CHAPTER 2 12
2.3 SYNTHESIS OF FRAGMENT COUPLING PARTNERS
2.3.1 Synthesis of [3.2.1]-Bicyclooctene C/D-Bicycle 90
As mentioned above, we envisioned synthesis of the [3.2.1]-bicyclooctane prior to fragment coupling. When considering methods to form these bridged bicycles,1,2 we were intrigued by a report from Sugimura and coworkers for a diastereoselective intramolecular arene-alkene meta-photocycloaddition (Scheme 2.1).3,4 Following the meta- photocycloaddition, Sugimura and coworkers hydrogenate the olefin; we, however, envision leveraging this alkene to incorporate the oxidation pattern of the natural product. Epoxidation of this olefin, followed by Grob-fragmentation would lead to formation of C/D-bicycle 82 which is oxidized at C16.
Scheme 2.1 Sugimura’s diastereoselective intramolecular meta-photocycloadition for the synthesis of [3.2.1]-bicyclooctanes.
To begin, chiral diol 84 was synthesized by Noyori hydrogenation of acetylacetone (83, Scheme 2.2).5 Mitsunobu reaction of 84 with phenol (85) followed by transetherfication of ethyl vinyl ether (86) affords meta-photocycloaddition substrate 78. Irradiation of 78 with UV
45–50% yield (2 steps)
O O
Me Me
OH
Me Me
O O
R S
hν (254 nm)
6
70% yield
1. H2, Pd/C 2. Hg(OAc)2, H2O then NaBH4
[2 steps from phenol]
meta-photocycloaddition H
H Me Me
O H O
6
7 7
7 6
Sugimura 2004
epoxidation O
Me Me
OH
O OH H
O H
Me Me
O H
O H H
H Me Me
O H O
6 7
78 xx
xx
Proposed Fragment Synthesis
79 81
82 Grob
Fragmentation
79 80
16 16
light results in formation of Sugimura’s product 79 in yields comparable to those reported in the original communication. These intramolecular photochemical reactions must be run at low concentrations (~0.01 M) to prevent intermolecular reactions, limiting the largest viable scale of this reaction to 1.5 grams per batch. With 79 in hand, we set out to test the proposed epoxidation and Grob-fragmentation to access 82. Epoxidation with mCPBA followed by treatment with aqueous hydrochloric acid furnishes the desired C/D-bicycle 82. Luche reduction of 82 yields the axial C14 alcohol 83. The C14/C16-1,3-diol is protected as the siliconide 84. Having functionalized the D-ring, the chiral auxiliary needed to be removed.
Oxidation of alcohol 84 using Stahl’s conditions produces β-alkoxyketone 85 which is treated directly with basic methanol to cleave the auxiliary via E1cB elimination to give alcohol 86 as a single enantiomer. This alcohol is then oxidized to give ketone 87.
Scheme 2.2 Synthesis of [3.2.1]-bicyclic ketone 87 enabled by Sugimura’s meta- photocycloaddition
hν (254 nm) pentane 67% avg. yield ( 5 x 1.5 g batches)
Me Me
O O
Ru[R-BINAP]Cl2 (0.1 mol %) H2 (1100 psi)
Me Me
OH OH
R R
84
$235/g from Sigma
Hg(OAc)2 (20 mol%) OEt reflux THF, 20 °C
OH (1.1 equiv) DIAD, PPh3
56% yield (2 steps) 85% yield
45 g scale EtOH 30 °C
1.
2.
Me Me
O O
R S
78
O Me Me
OH
O OH
H
H Me Me
O H O
79 82
m-CPBA CH2Cl2, 0 to 19 °C;
then HCl (aq.) 19 °C 82% yield O
Me Me
OH
OH 83
NaBH4 CeCl3•7H2O MeOH, -78 °C
89% yield OH
t-Bu2Si(OTf)2 2,6-lutidine
O Me Me
OH
O Si O
t-Bu t-Bu
CH2Cl2, –78 °C 93% yield
HO
O Si O t-Bu t-Bu then K2CO3
93% yield O
O Si O t-Bu t-Bu
Me Me
O
not isolated
MeOH
86 84
83
C D
9
13 14
12 10
12 10
9 13 14 12 10
9 13 14
85
86
Cu(MeCN)4OTf (5 mol %)
MeOBpy (5 mol %) ABNO (5 mol %) NMI (10 mol %) MeCN, air, 20 °C
91% yield Cu(MeCN)4OTf (5 mol %)
MeOBpy (5 mol %) ABNO (5 mol %) NMI (10 mol %) MeCN, air, 20 °C
85 O Si O
t-Bu t-Bu 87 O
To access a precursor to an organometallic C/D-bicycle fragment, C10-ketone 87 was converted to an alkenyl halide (Scheme 2.3). The ketone was first converted to alkenyl triflate 88 using KHMDS and Comins’ reagent. A Stille coupling of 88 and hexamethylditin forms the corresponding alkenyl stannane which is converted to alkenyl iodide 89 upon treatment with N-iodosuccinimide. While this sequence was effective, it requires the use of stoichiometric quantities of the expensive and highly toxic reagent hexamethylditin. Recently, our lab reported a convenient nickel-catalyzed method to achieve the same transformation.6 The conditions were optimized for substrate 88, screening nickel (II) catalysts, catalyst loading and additives (Table 2.1). 5 mol % loading of Ni(OAc)2•4H2O with NMI as the additive were the optimal conditions, delivering alkenyl bromide 90 in 87% yield. The main limitation was scalability of the reaction—scaling the reaction past 2.3 mmol (1.0 grams) of substrate results in incomplete conversion. This is likely due to the heterogeneity of the reaction; vigorous stirring was key to achieving complete conversion of starting material. In all, this represents a 10-step synthesis of the C/D-bicycle coupling partner 90.
