11-step asymmetric synthesis of (–)-bilobalide · 2019. 5. 30. · 3 the synthesis commenced with...
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doi.org/10.26434/chemrxiv.8202053.v1
11-Step Asymmetric Synthesis of (–)-BilobalideMeghan Baker, Robert Demoret, Masaki Ohtawa, Ryan Shenvi
Submitted date: 29/05/2019 • Posted date: 30/05/2019Licence: CC BY-NC-ND 4.0Citation information: Baker, Meghan; Demoret, Robert; Ohtawa, Masaki; Shenvi, Ryan (2019): 11-StepAsymmetric Synthesis of (–)-Bilobalide. ChemRxiv. Preprint.
The Ginkgo biloba metabolite bilobalide (BB) is widely ingested but poorly understood. However, itsantagonism of gamma-aminobutyric acid A receptors (GABAAR) has been tied to rescue of cognitive deficitsin mouse models of Down syndrome. Prior syntheses required multistep redox strategies to mitigatecompeting reactions of functional groups—emergent properties of the BB scaffold that cause unexpectedreactivity. Here we exploit the unusual reactivity of bilobalide to affect a late-stage ‘inside-out’ oxidation thatsymmetrizes the molecular core and allows oxidation states to be embedded in the starting material, resultingin an 11-step synthesis. The stereochemically dense scaffold is accessed in asymmetric fashion through anovel catalytic enantioselective Reformatsky reaction and a solvent-dependent radical hydration. Stericcompression and a parallel kinetic resolution result in the diastereoselective formation of a remarkablyacid-stable oxetane acetal that proves crucial to relay stereochemical information.
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Title: 11-Step Asymmetric Synthesis of (–)-Bilobalide Meghan A. Baker,1* Robert M. Demoret,1* Masaki Ohtawa1†‡ and Ryan A. Shenvi1‡
Affiliations: 1Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States. †Present Address: Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan ‡Correspondence to: [email protected], [email protected] *These authors contributed equally to this work. Abstract: The Ginkgo biloba metabolite bilobalide (BB) is widely ingested but poorly understood. However, its antagonism of gamma-aminobutyric acid A receptors (GABAAR) has been tied to rescue of cognitive deficits in mouse models of Down syndrome. Prior syntheses required multistep redox strategies to mitigate competing reactions of functional groups—emergent properties of the BB scaffold that cause unexpected reactivity. Here we exploit the unusual reactivity of bilobalide to affect a late-stage ‘inside-out’ oxidation that symmetrizes the molecular core and allows oxidation states to be embedded in the starting material, resulting in an 11-step synthesis. The stereochemically dense scaffold is accessed in asymmetric fashion through a novel catalytic enantioselective Reformatsky reaction and a solvent-dependent radical hydration. Steric compression and a parallel kinetic resolution result in the diastereoselective formation of a remarkably acid-stable oxetane acetal that proves crucial to relay stereochemical information. Main Text: The leaves of Ginkgo biloba have been used historically as insecticides and helminthicides1,2, activity attributed to its constituent terpene trilactones, including bilobalide (BB, 1)3,4. Ginkgo extracts have seen use in traditional Chinese medicine to treat senility, a practice that has penetrated the Western world, albeit controversially, due to opposing claims of efficacy5,6 and serious adverse effects associated with Ginkgo toxin (4-O-methylpyridoxine)7 or inhibition of platelet aggregating factor (PAF)8 by ginkgolides. In 2012, over 1 million US adults reported ingestion of Ginkgo extracts, despite lack of clear benefit for healthy individuals and uncertain mechanisms (see below). Animal models demonstrate some credible effects on impaired cognition: Down syndrome model mice (Ts65DN), which show deficits in declarative learning and memory, exhibit normalized novel object recognition after treatment by pure BB9. Rescue of learning and memory is proposed to arise through neuronal excitation by antagonism of gamma-amino butyric acid-gated ion channels (GABAA receptors, GABAARs), which are homologous to insect GABA-gated ion channels, common targets of insecticides10. GABAARs are chloride-selective ionotropic receptors gated by the ligand gamma-amino butyric acid. They mediate fast synaptic transmission via inhibitory currents that lower the membrane potential away from the threshold necessary to generate an action potential. Unlike the plant metabolite and GABAA antagonist picrotoxinin (PXN, Figure 1), BB is not acutely toxic, and unlike the gingkolides, BB does not affect PAF. Despite their disparate toxicity, BB and PXN exhibit similar inhibitory potencies at recombinant GABAΑRs (IC50 = 4.6 μM vs. 2.0 μM, respectively; α1β2γ2L, Xenopus laevis oocytes), but differentially inhibit the actions of GABAΑR positive modulators and occupy distinct binding sites within the ion channel11. The lack of convulsant activity coupled with neuroprotective effects have led some to postulate an alternative, unidentified target12. However,
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steric congestion and the well-known instability of 14,13 have prevented pulldown of biological targets other than GABAΑRs. A concise and flexible synthesis of 1 would provide a platform to generate probes for identification of potential new targets; analogs with differential selectivity between insect and human GABAΑRs; and stabilized analogs that enhance serum half-life 14.
In addition to incomplete approaches15–17, two prior syntheses of BB have been completed [24 steps enantioselective18,19; 17 steps racemic20], both of which established the cyclopentane core with efficiency but required 8-11 subsequent redox steps to reach the target. Guided by these challenges, we realized that a single oxidation transform might reduce synthetic complexity by unmasking a pseudosymmetric fused dilactone, ultimately leading to a symmetric starting material (see Figure 1). However, late-stage installation of the deep C10 hydroxyl (Figure 1, highlighted in red) presented a problem. Neither hydrogen of its precursor inner-lactone (shown in green) seemed accessible, whereas a hydrogen of the outer-lactone (shown in blue) resided at the surface of bilobalide’s bowl-like scaffold. If this single oxidation were possible, the dense, oxidized core of 5 might be quickly assembled via radical reactions that mitigate the high transition state barriers associated with forming four contiguous fully-substituted carbon atoms of the bilobalide core. However, the close proximity of functional groups and steric compression imparted by a tert-butyl substituent result in unusual emergent properties21,22 of the scaffold: unanticipated reactivity not associated with an individual component, but multiple interacting components22,23. The form emergence commonly takes in natural product syntheses is to complicate synthetic planning and execution, which cannot anticipate all reactivity of all possible transforms a priori from first principles24, an important consideration given recent interest in computer-assisted design25,26. In this case, however, the unexpected properties of the bilobalide scaffold are used advantageously in a 10-step synthesis of (–)-des-hydroxybilobalide (>99% ee, 5, Figure 1), which relies on stereocontrol transmitted from an unusual oxetane acetal stabilized by steric compression. A surprising late-stage oxidation is rendered regioselective using skeletal rearrangement and anomeric acidification, completing the synthesis of (–)-bilobalide in a single additional step.
t-Bu
OO
O
O
O
O
HO
O
Me
OH
H OHH
H
O
O
O
HOt-Bu
O
H
O
HHO
H
O
1: bilobalide 3: ginkgolide A
O
OHOO
Me
O O
H
Me
2: picrotoxinin
O
O
O
t-Bu
O
H
O
HO
H
O
embeddedsymmetry
CO2Bn
CH(OMe)2
CO2Bn
O
O
O
O
HHOH
H
O OOH
Me
Me
Me
10
buriedhydroxyl
a
b
surfaceproton
10
O
O
O
O
HHH
H
O OOH
Me
Me
Me
10 [O]
buriedproton
5 1
NMe
HO
MeO
OH
4: ginkgotoxin
OH
t-Bu
7-carbonfragment
symmetricdiester
rac-1(–)-1
O
RO2C
RO2C
t-Bu
R = (+)-menthyl
O
O
OPiv
H
TMSO
t-BuHO
11 redoxsteps
8 redoxsteps
c Previous synthesesCorey et al. 24 total steps Crimmins et al. 17 total steps (racemic)
10steps
3 redoxsteps
'insideout'
[Ref. 19] [Ref. 20]
Figure 1. a. Plant metabolites active in the human nervous system; b. late-stage excision of a buried C-H bond in bilobalide (BB) allows oxygens to be placed in a symmetric starting material; c. prior work iteratively changed oxidation states.
[innerlactone]
[outerlactone]
3
The synthesis commenced with a methodological challenge: an asymmetric Reformatsky reaction between 6a and 6b (both available in one step, see Supplementary Information). Reformatsky conditions proved necessary due to the tendency of 7 to undergo retro-aldol cleavage under basic conditions, whereas zinc, chromium and samarium alkoxides were stable at -78 °C. Although there are examples of chiral auxiliary-mediated Reformatsky reactions27, incorporation of, for example, a chiral oxazolidinone into 6a was unsuccessful. There have been no examples of catalytic enantio- and diastereoselective zinc Reformatsky reactions27, nor use of simple, chiral L-type ligands like bisoxazolines. Wolf has demonstrated the use of electron-rich X-type hemiaminals to control single stereocenters28, and the simplicity of these conditions provided a foundation to explore. Bromide 6a benefits from double activation by both carbonyl and alkene moieties, which we hypothesized might allow for the use of more standard chiral ligands and simultaneously induce diastereocontrol through an allylation mechanism. After a ligand screen, we found that a combination of diethylzinc and indabox (10 mol% A) were effective to provide secondary alcohol 7 in 97:3 er in favor of syn-diastereomer 7 (2.3:1). Route-scouting determined that the corresponding anti-diastereomer was ineffective and led to the undesired diastereomer in the next step, but ligands that increasingly favored syn-7 provided lower enantioselectivity. To the best of our knowledge, this is the first example of a catalytic enantioselective zinc Reformatsky reaction with a branched nucleophile. The doubly-activated nucleophile may uniquely enable use of simple bisoxazoline ligands, which have eluded use for enantioselective Reformatsky reactions27. The synthesis had been designed to benefit from radical reactivity, but early strategies to form the hindered cyclopentane core via sp3-hybridized carbon-centered radicals failed. However, we reasoned that a sp2-hybridized radical might possess higher potential energy and benefit from lower steric repulsion in the transition state. In fact, a Giese-type 5-exo-trig cyclization of 7 occurred with high regio- and diastereoselectivity (20:1 dr; 6-endo-trig n.d.) to form the quaternary carbon of cyclopentene 829. Recrystallization purified the material to >99% enantiomeric excess; the relative and absolute stereochemistry was confirmed by x-ray crystallography (see SI). Prior syntheses of 1 installed the extremely hindered tert-alkyl, bis-neo-pentyl C8 hydroxyl either by late-stage dihydroxylation with stoichiometric OsO4 (23 °C, 12 hr) followed by mono-deoxygenation18; or by early-stage nitrile anion addition to a tert-butyl ketone, which rendered the synthesis racemic20. The intervening years have established the Drago-Mukaiyama hydration as an effective method to chemoselectively hydrate alkenes, even in cases of extreme hindrance. Steric tolerance is thought to derive from a metal-hydride hydrogen atom transfer (MHAT) mechanism, which generates a reactive intermediate without the need for alkene coordination. Stereochemistry, however, can be capricious and substrate dependent. In this case, application of standard conditions delivered a low-yield of 9 with no diastereoselectivity (Figure 2b, entry 4). We recently discovered that the kinetically-relevant reductant in many Mukaiyama reactions is an alkoxysilane (e.g. Ph(i-PrO)SiH2) formed in situ by silane alcoholysis30. This custom, commercially available silane allowed us to screen a diverse range of solvents, whereas standard conditions are restricted to alcoholic solvents. In this case, we identified a correlation between solvent polarity and diastereoselectivity—a helpful observation since ligands on the metal catalyst had no effect on dr. Although tert-butylmethyl ether favored the wrong (S)-C8 diastereomer of alcohol (which cyclized to a lactone), methylcyclohexane reversed this stereoselectivity to favor (R)-C8 diastereomer 9 in a 3:1 excess. This effect may derive from an internal hydrogen bond enforced by nonpolar solvent that favors one pyramidalized carbon radical over the other (see Figure 2b). Solvent-controlled stereochemical reversal has never been observed in the broadly-applied Mukaiyama hydration, and is only possible due to the solvent tolerance of Ph(i-PrO)SiH2.
