol) in THF. A stirring solution was cooled to 0 oC for 2 h. After completion of the reaction, it was quenched with water and sodium hydroxide. The desired product was extracted with DCM and directly used for next step without further purification.
2-(Allyl-tosyl-amino)-2-methlyethanol (29c) A solution of (N,N-allyl-tosyl)-alanine methyl ester 29b (0.5 g, 1.8 mmol) was added to a stirred solution of LAH (0.1 g, 2.7 mmol) in THF. A stirring solution was cooled to 0 oC for 2 h. After completion of reaction, quench with water and sodium hydroxide. The desired product was extracted with DCM and directly used for next step without further purification.
2-(Allyl-tosyl-amino)-acetaldehyde (28d) A solution of oxalyl chloride (0.7 mL, 8.1 mmol) in DCM (13 mL) at –78 oC was treated with dimethyl sulfoxide (2 mL, 27 mmol). The resulting solution was stirred for 5 min, treated with 2-(allyl-tosyl-amino)-ethanol 28c (1.4 g, 5.4 mmol) in DCM (10 mL),
52 and further stirred at –78 oC for 15 min. Following the addition of triethylamine (7.5 mL, 74 mmol), the reaction mixture was stirred for 5 min (–78 oC) and the cooling bath was removed. The solution was allowed to warm to room temperature over a period of 20 min. The reaction mixture quenched with the addition of 10 % aqueous hydrochloric acid, dilute with water, and extracted with ether. The combined ether extracts were dried 61 (MgSO4) and concentrated in vacuo. Flash chromatography affords 28d (0.9 g, 88 %).
2-(Allyl-tosyl-amino)-2-methylacetaldehyde (29d) A solution of oxalyl chloride (1.4 mL, 15 mmol) in DCM (13mL) at –78 oC was treated with dimethyl sulfoxide (3.7 mL, 50 mmol). The resulting solution was stirred for 5 min, treated with 2-(allyl-tosyl-amino)-2-methanol 29c (2.8 g, 10.4 mmol) in DCM (10 mL), and further stirred at –78 oC for 15 min. Following the addition of triethylamine (10.5 mL, 10.2 mmol), the reaction mixture was stirred for 5 min (–78 oC) and the cooling bath was removed. The solution was allowed to warm to room temperature over a period of 20 min. The reaction mixture quenched with the addition of 10 % aqueous hydrochloric acid, dilute with water, and extracted with ether. The combined ether extracts were dried (Na2SO4) and concentrated in vacuo. Flash chromatography affords 29d (2.3 g, 85 %).60
BH adduct (30) To a stirred mixture of 2-(allyl-tosyl-amino)-acetaldehyde 28d (0.9 g, 3.6 mmol) and methyl acrylate (0.4 mL, 4.3 mmol) were added quinuclidine (40 mg, 1 mmol) and methanol (0.12 mL, 2.7 mmol). The homogeneous reaction mixture was stirred at room temperature for 8 h and the reaction progress was monitored by TLC. The reaction mixture was purified by flash column chromatography to give 30 in good yield (0.95 g, 1 78 %). 500 MHz H NMR: δ 2.45 (s, 3H, ArCH3), 3.25 (dd, 1H, J = 14.5, 7.8, TsNCHHCHOHC=C), 3.35 (dd, 1H, J = 14.5, 3.4, TsNCHHCHOHC=C), 3.75 (s, 3H,
OCH3), 3.91 (dd, 2H, J = 4.0, 6.0, TsNCH2CH=C), 4.69 (dd, 1H, J = 7.6, 3.9,
CH2CHOHC=C), 5.18 (dm, 1H, J = 10, CH=CHH), 5.21 (dm, 1H, J = 15.4, CH=CHH),
53 5.68 (ddt, 1H, J = 17.1, 9.8, 6.3, CH2CH=CH2), 6.11 (t, 1H, J = 1.8, C=CHH), 6.39 (t, 1H, J = 1.2, C=CHH), 7.32 (d, 2H, J = 13, aromatics), 7.73 (d, 2H, J = 13.5, aromatics). 75 MHz 13C NMR: δ 21.50, 51.86, 52.30, 52.89, 69.42, 119.73, 127.30, 129.78, 132.47, 136.31, 139.26, 143.66, 166.31. IR (cm-1): 1089, 1156, 1336, 1715, 2951, 3499. Mass spectrum m/z (CI+): 340.
