Synthesis of hybrid natural product analogues with anti-tumour properties

Article abstract of DOI:10.1016/j.tet.2016.07.033

High yielding and diastereoselective conjugate addition reactions of a (?)-quinic acid derived enone have provided access to a small library of hybrid analogues of the anti-tumour natural products antheminone A and COTC. The novel compounds were assessed

Full text of DOI:10.1016/j.tet.2016.07.033

Accepted Manuscript
Synthesis of hybrid natural product analogues with anti-tumour properties
Stephania Christou, Alyn C. Edwards, Robin G. Pritchard, Peter Quayle, Yiwei Song,
Ian J. Stratford, Katharine F. Williams, Roger C. Whitehead
PII:
S0040-4020(16)30656-1
10.1016/j.tet.2016.07.033
TET 27929
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 April 2016
Revised Date: 28 June 2016
Accepted Date: 7 July 2016
Please cite this article as: Christou S, Edwards AC, Pritchard RG, Quayle P, Song Y, Stratford IJ,
Williams KF, Whitehead RC, Synthesis of hybrid natural product analogues with anti-tumour properties,
Tetrahedron (2016), doi: 10.1016/j.tet.2016.07.033.
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ACCEPTED MANUSCRIPT

Synthesis of Hybrid Natural Product Analogues with Anti-tumour
ACCEPTED MANUSCRIPT
Properties
Stephania Christou,a Alyn C. Edwards,a Robin G. Pritchard,a Peter Quayle,a Yiwei Song,a Ian
b
a
a
*
J. Stratford, Katharine F. Williams, Roger C. Whitehead
a
School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
Manchester Pharmacy School, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
b
High yielding and diastereoselective conjugate addition reactions of a (-)-quinic acid derived enone have
provided access to a small library of hybrid analogues of the anti-tumour natural products antheminone A
and COTC. The novel compounds were assessed for their antiproliferative activities towards the A549 non-
small-cell lung cancer cell line revealing some useful structure-activity relationships.
Keywords: anti-tumour; natural product analogue; conjugate addition; transition metal; catalysis; rhodium.
1. Introduction
The α-oxyalkylcyclohex-2-enone moiety is a common structural feature of many natural products including
poly-oxygenated metabolites (e.g. COTC 1),1 carvotacetone derivatives such as 22 and terpenoid derivatives
exemplified by phorbasin B (3)3 and antheminone A (4).4 A number of these compounds have been found to
display notable biological activities: for example, both 1 and 4 show significant toxicity towards a variety of
different cancer cell lines.4,5
Figure 1 Natural products containing the α-oxyalkylcyclohex-2-enone moiety.
During the course of our investigations into the anti-tumour properties of a variety of α-oxyalkylcyclohex-2-
enones, we had cause to focus our attention on compounds bearing a carbon-linked substituent at C5 (i.e.
analogues of 2, 3, and 4).6 We describe, herein, a synthetic approach to compounds of this type (general
structure 5), which utilises (_)-quinic acid (6) as starting material (Figure 2). The results of assays of the
anti-proliferative activities of the novel analogues towards the A549 non-small-cell lung cancer cell line are
also provided.
*
Corresponding author. Tel: +44-161-275-7856; Fax: +44-161-275-4939; e-mail: roger.whitehead@manchester.ac.uk
1

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Figure 2 Generic structure of target compounds and the structure of (-)-quinic acid.
2. Results and Discussion
A number of previous literature reports have described conjugate addition reactions to the isopropylidene
protected dioxygenated cyclohexenone 7, some of which report poor to average yields due, in part, to the
lability of enone 7 and/or adducts 8 towards the reaction conditions (Scheme 1).7,8 Bräse and co-workers, for
example, reported that treatment of 7 with Ph2CuMgBr.S(CH3)2 in THF furnished adduct 8 (R = Ph) in just
27% yield, while reaction with (2-propyl)2CuMgBr.S(CH3)2 furnished no isolable quantities of the
corresponding conjugate adduct (8, R = 2-propyl).8
Scheme 1
It was envisaged that a compound possessing the functionality of enone 7 would represent a versatile
intermediate for the synthesis of α-oxyalkylcyclohexenones bearing a carbon-linked substituent at C5 and an
anti-stereochemical relationship between substituents at C4 and C5, as proposed for the structure of
antheminone A. An investigation was carried out, therefore, into the use of cyclohexenone 9 as a Michael
acceptor with a variety of organometallic reagents. Compound 9, which can be prepared expediently and on
a preparative scale from (-)-quinic acid (6),6d possesses a cyclohexylidene ketal moiety which was predicted
to offer greater resilience to the reaction conditions for conjugate addition than its isopropylidene
counterpart 7. Gratifyingly, exposure of enone 9 to a range of organometallic reagents under either
stoichiometric or catalytic conditions, resulted in formation of adducts 10a-f in good to excellent yields
(Scheme 2 and Table 1).
Scheme 2
2

Entry
Reaction Conditions
Product
Yield / %
82
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2-propylMgBr (3 eq.), ZnCl2.TMEDA (1 eq.), (CH3)3SiCl (3.3 eq.) ,
1
10a
THF, –50 oC
PhMgBr (2 eq.), CuI (1 eq.), THF, 0 oC
73
93
93
2
3
4
10b
10b
10c
PhB(OH)2, [RhCl(cod)]2 (5 mol%), 1,4-dioxane:water (10:1), Et3N, rt
4-(CH3O)PhB(OH)2, [Rh(µ-OH)(cod)]2 (5 mol%), 1,4-dioxane:water
(10:1), Et3N, rt
4-(Br)PhB(OH)2, [RhCl(cod)]2 (5 mol%), 1,4-dioxane:water (10:1),
Et3N, rt
87
83
78
5
6
7
10d
10e
10f
2-naphthylB(OH)2, [RhCl(cod)]2 (5 mol%), 1,4-dioxane:water (10:1),
Et3N, rt
4-biphenylB(OH)2, [Rh(µ-OH)(cod)]2 (5 mol%), 1,4-dioxane:water
(10:1), Et3N, rt
Table 1 Isolated yields of conjugate addition reactions to enone 9.
Thus, use of the appropriate tri-organozincate reagent allowed access to 2-propyl substituted compound 10a
(entry 1)9 whereas aryl substituents could be readily introduced using Gilman cuprates derived from the
corresponding Grignard reagents and CuI (entry 2) or alternatively using rhodium catalysis ([RhCl(cod)]2 or
[Rh(µ-OH)(cod)]2 and the appropriate arylboronic acid (entries 3 to 7).10a,b In the latter case, 5 mol % of
transition metal catalyst was routinely employed however loadings as low as 2 mol % were also used
successfully without significant detrimental effect to isolated yields or reaction times.
Only a single diastereoisomer was obtained from each of these reactions which, in the first instance, was
presumed to have arisen from addition of the organometallic reagent to the sterically more accessible
“convex” face of enone 9. Initial evidence to support this conjecture was the observation of nOe’s between
C(4)H of 10e and both C(1’)H and C(3’)H of the naphthalene substituent: analogous enhancements were
also observed for the biphenyl adduct 10f. In both cases, there was no observable transannular nOe between
C(3)H and C(5)H. Unambiguous structural confirmation was ultimately made possible by X-ray analysis of
a crystalline sample of the biphenyl adduct 10f (Figure 2).11
Figure 2 Crystal structure of biphenyl adduct 10f with ellipsoids at 50% probability
Studies carried out recently on an enantiomeric series of α-oxyalkylcyclohex-2-enones indicated that an
aromatic substituent at C5 was an important requirement for good anti-proliferative activity towards lung
cancer cell lines.6e Efforts were focussed, therefore, on the preparation of a range of aryl-substituted hybrid
3

analogues of antheminone A and COTC (generic structure 5, R = aryl) using the synthetic approach outlined
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in Scheme 3.
Scheme 3
In a first generation approach, attention was focused on the phenyl adduct 10b which could be prepared in
excellent yield from enone 9 via the rhodium catalysed conjugate addition of phenylboronic acid. The first
goal was the development of efficient and high yielding conditions for eliminative removal of the
cyclohexylidene moiety of 10b followed by reprotection of the resulting allylic alcohol (γ-
hydroxycyclohexenones of this type are known to undergo quite facile base-catalysed tautomerism to
cyclohexan-1,4-diones making this a non-trivial transformation). In this context, Danishefsky and co-
workers previously reported that acetonide-protected compound 15 could be converted to γ-silyloxy-enone
18 by reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in the presence of TBSCl at elevated
temperature (Scheme 4).12 In our hands, and under similar reaction conditions, cyclohexylidene ketal 16 also
underwent clean conversion to 18 in comparable yield.6d Unfortunately, exposure of phenyl-substituted
cyclohexanone 10b to these reaction conditions met with little success, however replacement of the silyl
trapping reagent with TBSOTf and conducting the reaction at room temperature ultimately allowed isolation
of the desired product 19 in an acceptable yield (Scheme 5).
Scheme 4
Scheme 5
Incorporation of a hydroxymethyl group at C2 of enone 19 was accomplished in moderate yield using an
imidazole-catalysed Morita-Baylis-Hillman reaction to give primary alcohol 20.13a,b Subsequent
esterification with crotonic anhydride gave crotonate 21, which after partial purification by silica
4

chromatography, was subjected to acid-mediated deprotection conditions to give the hybrid analogue 22b.
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Similar deprotection of hydroxymethyl compound 20 gave antheminone A analogue 23b (Scheme 6).
Scheme 6
Although successful for the preparation of 22b and 23b, the approach outlined above proved unreliable for
the synthesis of target compounds bearing alternative aromatic substituents, particularly with regard to the
eliminative deprotection/reprotection sequence and the Morita-Baylis-Hillman reaction. A more robust
‘second generation’ approach was developed, therefore, for the preparation of the remaining target
compounds wherein the deprotection/reprotection sequence was carried out in two discrete synthetic
operations.
Accordingly, exposure of the conjugate adducts 10c-f to either DBU in dichloromethane or a catalytic
quantity of aqueous sodium hydroxide in THF (for ~ 4 hours) furnished the γ-hydroxycyclohexenones 11c-f
in good to excellent yields.14 Subsequent reprotection of the liberated C4-hydroxyl group as its triethylsilyl
(TES) ether proved to be surprisingly problematic due mostly to competitive silylenol ether formation. This
difficulty was ultimately overcome, however, by pre-mixing TES-triflate and 2,6-lutidine in
dichloromethane (to neutralise residual triflic acid) prior to stirring very briefly with the substrate at -78 oC.
Under these conditions, TES ethers 24c-f were obtained in yields greater than 70% (Scheme 7).
Reagents and Conditions: i) DBU, CH2Cl2, rt, 2 h or 0.5M aq NaOH (cat.), THF, 4 h, 67-87%; ii) TESOTf, 2,6-lutidine, CH2Cl2,
o
-78 C, 10 min. 75-89%; iii) DMAP, formaldehyde (37% in H2O), sodium dodecyl sulfate, rt, 22 h, 30-75%; crotonylation and
deprotection conditions as in Scheme 6.
Scheme 7
5