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Figure 2. Synthesis of (–)-bilobalide. Reagents and conditions: (1) 6a, 6b (1.2 equiv.), A (10 mol%), Et2Zn (3.0 equiv.), THF, -78 °C; (2) Bu3SnH (1.5 equiv.), AIBN (0.1 equiv.), PhMe, 85 °C (3) Mn(dpm)3 (10 mol%), Ph(i-PrO)SiH2 (3.0 equiv.), PPh3 (1.5 equiv.), methylcyclohexane, O2 (1 atm), 50 °C; (4) (–)-B4 (10 mol%), THF/H2O (2:1), 23 °C; (5) IBX (3.0 equiv.), DMSO, 23 °C; (6) TMS-EBX (3.0 equiv.), TBAF (3.0 equiv.), THF, -78 °C to -20 °C; (7) SmI2 (8.4 equiv.), THF/H2O (5:1), 0 °C; (8) LiHMDS (3.0 equiv.), THF, -78 °C; B(OMe)3 (5.0 equiv.), 23 °C; mCPBA (5.0 equiv.), 0 °C; (9) H2, Pd/C (10 wt%), MeOH, 23 °C; 3M HCl (aq.), 80 °C; (10) Bz2O (1.5 equiv.), DMAP (1.5 equiv.), THF, 23 °C; KHMDS (3.0 equiv.), -78 °C, (±)-C (3 equiv.), -78 °C; 3M HCl (aq.), 80 °C.
CO2Bn
CH(OMe)2
Br
BnO2C
(±)-6a (one step) (–)-7 (97:3 er)
1. 3 equiv. Et2Zn 10 mol% (–)-A
HO
t-BuCH(OMe)2
CO2Bn
CO2Bn
H2. Bu3SnH, AIBN
3. Mn(dpm)3, Ph(i-PrO)SiH2 C7H14, O2
HO
HO
CO2Bn
CO2Bn
H
CH(OMe)2
3:1 dr, 67%(singleisomer)
4.5:1 dr71% (single isomer)
t-Bu
CO2BnCO2Bn
OR1
R2
HO
t-Bu
HOCO2Bn
CO2Bn
OOMe
H
H 4. 10 mol% (–)-B
t-Bu OH
O
CO2BnH
O
CO2BnOMe
8. LHMDS B(OMe)3;
m-CPBA55%
2M HCl, 70 °C90%
9. H2, Pd/C;
(–)-8
(+)-9(+)-12
(–)-5(+)-13
5. IBX6. TMS-EBX7. SmI2
20:1 dr60% (3 steps)
20:1 dr60% (single isomer)
Br
t-BuCHO
(+)-10: R1 = OMe, R2 = H(+)-11: R1 = H, R2 = OMe
Ar
O
Ar
OP
O
OH64%, 2.3:1 dr
TMSIOO
TMS-EBX
CH(OMe)2
CO2Bn
CO2Bn
OH
t-Bu
BrH6b
55
HO
t-BuCH(OMe)2
CO2Bn
CO2Bn
H 10 mol% Mn(dpm)3,Ph(i-PrO)SiH2,
HO
t-Bu
HO
CO2Bn
CO2Bn
H
CH(OMe)2
(–)-8 (+)-14
Entry Variations 9 : 14
1 none
i-PrOH / PhSiH3 not C7H14 / Ph(i-PrO)SiH2
75 : 25t-BuOMe not C7H14
a
PhSiH3 not Ph(i-PrO)SiH2
234
36 : 64NR
50 : 50
O2, PPh3,C7H14, 50 °C
+
(+)-9
HOCO2BnH
O
O
CH(OMe)2
t-Bu
t-BuBnO2C
O
MeO H
H
BnO
MeO
b. Solvent screen enabled by Ph(i-PrO)SiH2
Entry Variations 10 : 11
(±)-(9) PTSA, THF/H2O (1:1)
(–)-B, THF/H2O, 22 °C
25 : 75(–)-B, THF/H2O, 50 °C(±)-(9)
(+)-(9)
63 : 37a
82 : 18
THF/H2O, 50 °C
HO
t-Bu
HO
CO2Bn
CO2Bn
H
CH(OMe)2
c. Acid-catalyzed oxetane acetal formation
10 mol% (–)-B
(–)-B, THF/H2O, 50 °C(-)-(9) 42 : 58
a10: 39:61 er, 11: 69:31 era C7H14 = methylcyclohexane
9
8
t-Bu
O H
O
O
O
O
HHOH
H
O OOHMe
Me
Me
O
O
O
O
HHH
H
O OOHMe
Me
Me10. Bz2O, DMAP;
KHMDS,Davis reagent (±)-C;
3 M HCl, 49%(75% based on recovered (–)-5)
10 + 11
(–)-1
a. Synthesis of (–)-bilobalide (1)
N N
OO
Me Me
(–)-A
(–)-B
NSO2PhO
PhH
(±)-C
Ar = 9-phenanthryl
10 10
H
5
Carbon-carbon bond formation to access the fourth contiguous, fully-substituted carbon atom was frustrated by substrate instability and stereoselectivity: 9 dehydrated under basic conditions, and many strategies for alkylation delivered the wrong diastereomer at C5. To reverse this diastereoselectivity, we sought global deprotection of the benzylesters and dimethyl acetal, and formation of the fused-bislactone motif of 1 prior to the final carbon installation. To our surprise, treatment of 9 with strong acid led to unexpectedly stable and highly unusual oxetane acetals 10 (endo-OMe) and 11 (exo-OMe). The rare oxetane acetal motif is characteristic of thromboxane A2 (TXA2)31 and dehydrated rhamnopyranoses32, where this strained ring is formed by base only and noted for its marked instability to acid. Not surprisingly, we could find no examples of an oxetane acetal formed under acidic conditions by trans-ketalization. Stabilization of 10 and 11 is likely driven by steric compression of the alcohol and acetal carbons from the adjacent tert-butyl and ester groups, respectively—a ‘corset effect’ that increases the barrier to ring-opening of strained molecules like tetrahedranes33.
To our frustration, only the minor endo-isomer 10 could be carried forward: the major exo-OMe diastereomer 11 dehydrated under basic conditions and its epimerization to 10 was unsuccessful. However, early racemic route scouting had provided a possible way forward. Screening a library of scalemic binolphosphoric acids had been expected to improve diastereoselectivity, but this effort yielded disappointing results: a 1.7:1 preference for 10 using catalyst B. Analysis by chiral chromatography, however, indicated that a moderate parallel kinetic resolution of (rac)-9 had occurred: each diastereomer possessed opposite enantiomeric excess [39:61 er versus 69:31 er]. In other words, in a striking example of match/mismatch pairing, each enantiomer of 9 had reacted with different and inverse diastereoselectivity in the presence of chiral acid B. Accordingly, a single enantiomer of 9, if matched with the correct enantiomer of chiral acid, would favor formation of the desired endo-10. Indeed, whereas (–)-9 reacted with (–)-B to favor (1.4:1) exo-acetal 11, (+)-9 reacted to favor (4.5:1) endo-acetal 10, isolated in 71% yield as a single enantiomer. Endo-acetal 10 proved crucial to control formation of the final quaternary carbon. Due to extreme steric hindrance in substrate 10, the final C–C bond could only be established using a sterically unencumbered alkyne electrophile. A 3-step sequence was run in quick succession due to intermediate instability; only alkyne 12 could be purified. First, IBX oxidation delivered an unstable β-keto ester that could undergo α-alkylation. Second, this mixture of keto-enol tautomers was treated with TMS-EBX and TBAF in the procedure developed by Waser34. The endo-methoxy oxetane effectively shielded one trajectory of electrophile approach and provided the product as a single diastereomer. In contrast, the exo-methoxy oxetane, if carried forward to this step, eliminated the tert-alkyl ether and did not undergo alkynylation. Alkynylation prior to oxetane formation delivered exclusively the incorrect diastereomer. The unstable alkynylation product was reduced with high stereoselectivity using SmI2 in a mixture of THF/H2O to provide the stable alcohol 12 in 60% yield over 3 steps. Traditional hydride reductants produced the opposite diastereomer. The excellent diastereoselectivity of the reduction may stem from chelation of samarium to the oxygen atom of the oxetane35,36. Anti-Markovnikov hydration of the alkyne to directly incorporate the northern lactone motif could not be accomplished under a variety of standard conditions37,38, including oxidation by lithium tert-butylperoxide39, so an alternative procedure was developed instead. Deprotonation of the terminal alkyne with LiHMDS followed by treatment with trimethylborate led to the formation of an alkynylborate intermediate. Addition of mCPBA to the reaction mixture likely formed an intermediate ketene and/or mixed anhydride that was captured by the adjacent alcohol to directly generate the northern lactone in a single step and in 50% yield. To the best of our knowledge, this procedure for alkyne oxidation has not been
6
reported. Hydrogenolysis of the benzyl esters followed by in situ acidic hydrolysis caused skeletal rearrangement to yield (–)-5 in excellent yield and a total of ten steps from commercially available materials. The brevity of this sequence to des-hydroxy-bilobalide validated the strategy of dilactone symmetrization by retrosynthetic C-O bond excision. Yet it also relied, crucially, on the ability to regio-, chemo- and stereoselectively install this final hydroxyl deep in the molecular cavity. Introduction of the final C10 oxygen proved challenging. The extreme steric hindrance and ‘bowl’ shape of 5, in addition to its base-lability, derailed many potential solutions to the problem of deep oxidation. For example, 5 contains three acidic sites—the hydroxyl, the inner-lactone and the outer-lactone—but addition of 3 equivalents of strong base, followed by acidic quench at -78 °C caused significant decomposition and poor mass recovery. Acidic conditions themselves were well tolerated. In fact, 5 and (–)-1 could be heated in 2 M HCl (aq.) for 48 hours with no effect. After some experimentation, we discovered that treatment with exactly one equivalent of KHMDS followed by addition of aqueous 1M HCl caused full mass recovery, but cleanly delivered the iso-bilobalide scaffold (e.g. 16a, Figure 3), a result of intramolecular translactonization. This same skeletal rearrangement has been reported to occur under conditions of acetylation and pivaloylation at room temperature 40. Similarly, we found translactonization to occur at low temperature with alkali amide bases or at room temperature with DBU (BB to iso-BB, see SI). This rearrangement is probably driven both by the proximity of the C8 hydroxyl to the Bürgi-Dunitz angle of C4, as well as delocalization of the lactone π-system into the adjacent C-O σ* orbital. Both of these idiosyncrasies of the BB ring system likely result in its extreme base lability (see above), yet the latter anomeric effect proved crucial to the synthesis, enabling a solution to the problem of deep oxidation. Molecular models revealed that the iso-BB rearrangement partially folds the skeletal cavity ‘inside-out’ (see Figure 3) to render the inner lactone protons more accessible to reagents. However, neither the alkoxide of 1 nor its tert-butyldimethylsilyl (TBS)
O
O
O
O
HHH
H
O OOHMe
Me
Me
10O
O
O
O
HHOH
H
O OOHMe
Me
Me
101O
O
O
O
OHHH
H
O OOHMe
Me
Me
1
+
O
O
O
O
OOO
Me
Me
Me
R
H
H
seeconditions
KHMDS, (±)-CTHF, -78 °C;2M HCl, 60 °C
NSO2PhO
PhH
(±)-C
1. TBSOTf, 2,6-lut;2. KHMDS, (±)-C THF, -78 °C 2M HCl, 60 °C
1. EDCI, BzOH, DMAP2. KHMDS, (±)-C THF, -78 °C 2M HCl, 60 °C
KHMDS
0% 100%
6% 94%
91% 9%
5 (–)-1a 15a
5
O
H
H
OBz
H
σ*
πO
O
O
O
O
HHH
H
O OOHMe
Me
Me
10 1
16a: R = K16b: R = TBS16c: R = Bz
16a: KHMDS
16b: TBSCl16c: BzOH
16c (Bz removed for clarity)
unfolding
HH
4
4
5
entry 1
entry 2
entry 3
Figure 3. 'Inside-out' oxidation to complete (– )-1. Reagents and conditions for entry 3: 1. EDCI (3 equiv.), BzOH (3 equiv.), DMAP (0.1 equiv.), THF; 2. KHMDS (1.5 equiv), (± )-C (1.5 equiv); 2M HCl, 60 ° C a Based on conversion.