BH adduct (31) To a stirred mixture of 2-(allyl-tosyl-amino)-2-methylacetaldehyde 29d (0.8 g, 3 mmol) and methyl acrylate (0.3 mL, 3.6 mmol) were added quinuclidine (33 mg, 0.8 mmol) and methanol (0.1 mL, 2.3 mmol). The homogeneous reaction mixture was stirred at room temperature fro 8 h and the reaction progress was monitored by TLC. The reaction mixture was purified by flash column chromatography to give 31 in good yield (8:1 mixture of isomers, 0.85 g, 80 %). 500 MHz 1H NMR: δ 1.08 (d, 3H, J = 6.8,
CH3CH), 2.44, (s, 3H, ArCH3), 3.70 (dd, 1H, J = 16.2, 8.4, TsNCHHCH=CH2), 3.83 (s,
3H, OCH3), 3.97 (ddt, 1H, J = 16.2, 5.4, 1.8, TsNCHHCH=CH2), 4.09 (qd, 1H, J = 6.8,
6.8, TsNCHCH3CH), 4.50 (d, 1H, J = 5.9, CHCHOHC), 5.14 (dm, 1H, J = 10.3, CH=CHH), 5.21 (dm, 1H, J = 17.1, CH=CHH), 5.81 (ddt, 1H, J = 17.1, 10.3, 7.8,
CH2CH=CH2), 5.93 (dm, 1H, C=CHH), 6.38 (dm, 1H, C=CHH), 7.29 (d, 2H, J = 7.8, aromatics), 7.71 (d, 2H, J = 7.8, aromatics). 75 MHz 13C NMR: δ 12.27, 21.02, 47.72, 51.53, 56.55, 74.78, 117.39, 126.71, 127.88, 129.12, 135.07, 137.53, 138.55, 142.71, 166.60. IR (cm-1): 1715, 2951, 3500. Mass spectrum m/z (CI+): 354.
1-Tosyl-1,2,3,6-tetrahydro-pyridin-3-ol-4-carboxylic methyl ester (32) A solution of BH adduct 30 (0.1 g, 0.3 mmol) was added to a stirring solution of Grubbs #2 catalyst (25 mg, 10 mol %) in DCM (0.01 M). The flask was fitted with a condenser and refluxed under nitrogen for 12 h. The reaction mixture was then reduced in volume to 0.5 mL and purified directly through flash column chromatography. The 1 desired 32 was obtained (81 mg, 87 %). 500 MHz H NMR: δ 2.45 (s, 3H, ArCH3), 3.15 (dd, 1H, J = 12, 4.4, TsNCHHCHOH), 3.41 (dd, 1H, J = 12.2, 4.9, TsNCHHCHOH),
54 3.62 (broad d, 1H, J = 19, TsNCHHCH=C), 3.79(s, 3H, OCH3), 3.91 (d, 1H, J = 3.4,
TsNCHHCH=C), 4.63 (broad s, 1H, CH2CHOHC=C), 6.94 (t, 1H, J = 3.5, CH2CH=C), 7.35 (d, 2H, J = 8, aromatics), 7.71 (d, 2H, J = 7, aromatics). 75 MHz 13C NMR: δ 21.79, 45.44, 49.37, 52.45, 62.75, 100.35, 127.98, 130.14, 136.47. IR (cm-1): 1164, 1718, 2952, + 3492. Mass spectrum m/z (CI ): 312. Anal.Calcd for C14H17NO5S: C, 54.01; H, 5.50; N, 4.56. Found: C, 54.06; H, 5.44; N, 4.59.