The ambiphilic nature of intermediates 24c-f prompted an investigation of surfactant conditions for the
ACCEPTED MANUSCRIPT
problematic Morita-Baylis-Hillman reaction and pleasingly, using the SDS-mediated procedure reported by
Williams and co-workers,15 hydroxymethyl compounds 25c-f could be prepared in yields generally in excess
of 60% (with the exception of a disappointingly low yield of 30% for biphenyl compound 25f). These
adducts were then converted to hybrid analogues 22c-f and antheminone A analogues 23c-f using similar
conditions to those described above for 22b and 23b.
Analogues 22b-f and 23b-f were initially selected as synthetic targets as they possess variable
hydrophobicities (as indicated by their predicted logP (miLogP16) values) and assessment of their bioactivity
was expected to provide useful structure activity relationship information. A549 non-small-cell lung cancer
cells were exposed, therefore, to varying concentrations of each of the compounds for 96 h and their anti-
proliferative activities were assessed using the MTT assay (Table 2).17
miLogP16
2.25
miLogP16
0.86
Compound
22b
Compound
23b
IC50 (µM)
2.3±0.8
3.2±0.2
3.0±0.2
2.5±0.3
3.3±0.4
IC50 (µM)
90±48
75±11
16.5±1.6
15.3±0.2
28.0±2.5
2.31
3.06
3.44
4.05
0.92
1.67
2.04
2.66
22c
22d
22e
22f
23c
23d
23e
23f
Table 2 Predicted log P (miLogP16) values and values of IC50 (the concentration required to reduce proliferation by 50%) of
hybrid analogues of antheminone A and COTC towards non-small-cell lung cancer cell line A549. Toxicity experiments were
repeated in triplicate and data within individual experiments were derived from four separate observations: average values are
given in the table.
The biological mode of action of COTC and related compounds is generally accepted to be mediated by the
detoxification enzyme glutathione transferase (GST) and requires a ‘reasonable leaving group’ attached to
the methylene side-chain which undergoes conjugate displacement by the tri-peptide glutathione (GSH)
(27
ꢀ
28 29) (Scheme 8). The ensuing highly reactive exocyclic enone 29 is then believed to alkylate
ꢀ
DNA/vital proteins, or deplete intracellular stores of GSH, leading to cell death.18
Scheme 8
To a degree, the cytotoxicity data in Table 2 are in accord with this proposal as compounds 22b-g, which
possess a carboxylate leaving group, are all more potent than their non-esterified counterparts 23b-g. It is
noteworthy, however, that the moderate toxicity of some of the less polar diols (e.g. 23c and 23d) indicates
that the requirement for a ‘reasonable leaving group’ is not absolute. In order to throw some light on this
observation, three of the γ-hydroxyenone intermediates 11c-e, which are simple Michael acceptors and are
6

unable to generate an exocyclic enone, were subjected to MTT assays. These compounds can be viewed as
ACCEPTED MANUSCRIPT
analogues of the plant-derived cyclohexenone (±)-rengyolone (35)19 which has previously been shown to
demonstrate weak toxicity towards the A549 cell line (IC50 = 16.2±0.8 µg/mL / 105±5 µM).20 All three
enones displayed significantly better antiproliferative activities than the corresponding diols 23c-e as well as
the natural product 35. Furthermore, the 2-naphthyl substituted compound 11e showed slightly improved
potency compared with all of the crotonylated compounds 22b-f (Table 3).
miLogP16
Compound
11c
IC50 (µM)
7.0±0.3
5.5±0.5
1.9±0.4
1.61
2.37
2.74
11d
11e
Table 3 Predicted log P (miLogP16) values and values of IC50 (the concentration required to reduce proliferation by 50%) of γ-
hydroxyenones 11c-e towards non-small-cell lung cancer cell line A549. Toxicity experiments were repeated in triplicate and data
within individual experiments were derived from four separate observations: average values are given in the table.
These findings raise some questions as to the mode of antiproliferative activity of the COTC/antheminone A
analogues described herein and some doubt as to the validity of the assumption that they operate in a similar
manner to COTC. This is further emphasised by the finding that phenyl substituted compound 22b is very
similar in potency to its optical antipode (ent-22b: IC50 = 1.3 ±02 µM)6e which is surprising for an enzyme
mediated mode of biological activity. Investigations are now underway in our laboratories to elucidate the
most likely mechanism(s) of action, the findings of which will be reported in due course.
3. Acknowledgements
NMR spectrometer and X-ray support for this work was funded by the Engineering and Physical Sciences
Research Council (grant number EP/K039547/1) who we also acknowledge, with thanks, for providing
financial support for K.F.W. and S.C.
4. Experimental Section
4.1 General
All reagents were purchased from Sigma-Aldrich, Alfa-Aesar or Fisher Scientific. Dichloromethane was
dried over and distilled from calcium hydride under an atmosphere of nitrogen. THF was distilled from
sodium-benzophenone ketyl under an atmosphere of nitrogen. All other solvents were used as supplied.
Flash chromatography was performed using technical grade silica gel (pore size 60Å 230-240, mesh 40-63
µm). IR spectra were recorded on an AT1-Mattson Genesis Series FTIR spectrometer or a Bruker Alpha FT-
7

1
13
19
IR spectrometer or a Thermo Scientific Nicolet iS5 FT-IR spectrophotometer. H, C and F spectra were
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recorded on Bruker Avance 300 MHz, Bruker Avance III 400 MHz or Bruker Avance II+ 500 MHz
spectrometers. Chemical shifts are referenced to the residual solvent peak. Mass spectra were recorded on a
Waters SQD2 (electrospray) spectrometer. Melting points were recorded using a Sanyo Gallenkamp
MPD350 heater and are uncorrected. Optical rotations were recorded using an automatic AA-10 polarimeter
with sodium D light (λ=589 nm) and values are given in 10-1 deg g-1 cm2.
4.2 Atom numbering
For simplicity and consistency the numbering systems illustrated below have been employed for the
assignment of NMR spectroscopic data.
4.3 Procedures and Analytical Data
(3aS,4S,7aR)-4-isopropyltetrahydrospiro[benzo[d][1,3]dioxole-2,1'-cyclohexan]-6(3aH)-one (10a)
To a solution of ZnCl2.TMEDA (564 mg, 2.23 mmol) in THF (9 mL) was added iso-propylmagnesium
chloride (2M in diethyl ether, 2.8 mL, 5.6 mmol) at 0 °C under an atmosphere of N2. The solution was
stirred at 0 °C for 15 min, cooled to –50 °C and chlorotrimethylsilane (0.8 mL, 6.3 mmol) was added
followed by a solution of enone 9 (387 mg, 1.86 mmol) in THF (16 mL). The reaction mixture was stirred at
–50 °C for 2 h when it was quenched by the addition of a saturated aqueous ammonium chloride/ammonium
hydroxide solution (9:1, 30 mL) and allowed to warm to room temperature over 45 min. The organic
material was extracted into ethyl acetate (2 x 50 mL) and the combined organic extracts were washed with
water (50 mL), dried (MgSO4) and concentrated in vacuo to give an orange liquid. This liquid was re-
dissolved in THF (4 mL), a 1M aqueous solution of hydrochloric acid (0.2 mL) was added and the solution
was stirred at room temperature for 15 min. The solution was neutralised by the addition of a saturated
aqueous solution of sodium bicarbonate (4 mL) and, after dilution with water (10 mL), organic material was
extracted into ethyl acetate (2 x 10 mL). The combined organic extracts were dried (MgSO4) and
concentrated in vacuo to give the crude product as an orange oil which was purified by flash silica
chromatography (ethyl acetate:40-60 petroleum ether, 1:9) to yield 10a as a colourless oil (386 mg, 82%). Rf
26
(ethyl acetate:40-60 petroleum ether, 1:9) 0.32; [α]D -67.1 (c 0.98 in CH2Cl2); νmax(film)/cm-1 2934s
(C-H), 2867m (C-H), 1716s (C=O); δH (400 MHz; CDCl3) 0.90 (3H, d, J 6.7, CH(CH3)), 1.00 (3H, d, J 6.7,
CH(CH3)), 1.38-1.67 (10H, m, 5 x CH2 of cyclohexane), 1.79 (1H, octet, J 6.7, CH(CH3)2), 1.89 (1H, dtd, J
10.2, 6.7, 3.9, C(5)H), 2.02 (1H, dd, J 17.1, 10.2, C(6)Hax), 2.42 (1H, dd, J 17.1, 3.9, C(6)Heq), 2.62 (2H, ~d,
8

J 5.8, C(2)H2), 4.25 (1H, ~t, J 6.7, C(4)H), 4.47 (1H, dt, J 6.7, 5.8, C(3)H); δC (100 MHz; CDCl3) 18.7
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(CH(CH3)), 20.9 (CH(CH3)), 23.6, 24.0 & 25.1 (3 x CH2 of cyclohexane), 28.3 (CH(CH3)2), 34.0 & 37.2 (2
x CH2 of cyclohexane), 37.8 (C(6)H2), 42.6 (C(2)H2), 43.3 (C(5)H), 72.0 (C(3)H), 74.7 (C(4)H), 109.2 (ketal
C), 209.8 (C=O); m/z (+ES) 275 ([M+Na]+, 100%); (Found 275.1613, C15H24NaO3 ([M+Na]+) requires
275.1623).
(3aS,4S,7aR)-4-phenyltetrahydrospiro[benzo[d][1,3]dioxole-2,1'-cyclohexan]-6(3aH)-one (10b).
To a stirred suspension of copper(I) iodide (100 mg, 0.53 mmol) in THF (1 mL) at 0 °C, was added
phenylmagnesium bromide (3M in Et2O) (0.35 mL, 1.06 mmol) and the reaction mixture was stirred for 1 h
at 0 °C under an atmosphere of N2. A solution of enone 9 (100 mg, 0.48 mmol) in THF (5 mL) was added
dropwise and the reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched by the addition of a
saturated aqueous ammonium chloride/ammonium hydroxide solution (9:1, 10 mL). The two layers were
separated and the aqueous layer was extracted with diethyl ether (3 x 15 mL). The combined organic extracts
were washed with brine (30 mL), dried over MgSO4 and concentrated in vacuo. The crude residue was
purified by flash silica chromatography (ethyl acetate:40-60 petroleum ether, 1:9) to give the title compound
28
10b as a pale yellow oil (98 mg, 73%). Rf (ethyl acetate:40-60 petroleum ether, 1:9) 0.18; [α]D -42.8 (c
1.0, CH2Cl2); νmax (film)/cm-1 2934w (C-H), 2883w (C-H), 1712s (C=O); δH (400MHz; CDCl3) 1.37-1.76
(10H, m, 5 x CH2 of cyclohexane), 2.60-2.66 (2H, m, one of C(2)H2 & one of C(6)H2), 2.73 (1H, dd, J 16.7,
4.4, one of C(2)H2), 2.79 (1H, dd, J 17.6, 4.8, one of C(6)H2), 3.44 (1H, d~t, J 8.5, 4.8, C(5)H), 4.57-4.68
(2H, m, C(3)H and C(4)H), 7.23-7.28 (3H, m, 3 x aryl-H), 7.33-7.37 (2H, m, 2 x aryl-H); δC (100MHz;
CDCl3) 23.6, 24.0, 25.1, 33.7 & 36.9 (5 x cyclohexane CH2), 40.7 (C(6)H2), 42.3 (C(5)H), 42.7 (C(2)H2),
72.2 (C(3)H or C(4)H), 76.7 (C(3)H or C(4)H), 109.3 (ketal C), 127.0, 127.5 & 128.8 (aryl-CH), 140.2 (aryl-
C), 208.9 (C=O); m/z (+ES) 309 ([M+Na]+, 100%); (Found 309.1461, C18H22NaO3 ([M+Na]+) requires
309.1467).
Representative procedure for the rhodium catalysed conjugate addition of an arylboronic acid to enone 9.
(3aS,4S,7aR)-4-(4-methoxyphenyl)tetrahydrospiro[benzo [d][1,3] dioxole-2,1'-cyclohexan]-6(3aH)-one
(10c)
To a solution of enone 9 (365 mg, 1.75 mmol) in dioxane:water (10:1, 4.0 mL) was added 4-
methoxyphenylboronic acid (800 mg, 5.26 mmol) and [Rh(µ-OH)(cod)]2 (44 mg, 5 mol%), followed by
Et3N (0.23 mL, 1.75 mmol). The reaction mixture was stirred under an atmosphere of nitrogen at room
temperature for 6.5 h when the solvents were removed in vacuo to give an orange residue. This residue was
dissolved in CH2Cl2 (10 mL) and washed with brine (10 mL). Removal of the CH2Cl2 in vacuo gave a crude
product which was purified by flash silica chromatography (ethyl acetate:40-60 petroleum ether, 1:12) to
give the adduct 10c as a pale yellow solid (516 mg, 93%). mp 109.8-111.1 °C; Rf (ethyl acetate:40-60
9