'inside-out'
180°
7
ether (16b) provided substantial BB upon treatment with oxidant (Davis’ oxaziridine, (±)-17). Despite the unfolding of the BB cavity and C10-proton exposure (highlighted in green), base still favored deprotonation of the outer lactone and therefore oxidation provided the isomeric ‘neo-bilobalide’ 15. We wondered if inner lactone deprotonation required both increased exposure (rearrangement) and increased acidification. Delocalization of the lactone π-system into an adjacent, withdrawn C-O σ* orbital might acidify the α-protons, i.e. stabilize the corresponding enolate41. To our surprise, conversion of 5 to the isomeric benzoate followed by deprotonation and oxidation at low temperature yielded (–)-1 with only a trace of 15. Comparison of available crystal structures revealed lactone C-O bond lengths of benzoate 16c consistent with decreased π-character (see Supplementary Information), which might acidify the inner lactone. Combination of benzoylation and oxidation into one step proved successful, scalable and selective; neo-bilobalide (11) could not be detected. As a consequence of this risky yet successful late-stage deep-oxidation, we were able to complete an eleven-step synthesis of (–)-(1). In summary, we have developed an 11-step synthesis of (–)-bilobalide that relies on the idiosyncratic properties of its complex, dense scaffold. The reactivity that emerges from multiple interacting components (double-activation of organobromide 6a, steric compression of 9, inside-out oxidation of 5) is both subtle and unprecedented. Yet the empirical discoveries reported here enable a flexible and concise synthesis: the sequence shown in Figure 2 has been completed in seven days by one person to produce 0.35 g of (–)-5. The brevity of the route is due to 1) a late-stage oxidation that symmetrizes the embedded fused dilactone; 2) a stereoselective alkynylation relayed by a corset-stabilized oxetane acetal; 3) a solvent-controlled Mukaiyama hydration made possible by the silane reagent Ph(i-PrO)SiH2; and 4) a catalytic enantio- and diastereoselective zinc Reformatsky reaction, the first of its kind. The same overall strategy disclosed here may be applicable to G. biloba congeners including the ginkgolides, some of which are glycine receptor (GlyR)-selective antagonists42. Access to 1 allows chemical modification for serum stability and derivatization for secondary target identification. In addition, we hope to perturb receptor selectivity between insect versus human homologues, and among GABAAR subtypes. The therapeutic potential of (–)-1 and its incompletely understood effects can now be interrogated through chemical synthesis.
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References and Notes:
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2. Thompson, A. J., McGonigle, I., Duke, R., Johnston, G. A. R., Lummis, S. C. R. A single amino acid determines the toxicity of Ginkgo biloba extracts, FASEB J. 26, 1884–1891 (2012).
3. Nakanishi, K. et al. Structure of bilobalide, a rare tert-butyl containing sesquiterpenoid related to the C20-ginkgolides, J. Am. Chem. Soc. 93, 3544-3546 (1971).
4. Strømgaard, K., Nakanishi, K. Chemistry and Biology of Terpene Trilactones from Ginkgo Biloba, Angew. Chem. Int. Ed. 43, 1640–1658 (2004).
5. Weinmann, S., Roll, S., Schwartzbach, C., Vauth, C., Willich, S. N. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis, BMC Geriatr. 10, 14 (2010).
6. Hashiguchi, M., Ohta, Y., Shimizu, M., Maruyama, J., Mochizuki, M. Meta-analysis of the efficacy and safety of Ginkgo biloba extract for the treatment of dementia, J. Pharm. Health Care Sci. 1, 14 (2015).
7. Wada, K. et al. Studies on the constitution of edible medicinal plants. Isolation and identification of 4-O-methyl-pyridoxine toxic principle from the seed of Ginkgo biloba, Chem. Pharm. Bull. 36, 1779–1782 (1998).
8. Vale, S. Subarachnoid haemorrhage associated with Ginkgo biloba, Lancet 352, 36 (1998). 9. Fernandez, F. et al. Pharmacotherapy for cognitive impairment in a mouse model of Down
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9
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35. Evans, D.A., Kaldor, S.W., Jones, T.K., Clardy, J., Stout, T.J. Total Synthesis of the Macrolide Antibiotic Cytovaricin, J. Am. Chem. Soc. 112, 7001-7031 (1990).
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37. Shu, C., Liu, M.Q., Sun, Y.Z., Ye, L.W. Efficient Synthesis of g-Lactones via Gold-Catalyzed Tandem Cycloisomerization/Oxidation, Org. Lett. 14, 4958-4961 (2012).
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39. Julia, M., Saint-Jalmes, V.P., Verpeaux, J.N. Oxidation of Carbanions with Lithium tert-Butyl Peroxide, Synlett 3, 233-234 (1993).
40. Weinges, K., Hepp, M., Huber-Patz, U., Irngartinger, H. Chemistry of ginkgolides. III. Bilobalide/isobilobalide. Structure determination by x-ray analysis, Liebigs Ann. Chem. 1079–1085 (1986).
10
41. Byun, K., Mo, Y., Gao, J. New Insight on the Origin of the Unusual Acidity of Meldrum's
Acid from ab Initio and Combined QM/MM Simulation Study, J. Am. Chem. Soc. 123, 3974–3979 (2001).
42. Ivic, L., Sands, T. T. J., Fishkin, N., Nakanishi, K., Kriegstein, A. R., Strømgaard, K. Terpene Trilactones from Ginkgo biloba Are Antagonists of Cortical Glycine and GABAA Receptors, J. Biol. Chem. 278, 49279–49285 (2003).
Acknowledgments: We thank Professors Phil Baran and Keary Engle for helpful conversations, and the Engle lab for generous donations of chiral phosphoric acids, including (–)-B. Professor Arnold Rheingold, Dr. Curtis Moore, and Dr. Milan Gembicky are gratefully acknowledged for X-ray crystallographic analysis. We thank Dr. Jason Chen and Brittany Sanchez in the Scripps Research Automated Synthesis Facility for purification assistance and for analysis of chiral non-racemic compounds. Funding: Generous support was provided by the National Institutes of Health (R35 GM122606) and the Uehara Memorial Foundation. Additional support was provided by Eli Lilly, Novartis, Bristol-Myers Squibb, Amgen, Boehringer-Ingelheim, the Sloan Foundation, and the Baxter Foundation. The structural parameters for (–)-5, (–)-8, 12, and 16c are available from the Cambridge Crystallographic Data Centre. The authors declare no competing financial interest. Data and materials availability: All data is made available in the main text or the Supplementary Materials.
download fileview on ChemRxivBB TEXT.pdf (1.95 MiB)
O
O
O
O
HHOH
H
O OOH
Me
Me
Me
buried hydroxyl
O
O
O
O
HHH
H
O OOH
Me
Me
Me
buried proton
inside-outoxidation
10 steps, catalytic asymmetric (–)-bilobalide
commonly ingested plant metabolite, poorly understood mechanism• new catalytic asymmetric reaction• 'corset effect' for stereocontrol
• radical stereochemical reversal• oxidation of a deep C-H bond
download fileview on ChemRxivTOC Graphic.pdf (892.92 KiB)
S1
11-Step Asymmetric Synthesis of (–)-Bilobalide
Meghan A. Baker,1* Robert M. Demoret,1* Masaki Ohtawa1†‡ and Ryan A. Shenvi1‡
1Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California, 92037,
United States.
‡Correspondence to: [email protected], [email protected]
*These authors contributed equally to this work.
Supporting Information
S2
Table of Contents
Supporting Information ......................................................................................................................................... S1
11-Step Asymmetric Synthesis of (–)-Bilobalide ................................................................................................. S1
1. General Methods ............................................................................................................................................... S3
2. Syntheses of Bilobalide..................................................................................................................................... S5
3. Experimental Procedures and Characterizations .............................................................................................. S8
(±)-6a: Wittig Olefination (two-step) procedure ............................................................................................... S8
(±)-6a: Wittig Olefination (one-step) procedure ........................................................................................... S8
(–)-7: Reformatsky (asymmetric) ................................................................................................................... S10
(±)-7: Reformatsky (racemic) ..................................................................................................................... S10
(–)-8: Giese Reaction ...................................................................................................................................... S11
(+)-9: Mukaiyama Hydration .......................................................................................................................... S12
(+)-10 and (+)-11: Oxetane-acetal Formation ................................................................................................ S13
(+)-12: Three -Step Alkynylation Sequence ................................................................................................... S14
IBX oxidation.............................................................................................................................................. S14
TMS-EBX alkynylation .............................................................................................................................. S14
SmI2-mediated ketone reduction ................................................................................................................. S14
(+)-13: Alkyne Oxidation ............................................................................................................................... S16
(–)-5: Global Deprotection to 10-Des-hydroxybilobalide .............................................................................. S17
(–)-1: alpha-hydroxylation to Bilobalide ........................................................................................................ S18
16c: Benzoylation of 5 .................................................................................................................................... S20
16b: TBS protection of 5................................................................................................................................. S20
15: alpha-hydroxylation to neo-bilobalide ...................................................................................................... S21
SI-6: Skeleton rearrangement to form iso-bilobalide ...................................................................................... S22
4. NMR Spectra .................................................................................................................................................. S24
5. X-Ray Data for bilobalide intermediates ........................................................................................................ S56
(–)-8 Giese Reaction ....................................................................................................................................... S56
(±)-12 Fully Substituted Cyclopentane ........................................................................................................... S57
(–)-5 Des-Hydroxy-Bilobalide ........................................................................................................................ S58
(±)-16c benzoyl-iso-deshydroxy-bilobalide .................................................................................................... S59
Chiral SFC Traces for (–)-7 ................................................................................................................................ S60
Chiral SFC Traces for (–)-8 ................................................................................................................................ S62
References ........................................................................................................................................................... S63
S3
1. General Methods
All reactions were carried out under positive pressure of nitrogen/argon unless otherwise noted. Glassware was oven-dried at
120 °C for a minimum of 12 hours, or flame-dried with a propane torch under high vacuum. Anhydrous dichloromethane (DCM)
was distilled from calcium hydride (5% w/v) under positive pressure of nitrogen. Anhydrous tetrahydrofuran (THF) was distilled
over sodium/benzophenone ketyl under positive pressure of nitrogen. Anhydrous toluene was was obtained by passing the
previously degassed solvent through an activated alumina column. Other commercially available solvents or reagents were used
without further purification unless otherwise noted. Reactions were monitored by thin layer chromatography (TLC) using
precoated silica gel plates from EMD Chemicals (TLC Silica gel 60 F254, 250 µm thickness). Flash column chromatography was
performed over Silica gel 60 (particle size 0.04-0.063 mm) from EMD Chemicals and activated neutral alumina (Brockmann I,
150 mesh) from Sigma-Aldrich.