Scheme 2.3 Synthesis alkenyl halide coupling partner 89 via Stille coupling.
KHMDS, THF, –78 °C then Comins’ reagent
96% yield
TfO
O Si O
t-Bu t-Bu
O Si O
t-Bu t-Bu
87 O
88 89
Me6Sn2, Pd(PPh3)4 LiCl, THF, 70 °C
I
O Si O
t-Bu t-Bu
then NIS 0 °C 80% yield
10
Table 2.1 Optimization of Ni-catalyzed conversion of enol triflate 88 to alkenyl bromide 90.
2.3.2 Enantioselective Synthesis of A/F-Bicycle Epoxy Ketone 71 Our synthesis of epoxy ketone fragment 71 began with an asymmetric Michael addition of dimethyl malonate (74) to 2-cyclopenten-1-one (73) using Shibasaki’s heterobimetallic catalyst 97 (Scheme 2.4).7 We developed a highly scalable protocol for this reaction, providing 91 in 88% yield and 91% enantiomeric excess (ee) on 31 g scale.8 The ketone of 91 was converted to ketal 92 by treating with ethylene glycol and catalytic acid in benzene at reflux using a Dean-Stark reaction setup. Alkylation of the malonate with three-carbon fragment 75 forms the C4 quaternary center in 93. Acid-catalyzed double dioxolane deprotection and concomitant aldol condensation closes the A-ring to give enone 94. A two-step sequence was employed to introduce the epoxide on the concave face: treatment of 94 with the strongly
Entry [Ni] loading (x) Temp
3 2.5 mol % 26 °C
4 5 mol % 26 °C
5 7.5 mol % 21 °C
Ni(OAc)2 •4H2O
“
"
[Ni]
6 “ 10 mol % 26 °C
1 NiBr2 10 mol % 21 °C
2 NiBr2•dme 10 mol % 21 °C
aNMR yield using dimethylfumarate as internal standard
yield
3:1 pdt:SM 1.4:1 pdt:SM
74%a 69%
30%a 60%a Scale (mmol)
0.1 0.1 0.1 0.1 0.1 0.1
Additive
“
‘’
‘’
‘’
DMAP
‘’
10 1.0 “ 5 mol % “ 21 °C 87%
8 0.3 “ 7.5 mol % “ 21 °C 78%
7 0.1 “ 10 mol % NMI 25 °C 66%
O Si O t-Bu t-Bu TfO
[Ni] (x mol %) Zn (2x mol %) additive (2x mol %)
LiBr (1.5 equiv.)
3:1 THF:DMA O Si O
t-Bu t-Bu Br
11 2.3 Ni(OAc)2 • 4H2O 5 mol % NMI 21 °C 87%
88 90
9 0.3 “ 5 mol % “ 21 °C 81%
electrophilic bromonium ion source N-bromosacharrin (95) and water furnishes bromohydrin 96, isolated as a single diastereomer in 63% yield. The crude diastereomeric ratio (d.r.) for this reaction was ~3:1. Elimination of HBr to yield the epoxide 71 was easily achieved by treating 96 with triethylamine at ambient temperature. 71 was recrystallized to enantiopurity, giving access to this A/F-fragment in six steps from commercial starting materials.
Scheme 2.4 Enantioselective synthesis of epoxy ketone 71.
2.4 1,2-ADDITION/SEMIPINACOL REARRANGEMENT FRAGMENT COUPLING SEQUENCE
Having synthesized our key fragments for the synthesis of 1, we set out to test our fragment coupling sequence (Scheme 2.5). Alkenyl bromide 90 was converted to the alkenyl lithium 72 upon treatment with tert-butyllithium at low temperature. This alkenyl lithium was added slowly by cannula to a solution of the epoxy ketone 71 at -94 °C. The 1,2-addition was quenched with TMSCl to give epoxy silyl ether 98 in good yield on 3.8 gram scale. Treatment of the 1,2-addition product 98 with a catalytic amount of the Lewis acid TMSNTf2 and a pyridine base affords semipinacol rearrangement product 99 in near quantitative yield on 4.3
+
H
O MeO2C
MeO2C GaNa-(S)-BINOL (10 mol%)
NaOt-Bu (7 mol%) THF/Et2O, 21 °C 88% yield, 91% ee
[31 g scale]
MeO2C O MeO2
74C 73 91
ethylene glycol p-TsOH•H2O benzene, reflux
85% yield
H MeO2C MeO2C
O O
91% yield
Br O
O
NaH, n-Bu4NI DMF, 0 to 21 °C
92
75 HCl (aq)
acetone 70 °C
74% yield H O
MeO2C O MeO2C
O O
2
H MeO2C
MeO2C O
MeCN/H2O, 21 °C 63% yield
CH2Cl2, 21 °C
99% yield H
MeO2C
MeO2C O
O H
MeO2C
MeO2C O
OH
Br Et3N
recrystallized to 99% ee S
N O
O O Br
94 93
95
96 71
A
F O
O O Ga O Na
GaNa-(S)-BINOL 97
4
gram scale. This remarkable two-step sequence brings together all of the carbon atoms needed to access the aconitine core and forms the key C11 quaternary center, demonstrating the power of 1,2-addition/semipinacol rearrangement as a fragment coupling tactic.
Scheme 2.5 1,2-Addition/semipinacol rearrangement fragment coupling to prepare 99.