petroleum ether, 1:5) 0.25; [α]D27 -60.3 (c 0.50 in CH2Cl2); νmax (film)/cm-1 2935s (C-H), 2856s (C-H), 1718s
ACCEPTED MANUSCRIPT
(C=O); δH (400MHz; CDCl3) 1.35-1.75 (10H, m, 5 x CH2 of cyclohexane), 2.59 (1H, dd, J 17.5, 8.4,
C(6)Hax), 2.62 (1H, dd, J 17.2, 4.6, one of C(2)H2), 2.73 (1H, dd, J 17.2, 4.6, one of C(2)H2), 2.75 (1H, dd, J
17.5, 4.6, C(6)Heq), 3.38 (1H, d t, J 8.4, 4.6, C(5)H), 3.80 (3H, s, OCH3), 4.54-4.60 (1H, m, C(3)H and
C(4)H), 6.88 (2H, d, J 8.6, aryl-H), 7.16 (2H, d, J 8.6, aryl-H); δC (100MHz; CDCl3) 23.6, 23.9, 25.1, 33.7 &
36.9 (5 x cyclohexane CH2), 40.9 (C(2)H2), 41.8 (C(5)H), 42.3 (C(6)H2), 55.2 (OCH3), 72.1 (C(3)H or
C(4)H), 77.4 (C(3)H or C(4)H), 109.3 (ketal C), 114.1 & 128.4 (aryl-CH), 132.0 & 158.4 (aryl-C), 209.0
(C=O); m/z (+ES) 339 ([M+Na]+, 100%); (Found 339.1584, C19H24NaO4 ([M+Na]+) requires 339.1572).
(3aS,4S,7aR)-4-(4-bromophenyl)tetrahydrospiro[benzo[d][1,3] dioxole-2,1'-cyclohexan]-6(3aH)-one (10d)
Using a similar procedure to that described above (replacing [Rh(µ-OH)(cod)]2 with [RhCl(cod)]2), enone 9
(370 mg, 1.78 mmol) was converted to adduct 10d (a viscous white oil, 567 mg, 87%). Rf (ethyl acetate:40-
29
60 petroleum ether, 1:5) 0.24; [α]D -77.0 (c 1.00 in CH2Cl2); νmax (film)/cm-1 2931s (C-H), 2857m (C-H),
1715s (C=O); δH (400 MHz; CDCl3) 1.28-1.75 (10H, m, 5 × CH2 of cyclohexane), 2.55 (1H, dd, J 17.1, 9.6,
C(6)Hax), 2.62-2.69 (2H, m, C(6)Heq & C(2)Hax), 2.75 (1H, dd, J 16.9, 5.1, C(2)Heq), 3.35 (1H, ddd, J 9.6,
6.7, 4.5, C(5)H), 4.50 (1H, t, J 6.7, C(4)H), 4.57 (1H, d~t, J 6.7, 5.1, C(3)H), 7.12 (2H, d, J 8.9, aryl-H), 7.47
(2H, d, J 8.9, aryl-H); δC (100 MHz; CDCl3) 23.6, 24.0, 25.1, 33.9 & 37.1 (5 × CH2 of cyclohexane), 41.0
(C(2)H2), 41.2 (C(5)H), 42.5 (C(6)H2), 72.1 (C(3)H), 77.4 (C(4)H), 109.7 (ketal C), 121.0 (aryl-C), 129.2
(C(3’)H & C(5’)H), 131.9 (C(2’)H & C(6’)H), 139.3 (aryl-C), 208.2 (C=O); m/z (+ES) 389 ([M(81Br)+Na]+,
50%), 387 ([M(79Br)+Na]+, 50%), 367 ([M(81Br)+H]+, 50%), 365 ([M(79Br)+H]+, 50%), 160 (100%); (Found
387.0566, C18H2179BrNaO3 ([M+Na]+) requires 387.0572).
(3aS,4S,7aR)-4-(naphthalen-2-yl)tetrahydrospiro [benzo [d][1,3] dioxole-2,1'-cyclohexan]-6(3aH)-one (10e)
Using a similar procedure to that described above (replacing [Rh(µ-OH)(cod)]2 with [RhCl(cod)]2), enone 9
(100 mg, 0.48 mmol) was converted to adduct 10e (a colourless crystalline solid, 134 mg, 83%). mp 83.3-
24
85.3 °C; Rf (ethyl acetate:40-60 petroleum ether, 1:5) 0.32; [α]D -74.4 (c 1.00 in CH2Cl2); νmax (film)/cm-1
3047w (C-H), 3017w (C-H), 2933s (C-H), 2861s (C-H), 1718s (C=O); δH (400MHz; CDCl3) 1.35-1.80
(10H, m, 5 x CH2 of cyclohexane), 2.68 (1H, dd, J 17.2, 5.1, one of C(2)H2), 2.76 (1H, dd, J 17.6, 8.0,
C(6)Hax), 2.77 (1H, dd, J 17.2, 5.1, one of C(2)H2), 2.87 (1H, dd, J 17.7, 5.1, C(6)Heq), 3.60 (1H, dt, J 8.0,
5.1, C(5)H), 4.64 (1H, dt, J 6.5, 5.1, C(3)H), 4.75 (1H, ~t, J 6.0, C(4)H), 7.43 (1H, dd, J 8.7, 1.9, C(3´)H),
7.46-7.53 (2H, m, C(6´)H and C(7´)H), 7.62 (1H, s, C(1´)H), 7.78-7.86 (3H, m, C(4´)H, C(5´)H & C(8´)H);
δC (100MHz; CDCl3) 23.6, 23.9, 25.1, 33.7 & 36.9 (5 x cyclohexane CH2), 40.6 (C(2)H2), 42.3 (C(6)H2),
42.8 (C(5)H), 72.2 (C(3)H), 77.1 (C(4)H), 109.3 (ketal C), 125.8, 125.9, 126.0, 126.4, 127.6, 127.8 & 128.6
(aryl-CH), 132.3, 133.4 & 137.6 (aryl-C), 208.8 (C=O); m/z (+ES) 359 ([M+Na]+, 100%); (Found 359.1616,
C22H24O3Na ([M+Na]+) requires 359.1623).
10

ACCEPTED MANUSCRIPT
(3aS,7aR)-4-([1,1'-biphenyl]-4-yl)tetrahydrospiro[benzo[d][1,3]dioxole-2,1'-cyclohexan]-6(3aH)-one (10f)
Using a similar procedure to that described above, enone 9 (0.250 g, 1.20 mmol) was converted to adduct
10f (an off-white solid, 0.340 g, 78 %). m.p. 103.7-104.3 °C; [α]D28 -70.8 (c 1.3 in CH2Cl2); νmax (film)/cm-1
2943s (C-H), 2900s (C-H), 1716s (C=O); δH (400 MHz; C6D6) 1.48-1.77 (10H, m, 5 x CH2, cyclohexane),
2.26 (1H, dd, J 17.3, 10.1, C(6)Hax), 2.36 (1H, dd, J 16.9, 5.3, one of C(2)H2), 2.56 (1H, dd, J 17.3, 4.6,
C(6)Heq), 2.61 (1H, dd, J 16.9, 5.3, one of C(2)H2), 3.15 (1H, ddd, J 10.1, 6.7, 4.6, C(5)H), 4.02 (1H, dt, J
6.7, 5.3, C(3)H), 4.15 (1H, t, J 6.7, C(4)H), 7.02-7.50 (9H, m, aryl-H); δC (100 MHz; C6D6) 24.3, 24.7, 25.9,
34.7 & 37.9 (5 x cyclohexane CH2), 41.6 (C(2)H2), 43.0 (C(6)H2), 43.3 (C(5)H), 72.9 (C(3)H), 78.2 (C(4)H),
109.6 (ketal C), 127.7, 128.0, 128.3, 128.5 & 129.4 (aryl-CH) 140.5, 140.6 & 141.6 (aryl-C), 206.5 (C=O);
m/z (+ES) 385 ([M+Na]+, 100 %); (Found 385.1770, C24H26NaO3 ([M+Na]+) requires, 385.1780).
First generation synthesis
(1S,6R)-6-((tert-butyldimethylsilyl)oxy)-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (19)
TBSOTf (50 µL mL, 0.22 mmol) and DBU (40 µL, 0.27 mmol) were added sequentially to a solution of
conjugate adduct 10b (57 mg, 0.199 mmol) in dichloromethane (2.2 mL) and the reaction mixture was
stirred at room temperature under an atmosphere of N2 for 4.5 h. A second portion of DBU (10 µL, 0.067
mmol) was then added and the reaction mixture was stirred for a further 1 h at room temperature. The
reaction mixture was diluted with dichloromethane (10 mL) and washed sequentially with water (10 mL), a
1M aqueous solution of hydrochloric acid (10 mL), a saturated aqueous solution of sodium bicarbonate (10
mL) and brine (10 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude
product as a yellow oil (92 mg). Purification by flash silica chromatography (ethyl acetate:40-60 petroleum
ether, 1:19) gave the title compound as a yellow crystalline solid (33 mg, 54%). Rf (ethyl acetate:40-60
petroleum ether, 1:19) 0.13; m.p. 75.2-76.7 °C [Lit. m.p. 74-75 °C]; [α]D36 -132.0 (c 0.85 in CH2Cl2) [Lit.
[α]D20 -158 (c 0.5 in CHCl3)]; νmax (film)/cm-1 3031w (C-H), 2951m (C-H), 2928m (C-H), 2894w (C-H),
2854m (C-H), 2817m (C-H), 1681s (C=O); δH (400 MHz; CDCl3) -0.50 (3H, s, Si(CH3)), -0.13 (3H, s,
Si(CH3)), 0.76 (9H, s, SiC(CH3)3), 2.67 (1H, ddd, J 16.4, 4.3, 1.4, C(6)Heq), 2.78 (1H, dd, J 16.4, 13.7,
C(6)Hax), 3.27 (1H, ddd, J 13.7, 9.4, 4.3, C(5)H), 4.53 (1H, d~t, J 9.4, 2.0, C(4)H), 6.03 (1H, ddd, J 10.4,
2.0, 1.4, C(2)H), 6.85 (1H, dd, J 10.4, 2.0, C(3)H), 7.24-7.36 (5H, m, aryl-H); δC (100 MHz; CDCl3) -5.9
(Si(CH3)), -5.2 (Si(CH3)), 17.9 (SiC(CH3)3), 25.6 (SiC(CH3)3), 42.6 (C(6)H2), 50.7 (C(5)H), 73.0 (C(4)H),
127.3, 128.2, 128.4 & 128.5 (aryl-CH & C(2)H), 140.6 (aryl-C), 153.9 (C(3)H), 198.5 (C=O); m/z (+ES) 357
([M+Na+CH3OH]+, 100%), 325 ([M+Na]+, 85); (Found 325.1591, C18H26NaO2Si ([M+Na]+) requires
325.1600).
(1S,6R)-6-((tert-butyldimethylsilyl)oxy)-4-(hydroxymethyl)-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (20)
11