NMR spectra were recorded on Varian-400, Bruker DPX-400, DRX-500, and DRX-600 (cryoprobe) spectrometers using residual
solvent peaks as an internal standard (CDCl3 @ 7.26 ppm 1H NMR, 77.16 ppm 13C NMR). The following abbreviations (or
combinations thereof) were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad. HRMS were aquired using a Waters Xero G-2-XS Tof. Optical rotations were measured on an MC-100 Modular Circular
Polarimeter from Anton Parr. Enantiomeric excess of chiral samples was determined using a Waters UPC2 SFC with a Daicel IC
Column (3mm, 4.6x250 mm). Some crude samples were separated and analyzed using heart-cutting 2D LC-SFC in which the LC
dimension consisted of a Waters I-Class LC with a Waters BEH C18 column (1.7 mm, 2.1x100 mm) and the SFC dimension
consisted of the Waters UPC2 SFC with a Daicel IC Column (3mm, 4.6x250 mm).
The following reagents were prepared according to their corresponding literature procedure:
1.) (+)-Indabox…….……………..(3aR,3a'R,8aS,8a'S)-2,2'-(propane-2,2-diyl)bis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole)43
2.) Mn(dpm)3……….………………………………………..…Tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III)44
3.) Ph(Oi-Pr)SiH2………..……………………………………….……………………………….…Isopropoxy(phenyl)silane30
4.) XcPA……….………(11bR)-2,6-Di-9-phenanthrenyl-4-hydroxy-dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-oxide45
5.) IBX…………….………………………………………………………………………….…………2-Iodoxybenzoic acid46
6.) TMS-EBX………….…………………………………………......1‐[(trimethylsilyl)ethynyl]‐1,2‐benziodoxol‐3(1H)‐one34
Abbreviations:
THF = Tetrahydrofuran
acac = Acetylacetonate
dpm = 2,2,6,6-tetramethyl-3,5-heptanedionato
BnOAc = Benzyl acetate
LDA = Lithium diisopropylamide
AIBN = Azobisisobutyronitrile
IBX = 2-iodoxybenzoic acid
TMS-EBX = 1-[(Trimethylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one
TBAF = tetrabutylammonium fluoride
LHMDS = Lithium bis(trimethylsilyl)amide
NaHMDS = Sodium bis(trimethylsilyl)amide
KHMDS = Potassium bis(trimethylsilyl)amide
DMAP = 4-(Dimethylamino)pyridine
mCPBA = meta-Chloroperoxybenzoic acid
NBS = N-Bromosuccinimide Scheme S1: Carbon Numbering
Numbering System: The carbon numbering system as outlined by Nakanishi3 is utilized throughout the Supplementary Materials
as well as in the text of the paper.
S4
S5
2. Syntheses of Bilobalide
Scheme S2: Corey’s synthesis of (±)-bilobalide18
S6
Scheme S3: Corey’s synthesis of (–)-bilobalide 19
Scheme S4: Crimmins’ synthesis of (±)-bilobalide 20
S7
Scheme S5: This synthesis of (–)-bilobalide
S8
3. Experimental Procedures and Characterizations
(±)-6a: Wittig Olefination (two-step) procedure
To a flame-dried 2-liter round bottom equipped with a magnetic stirbar was added SI-1 (164 g, 400 mmol, 1.0 equiv) followed
by the addition of 800 mL of anhydrous DCM. The solution was cooled to 0 °C, then a solution of Br2 (20.6 mL, 400 mmol, 1.0
equiv) in 50 mL of anhydrous DCM was added and the reaction was allowed to warm to room temperature and stir for 5 hours.
The reaction was then transferred to a 1-liter separatory funnel and washed sequentially with H2O, sat. NaHCO3 2 times, and then
dried with Na2SO4 and concentrated in vacuo. The crude material was recrystallized from hot DCM/Et2O/Hex (1:2:10) to afford
bromo ylide SI-2 as a yellow solid (152 g, 76.3% yield). Note: The product is a strong lachcrymtor and should be weighed out in a well-ventilated fume hood.
To a flame-dried 250 mL-liter round bottom equipped with a magnetic stirbar was added SI-2 (54.73 g, 111.8 mmol, 1.1 equiv)
followed by SI-3 (25.65 g, 101.1 mmol, 1.0 equiv). Anhydrous DCM was added until both of the reagents were completely
dissolved (approx. 70 mL) and then the reaction was allowed to stir overnight. The reaction was concentrated in vacuo.
Purification by silica gel flash column chromatography (hexanes/EtOAc = 9:1) afforded (±)-6a as a colorless oil (37.0 g, 78.5%)
and as a mixture of E/Z isomers.
(±)-6a: Wittig Olefination (one-step) procedure
To a flame-dried, 25 mL round bottom flask with a magnetic stirbar were added ylide SI-1 (225.8 mg, 0.55 mmol, 1.1 equiv)
and 1.0 mL of DCM (0.5 M). NBS (107 mg, 0.6 mmol, 1.2 equiv) was added and the reaction was stirred for 12 hours followed
by addition of diketone SI-3 (126.1 mg equiv, 0.5 mmol) as a solution in DCM. Once the diketone was consumed (monitored by
TLC, approx. 12 hours), the reaction was concentrated in vacuo. Purification by silica gel flash column chromatography
(hexanes/EtOAc = 9:1) afforded (±)-6a as a colorless oil 204 mg, 88%) and a mixture of E/Z isomers.
Characterization data for major isomer:
Rf 0.60 (hexanes/EtOAc = 5:1, KMnO4) 1H NMR
(600 MHz, CDCl3)
δ 7.39-7.31 (m, 10H), 6.62 (s, 1H), 5.91 (d, 1H, J = 0.6 Hz), 5.28 (d, 1H, J = 0.6 Hz), 5.22-5.15 (m, 4H), 3.39
(s, 3H), 3.22 (s, 3H). 13C NMR (151 MHz, CDCl3)
δ 167.9, 165.2, 148.7, 125.5, 125.3, 128.8, 128.7, 128.6, 128.6, 128.5, 128.4, 126.0, 100.0, 68.0, 66.9, 55.7,
55.5, 41.6.
HRMS (ESI) Calcd. for C22H23BrO6Na 485.0576 (M+Na+) found 485.0572.
S9
Note: Both SI-1 and SI-3 are commercially available however SI-3 can be prepared according to the procedure shown below.
Claisen Reaction for Formation of SI-3
To a flame-dried, 1L round bottom flask with a magnetic stirbar were added diisopropylamine (30.8 mL, 220 mmol, 1.15 equiv)
and 400 mL of THF. This solution was cooled to -78 °C followed by addition of n-BuLi (2.6 M in hexanes, 81.0 mL, 210 mmol,
1.1 equiv) and the solution was warmed to 0 °C and stirred for 1 hr to ensure formation of LDA. After cooling again to -78 °C,
BnOAc (27.2 mL, 190.4 mmol, 1.0 equiv) was added and the reaction was stirred for 30 minutes. Finally, methyl
dimethoxyacetate (24.4 mL, 200 mmol, 1.05 equiv) was added and the reaction was slowly warmed to room temperature over 1.5
hours before being quenched with saturated NH4Cl (aq.). The aqueous phase was then extracted 3 times with EtOAc, and the
combined organic layers were dried with Na2SO4 and concentrated in vacuo to provide SI-3 as a light orange oil. SI-3 was then
used directly without purification.
S10
(–)-7: Reformatsky (asymmetric)
Note: The results of the catalytic asymmetric Reformatsky reaction vary depending on reaction scale. On small scale (1 mmol or
less) the ee is consistently 94%, the dr is 2.3:1, and the yield of the combination of diastereomers is 64%. On large scale, if the
rate of addition or temperature is not carefully controlled, the ee can erode to as low as 85% with a concommitant loss of
stereoselectivity (2.0:1.0 dr).
To a flame dried reaction flask containing a magnetic stirbar were added 𝛼-bromo ester 6a (36 g, 77.8 mmol, 1.0 equiv), aldehyde
6b47 (16.9 g, 88.5 mmol, 1.14 equiv), and bisoxazoline ligand A (2.79 g, 7.8 mmol, 10 mol%), followed by 972 mL of THF
(0.08M). The solution was cooled to -78 °C in a dry ice/acetone bath and diethyl zinc (1 M in hexanes, 233.3 mL, 233.3 mmol,
3.0 equiv) was added dropwise via additional funnel. Upon completion of the addition, the mixture was stirred at -78 °C for 4 hrs
(time necessary for full consumption of starting material at 10 mol% ligand). The reaction was then carefully quenched at -78 °C
with a 3M methanolic HCl solution (6 equiv) and warmed to room temperature. The mixture was then diluted with EtOAc and
sat. aq. NH4Cl and the aqueous layer extracted 3 times with EtOAc. The combined organic layers were then washed with a 10%
CuSO4 solution to remove ligand, followed by a 2M HCl wash to remove any residual zinc or copper salts. Finally, the organic
layer was washed with saturated NaHCO3 (aq.), brine, and then dried over Na2SO4 before being filtered and concentrated in vacuo.
The crude reaction mixture (2.0:1 dr, 92% ee) was used in the subsequent reaction. The yield of the mixture of diastereomers was
calculated to be 64% from an internal standard (1,3,5-trimethoxybenzene) added to the crude NMR; the yield of the desired anti-
diastereomer was calculated to be 44% and the yield of the syn-diastereomer was calculated to be 20%.
Diastereomers were inseparable via silica gel chromatography and were ultimately separated by preparative HPLC for
characterization purposes. However, for material throughput purposes, they were carried into the subsequent reaction together,
after which they were easily separable by column chromatography or recrystallization.
Note: A major byproduct of the reaction is the proto-debrominated starting material.