1-Tosyl-2-methyl-1,2,3,6-tetrahydro-pyridin-3-ol-4-carboxylic methyl ester (33) A solution of BH adduct 31 (50 mg, 0.15 mmol) was added to a stirring solution of Grubbs #2 catalyst (12 mg, 10 mol %) in DCM (0.01 M). The flask was fitted with a condenser and refluxed under nitrogen for 12 h. The reaction mixture was then reduced in volume to 0.5 mL and purified directly through flash column chromatography. The desired product 33 was obtained in good yield (42 mg, 87 %). 500 MHz 1H NMR: δ 0.87
(d, 3H, J = 4.5, CH3CH), 2.43 (s, 3H, ArCH3), 3.69 (dd, 1H, J = 20, 1.5, TsNCHHCH=C),
TsNCHCH3CHOHC=C), 3.80 (s, 3H, OCH3), 4.28- 4.37 (m, 3H, CHCHOHC=C,
TsNCHCH3CHOHC=C, TsNCHHCH=C), 7.02 (m, 1H, CH2CH=C), 7.32 (d, 2H, J = 8, aromatics), 7.78 (d, 2H, J = 7.5, aromatics). 75 MHz 13C NMR: δ 13.46, 21.53, 40.65, 52.20, 53.91, 66.71, 127.33, 129.70, 129.80, 136.52, 143.79, 165.90. IR (cm-1): 1714, + 2952, 3499. Mass spectrum m/z (CI ): 335. Anal.Calcd for C15H19NO5S: C, 55.37; H, 5.89; N, 4.30. Found: C, 55.27; H, 5.88; N, 4.20.
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144 REFERENCES
1 Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653. 2 Jacobson, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis; Springer: Berlin. 1999; Vol.1-3. 3 Baylis, A.B.; Hillman, M. E. D. German Patent 2155113, 1972; Chem. Abstr. 1972, 77, 34174. 4 T. M. Trnka; R. H. Grubbs, Acc. Chem. Res. 2001, 34, 18. 5 Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815. 6 Hill, J. S.; Issacs, N. S. J. Phys. Org. Chem. 1990, 3, 285. 7 Roos, G. H.; Rampersadh, P. Synth. Commun. 1993, 23, 1261. 8 Kundu, M. K.; Mukherjee, S. B.; Balu, N.; Padmakumar, R.; Bhat, S. V. Synlett. 1994, 444. 9 Rafel, S.; Leahy, J. W. J. Org. Chem. 1997, 62, 1521. 10 Aggarwal, V. K.; Mereu, A.; Tarver, G. J.; McCague, R. J. Org.Chem. 1998, 63, 7183. 11 Yu, C.; Hu, L. J. Org. Chem. 2001, 66, 5413. 12 Kawamura, M.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 1539. 13 Aggarwal, V. K.; Emme, I.; Mereu, A. Chem. Commun. 2001. 1612. 14 Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. J. Org. Chem. 2002, 67, 510 15 Black, G. P.; Dinon, F.; Fratucello, S.; Murphy, P. J.; Nielsen, M.; Eilliams, H. L.; Walshe, N. D. A. Tetrahedron Lett. 1997, 38, 8561. 16 Keck, G. E.; Welch, D. S. Org. Lett. 2002, 4, 3687. 17 Ameer, F.; Drewes, S. E.; Freese, S.; Kayr, P. T. Synth. Commun. 1988, 18, 495. 18 Aggarwal, V. K.; Emme, Ingo.; Fulford, S. Y. J. Org. Chem. 2003, 68, 692. 19 Marko, I. E.; Giles, P. R.; Hindley, N. J. Tetrahedron. 1997, 53, 1015. 20 Adlhart, C.; Chen, P. J. Am. Chem. Soc. 2004, 126, 3496. 21 Lee, C. W.; Grubbs, R. H. J. Org. Chem. 2001, 66, 7155. 22 Calderon, N. Acc. Chem. Res. 1972, 5, 127. 23 Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. 24 Nguyen, S. T.; Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1992, 114, 3974. 25 Huang, J.; Stevens, E. D.; Nolan, S. P.; Perterson, J. L. J. Am. Chem. Soc. 1999, 121, 2674. 26 Love, J. A.; Sanford, M. S.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 10103. 27 Herisson, J. L.; Chauvin, Y. Macromol. Chem. 1970, 141, 161. 28 Crowe, W. E.; Goldberg, D.R. J. Am. Chem. Soc. 1995, 117, 5162-5163 29 Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783. 30 Ameer, F.; Drewes, S. E.; Freese, S.; Kayr, P. T. Synth. Commun. 1988, 18, 495. 31 Gessler, S.; Randl, S.; Blechert, S. Tertahedron Lett. 2000, 41, 9973. 32 Kim, J. M.; Lee, K. Y.; Lee, S.; Kim, J. N. Tertahedron Lett. 2004, 45, 2805.