Formaldehyde (37%) (20 µL, 0.27 mmol) and imidazole (1.4 mg, 0.02 mmol) were added to a solution of
ACCEPTED MANUSCRIPT
enone 19 (61 mg, 0.20 mmol) in a mixture of THF (1.2 mL) and 1M aqueous sodium bicarbonate (0.6 mL).
After stirring at room temperature under N2 for 5 days, further portions of formaldehyde (37%) (15 µL, 0.20
mmol) and imidazole (1.4 mg, 0.02 mmol) were added. After a further 3 days, additional formaldehyde
(37%) (15 µL, 0.20 mmol) and imidazole (1.4 mg, 0.02 mmol) were added. After a total reaction time of 12
days, the reaction was quenched with a 1M aqueous solution of hydrochloric acid (1 mL) and diluted with
water (10 mL). The organic material was extracted into dichloromethane (3 x 10 mL) then washed
sequentially with brine (15 mL) and a saturated aqueous solution of sodium bicarbonate (15 mL). The
combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the crude product as a
pink oil (84 mg). This residue was purified by flash silica chromatography (ethyl acetate:40-60 petroleum
ether, 1:5) to give the title compound as a colourless oil (32 mg, 48%). Rf (ethyl acetate:40-60 petroleum
ether, 1:5) 0.19; [α]D30 -126.7 (c 0.55 in CH2Cl2); νmax (film)/cm-1 3436br (O-H), 2954m (C-H), 2928m (C-
H), 2890w (C-H), 2855m (C-H), 1675s (C=O); δH (400 MHz; CDCl3) -0.51 (3H, s, Si(CH3)), -0.12 (3H, s,
Si(CH3)), 0.76 (9H, s, SiC(CH3)3), 2.39 (1H, ~t, J 6.4, CH2OH), 2.71 (1H, dd, J 16.5, 4.3, C(6)Heq), 2.81
(1H, dd, J 16.5, 13.6, C(6)Hax), 3.26 (1H, ddd, J 13.6, 9.5, 4.3, C(5)H), 4.28 (1H, br dd, J 13.5, 6.4,
C(7)HaHb), 4.39 (1H, br dd, J 13.5, 6.4, C(7)HaHb), 4.56 (1H, d~q, J 9.5, 1.5, C(4)H), 6.77 (1H, dm, J 1.5,
C(3)H), 7.24-7.26 (5H, m, aryl-H); δC (100 MHz; CDCl3) -5.9 (Si(CH3)), -5.1 (Si(CH3)), 17.8 (SiC(CH3)3),
25.6 (SiC(CH3)3), 42.9 (C(6)H2), 50.8 (C(5)H), 61.3 (C(7)H2), 73.0 (C(4)H), 127.4, 128.2 & 128.5 (aryl-
CH), 136.9 (C(2)), 140.4 (aryl-C), 149.7 (C(3)H), 199.2 (C=O); m/z (+ES) 355 ([M+Na]+, 100%); (Found
355.1711, C19H28NaO3Si ([M+Na]+) requires 355.1705).
((1S,6R)-6-hydroxy-3-oxo-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)methyl (E)-but-2-enoate (22b)
Crotonic anhydride (70 µL, 0.47 mmol), DMAP (2.8 mg, 0.02 mmol) and pyridine (160 µL, 1.98 mmol)
were added sequentially to a solution of hydroxymethyl compound 20 (76 mg, 0.23 mmol) in
dichloromethane (1.3 mL) under an atmosphere of N2. The reaction mixture was stirred at room temperature
for 45 min when it was quenched by the addition of a saturated aqueous solution of sodium bicarbonate (1.5
mL). Water (10 mL) was added and the organic material was extracted into dichloromethane (3 x 10 mL).
The combined organic extracts were washed with a saturated aqueous solution of sodium bicarbonate (15
mL), dried (MgSO4) and concentrated in vacuo to give the crude product as a brown oil (171 mg). This
residue was partially purified by flash silica chromatography (ethyl acetate:40-60 petroleum ether, 1:19) to
give a colourless oil (59 mg). δH (400 MHz; CDCl3) -0.46 (3H, s, Si(CH3)), -0.14 (3H, s, Si(CH3)), 0.76 (9H,
s, SiC(CH3)3), 1.91 (3H, dd, J 7.0, 1.6, CH=CHCH3), 2.72 (1H, dd, J 16.4, 4.3, C(6)Heq), 2.82 (1H, dd, J
16.4, 13.6, C(6)Hax), 3.28 (1H, ddd, J 13.6, 9.4, 4.3, C(5)H), 4.58 (1H, d~q, J 9.4, 1.5, C(4)H), 4.84 (1H, dm,
J 14.0, C(7)HaHb), 4.91 (1H, d~t, J 14.0, 1.5, C(7)HaHb), 5.91 (1H, dq, J 15.6, 1.6, CH=CHCH3), 6.80 (1H,
~q, J 1.5, C(3)H), 7.05 (1H, dq, J 15.6, 7.0, CH=CHCH3), 7.24-7.36 (5H, m, aryl-H); δC (100 MHz; CDCl3)
-5.8 (Si(CH3)), -5.3 (Si(CH3)), 17.9 (SiC(CH3)3), 18.0 (CH=CHCH3), 25.6 (SiC(CH3)3), 42.8 (C(6)H2), 50.7
12

(C(5)H), 60.3 (C(7)H2), 70.0 (C(4)H), 122.2 (CH=CHCH3), 127.4, 128.1 & 128.5 (aryl-CH), 133.4, 140.4
ACCEPTED MANUSCRIPT
(aryl-C & C(2)), 145.4 (CH=CHCH3), 150.2 (C(3)H), 165.9 (C=O, ester), 196.8 (C=O, enone).
Partially purified ester 21 (59 mg) was stirred in TFA/H2O (7:1) (1.6 mL) under an atmosphere of N2 at 0 °C
for 45 min and the solution was then concentrated in vacuo to give a brown oil (32 mg). This residue was
partially purified by flash silica chromatography (ethyl acetate:40−60 petroleum ether, 1:5) to give a
colourless oil (30 mg) which was further purified by preparative HPLC (ethyl acetate:hexane, 2:3) to yield
the title compound as a colourless oil (16 mg, 25% from 20). Rf (ethyl acetate:40-60 petroleum ether, 1:2)
28
0.24; [α]D -71.7 (c 0.82 in CH2Cl2); νmax (film)/cm-1 3445br (O-H), 3060w (C-H), 3029w (C-H), 2956w
(C-H), 1718s (C=O, ester), 1676s (C=O, enone); δH (400 MHz; CDCl3) 1.91 (3H, dd, J 6.9, 1.7,
CH=CHCH3), 2.03 (1H, br s, OH), 2.71-2.80 (2H, m, C(6)H2), 3.22-3.29 (1H, m, C(5)H), 4.72 (1H, br d, J
9.8, C(4)H), 4.86 (1H, d~t, J 14.3, 1.7, C(7)HaHb), 4.91 (1H, ddd, J 14.3, 2.2, 1.7, C(7)HaHb), 5.91 (1H, dq, J
15.5, 1.7, CH=CHCH3), 6.96 (1H, ~q, J 1.7, C(3)H), 7.05 (1H, dq, J 15.5, 6.9, CH=CHCH3), 7.29-7.36 (3H,
m, aryl-H), 7.39-7.43 (2H, m, aryl-H); δC (100 MHz; CDCl3) 18.1 (CH=CHCH3), 43.2 (C(6)H2), 50.6
(C(5)H), 60.2 (C(7)H2), 71.9 (C(4)H), 122.1 (CH=CHCH3), 127.7, 128.0 & 129.2 (aryl-CH), 134.2, 139.2
(aryl-C & C(2)), 145.7 (CH=CHCH3), 148.1 (C(3)H), 165.9 (C=O, ester), 196.3 (C=O, enone); m/z (+ES)
595 ([2M+Na]+, 100%), 309 ([M+Na]+, 40), 287 ([M+H]+, 20); (Found 309.1087, C17H18NaO4 ([M+Na]+)
requires 309.1098).
(1S,6R)-6-hydroxy-4-(hydroxymethyl)-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (23b)
Hydroxymethyl compound 20 (27 mg, 0.081 mmol) was stirred in a mixture of TFA and H2O (7:1, 0.8 mL)
at 0 °C under an atmosphere of N2. After 5 h the reaction mixture was allowed to warm to room temperature
when it was concentrated in vacuo to give a brown oil (26 mg). The residue was purified by flash silica
chromatography (ethyl acetate:40-60 petroleum ether, 2:1) to yield the title compound as a colourless
crystalline solid (7.9 mg, 45%). (Found: C, 71.2; H, 6.5. C13H14O3 requires C, 71.5; H, 6.5%); m.p. 103.1-
104.4 °C; Rf (ethyl acetate:40-60 petroleum ether, 2:1) 0.24; [α]D28 -93.6 (c 1.2 in CH2Cl2); νmax (film)/cm-1
3375br (O-H), 2959w (C-H), 2916m (C-H), 2845w (C-H), 1668s (C=O); δH (400 MHz; CDCl3) 1.96 (1H, d,
J 3.9, C(4)OH), 2.35 (1H, ~t, J 6.2, CH2OH), 2.72 (1H, dd, J 16.9, 6.6, C(6)Heq), 2.77 (1H, dd, J 16.9, 11.5,
C(6)Hax), 3.26 (1H, ddd, J 11.5, 9.9, 6.6, C(5)H), 4.32 (1H, ddm, J 13.7, 6.2, C(7)HaHb), 4.39 (1H, ddm, J
13.7, 6.2, C(7)HaHb), 4.73 (1H, dd~q, J 9.9, 3.9, 1.7, C(4)H), 6.96 (1H, d, J 1.7, C(3)H), 7.30-7.37 (3H, m,
aryl-H), 7.40-7.44 (2H, m, aryl-H); δC (100 MHz; CDCl3) 43.3 (C(6)H2), 50.8 (C(5)H), 61.2 (C(7)H2), 71.8
(C(4)H), 127.7, 128.0 & 129.2 (aryl-CH), 137.7 & 139.2 (aryl-C & C(2)), 147.7 (C(3)H), 198.5 (C=O); m/z
(+ES) 241 ([M+Na]+, 100%), 219 ([M+H]+, 55%); (Found 241.0824, C13H14NaO3 ([M+Na]+) requires
241.0836).
Second generation synthesis
13