(±)-7: Reformatsky (racemic)
A solution of 6a (23.8 g, 51.3 mmol, 1.0 equiv.) in 25 mL of THF was added to a flame-dried 2-liter round bottom flask
equipped with a magnetic stirbar and backfilled with argon. The solution was treated with SmI2 (0.1 M THF sol. 1-liter, 100
mmol, 1.95 equiv) via a cannula at – 78 ˚C. After addition of the SmI2 solution, 6b (11.8 g, 61.6 mmol, 1.2 equiv) was added
slowly at – 78 ˚C and stirred for 10 min at –78 ˚C. The reaction was quenched with AcOH (3.52 mL, 61.6 mmol, 1.2 equiv) at –
78 ˚C, followed by the addition of sat. NH4Cl aq. (150 ml) and subsequent warming to room temperature. Saturated Na2S2O3
(aq.) (150 mL) was added and the solution was stirred for 10 minutes before the mixture was concentrated in vacuo until
aprroximately 200 mL of THF remained. The resulting mixture was diluted with 800 mL of EtOAc and the organic layer was
washed with 1 M HCl, sat. Na2S2O3 aq. and H2O (2 times), dried over Na2SO4, filtered and concentrated in vacuo. The residue
was semi-purified by flash column chromatography (hexanes/EtOAc = 5:1) to provide a semi-pure 7.
Note: We found that the addition of sat. Na2S2O3 aq. was crucial after the Reformatsky reaction was quenched to reduce any
iodine that is generated in situ. The solution turns from a dark brown color to a light yellow color after addition of sat. Na2S2O3
aq. Concentration of the crude mixture after work-up without the addition of sat. Na2S2O3 aq. lead to complete decomposition of
the product on scales larger than 25 mmol.
S11
(–)-8: Giese Reaction
Scheme S6: Diastereoselectivity model for the Giese reaction
A 1-liter oven dried 3-neck flask was equipped with a reflux condenser, a 250 mL oven-dried addition funnel, a magnetic stirbar,
and a septum. The flask was then charged with crude (–)-7 followed by 390 mL of anhydrous toluene. The mixture was then
heated to 85 °C and then a solution of Bu3SnH (31.5 mL, 116.7 mmol, 1.5 equiv) and AIBN (1.3g, 7.8 mmol, 0.1 equiv) in toluene
(100 mL) was slowly added dropwise via the addition funnel over 1 hour. Once the solution had finished adding to the reaction,
the addition funnel was rinsed with one portion of toluene (10 ml) and then stirred for an additional 30 min at 85 ˚C. Once TLC
had indicated that the SM was consumed, the mixture was removed from the oil bath and allowed to cool to room temperature.
The resulting mixture was concentrated in vacuo in a well-ventilated fume hood. The Bu3SnH and its byproducts were removed
by passing the material through a plug of 10% KF impregnated silica (hexanes/EtOAc = 8:1 → 1:1). After concentrating the
filtered material in vacuo, the yield of the desired cyclopentene diastereomer was calculated to be 60% via addition of an internal
standard (1,3,5-trimethoxybenzene) to the crude NMR. Recrystallization of the crude mixture from hot Et2O/pentane (1:4)
provided 8 as a white crystalline solid in excellent ee (8.050 g, 2 steps, 21 %, >99% ee).
Note: When we performed this two-step sequence using the racemic procedure, we obtained an isolated yield of 12.3 g of 8 after
the radical conjugate addition (54% yield over 2 steps after column chromatography). However, 8 can be purified without
chromatography via recrystallization from hot Et2O/pentanes 1:4 to afford a white powder in 39% yield over 2 steps. Recovery
and concentration of the mother liquor shows a complex mixture of 8 and uncharacterized byproducts from which 8 could not be
recovered.
Rf 0.45 (hexanes/EtOAc = 3:1, anisaldehyde) 1H NMR
(600 MHz, CDCl3)
δ 7.39-7.33 (m, 10H), 5.85 (d, 1H, J = 2.4 Hz), 5.21 (d, 1H, J = 12.6 Hz), 5.15 (d, 1H, J = 12.0 Hz), 5.11 (d,
1H, J = 12.6 Hz), 5.04 (d, 1H, J = 12.0 Hz), 4.78 (ddd, 1H, J = 2.4, 7.8, 12.0 Hz), 4.57 (d, 1H, J = 12.0 Hz),
4.29 (s, 1H), 3.73 (d, 1H, J = 7.8 Hz), 3.54 (d, 1H, J = 18.0 Hz), 3.51 (s, 3H), 3.36 (s, 3H), 2.78 (d, 1H, J = 18.0
Hz), 1.09 (s, 9H). 13C NMR (151 MHz, CDCl3)
δ 173.4, 171.6, 154.6, 136.8, 135.8, 130.4, 128.8, 128.6, 128.5, 128.4, 127.9, 127.8, 110.8, 74.5, 66.7, 65.7,
60.8, 60.8, 56.2, 51.5, 37.0, 34.3, 32.0, 29.9, 28.4.
HRMS (ESI) Calcd. for C29H36O7Na 519.2359 (M+Na+) found 519.2357.
[α]D20 –4.1 (c = 1.0, CHCl3)
S12
(+)-9: Mukaiyama Hydration
A one liter oven-dried round bottom flask equipped with a magnetic stir bar was charged with 8 (8.050g, 16.2 mmol, 1.0
equiv). To the flask was then added 320 mL of methyl-cyclohexane, Mn(dpm)3 (980 mg, 1.62 mmol, 0.1 equiv),
triphenylphosphine (6.34 g, 24.3 mmol, 1.5 equiv), and the solution was placed under an O2 atmosphere (balloon). The reaction
was heated to 50 °C followed by the dropwise addition of monoisopropoxy(phenyl)silane (8.9 mL, 48.3 mmol, 3 equiv). The
mixture was then stirred under an oxygen atmosphere for 1.5 hrs. After completion, the reaction was cooled to 0 °C and quenched
with a freshly prepared 10% (aq.) solution of KF (150 mL), extracted 3 times with EtOAc and dried over Na2S2O4. The crude
mixture was filtered through a celite plug and eluted with EtOAc to remove any remaining Mn salts and then concentrated under
reduced pressure. The crude product was purified via flash column chromatography (Et2O/Hexanes 2:3) to provide 9 as a colorless
oil (5.58 g, 67 %) (d.r. = 3:1).
(+)-9
Rf
0.55 (hexanes/EtOAc = 3:1, anisaldehyde) 1H NMR
(600 MHz, CDCl3)
δ 7.48-7.30 (m, 10H), 5.44 (s, 1H), 5.19 (d, 1H, J = 12.0 Hz), 5.08 (d, 2H, J = 12.0 Hz), 5.03 (d, 1H, J = 12.0
Hz), 4.99 (br d, 1H, J = 1.8 Hz), 4.75 (br s, 1H), 4.56-4.53 (m, 1H), 3.72 (d, 1H, J = 6.0 Hz), 3.39 (s, 3H), 3.28
(s, 3H), 3.17 (d, 2H, J = 6.0 Hz), 2.14 (dd, 1H, J = 7.8, 14.4 Hz), 1.99 (dt, 1H, J = 3.0, 14.4 Hz), 1.05 (s, 9H). 13C NMR (151 MHz, CDCl3)
δ 175.0, 172.3, 136.1, 135.5, 129.4, 128.7, 128.7, 128.6, 128.4, 128.3, 127.8, 127.1, 109.6, 90.6, 68.8, 67.5,
66.1, 65.5, 60.0, 58.4, 58.3, 49.7, 44.3, 39.4, 36.5, 28.4.
HRMS (ESI) Calcd. for C29H38O8Na 537.2464 (M+Na+) found 537.2469.
[α]D20 +11.9 (c = 1.0, CHCl3)
(+)-14
Rf
0.05 (hexanes/EtOAc = 3:1, anisaldehyde) 1H NMR
(600 MHz, CDCl3)
δ 7.43 – 7.29 (m, 5H), 5.21 (d, J = 12.3 Hz, 1H), 5.14 (d, J = 12.3 Hz, 1H), 4.56 – 4.42 (m, 2H), 3.65 (d, J = 5.9
Hz, 1H), 3.47 (s, 3H), 3.37 (s, 3H), 3.26 (d, J = 18.3 Hz, 1H), 2.73 – 2.61 (m, 2H), 2.31 (dd, J = 15.0, 6.0 Hz,
1H), 2.22 (dd, J = 14.9, 2.2 Hz, 1H), 1.07 (s, 9H). 13C NMR (151 MHz, CDCl3)
δ 174.88, 171.54, 135.82, 128.70, 128.50, 128.45, 108.07, 102.99, 71.63, 66.72, 62.14, 59.51, 56.13, 53.16,
42.17, 38.66, 37.12, 27.37.
HRMS (ESI) Calcd. for C22H30O7Na 429.1889 (M+Na+) found 429.1883.
[α]D20 +1.6 (c = 1.0, CHCl3)
S13
(+)-10 and (+)-11: Oxetane-acetal Formation
To a 14.7 mL solution of THF/H2O (2:1) in a 50 mL round bottom flask equipped with a magnetic stirbar was added 9 (5.34
g, 10.4 mmol, 1.0 equiv.) and (–)-B45 (730 mg, 1.04 mmol, 0.1 equiv.) and the reaction was stirred for 12 hours at room
temperature. The reaction was monitored by TLC and upon completion was diluted with EtOAc and the layers were separated.
The aqueous phase was extracted 3 times with EtOAc and then the combined organic layers were dried with Na2SO4, filtered and
concentrated in vacuo. The residue was purified by flash column chromatography (Hexanes/EtOAc 2:1) to provide 10 as a
colorless viscous oil (3.55 g, 71% yield).
Re-isolation of the XcPA:
After the endo product 10 had finished eluting off the column, the eluent was increased to (Hexanes/EtOAc 1:1) in order to
isolate 11 as a colorless viscous oil. The column was subsequently flushed with two column volumes of DCM and then 1:19
MeOH/DCM was used to elute the XcPA B as a pale yellow solid. The XcPA should be dissolved in DCM and washed with 6M
HCl prior to use.
endo (+)-10
Rf 0.25 (hexanes/EtOAc = 2:1, anisaldehyde) 1H NMR
(600 MHz, CDCl3)
δ 7.38-7.27 (m, 10H), 5.18 (d, 1H, J = 12.6 Hz), 5.09 (s, 1H), 5.06-5.03 (m, 1H), 5.02 (d, 1H, J = 12.0 Hz), 4.91
(d, 1H, J = 12.6 Hz), 4.86 (d, 1H, J = 12.0 Hz), 3.68 (d, 1H, J = 7.8 Hz), 3.35 (s, 3H), 3.14 (d, 1H, J = 15.0
Hz), 2.92 (d, 1H, J = 15.0 Hz), 2.23 (dd, 1H, J = 10.8, 13.2 Hz), 2.11 (dt, 1H, J = 6.6, 13.2 Hz), 1.04 (s, 9H).
13C NMR (151 MHz, CDCl3)
δ 172.26, 170.24, 135.77, 135.60, 128.68, 128.66, 128.63, 128.50, 128.48, 128.35, 105.22, 95.40, 72.03, 66.72,
66.44, 56.54, 55.34, 52.76, 41.65, 36.89, 36.22, 26.58.
HRMS (ESI) Calcd. for C28H34O7 483.2383 (MH+) found 483.2389.