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33 Lee, M. J.; Lee, K.Y.; Lee, J. Y.; Kim, J. M. Org. Lett. 2004, 6, 3313. 34 Rafel. S.; Leahy, J. W. J. Org. Chem. 1997, 62, 1521. 35 Kim, J. M.; Lee, K. Y.; Lee, S.; Kim, J. N. Org. Lett. 2004, 6, 3313. 36 Boger, D. L.; Jacobson, I. C. J. Org. Chem. 1991, 56, 2115. 37 Furstner, A.; Thiel, O.; Ackermann, L. Org. Lett. 2001, 3, 449. 38 Morgan, J. P.; Grubbs, R. H. Org. Lett. 2000, 2, 3153. 39 Hill, J. S.; Issacs, N. S.; Tetrahedron Lett. 1986, 27, 5007. 40 Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165. 41 Kingsbury, J. S.; Harrity, J. P.; Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791. 42 Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868. 43 Krafft, M.E.; Chirico, X. Tetrahedron Lett. 1994, 35, 4511. 44 Hill, E. A. J. Organometal. Chem. 1996, 514, 1. 45 Robert B. G, The Art of Writing Reasonable Organic Reaction Mechanisms, 2nd ed.; Springer: New York, 2003. 46 Pattenden, G.; Teague, S. J. Tetrahedron. 1987, 43, 5637. 47 Hover, J. A.; Bock, C. W; Bhat, K. L. Heterocycles, 2003, 60, 791. 48 Kampmeier, J. A.; Harris, S. H.; Mergelsberg, I. J. Org. Chem. 1984, 49, 621. 49 Marvell,E.N.; Fleming,M. Tetrahedron Lett. 1973, 24, 3789. 50 Cope, A.C.; Hecht, J.K. J. Am. Chem. Soc. 1962, 84, 4872. 51 Wilson, S.R.; Zucker, P.A.; Kim, C.; Villa, C.A. Tetrahedron Lett. 1985, 26, 1969. 52 Graff, M.; Dilaimi, A. A.; Seguineau, P.; Rambaud, M.; Villieras, J.; TELEAY; Tetrahedron Lett. 1986, 27, 1577. 53 Hamilton, G. S.; Huang, Z.; Yang, X.; Patch, R. J. J. Org. Chem. 1993, 58 7263. 54 Hudlicky, T.; Luna, H. J. Org. Chem. 1990, 55 4683. 55 Suzuki, H.; Monda, A.; Kuroda, C. Tetrahedron Lett. 2001, 42, 1915. 56 Fuerstner, A.; Jumbam, D.; Teslic, J.; Weidmann, H. J. Org. Chem. 1991, 56, 2213. 57 Larock, R. C.; Oertle, K.; Potter, G. F. J. Am. Chem. Soc. 1980, 102, 190. 58 Lee, E.; Lee, Y.; Moon, B.; Kwon, O.; Shim, M.; Yun, J. J. Org. Chem. 1994, 59, 1444. 59 Jumnah, R; Williams, J. M.; Williams, A. C. Tetrahedron Lett. 1993, 34, 6619. 60 Kataoka, T.; Yoshimatsu, M.; Noda, Y.; Sato, T. J. Chem. Soc. Perkin Trans. 1, 1993, 1, 121. 61 Tsuritani, T; Shinokubo, H; Oshima, K. Org. Lett. 2001, 3, 2709.
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BIOGRAPHICAL SKETCH
Eunho Song was born on March 31, 1974 in Seoul, Korea. He graduated from Sungkyunkwan University and received a Bachelor of Science in Chemistry in 1999. In 2001, he received a Master of Science from Sungkyunkwan University in Organic Chemistry. He came to Florida State University in September 2002 to pursue graduate studies in Organic Chemistry.
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