ACCEPTED MANUSCRIPT
Representative procedure for eliminative deprotection using DBU
(4R,5S)-4-hydroxy-5-(naphthalen-2-yl)cyclohex-2-enone (11e)
To a stirred solution of 10e (70 mg, 0.21 mmol) in dichloromethane (4 mL), under an atmosphere of
nitrogen, was added DBU (30 ꢀL, 0.23 mmol). The reaction mixture was stirred at room temperature for 2 h
45 mins when it was quenched by the addition of a saturated aqueous solution of NH4Cl (5 mL). The two
layers were separated and the aqueous phase was extracted with dichloromethane (3 x 5 mL). The combined
organic extracts were washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo to give the
crude product as a brown gum. Purification by flash silica chromatography (ethyl acetate:40-60 petroleum
ether, 1:2) gave the title compound as a viscous oil (37 mg, 75%). Rf (ethyl acetate:40-60 petroleum ether,
33
1:5) 0.04; [α]D -88.5 (c 0.40 in CH2Cl2); νmax (film)/cm-1 3393br (O-H), 3051w (C-H), 2962w (C-H),
2931w (C-H), 2901w (C-H), 2874w (C-H), 1667s (C=O); δH (400MHz; CDCl3) 1.95 (1H, d, J 3.8, OH),
2.77 (1H, ddd, J 16.8, 4.8, 1.2, C(6)Heq), 2.85 (1H, dd, J 16.8, 13.4, C(6)Hax), 3.44 (1H, ddd, J 13.4, 9.7, 4.8,
C(5)H), 4.83 (1H, ddt, J 9.7, 3.8, 2.2, C(4)H), 6.12 (1H, ddd, J 10.3, 2.2, 1.2, C(2)H), 7.05 (1H, dd, J 10.3,
2.2, C(3)H), 7.45 (1H, dd, J 8.4, 1.9, C(3´)H), 7.49-7.56 (2H, m, C(6´)H and C(7´)H), 7.77 (1H, s, C(1´)H),
7.84-7.88 (2H, m, C(5´)H and C(8´)H), 7.91 (1H, d, J 8.4 C(4´)H); δC (100 MHz; CDCl3) 43.1 (C(6)H2),
50.9 (C(5)H), 71.8 (C(4)H), 125.0, 126.3, 126.7, 127.0 & 127.8 (aryl-CH), 129.1 (C(2)H), 129.2 (aryl-CH),
132.9, 133.5 & 136.7 (aryl-C), 152.0 (C(3)H), 197.8 (C=O); m/z (-ES) 237 ([M-H]-, 100%); (Found
237.0916, C16H13O2 ([M-H]-) requires 237.0916).
(1S,6R)-6-hydroxy-4'-methoxy-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (11c)
Using a similar method to that described above ketone 10c (508 mg, 1.61 mmol) was converted to enone 11c
26
(a white solid, 236 mg, 67%). mp. 119.3-121.7 ºC; Rf (ethyl acetate:40-60 petroleum ether, 1:5) 0.03; [α]D
-134 (c 0.9, CH2Cl2); νmax (film)/cm-1 3494br (O-H), 2961w (C-H), 2895w (C-H), 1665s (C=O), 1650s
(C=C); δH (400MHz; CDCl3) 2.62-2.73 (2H, m, C(6)H2), 3.20 (1H, td, J 10.0, 7.8, C(5)H), 3.83 (3H, s,
OCH3), 4.62 (1H, dt, J 10.0, 2.1, C(4)H), 6.06 (1H, dd, J 10.3, 2.1, C(2)H), 6.94 (2H, d, J 8.6, 2 x aryl-H),
7.01 (1H, dd, J 10.3, 2.1, C(3)H), 7.23 (2H, d, J 8.6, 2 x aryl-H); δC (100MHz; CDCl3) 43.3 (C(6)H2), 50.0
(C(5)H), 55.4 (OCH3), 72.1 (C(4)H), 114.6 & 128.7 (aryl-CH), 129.0 (C(2)H), 131.3 (aryl-C), 152.1
(C(3)H), 159.2 (aryl-C), 198.2 (C=O); m/z (+ES) 241 ([M+Na]+, 100%); (Found 241.0836, C13H14O3Na
([M+Na]+) requires 241.0841).
Representative procedure for eliminative deprotection using sodium hydroxide
(1S, 6R)-6-hydroxy-1,6-dihydro-[1,1':4',1''-terphenyl]-3(2H)-one (11f)
14

A stirred solution of ketone 10f (100 mg, 0.28 mmol) in THF (4 mL) at 0 °C was treated with four aliquots
ACCEPTED MANUSCRIPT
of a 0.5 M aqueous sodium hydroxide solution (30 ꢀL, 0.015 mmol) at equally spaced intervals over a period
of 4 h. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (15
mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with brine (2
x 15 mL), dried over MgSO4 and concentrated in vacuo to yield the crude product which was purified by
flash silica chromatography (ethyl acetate:40-60 petroleum ether, 1:1) to give the title compound as
24
colourless crystals (58 mg, 79%). m.p. 108.6-109.2 °C; [α]D -106.5 (c 1.3 in CH2Cl2); νmax (film)/cm-1
3423br (O-H), 3028m (C-H), 2932s (C-H), 2855s (C-H), 1682s (C=O); δH (300 MHz; CDCl3) 2.05 (1H, br s,
OH), 2.69-2.81 (2H, m, C(6)H2), 3.31 (1H, td, J 10.1, 7.4, C(5)H), 4.72 (1H, dd, J 10.1, 2.0, C(4)H), 6.09
(1H, dd, J 10.1, 2.0, C(2)H), 7.03 (1H, dd, J 10.1, 2.0, C(3)H), 7.35-7.64 (9H, m, 9 x aryl-H); δC (75 MHz;
CDCl3) 43.0 (C(6)H2), 50.4 (C(5)H), 71.9 (C(4)H), 127.0, 127.5, 127.9, 128.1, 128.9 & 129.0 (aryl-CH and
C(2)H), 138.4, 140.4 & 140.9 (aryl-C), 152.1 (C(3)H), 197.9 (C=O); m/z (-ES) 301 ([M+37Cl]-, 7 %), 299
([M+35Cl]-, 20 %).
(1S,6R)-4'-bromo-6-hydroxy-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (11d)
Using a similar method to that described above method ketone 10d (567 mg, 1.55 mmol) was converted to
enone 11d (a viscous oil, 358 mg, 87%). Rf (ethyl acetate:40-60 petroleum ether, 1:5) 0.04; [α]D29 -105.1 (c
0.50 in CH3OH); νmax (film)/cm-1 3388br (O-H), 2953w (C-H), 2846w (C-H), 1665s (C=O); δH (400 MHz;
CDCl3) 1.96 (1H, s, OH), 2.67 (2H, d, J 9.3, C(6)H2), 3.23 (1H, q, J 9.3, C(5)H), 4.65 (1H, dt, J 9.3, 2.0,
C(4)H), 6.08 (1H, dd, J 10.2, 2.0, C(2)H), 6.99 (1H, dd, J 10.2, 2.0, C(3)H), 7.20 (2H, d, J 8.4, aryl-H), 7.53
(2H, d, J 8.4, aryl-H); δC (100 MHz; CDCl3) 42.8 (C(6)H2), 50.1 (C(5)H), 71.7 (C(4)H), 121.8 (aryl-C),
129.1 & 129.4 (aryl-CH), 132.3 (C(2)H), 138.5 (aryl-C), 151.9 (C(3)H), 197.5 (C=O); m/z (+ES) 291
([M(81Br)+Na]+, 100%), 289 ([M(79Br)+Na]+, 100%); (Found 288.9843, C12H1179BrNaO2 ([M+Na]+)
requires 288.9840).
Representative procedure for preparation of TES-ethers
(4R,5S)-5-(naphthalen-2-yl)-4-((triethylsilyl)oxy)cyclohex-2-enone (24e)
To a solution of 2,6-lutidine (0.24 mL, 2.09 mmol) in dry dichloromethane (5 mL), at -78 °C under an
atmosphere of nitrogen, was added TESOTf (0.44 mL, 1.94 mmol) followed, a few minutes later, by
dropwise addition of a solution of alcohol 11e (170 mg, 0.71 mmol) in dry dichloromethane (2 mL). The
reaction mixture was stirred at -78 °C for 35 min when it was quenched by the addition of a saturated
aqueous solution of NH4Cl (5 mL) and allowed to warm to room temperature. The two layers were separated
and the aqueous layer was extracted with dichloromethane (3 x 5 mL). The combined organic extracts were
washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash
silica chromatography (ethyl acetate:40-60 petroleum ether, 1:19) to give the title compound as a viscous oil
15