[α]D20 +42.5 (c = 1.0, CHCl3)
exo (+)-11
Rf 0.30 (hexanes/EtOAc = 2:1, anisaldehyde) 1H NMR
(600 MHz, CDCl3)
δ 7.34-7.25 (m, 10H), 5.10 (d, 1H, J = 12.6 Hz), 5.01 (d, 1H, J = 12.6 Hz), 4.99 (d, 1H, J = 12.6 Hz), 4.89 (d,
1H, J = 12.6 Hz), 4.81 (s, 1H), 4.81-4.77 (m, 1H), 3.78 (d, 1H, J = 7.8 Hz), 3.47 (d, 1H, J = 17.4 Hz), 3.30 (s,
3H), 2.59 (d, 1H, J = 17.4 Hz), 2.33 (dd, 1H, J = 10.8, 13.2 Hz), 2.14 (dd, 1H, J = 6.6, 13.2 Hz), 1.00 (s, 9H). 13C NMR (151 MHz, CDCl3)
δ 171.74, 170.85, 136.02, 135.64, 128.67, 128.63, 128.51, 128.47, 128.32, 128.27, 105.11, 97.90, 71.77, 66.55,
66.27, 56.24, 55.45, 54.92, 41.19, 36.17, 32.50, 26.73, 1.16.
HRMS (ESI) for C28H34O7 483.2383 (M+H+) found 483.2379.
[α]D20 +3.9 (c = 1.0, CHCl3)
S14
(+)-12: Three -Step Alkynylation Sequence
Scheme S7: Diastereoselectivity model for the alkynylation
IBX oxidation
A solution of 10 (172 mg, 0.36 mmol, 1.0 equiv) and freshly prepared IBX (301 mg, 1.074 mmol, 3 equiv) in 3.0 mL of DMSO
was stirred for 2.5 h at 22 ˚C in a 10 mL round bottom requipped with a magnetic stirbar. The solution was then cooled to 0 °C
followed by the slow addition of sat. Na2S2O3 aq. (3.0 mL) and EtOAc (15.0 mL). The organic layer was subsequently washed
with dH2O 4 times and then dried over Na2SO4, filtered, and concentrated in vacuo to give crude SI-4.
TMS-EBX alkynylation
A flame-dried 25 mL round bottom flask equipped with a magnetic stirbar was charged with TMS-EBX (370 mg, 1.074 mmol,
equiv) followed by a solution of crude SI-4 in 7.16 mL of THF. The solution was cooled to –78 ˚C followed by addition of TBAF
(1.0 M in THF, 1.07 mL, 1.074 mmol, 3 equiv), and then the solution was warmed slowly to –20 °C over 1hr. Note: The reaction
precipitates a brown solid which can cause the reaction to stop stirring, so a mechanical stirring apparatus is recommended.
Once the solution had reached –20 °C the reaction was monitored by TLC and once SM was consumed the reaction was quenched
with sat. NH4Cl aq. and warmed to room temperature. The layers were separated, and the aqueous phase was extracted 3 times
with EtOAc. The organic layers were combined, and then washed with sat. NaHCO3 aq. (1x) and H2O (2x), dried over Na2SO4,
filtered, and concentrated in vacuo to give afford SI-5. The crude mixture was dissolved in Et2O and then filtered through a fritted
funnel to remove insoluble salts that effect the next reaction.
Note: Filtration of the crude material through a silica, florisil, or celite plug led to decomposition of SI-5 via elimination of the
oxetane acetal. The insoluble salts do not have to be removed; however, if they are not, a large excess of SmI2 must be used in the
subsequent reaction.
Note: This alkynylated intermediate is highly unstable and cannot be purified. The ketone should be immediately reduced using
the procedure that follows to provide a stable secondary alcohol that can be purified.
SmI2-mediated ketone reduction
A solution of crude SI-5 in 1.0 mL of THF and 1.0 mL of degassed H2O were added to a 100 mL round bottom flask under an
argon atmosphere. The solution was then cooled to 0 ˚C, treated with SmI2 (0.1 M in THF, 30 mL, 3.0 mmol, 8.4 equiv), and
stirred for 30 mins at 0 ˚C. EtOAc (120 mL) was then added and the reaction was transferred to a separatory funnel. The organic
layer was washed sequentially with 1 M HCl and H2O, followed by Na2S2O3 and H2O again, before being dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexanes/EtOAc = 5:1 → 4:1) to
provide 12 as a colorless oil (111 mg, 3 steps, 61 %).
S15
Note: When this three-step sequence was performed on a scale of 5.16 mmol, the alkynylation reaction did not go to completion
do to the formation of an unstirrable slurry as the reaction warmed from -78 °C to -20°C. As a consequence of this, only 1.0g of
pure 12 was isolated after flash column chromatography (1.0g, 3 steps, 38%).
Note: On larger scales (e.g. greater than 1 mmol), the pure material is contaminated with benzyl alcohol, likely from ester
hydrolysis. The benzyl alcohol can be azeotroped away from the pure product by concentrating the oil with a 2:1 mixture of
H2O:MeCN at least 3 times.
Rf 0.40 (hexanes/acetone = 3:1, anisaldehyde or CAM) 1H NMR
(600 MHz, CDCl3)
δ 7.36-7.28 (m, 10H), 5.71 (s, 1H), 5.30 (d, 1H, J = 12.6 Hz), 5.27 (ddd, 1H, J = 4.2, 6.0, 10.8 Hz), 5.07 (d, 1H,
J = 12.0 Hz), 5.01 (d, 1H, J = 12.6 Hz), 4.84 (d, 1H, J = 12.0 Hz), 3.48 (d, 1H, J = 15.6 Hz), 3.30 (d, 1H, J =
15.6 Hz), 3.19 (s, 3H), 2.81 (d, 1H, J = 4.2 Hz), 2.58 (s, 1H), 2.09 (dd, 1H, J = 6.0, 13.2 Hz), 2.02 (dd, 1H, J =
10.8, 13.2 Hz), 1.04 (s, 9H). 13C NMR (151 MHz, CDCl3)
δ 170.55, 169.47, 136.03, 135.64, 128.71, 128.60, 128.52, 128.42, 128.30, 128.22, 102.93, 93.07, 78.75, 78.00,
72.69, 67.13, 66.49, 59.03, 58.80, 56.68, 38.65, 36.29, 35.69, 26.26.
HRMS (ESI) Calcd. for C30H34O7 507.2383 (M+H+) found 507.2393.
[α]D20 +26.9 (c = 1.0, CHCl3)
S16
(+)-13: Alkyne Oxidation
Scheme S8: A possible reaction mechanism for alkyne oxidation.
A solution of 12 (100.0 mg, 0.2 mmol, 1.0 equiv) in 2.0 mL of THF was added to a flame dried reaction vial equipped with a
magnetic stir bar. The solution was cooled to –78 ˚C followed by addition of LHMDS (1.0M in THF, 600 L, 0.6 mmol, 3 equiv),
and the solution was stirred for 1 hr at 0 ˚C. B(OMe)3 (111 L, 1.0 mmol, 5 equiv) was added and the resulting solution was
warmed to room temperature and stirred for 1.5 hrs. The solution was cooled to 0 °C and then m-CPBA (100%, 172 mg, 1.0
mmol, 5 equiv) was added portionwise (Note: The reaction exotherms violently if mCPBA is added in a single portion), and the
reaction was stirred for 30 min. The reaction was quenched with sat. NH4Cl aq. and extracted 3 times with EtOAc. The organic
layer was then washed 1 time with sat. Na2S2O3 aq., 1 time with sat. NaHCO3 aq., 1 time with 3 M HCl, and then dried with
Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (hexanes/EtOAc = 5:1 → 4:1) to
provide 13 as a colorless oil (57 mg, 55 %)
Rf 0.60 (hexanes/EtOAc = 2:1, CAM) 1H NMR
(600 MHz, CDCl3)
δ 7.37-7.30 (m, 10H), 5.68 (t, 1H, J = 7.8 Hz), 5.56 (s, 1H), 5.24 (d, 1H, J = 12.0 Hz), 5.15 (d, 1H, J = 12.0 Hz),
5.06 (d, 1H, J = 12.0 Hz), 5.00 (d, 1H, J = 12.0 Hz), 3.35 (d, 1H, J = 14.4 Hz), 3.10 (s, 3H), 2.69 (d, 1H, J =
17.4 Hz), 2.63 (d, 1H, J = 14.4 Hz), 2.62 (d, 1H, J = 17.4 Hz), 2.51 (dd, 1H, J = 7.8, 15.0 Hz), 1.83 (dd, 1H, J
= 7.8, 15.0 Hz), 1.04 (s, 9H). 13C NMR (151 MHz, CDCl3)
δ 173.39, 171.58, 169.83, 141.03, 135.58, 128.79, 128.68, 128.67, 128.65, 128.48, 128.41, 128.31, 127.73, 127.08,
103.21, 95.99, 83.21, 67.18, 66.99, 65.44, 60.26, 58.69, 56.56, 40.29, 36.98, 36.57, 36.29, 26.06
HRMS (ESI) Calcd. for C30H34O8 523.2332 (M+H+) found 523.2332.
[α]D20 +45.7 (c = 1.0, CHCl3)
S17
(–)-5: Global Deprotection to 10-Des-hydroxybilobalide
A reaction vial equipped with a magnetic stir bar was charged with a solution of 13 (50.0 mg, 0.0957 mmol) in 1.1 mL of
MeOH and Pd/C (10%, 6.0 mg). The vial was evacuated under vacuum, backfilled with H2, and then stirred under a H2 atmosphere
for 2h at 22 ˚C. After the starting material had been completely consumed, the flask was placed under vacuum to remove the H2
atmosphere and backfilled with N2. This process was repeated three times to ensure all the H2 had been removed. 2.0 mL of 3M
HCl was then added to the mixture and the reaction was heated to 80 ˚C overnight open to air. The resulting mixture was filtered
off through a Celite pad and washed with MeOH. The filtrate was concentrated in vacuo and azeotroped two times with toluene
to provide 5 as a light brown solid (26.5 mg, 90% yield).
Note: Compound 5 does not stain under any traditional staining methods. In order to develop TLC’s with 5 the compound must
be run up the plate in Hexanes/Acetone (3:2) followed by direct heating of the TLC plate on a hot plate at 350 °C for 10 minutes,
after which a brown spot will appear on the plate, which indicates 5 (This new band is also UV active and stains with KMnO4, or
anisaldehyde). This method is used to locate 5 when running a preparative TLC plate. A thin portion of the plate is cut off with a
TLC cutter and then heated as mentioned above to locate 5. The Rf is marked and then the appropriate band is cut from the
remainder of the undeveloped preparative TLC plate. Due to the unique solubility profile of 5, column chromatography was
unsuccessful to purify the product. However, on larger scales triturating the crude mixture 3 times with Et2O afforded the pure
product. The Et2O was then concentrated in vacuo and 5 was then purified from the mixture via pTLC.
Rf 0.50 (hexanes/acetone = 3:2, UV detection after heating over 15 min. on TLC plate) 1H NMR
(600 MHz, acetone-d6)
δ 6.50 (s, 1H), 5.05 (dd, 1H, J = 7.2, 8.4 Hz), 4.63 (br s, 1H), 3.58 (d, 1H, J = 18.6 Hz), 3.21 (d, 1H, J = 18.6
Hz), 2.99 (d, 1H, J = 19.2 Hz), 2.78 (d, 1H, J = 19.2 Hz), 2.75 (dd, 1H, J = 7.2, 13.2 Hz), 2.22 (dd, 1H, J = 8.4,
13.2 Hz), 1.19 (s, 9H). 13C NMR (151 MHz, acetone-d6)
δ 179.2, 173.7, 171.7, 104.8, 87.6, 85.3, 63.3, 58.7, 43.0, 38.3, 35.1, 34.8., 27.13
HRMS (ESI) Calcd. for C15H18O7 311.1131 (M+H+) found 311.1135.
[α]D20 –50.0 (c =0.7, CHCl3)
S18
(–)-1: alpha-hydroxylation to Bilobalide
To a flame dried reaction vial containing a magnetic stirbar was transferred des-hydroxybilobalide 5 (3 mg, 0.00967 mmol).
To remove any trace water, the starting material was azeotroped with toluene at least three times by heating to 80 °C under a
strong positive pressure of dry N2 until all solvent was evaporated and only a white solid remained in the flask. The reaction was
then placed back under high vacuum. DMAP (1.8 mg, 0.0145 mmol, 1.5 equiv) and benzoic anhydride (3.3 mg, 0.0145 mmol,
1.5 equiv) were added, and the vial was evacuated and backfilled three times with dry argon gas followed by addition of 0.38 mL
of THF. The reaction was then heated to 60 °C until the starting material was fully consumed, resulting in the formation of a new
spot representing the benzoyl-iso-deshydroxy-bilobalide (intermediate 16c). The same staining procedure for 5 had to be applied
for 1 as well, since both 16c and 1 do not stain under any traditional methods. At this point, the reaction was cooled to room
temperature, and then to -78 °C followed by the addition of a KHMDS solution (0.1 ml, 0.029mmol, 3 equiv). After stirring for
1 hour at -78 °C, Davis reagent was added dropwise from a stock solution in THF (7.6 mg/50 µL THF, 0.029 mmol, 3 equiv) and
the resulting mixture was stirred for additional 2 hours (the conversion was lower after 1 hour, but did not increase after 2 hours)
at -78 °C. At this point, the reaction was quenched with 3.0M methanolic HCl (33 µL, 0.0967 mmol, 10 equiv) and warmed to
room temperature. Aqueous 3M HCl (0.3 mL) was then added and the reaction was heated to 85 °C for 24 hours to deprotect and
isomerize all material in the iso-bilobalide form, back to the bilobalide scaffold. The reaction was then concentrated and the yield
of 1 (49%, 73% brsm) was obtained via NMR with dibromomethane as an internal standard made as a stock solution in acetone-
d6 in a 1 mL volumetric flask..
Note: Formation of neo-bilobalide (15) often arises as a regiochemical byproduct of this reaction when enough care is not taken
to effectively purify all reagents and remove any trace of water from the reaction. This is likely due to hydrolysis of the benzoate
and reformation of des-OH-bilobalide from which neo-bilobalide is known to form under these reaction conditions from our own
experiments. Further study of this process and of the intracacies of this reaction are underway.
Notes on the oxidation of des-hydroxy-bilobalide to bilobalide: Both the regioselectivity and yield of this reaction were sensitive
to reagent quality, as well as thorough exclusion of water from the reaction. DMAP was recrystallized from hot toluene and then
cooling to -20 °C overnight. Bz2O was purified by dissolving the commercial material in Et2O and then washing 3 times with
NaHCO3. The organic layer was then dried with MgSO4 and concentrated to afford a solid white powder free of any detectable
benzoic acid. The reaction never exceeded 50% conversion by crude NMR, and yields and selectivities were best on small scale.
Notes on the purification of bilobalide from the reaction: Due to the high solubility of 1 in water, the crude reactions were
directly concentrated and then semi-purified by pTLC (3:1 DCM/Acetone) to remove some of the oxaziridine byproducts. The
semi-pure material was then purified by preparative HPLC to afford pure 1. Mass-directed preparative HPLC conditions: Waters
Autopurification LC with a Waters BEH C13 Column (5 mm, 19x160 mm) using a 0.1% aqueous formic acid:acetonitrile gradient
(30 mL/min, main segment of gradient at 10-25% acetonitrile over 8 minutes) at ambient temperature. Fractionation was triggered
by a Waters QDa single quadrupole mass spec (ESI+)
Rf
0.50 (DCM/acetone = 4:1, UV detection after heating over 15 min. on TLC plate) 1H NMR
(600 MHz, acetone-d6)
δ 6.39 (d, J = 4.2 Hz, 1H), 6.37 (s, 1H), 5.40 (d, J = 4.1 Hz, 1H), 5.00 (t, J = 7.0 Hz, 1H), 4.63 (s, 1H), 3.03 (d,
J = 18.1 Hz, 1H), 2.81 (d, J = 18.2 Hz, 3H), 2.75 (dd, J = 13.6, 7.2 Hz, 1H), 2.33 (dd, J = 13.7, 6.9 Hz, 1H),
1.22 (s, 9H). 13C NMR (151 MHz, acetone-d6)
δ 178.43, 173.77, 173.58, 100.61, 87.59, 83.93, 69.89, 66.58, 59.18, 43.34, 38.37, 37.01, 27.19.
HRMS (ESI) Calcd. for C15H18O8 327.1080 (M+H+) found 327.1069.
Synthetic [α]D20
Aunthetic [α]D20
–49.0 (c =0.10, acetone)
–50.7 (c =0.14, acetone)
S19
Table S1: Comparison of 1H and 13C NMR data for Authentic vs. Synthetic (–)-bilobalide
Comparison of 1H NMR data for Authentic vs. Synthetic (–)-bilobalide
Comparison of 13C NMR data for Authentic vs. Synthetic (–)-bilobalide
S20
16c: Benzoylation of 5
To a flame dried reaction vial containing a magnetic stirbar was added deshydroxybilobalide 5 (3 mg, 0.0097 mmol, 1.0 equiv),
EDCI (4.51 mg, 0.029 mmol, 3.0 equiv), benzoic acid (3.54 mg, 0.029 mmol, 3.0 equiv), and DMAP (3 mg, 0.00967 mmol),
followed by addition of DCM (0.1M) at room temperature. The reaction was stirred at room temperature until the starting material
was consumed, after which the reaction was concentrated and loaded directly onto a preparative TLC plate for purification (40%
acetone/hexanes) to afford 16c as a white solid and in quantitative conversion.
Rf 0.50 (hexanes:acetone = 2:1, UV detection after heating over 15 min. on TLC plate) 1H NMR
(600 MHz, acetone-d6)
δ 8.18 (dd, J = 8.4, 1.4 Hz, 2H), 7.80 – 7.70 (m, 1H), 7.65 – 7.58 (m, 2H), 4.76 (dd, J = 7.9, 3.9 Hz, 1H), 3.35
(d, J = 18.1 Hz, 1H), 3.31 (d, J = 18.1 Hz, 1H), 3.21 (d, J = 18.8 Hz, 1H), 3.07 (d, J = 18.8 Hz, 1H), 2.89 (dd,
J = 15.2, 3.9 Hz, 1H), 2.83 (dd, J = 15.1, 7.8 Hz, 1H), 1.24 (s, 9H). 13C NMR (151 MHz, acetone-d6)
13C NMR (151 MHz, Acetone) δ 174.61, 173.71, 170.22, 165.24, 135.54, 131.09, 130.07, 129.10, 101.58,
95.31, 79.86, 63.37, 62.04, 36.10, 35.13, 31.40, 30.69, 26.79.
16b: TBS protection of 5
To a flame dried reaction vial containing a magnetic stirbar was added deshydroxybilobalide 5 (3 mg, 0.0097 mmol, 1.0 equiv)
and DCM (0.1M). 2,6-lutidine (2.25 𝜇𝐿, 0.019 mmol, 2.0 equiv) and TBSOTf (4.37 𝜇𝐿, 0.019 mmol, 2.0 equiv) were then added
at room temperature and the reaction was stirred until starting material was fully consumed, after which the reaction was
concentrated and loaded directly onto a preparative TLC plate for purification (40% acetone/hexanes) to afford 16b as a colorless
oil and in quantitative conversion.
Rf
1H NMR
0.50 (hexanes:acetone = 2:1, UV detection after heating over 15 min. on TLC plate)
(600 MHz, acetone-d6)
δ 6.11 (s, 1H), 4.68 (dd, J = 7.9, 3.8 Hz, 1H), 3.28 (d, J = 18.2 Hz, 1H), 3.07 (d, J = 18.2 Hz, 1H), 2.84 (d, J =
18.6 Hz, 1H), 2.78 (dd, J = 15.2, 3.8 Hz, 1H), 2.76 (d, J = 18.2 Hz, 1H), 2.72 (dd, J = 15.1, 8.0 Hz, 1H), 1.14
(s, 9H), 0.93 (s, 9H), 0.19 (d, J = 1.5 Hz, 6H).
S21
15: alpha-hydroxylation to neo-bilobalide
To a flame dried reaction vial containing a magnetic stirbar was transferred deshydroxybilobalide 5 (3 mg, 0.0097 mmol).
To remove any trace water, the starting material was azeotroped with toluene at least three times by heating to 80 °C under a
strong positive pressure of dry N2 until all solvent was evaporated and only a white solid remained in the flask. The reaction vial
was placed under an argon atmosphere and then THF (300 µL) was added. The reaction was cooled to -78 °C followed by the
addition of a KHMDS solution (0.19M in THF, 0.1 ml, 0.019mmol, 2 equiv). After stirring for 1 hour at -78 °C, Davis reagent
was added dropwise from a stock solution in THF (7.6 mg/50 µL THF, 0.019 mmol, 2 equiv) and the resulting mixture was stirred
for additional 2 hours at -78 °C. At this point, the reaction was quenched with 3.0M methanolic HCl (33 µL, 0.0967 mmol, 10
equiv) and warmed to room temperature. Aqueous 3M HCl (0.3 mL) was then added and the reaction was heated to 85 °C for 24
hours to deprotect and isomerize all material in the iso-bilobalide form, back to the bilobalide scaffold. The reaction was then
concentrated and the crude NMR showed the ratio of 15 to 1 to be 100:1.
To a flame dried reaction vial containing a magnetic stirbar was transferred deshydroxybilobalide 5 (4.1 mg, 0.00967
mmol). To remove any trace water, the starting material was azeotroped with toluene at least three times by heating to 80 °C
under a strong positive pressure of dry N2 until all solvent was evaporated and only a white solid remained in the flask. The
reaction vial was placed under an argon atmosphere and then THF (300 µL) was added. The reaction was cooled to -78 °C
followed by the addition of a KHMDS solution (0.15M in THF, 0.1 ml, 0.015 mmol, 1.5 equiv). After stirring for 1 hour at -78 °C,
Davis reagent was added dropwise from a stock solution in THF (3.8 mg/50 µL THF, 0.015 mmol, 1.5 equiv) and the resulting
mixture was stirred for additional 2 hours at -78 °C. At this point, the reaction was quenched with 3.0M methanolic HCl (33 µL,
0.0967 mmol, 10 equiv) and warmed to room temperature. Aqueous 3M HCl (0.3 mL) was then added and the reaction was heated
to 85 °C for 24 hours to deprotect and isomerize all material in the iso-bilobalide form, back to the bilobalide scaffold. The
reaction was then concentrated and the crude NMR showed the ratio of 15 to 1 to be 94:6.