29
(224 mg, 89%). Rf (ethyl acetate:40-60 petroleum ether, 1:5) 0.60; [α]D -82.4 (c 0.50 in CH2Cl2); νmax
ACCEPTED MANUSCRIPT
(film)/cm-1 2955w (C-H), 2877s (C-H), 1683s (C=O); δH (400MHz; CDCl3) 0.16-0.38 (6H, m,
Si(CH2CH3)3), 0.69 (9H, t, J 8.1, Si(CH2CH3)3), 2.77 (1H, ddd, J 16.6, 4.1, 1.2, C(6)Heq), 2.88 (1H, dd, J
16.6, 13.6, C(6)Hax), 3.45 (1H, ddd, J 13.6, 9.3, 4.1, C(5)H), 4.64 (1H, d~t, J 9.3, 2.0, C(4)H), 6.07 (1H, d~t,
J 10.3, 2.0, C(2)H), 6.89 (1H, dd, J 10.3, 2.0, C(3)H), 7.41 (1H, dd, J 8.6, 1.8, C(3´)H), 7.45-7.52 (2H, m,
C(6´)H and C(7´)H), 7.70 (1H, s, C(1´)H), 7.80-7.85 (3H, m, C(4´)H, C(5´)H & C(8´)H); δC (100MHz;
CDCl3) 4.4 (Si(CH2CH3)3), 6.5 (Si(CH2CH3)3), 42.8 (C(6)H2), 50.8 (C(5)H), 72.6 (C(4)H), 125.7, 126.2,
127.1, 127.6, 127.7 & 128.2 (aryl-CH), 128.5 (C(2)H), 132.7, 133.4 & 138.0 (aryl-C), 153.8 (C(3)H), 198.4
(C=O); m/z (+ES) 375 ([M+Na]+, 100%); (Found 353.1947, C22H29O2Si ([M+H]+) requires 353.1937).
(1S,6R)-4'-methoxy-6-((triethylsilyl)oxy)-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (24c)
Using a similar method to that described above, alcohol 11c (80 mg, 0.37 mmol) was converted to TES-
ether 24c (a yellow oil, 105 mg, 86%). Rf (ethyl acetate:40-60 petroleum ether, 1:5) 0.58; [α]D26 -149.6 (c
0.50, CH2Cl2); νmax (film)/cm-1 2957m (C-H), 2908m (C-H), 2874m (C-H), 1684s (C=O); δH (400MHz;
CDCl3) 0.25-0.44 (6H, m, Si(CH2CH3)3), 0.79 (9H, t, J 8.1, Si(CH2CH3)3), 2.66 (1H, ddd, J 16.4, 4.8, 1.0,
C(6)Heq), 2.73 (1H, dd, J 16.4, 13.4, C(6)Hax), 3.21 (1H, ddd, J 13.4, 9.7, 4.8, C(5)H), 3.82 (3H, s, OCH3),
4.51 (1H, dt, J 9.7, 1.9, C(4)H), 6.02 (1H, ddd, J 10.2, 1.9, 1.0, C(2)H), 6.84 (1H, dd, J 10.2, 1.9, C(3)H),
6.88 (2H, d, J 8.6, 2 x aryl-H), 7.17 (2H, d, J 8.6, 2 x aryl-H); δC (100MHz; CDCl3) 4.4 (Si(CH2CH3)3), 6.6
(Si(CH2CH3)3), 43.0 (C(6)H2), 49.8 (C(5)H), 55.4 (OCH3), 72.9 (C(4)H), 113.8 (aryl-CH), 128.4 (C(2)H),
128.9 (aryl-CH), 132.9 (aryl-C), 153.9 (C(3)H), 158.8 (aryl-C), 198.7 (C=O); m/z (+ES) 355 ([M+Na]+,
100%); (Found 355.1692, C19H28O3NaSi ([M+Na]+) requires 355.1705).
(1S,6R)-4'-bromo-6-((triethylsilyl)oxy)-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (24d)
Using a similar method to that described above, alcohol 11d (133 mg, 0.50 mmol) was converted to TES-
29
ether 24d (a pale yellow oil, 190 mg, 81%). Rf (ethyl acetate:40-60 petroleum ether, 1:5) 0.57; [α]D -91.7
(c 0.50 in CH3OH); νmax (film)/cm-1 3040w (ArC-H), 2953m (C-H), 2910w (C-H), 2873m (C-H), 1685s
(C=O); δH (500 MHz; CDCl3) 0.20-0.36 (6H, m, Si(CH2CH3)3), 0.79 (9H, t, J 8.0, Si(CH2CH3)3), 2.63 (1H,
ddd, J 17.0, 4.6, 1.0, C(6)Heq), 2.70 (1H, dd, J 17.0. 13.1, C(6)Haq), 3.23 (1H, ddd, J 13.1, 9.2, 4.6, C(5)H),
4.52 (1H, dt, J 9.2, 2.0, C(4)H), 6.04 (1H, ddd, J 10.1, 2.0, 1.0, C(2)H), 6.83 (1H, dd, J 10.1, 2.0, C(3)H),
7.14 (2H, d, J 8.3, 2 x aryl-H), 7.47 (2H, d, J 8.3, 2 x aryl-H); δC (100 MHz; CDCl3) 4.5 (Si(CH2CH3)3), 6.6
(Si(CH2CH3)3), 42.5 (C(6)H2), 50.1 (C(5)H), 72.6 (C(4)H), 121.1 (aryl-C), 128.4 (C(2)H), 129.7 & 131.5
(aryl-CH), 139.7 (aryl-C), 153.6 (C(3)H), 197.9 (C=O); m/z (+ES) 405 ([M(81Br)+Na]+, 100%), 403
([M(79Br)+Na]+, 100%); (Found, 403.0706 C18H2579BrNaO2 ([M+Na]+) requires 403.0705).
(1S,6R)-6-((triethylsilyl)oxy)-1,6-dihydro-[1,1':4',1''-terphenyl]-3(2H)-one (24f)
16

Using a similar method to that described above, alcohol 11f (100 mg, 0.39 mmol) was converted to TES-
ACCEPTED MANUSCRIPT
ether 24f (a yellow oil, 110 mg, 75 %). [α]D24 -109.3 (c 0.6 in CH2Cl2); νmax (film)/cm-1 3028m (C-H), 2954s
(C-H), 2874s (C-H), 1691s (C=O); δH (300 MHz; CDCl3) 0.24-0.46 (6H, m, Si(CH2CH3)3), 0.78 (9H, t, J
7.9, Si(CH2CH3)3), 2.73 (1H, ddd, J 16.7, 4.9, 0.8, C(6)Heq), 2.80 (1H, dd, J 16.7, 13.5, C(6)Hax), 3.32 (1H,
ddd, J 13.5, 9.4, 4.9, C(5)H), 4.60 (1H, dt, J 9.4, 1.6 C(4)H), 6.05 (1H, dt, J 10.3, 1.6 C(2)H), 6.87 (1H, dt, J
10.3, 1.6 C(3)H), 7.27-7.61 (9H, m, 9 x aryl-H). δC (75 MHz; CDCl3) 4.5 (Si(CH2CH3)3), 6.6
(Si(CH2CH3)3), 42.7 (C(6)H2), 50.3 (C(5)H), 72.8 (C(4)H), 127.1, 127.2, 127.3, 128.4 & 128.8 (aryl-CH &
C(2)H), 139.8, 140.4 & 140.9 (aryl-C), 153.8 (C(3)H), 198.4 (C=O); m/z (+ES) 401 ([M+Na]+, 100 %).
Representative procedure for surfactant mediated Morita-Baylis-Hillman reactions
(4R,5S)-2-(hydroxymethyl)-5-(naphthalen-2-yl)-4-((triethylsilyl)oxy)cyclohex-2-enone (25e)
To a suspension of compound 24e (50 mg, 0.14 mmol) in water (0.4 mL) was added SDS (12 mg, 0.04
mmol) and DMAP (17 mg, 0.14 mmol). The reaction mixture was stirred for 5 min at room temperature and
then formaldehyde 37% (0.19 mL, 1.96 mmol) was added. The resulting mixture was stirred at room
temperature for 22 h. The reaction was quenched by the addition of brine (2 mL) and extracted with ethyl
acetate (2 x 5 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO4 and
concentrated in vacuo to give a waxy solid which was purified by flash silica chromatography (ethyl
acetate:40-60 petroleum ether, 1:6) to furnish hydroxymethyl compound 25e as an oil (35 mg, 64 %). Rf
(ethyl acetate:40-60 petroleum ether, 1:5) 0.12; [α]D -103.3 (c 1.2 in CH2Cl2); νmax (film)/cm-1 3420br (O-
29
H), 2955s (C-H), 2910s (C-H), 2874s (C-H), 1672s (C=O); δH (400MHz; CDCl3) 0.16-0.37 (6H,
m, Si(CH2CH3)3), 0.69 (9H, t, J 7.6, Si(CH2CH3)3), 2.78 (1H, dd, J 16.4, 4.2, C(6)Heq), 2.91 (1H, dd, J 16.4,
13.6, C(6)Hax), 3.44 (1H, ddd, J 13.6, 9.5, 4.2, C(5)H), 4.30 (1H, d, J 13.6, C(7)HaHb), 4.42 (1H, d, J 13.6,
C(7)HaHb), 4.73 (1H, dd, J 9.5, 0.8, C(4)H), 6.82 (1H, s, C(3)H), 7.40 (1H, dd, J 8.8, 1.5, C(3´)H), 7.45-7.51
(2H, m, C(6´)H & C(7´)H), 7.70 (1H, s, C(1´)H), 7.80-7.85 (3H, m, C(4´)H, C(5´)H & C(8´)H); δC
(100MHz; CDCl3) 4.4 (Si(CH2CH3)3), 6.5 (Si(CH2CH3)3), 43.1 (C(6)H2), 50.9 (C(5)H), 61.3 (C(7)H2),
72.6 (C(4)H), 125.7, 125.8, 126.2, 127.1, 127.6, 127.6 & 128.2 (aryl-CH), 132.7, 133.3, 136.8 & 137.7 (aryl-
C & C(2)), 149.8 (C(3)H), 199.2 (C=O); m/z (+ES) 383 ([M+H]+, 100%); (Found 383.2048, C23H31O3Si
([M+H]+) requires 383.2042).
(1S,6R)-4-(hydroxymethyl)-4'-methoxy-6-((triethylsilyl)oxy)-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (25c)
Using a similar method to that described above, TES-ether 24c (177 mg, 0.53 mmol) was converted to
hydroxymethyl compound 25c (a colourless oil, 146 mg, 75 %). Rf (ethyl acetate:40-60 petroleum ether, 1:5)
0.11; [α]D26 -91.2 (c 0.50, CH2Cl2); νmax (film)/cm-1 3423br (O-H), 2955s (C-H), 2911m (C-H), 2876m (C-
H), 1674s (C=O); δH (400MHz; CDCl3) 0.25-0.44 (6H, m, Si(CH2CH3)3), 0.79 (9H, t, J 7.8, Si(CH2CH3)3),
2.68 (1H, dd, J 16.7, 4.8, C(6)Heq), 2.75 (1H, dd, J 16.7, 13.4, C(6)Hax), 3.20 (1H, ddd, J 13.4, 9.3, 4.8,
C(5)H), 3.81 (3H, s, OCH3), 4.25 (1H, dt, J 13.5, 1.4, C(7)HaHb), 4.38 (1H, dt, J 13.5, 1.4, C(7)HaHb), 4.54
17

(1H, dq, J 9.3, 1.4, C(4)H), 6.76 (1H, q, J 1.4, C(3)H), 6.88 (2H, d, J 8.6, 2 x aryl-H), 7.17 (2H, d, J 8.6, 2 x
ACCEPTED MANUSCRIPT
aryl-H); δC (100MHz; CDCl3) 6.4 (Si(CH2CH3)3), 6.8 (Si(CH2CH3)3), 43.5 (C(6)H2), 50.0 (C(5)H), 55.3
(OCH3), 61.2 (C(7)H2), 72.0 (C(4)H), 114.5 (aryl-CH), 128.7 (aryl-CH), 131.0 & 137.6 (aryl-C & C(2)),
147.8 (C(3)H), 159.2 (aryl-C), 198.8 (C=O); m/z (+ES) 385 ([M+Na]+, 100%); (Found 363.1989,
C20H31O4Si ([M+H]+) requires 363.1992).
(1S,6R)-4'-bromo-4-(hydroxymethyl)-6-((triethylsilyl)oxy)-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (25d)
Using a similar method to that described above, TES-ether 24d (195 mg, 0.513 mmol) was converted to
hydroxymethyl compound 25d (a colourless oil, 120 mg, 55%). Rf (ethyl acetate:40-60 petroleum ether, 1:5)
30
0.11; [α]D -74.7 (c 0.50 in CH3OH); νmax (film)/cm-1 3341br (O-H), 2959m (C-H), 2907m (C-H), 2871m
(C-H), 1675s (C=O); δH (400 MHz; CDCl3) 0.25-0.46 (6H, m, Si(CH2CH3)3), 0.79 (9H, t, J 8.0,
Si(CH2CH3)3), 2.32 (1H, t, J 6.0, OH), 2.65 (1H, dd, J 16.2, 5.1, C(6)Heq), 2.73 (1H, dd, J 16.2, 13.0,
C(6)Hax), 3.22 (1H, ddd, J 13.0, 9.5, 5.1, C(5)H), 4.26 (1H, dd, J 13.9, 6.0, C(7)HaHb), 4.38 (1H, dd, J 13.9,
6.0, C(7)HaHb), 4.55 (1H, dd, J 9.5, 1.6, C(4)H), 6.77 (1H, d, J 1.6, C(3)H), 7.14 (2H, d, J 8.4, 2 × aryl-H),
7.48 (2H, d, J 8.4, 2 × aryl-H); δC (100 MHz; CDCl3) 4.5 (Si(CH2CH3)3), 6.6 (Si(CH2CH3)3), 42.8 (C(6)H2),
50.2 (C(5)H), 61.2 (C(7)H2), 72.6 (C(4)H), 121.2 (aryl-C), 129.7 & 131.6 (aryl-CH), 137.1 & 139.5 (aryl-C
& C(2)), 149.2 (C(3)H), 198.6 (C=O); m/z (+ES) 435 ([M(81Br)+Na]+, 100%), 433 ([M(79Br)+Na]+, 100%);
(Found 433.0825, C18H2579BrNaO2 ([M+Na]+) requires 433.0811).
(1S, 6R)-4-(hydroxymethyl)-6-((triethylsilyl)oxy)-1,6-dihydro-[1,1':4',1''-terphenyl]-3(2H)-one (25f)
Using a similar method to that described above, TES-ether 24f (100 mg, 0.26 mmol) was converted to
hydroxymethyl compound 25f (a yellow oil, 25 mg, 30 %). νmax (film)/cm-1 3435br (O-H), 2954m (C-H),
2908m (C-H), 2875m (C-H), 1664s (C=O); δH (300 MHz; CDCl3) 0.24-0.46 (6H, m, Si(CH2CH3)3), 0.78
(9H, t, J 7.9, Si(CH2CH3)3), 2.18 (1H, br, C(7)H2OH), 2.74 (1H, dd, J 16.6, 4.9, C(6)Heq), 2.83 (1H, dd, J
16.6, 13.4, C(6)Hax), 3.30 (1H, ddd, J 13.4, 9.4, 4.9, C(5)H), 4.04 (1H, d, J 13.3, C(7)HaHb), 4.17 (1H, d, J
13.3, C(7)HaHb), 4.63 (1H, dd, J 9.4, 1.4, C(4)H), 6.80 (1H, s, C(3)H), 7.27-7.61 (9H, m, aryl-H); δC (75
MHz; CDCl3) 4.5 (Si(CH2CH3)3), 6.6 (Si(CH2CH3)3), 43.0 (C(6)H2), 50.5 (C(5)H), 61.3 (C(7)H2), 72.8
(C(4)H), 127.1, 127.2, 127.3, 128.5 & 128.8 (aryl-CH), 137.0, 139.5, 140.5 & 140.9 (aryl-C & C(2)), 149.5
(C(3)H), 199.1 (C=O); m/z (+ES) 839 ([2M+Na]+, 100 %), 431 ([M+Na]+, 12 %); (Found (-ES) 407.2057,
C25H31O3Si ([M-H]-) requires 407.2042).
Representative procedure for TES deprotection of Morita-Baylis-Hillman adducts
(4R,5S)-4-hydroxy-2-(hydroxymethyl)-5-(naphthalen-2-yl) cyclohex-2-enone (23e)
A solution of hydroxymethyl compound 25e (25 mg, 0.07 mmol) in TFA:H2O (7:1, 0.56 mL) was stirred at
room temperature for 30 min. The solvents were removed in vacuo to give a yellow gum which was purified
18

by flash silica chromatography (ethyl acetate:40-60 petroleum ether, 1:2) to furnish the diol 23e as a
ACCEPTED MANUSCRIPT
28
colourless oil (18 mg, 93 %). Rf (ethyl acetate:40-60 petroleum ether, 1:1) 0.24; [α]D -96.4 (c 0.50,
CH2Cl2); νmax (film)/cm-1 3368br (O-H), 3047w (C-H), 3014w (C-H), 2953w (C-H), 2919w (C-H), 2898w
(C-H), 2864w (C-H), 1663s (C=O); δH (400MHz; CDCl3) 2.78 (1H, dd, J 16.7, 4.8, C(6)Heq), 2.87 (1H, dd, J
16.7, 13.2, C(6)Hax), 3.42 (1H, ddd, J 13.2, 9.8, 4.8, C(5)H), 4.34 (1H, d, J 13.6, C(7)HaHb), 4.40 (1H, d, J
13.6, C(7)HaHb), 4.83 (1H, dd, J 9.8, 0.9, C(4)H), 6.99 (1H, s, C(3)H), 7.43 (1H, d, J 8.6, C(3´)H), 7.49-7.56
(2H, m, C(6´)H and C(7´)H), 7.76 (1H, s, C(1´)H), 7.84-7.88 (2H, m, C(5´)H and C(8´)H), 7.90 (1H, d, J
8.6, C(4´)H); δC (100MHz; CDCl3) 43.3 (C(6)H2), 50.9 (C(5)H), 61.1 (C(7)H2), 71.7 (C(4)H), 124.9, 126.3,
126.6, 127.0, 127.7, 127.8 & 129.1 (aryl-CH), 132.9, 133.4, 136.5 & 137.7 (aryl-C & C(2)), 147.8 (C(3)H),
198.5 (C=O); m/z (+ES) 291 ([M+Na]+, 100%); (Found 291.0997, C17H16O3Na ([M+Na]+) requires
291.0997).
(1S,6R)-6-hydroxy-4-(hydroxymethyl)-4'-methoxy-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (23c)
Using a similar procedure to that described above, hydroxymethyl compound 25c (40 mg, 0.11 mmol) was
converted into diol 23c (a white solid, 18 mg, 66 %). mp. 108.7-110.9 °C; Rf (ethyl acetate:40-60 petroleum
ether, 1:1) 0.14; [α]D -97.5 (c 0.45, CH2Cl2); νmax (film)/cm-1 3367br (O-H), 2926w (C-H), 2901w (C-H),
28
1668s (C=O); δH (400 MHz; CDCl3) 1.97 (1H, s, OH), 2.32 (1H, br s, OH), 2.71 (2H, ~d, J 9.9, C(6)H2),
3.21 (1H, q, J 9.9, C(5)H), 3.83 (3H, s, OCH3), 4.31 (1H, d, J 13.5, C(7)HaHb), 4.39 (1H, d, J 13.5,
C(7)HaHb), 4.66 (1H, d, J 9.9, C(4)H), 6.93-6.95 (3H, m, C(3)H and 2 x aryl-H), 7.22-7.24 (2H, m, aryl-H);
δC (100MHz; CDCl3) 43.5 (C(6)H2), 50.0 (C(5)H), 55.3 (OCH3), 61.2 (C(7)H2), 72.0 (C(4)H), 114.6 &
128.7 (aryl-CH), 131.0 & 137.6 (aryl-C and C(2)), 147.8 (C(3)H), 192.0 (C=O); m/z (+ES) 287 ([M+K]+,
30%), 271 ([M+Na]+, 60%), 129 (100%); (Found 271.0939, C14H16O4Na ([M+Na]+), requires 271.0941).
(4R, 5S)-4-hydroxy-2-(hydroxymethyl)-5-(4-bromophenyl)-cyclohex-2-enone (23d)
Using a similar procedure to that described above, hydroxymethyl compound 25d (96 mg, 0.23 mmol) was
converted into diol 23d (off-white wax, 39 mg, 56%). Rf (ethyl acetate:40-60 petroleum ether, 1:5) 0.03;
28
[α]D -86.4 (c 0.50 in CH3OH); νmax (film)/cm-1 3368br (O-H), 2953w (C-H), 2923w (C-H), 2901w (C-H),
2865w (C-H), 1664s (C=O); δH (400 MHz; CDCl3) 2.59 (2H, d, J 9.2, C(6)H2), 3.12 (1H, q, J 9.2, C(5)H),
4.18-4.28 (2H, m, C(7)H2), 4.56 (1H, d, J 9.2, C(4)H), 6.84br (1H, s, C(3)H), 7.10 (2H, d, J 8.3, aryl-H),
7.44 (2H, d, J 8.3, aryl-H); δC (100 MHz; CDCl3) 43.2 (C(6)H2), 50.0 (C(5)H), 60.5 (C(7)H2), 71.6 (C(4)H),
121.7 (aryl-C), 129.4 & 132.2 (aryl-CH), 137.7 & 138.5 (aryl-C & C(2)), 148.0 (C(3)H), 198.2 (C=O); m/z
(+ES) 321 ([M(81Br)+Na]+, 100%), 319 ([M(79Br)+Na]+, 100%); (Found 318.9954, C13H1379BrNaO3
([M+Na]+) requires 318.9946).
(1S,6R)-6-hydroxy-4-(hydroxymethyl)-1,6-dihydro-[1,1':4',1''-terphenyl]-3(2H)-one (23f)
19