Rf 0.50 (DCM:acetone = 7:3, UV detection after heating over 15 min. on TLC plate)
1H NMR
(600 MHz, acetone-d6)
δ 6.50 (s, 1H), 5.92 (d, J = 6.1 Hz, 1H), 5.01 – 4.92 (m, 2H), 4.67 (s, 1H), 3.58 (d, J = 18.6 Hz, 1H), 3.27 (d, J
= 18.5 Hz, 1H), 2.65 (dd, J = 13.0, 6.4 Hz, 1H), 2.23 (dd, J = 12.9, 9.9 Hz, 1H), 1.17 (s, 9H). 13C NMR
HRMS (ESI)
(151 MHz, acetone-d6)
δ 175.19, 174.69, 171.64, 104.71, 88.21, 82.70, 69.55, 63.15, 62.81, 41.51, 38.25, 34.77, 27.01.
Calcd. for C15H18O8 327.1080 (M+H+) found 327.1068.
S22
SI-6: Skeleton rearrangement to form iso-bilobalide
To an oven-dried NMR-tube was added (–)-1 (2.0mg, 0.0061 mmol) followed by CDCl3 (500µL) and was subsequently
capped with an NMR tube septum. DBU (0.84µL, 0.0061 mmol) was added as a stock solution in 100µL of CDCl3 to the NMR
tube and the spectrum was taken within 5 minutes of preparing the sample. The product observed in non-isolable, and decomposes
back to starting material immediately upon acidification. Structure assignment was determined by homology to the known iso-
bilobalide scaffold as well as 2D NMR (see pages S45-S49). All attemps to recrystallize the product resulted in the isolation of
an amorphous solid.
S23
Table S2: Bond lengths of a representative example of gamma-lactones lacking an electron withdrawn hydroxy vs those
containing an electron withdrawn hydroxy group.
The .cif files for compounds SI-748, SI-849, SI-950, SI-1051, SI-1152, SI-1253, SI-1354, SI-1455, were obtained from the
Crystallography Open Database which can be accessed at http://www.crystallography.net/cod/
S24
4. NMR Spectra
(±)-6, 1H NMR, 600MHz, CDCl3, major isomer’s peaks are integrated
S25
(±)-6, 13C NMR, 151MHz, CDCl3
S26
(–)-7 crude, 1H NMR, 600MHz, CDCl3
S27
(–)-8, 1H NMR, 600MHz, CDCl3
S28
(–)-8, 13C NMR, 151MHz, CDCl3
S29
(+)-9, 1H NMR, 600MHz, CDCl3
S30
(+)-9, 13C NMR, 151MHz, CDCl3
S31
(+)-14, 1H NMR, 600MHz, CDCl3
S32
(+)-14, 13C NMR, 151MHz, CDCl3
S33
(+)-10, 1H NMR, 600MHz, CDCl3
S34
(+)-10, 13C NMR, 151MHz, CDCl3
S35
(+)-11, 1H NMR, 600MHz, CDCl3
S36
(+)-11, 13C NMR, 151MHz, CDCl3
S37
(+)-12, 1H NMR, 600MHz, CDCl3
S38
(+)-12, 13C NMR, 151MHz, CDCl3
S39
(+)-13, 1H NMR, 600MHz, CDCl3
S40
(+)-13, 13C NMR, 151MHz, CDCl3
S41
(–)-5, 1H NMR, 600MHz, acetone-D6
S42
(–)-5, 13C NMR, 151MHz, acetone-D6
S43
(–)-1, 1H NMR, 600MHz, acetone-D6
S44
(–)-1, 13C NMR, 151MHz, acetone-D6
S45
(–)-1, Synthetic (–)-bilobalide 1H NMR, 600MHz, acetone-D6
(–)-1, Authentic (–)-bilobalide 1H NMR, 600MHz, acetone-D6
S46
16c, 1H NMR, 600MHz, acetone-D6
S47
16c, 13C NMR, 151MHz, acetone-D6
S48
16b, 1H NMR, 600MHz, acetone-D6
S49
15, 1H NMR, 600MHz, acetone-D6
S50
15, 1H NMR, 600MHz, acetone-D6
S51
SI-6, 1H NMR, 600MHz, CDCl3
S52
SI-6, 13C NMR, 151MHz, CDCl3
S53
SI-6, HMBC, 600MHz, CDCl3
S54
C10, 1H
C6, 1H
C7, 1H C7, 1H
C1, 1H C1, 1H
SI-6, HSQC, 600MHz, CDCl3
(Zoomed in to the region highlighed above)
S55
SI-6, HMBC, 600MHz, CDCl3
S56
5. X-Ray Data for bilobalide intermediates
(–)-8 Giese Reaction
Table S3. Crystal data and structure refinement for Shenvi164.
Report date 2019-02-22
Identification code shenvi164
Empirical formula C29 H36 O7
Molecular formula C29 H36 O7
Formula weight 496.58
Temperature 100.0 K
Wavelength 1.54178 Å
Crystal system Monoclinic
Space group P 1 21 1
Unit cell dimensions a = 10.5436(2) Å = 90°.
b = 11.0100(2) Å = 109.0470(10)°.
c = 11.7398(2) Å = 90°.
Volume 1288.20(4) Å3
Z 2
Density (calculated) 1.280 Mg/m3
Absorption coefficient 0.739 mm-1
F(000) 532
Crystal size 0.215 x 0.125 x 0.1 mm3
Crystal color, habit colorless block
Theta range for data collection 3.983 to 71.019°.
Index ranges -10<=h<=12, -13<=k<=13, -14<=l<=13
Reflections collected 11031
Independent reflections 4674 [R(int) = 0.0197]
Completeness to theta = 67.500° 99.7 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.7534 and 0.6507
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 4674 / 1 / 331
Goodness-of-fit on F2 1.026
Final R indices [I>2sigma(I)] R1 = 0.0245, wR2 = 0.0633
R indices (all data) R1 = 0.0248, wR2 = 0.0635
Absolute structure parameter -0.01(3)
Largest diff. peak and hole 0.259 and -0.159 e.Å-3
S57
(±)-12 Fully Substituted Cyclopentane
Table S4. Crystal data and structure refinement for shenvi158_0m_a.
Identification code RMD 1006-P
Empirical formula C30 H34 O7
Formula weight 506.57
Temperature 100.0 K
Wavelength 0.71073 Å
Crystal system Monoclinic
Space group P 21/c [racemic]
Unit cell dimensions a = 8.7120(4) Å = 90°.
b = 22.5701(10) Å = 100.619(3)°.
c = 13.2257(6) Å = 90°.
Volume 2556.0(2) Å3
Z 4
Density (calculated) 1.316 Mg/m3
Absorption coefficient 0.093 mm-1
F(000) 1080
Crystal size 0.33 x 0.32 x 0.30 mm3
Theta range for data collection 2.749 to 27.132°.
Index ranges -11<=h<=11, -28<=k<=28, -15<=l<=16
Reflections collected 17895
Independent reflections 5638 [R(int) = 0.0588]
Completeness to theta = 25.242° 99.9 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.7455 and 0.6948
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 5638 / 0 / 339
Goodness-of-fit on F2 1.010
Final R indices [I>2sigma(I)] R1 = 0.0480, wR2 = 0.0917
R indices (all data) R1 = 0.0873, wR2 = 0.1068
Extinction coefficient n/a
Largest diff. peak and hole 0.332 and -0.261 e.Å-3
S58
(–)-5 Des-Hydroxy-Bilobalide
Table S5. Crystal data and structure refinement for Shenvi163.
Report date 2019-02-22
Identification code shenvi163
Empirical formula C15 H20 O8
Molecular formula C15 H18 O7, H2 O
Formula weight 328.31
Temperature 100.0 K
Wavelength 1.54178 Å
Crystal system Monoclinic
Space group P 1 21 1
Unit cell dimensions a = 6.4622(2) Å = 90°.
b = 14.0095(4) Å = 109.8840(10)°.
c = 8.7984(2) Å = 90°.
Volume 749.05(4) Å3
Z 2
Density (calculated) 1.456 Mg/m3
Absorption coefficient 1.013 mm-1
F(000) 348
Crystal size 0.2 x 0.16 x 0.04 mm3
Crystal color, habit colorless plate
Theta range for data collection 5.346 to 68.369°.
Index ranges -7<=h<=7, -16<=k<=16, -10<=l<=10
Reflections collected 7420
Independent reflections 2652 [R(int) = 0.0214]
Completeness to theta = 67.500° 99.7 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.7531 and 0.6695
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 2652 / 1 / 215
Goodness-of-fit on F2 1.051
Final R indices [I>2sigma(I)] R1 = 0.0244, wR2 = 0.0620
R indices (all data) R1 = 0.0249, wR2 = 0.0623
Absolute structure parameter 0.04(5)
Largest diff. peak and hole 0.182 and -0.152 e.Å-3
S59
(±)-16c benzoyl-iso-deshydroxy-bilobalide
Table S6. Crystal data and structure refinement for shenvi135.
Identification code MB-02-229
Empirical formula C22 H22 O8
Formula weight 414.39
Temperature 100.0 K
Wavelength 0.71073 Å
Crystal system Monoclinic
Space group P 21/c
Unit cell dimensions a = 14.6104(16) Å = 90°.
b = 15.3669(16) Å = 105.350(3)°.
c = 8.9641(9) Å = 90°.
Volume 1940.8(4) Å3
Z 4
Density (calculated) 1.418 Mg/m3
Absorption coefficient 0.109 mm-1
F(000) 872
Crystal size 0.28 x 0.26 x 0.04 mm3
Theta range for data collection 1.445 to 25.373°.
Index ranges -14<=h<=17, -17<=k<=12, -10<=l<=10
Reflections collected 6293
Independent reflections 3473 [R(int) = 0.0385]
Completeness to theta = 25.242° 98.2 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.2589 and 0.2076
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 3473 / 0 / 274
Goodness-of-fit on F2 1.007
Final R indices [I>2sigma(I)] R1 = 0.0542, wR2 = 0.1189
R indices (all data) R1 = 0.1041, wR2 = 0.1338
Extinction coefficient n/a
Largest diff. peak and hole 0.301 and -0.250 e.Å-3
S60
Chiral SFC Traces for (–)-7
2D LC-SFC Conditions (heart-cutting method): LC Dimension: 0.1% aqueous formic acid:acetonitrile gradient
(0.6 mL/min, 15-99% acetonitrile over 2.1 minutes) at 55 °C. The heart cut was performed at 2.18 minutes
using a 6-port 2-position valve equipped with a 10 mL transfer loop; SFC Dimension: isocratic conditions (4
mL/min, 15% MeOH / CO2, 1600 psi backpressure) at 30 °C. The enantiomers were detected by UV light (214
nm).
Chromatogram of (±)- 7
Chromatogram of enantioenriched (–)-7 following large-scale asymmetric Reformatsky reaction
MB_04_071A
SHE0110_SFC
S61
Chromatogram of enantioenriched (–)-7 following small-scale asymmetric Reformatsky reaction
MB_03_240
S62
Chiral SFC Traces for (–)-8
Chiral SFC conditions: Isocratic conditions (4 mL/min, 25% MeOH / CO2, 1600 psi backpressure) at 30 °C.
The enantiomers were detected by UV light (214 nm).
Chromatogram of (±)-8
Chromatogram of enantipure (–)-8
MB_04_RADC4C-Rac
MB_04_RADC4C-Ent
S63
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