Using a similar procedure to that described above, hydroxymethyl compound 25f (25 mg, 0.09 mmol) was
ACCEPTED MANUSCRIPT
converted into diol 23f (a white powder, 6 mg, 23 %). νmax (film)/cm-1 3414br (O-H), 2965w (C-H), 2958m
(C-H), 2880w (C-H), 1673s (C=O); δH (300 MHz; CD3OD) 2.54 (1H, dd, J 16.3, 3.9, C(6)Heq), 2.83 (1H,
dd, J 16.3, 13.9, C(6)Hax), 3.21 (1H, ddd, J 13.9, 9.9, 3.9, C(5)H), 4.22 (2H, t, J 1.8 C(7)H2), 4.71 (1H, dq, J
9.9, 1.8 C(4)H), 6.96 (1H, q, J 1.8 C(3)H), 7.28 (1H, t, J 7.5, aryl-H), 7.36-7.42 (4H, m, aryl-H,), 7.57 (4H,
d, J 7.5, aryl-H); δC (75 MHz; CD3OD) 45.2 (C(6)H2), 51.8 (C(5)H), 59.6 (C(7)H2), 72.4 (C(4)H), 128.0,
128.3, 128.4, 129.6 & 130.0 (aryl-CH), 139.2, 141.5, 141.7 & 142.3 (aryl-C & C(2)), 150.2 (C(3)H), 199.9
(C=O); m/z (+ES) 317 ([M+Na]+, 100 %); (Found 317.1137, C19H18O3Na ([M+Na]+) requires 317.1148).
General two-step procedure for the preparation of hybrid analogues
((3R, 4S)-3-hydroxy-4-(naphthalen-2-yl)-6-oxocyclohex-1-en-1-yl)methyl (E)-but-2-enoate (22e)
To a solution of alcohol 25e (88 mg, 0.23 mmol) in dichloromethane (1.8 mL) at room temperature under an
atmosphere of nitrogen, was added crotonic anhydride (0.08 mL, 0.51 mmol), followed by DMAP (3 mg,
0.023 mmol) and pyridine (0.16 mL, 2.02 mmol). The reaction mixture was stirred at room temperature for 3
h when it was quenched by the addition of a saturated aqueous solution of NaHCO3 (2 mL). The mixture
was diluted with water (2 mL) and organic material was extracted into dichloromethane (3 x 4 mL). The
combined organic extracts were washed with a saturated aqueous solution of NaHCO3 (2 x 5 mL), dried over
MgSO4, and concentrated in vacuo. The resulting residue was partially purified by flash silica
chromatography (ethyl acetate:40-60 petroleum ether, 1:18) to give a mixture of 26e and an unknown
impurity (60 mg). TFA:H2O (7:1, 1.20 mL) was added to the mixture at room temperature and the resulting
solution was stirred for 1 h when the solvents were removed in vacuo to give a brown oil. This material was
purified by flash silica chromatography (ethyl acetate:40-60 petroleum ether, 2:7) to give the title compound
29
as a white waxy solid (37 mg, 48% from 25e). Rf (ethyl acetate:40-60 petroleum ether, 1:5) 0.09; [α]D
-
57.0 (c 0.4 in CH2Cl2); νmax (film)/cm-1 3426br (O-H), 2962m (C-H), 2915w (C-H), 1722s (C=O, ester),
1682s (C=O, ketone); δH (400MHz; CDCl3) 1.92 (3H, dd, J 7.0, 1.8, CH=CHCH3), 2.81 (1H, dd, J 16.6, 5.0,
C(6)Heq), 2.88 (1H, dd, J 16.6, 12.9, C(6)Hax), 3.44 (1H, ddd, J 12.9, 9.8, 5.0, C(5)H), 4.83-4.86 (1H, m,
C(4)H), 4.87 (1H, dt, J 14.4, 1.8, C(7)HaHb), 4.97 (1H, dt, J 14.4, 1.8, C(7)HaHb), 5.92 (1H, dq, J 15.5, 1.8,
CH=CHCH3), 7.00 (1H, q, J 1.8, C(3)H), 7.07 (1H, dq, J 15.5, 7.0, CH=CHCH3), 7.43 (1H, dd, J 8.4, 2.0,
C(3´)H), 7.50-7.56 (2H, m, C(6´)H and C(7´)H), 7.76 (1H, s, C(1´)H), 7.84-7.88 (2H, m, C(5´)H and
C(8´)H), 7.91 (1H, d, J 8.4, C(4´)H); δC (100MHz; CDCl3) 18.1 (CH=CHCH3), 43.2 (C(6)H2), 50.8 (C(5)H),
60.2 (C(7)H2), 71.8 (C(4)H), 122.2 (CH=CHCH3), 125.0, 126.3, 126.7, 127.0, 127.7 & 129.2 (aryl-CH),
133.0, 133.5, 134.3, 136.5 (aryl-C & C(2)), 145.7 (CH=CHCH3), 148.0 (C(3)H), 165.9 (C=O, ester), 196.7
(C=O, ketone); m/z (+ES) 359 ([M+Na]+, 100%); (Found 359.1259, C21H20NaO4 ([M+Na]+) requires
359.1259).
((1S,6R)-6-hydroxy-4'-methoxy-3-oxo-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)methyl (E)-but-2-enoate (22c)
20

Using a similar procedure to that described above, hydroxymethyl compound 25c (72 mg, 0.198 mmol) was
ACCEPTED MANUSCRIPT
converted to hybrid analogue 22c (a pale yellow solid, 19 mg, 30 % from 25c). mp. 99-101 ̊C; Rf (ethyl
27
acetate:40-60 petroleum ether, 1:5) 0.06; [α]D -83.5 (c 0.33, CH2Cl2); νmax (film)/cm-1 3415br (O-H),
2922w (C-H), 2901w (C-H), 1717s (C=O, ester), 1699s (C=O, ketone); δH (400MHz; CDCl3) 1.91 (3H, dd, J
6.8, 1.6, CH=CHCH3), 2.72 (2H, ~d, J 9.3, C(6)H2), 3.21 (1H, q, J 9.3, C(5)H), 3.82 (3H, s, OCH3) 4.66
(1H, dq, J 9.3, 1.8, C(4)H), 4.87 (1H, dt, J 14.4, 1.8, C(7)HaHb), 4.91 (1H, dt, J 14.4, 1.8, C(7)HaHb), 5.90
(1H, dq, J 15.5, 1.6, CH=CHCH3), 6.93 (2H, d, J 8.5, aryl-H), 6.96 (1H, q, J 1.8, C(3)H), 7.05 (1H, dq, J
15.5, 6.8, CH=CHCH3), 7.22 (2H, d, J 8.5, aryl-H); δC (100MHz; CDCl3) 18.1 (CH=CHCH3), 43.4 (C(6)H2),
49.9 (C(5)H), 55.3 (CH3O), 60.2 (C(7)H2), 72.1 (C(4)H), 114.6 (aryl-CH), 122.1 (CH=CHCH3), 128.7 (aryl-
CH), 131.0 & 134.2 (aryl-C & C(2)), 145.7 (CH=CHCH3), 148.1 (C(3)H), 159.2 (aryl-C), 165.9 (C=O,
ester), 196.5 (C=O, ketone); m/z (+ES) 339 ([M+Na]+, 100%); (Found 317.1384, C18H21O5 ([M+H]+)
requires 317.1389).
((1S,6R)-4'-bromo-6-hydroxy-3-oxo-1,2,3,6-tetrahydro-[1,1'-biphenyl]-4-yl)methyl (E)-but-2-enoate (22d)
Using a similar procedure to that described above, hydroxymethyl compound 25d (135 mg, 0.33 mmol) was
converted to hybrid analogue 22d (an off-white oil, 50 mg, 39% from 25d). Rf (ethyl acetate:40-60
29
petroleum ether, 1:5) 0.05; [α]D -44.0 (c 0.53 in CH3OH); νmax (film)/cm-1 3432br (O-H), 2975w (C-H),
2932w (C-H), 2917w (C-H), 2877w (C-H), 1717s (C=O, ester), 1677s (C=O, ketone); δH (400 MHz; CDCl3)
1.91 (3H, dd J 7.0, 1.7, CH=CHCH3), 2.69-2.73 (2H, m, C(6)H2), 3.24 (1H, td, J 9.6, 8.1, C(5)H), 4.68 (1H,
dq, J 9.6, 1.7, C(4)H), 4.82 (1H, dt, J 14.5, 1.7, C(7)HaHb), 4.91 (1H, dt, J 14.5, 1.7, C(7)HaHb), 5.90 (1H,
dq, J 15.6, 1.7, CH=CHCH3), 6.93 (1H, d J 1.7, C(3)H), 7.05 (1H, dq, J 15.6, 7.0, CH=CHCH3), 7.19 (2H, d,
J 8.3, aryl-H), 7.54 (2H, d, J 8.3, aryl-H); δC (100 MHz; CDCl3) 18.1 (C(11)H3), 42.9 (C(6)H2), 50.0
(C(5)H), 60.1 (C(7)H2), 71.7 (C(4)H), 121.8 (aryl-C), 122.0 (CH=CHCH3), 129.4 & 132.3 (aryl-CH), 134.3
& 138.2 (aryl-C & C2), 145.9 (CH=CHCH3), 147.9 (C(3)H), 165.9 (C=O, ester), 195.9 (C=O, ketone); m/z
(+ES) 389 ([M(81Br)+Na]+, 100%), 387 ([M(79Br)+Na]+, 100%); (Found, 387.0206 C17H1779BrNaO4
([M+Na]+) requires 387.0208).
((1S,6R)-3-oxo-6-((triethylsilyl)oxy)-1,2,3,6-tetrahydro-[1,1':4',1''-terphenyl]-4-yl)methyl (E)-but-2-enoate
(26f)
To a stirred solution of alcohol 25f (34 mg, 0.08 mmol) in dichloromethane (0.6 mL) at room temperature
under an atmosphere of nitrogen, was added crotonic anhydride (30 µL, 0.18 mmol) followed by DMAP (1
mg, 0.08 mmol) and pyridine (60 µL, 0.73 mmol). The reaction mixture was stirred at room temperature for
2.5 h when it was quenched by the addition of a saturated aqueous solution of NaHCO3 (1 mL). The mixture
was diluted with water (8 mL) and organic material was extracted into dichloromethane (3 x 8 mL). The
combined organic extracts were washed with brine (2 x 10 mL), dried over magnesium sulphate and
concentrated in vacuo. The resulting solid was purified by flash silica chromatography (ethyl acetate:40-60
21

petroleum ether, 1:3) to give crotonate ester 26f as a sticky white solid (26 mg, 60 %). [α]D24 -47.9 (c 1.0 in
ACCEPTED MANUSCRIPT
CH2Cl2); νmax (film)/cm-1 3029w (C-H), 2953s (C-H), 2909s (C-H), 2875s (C-H), 1723s (C=O, ester), 1680s
(C=O, ketone); δH (500 MHz; CDCl3) 0.28-0.46 (6H, m, Si(CH2CH3)3), 0.78 (9H, t, J 8.2 Si(CH2CH3)3),
1.91 (3H, dd, J 6.9, 1.7, CH=CHCH3), 2.78 (1H, dd, J 16.4, 4.6, C(6)Heq), 2.79 (1H, dd, J 16.4, 13.6,
C(6)Hax), 3.32 (1H, ddd, J 13.6, 9.3, 4.6, C(5)H), 4.63 (1H, dd, J 9.3, 1.8, C(4)H), 4.84 (1H, dt, J 14.2, 1.8,
C(7)HaHb), 4.92 (1H, dt, J 14.2, 1.8 C(7)HaHb), 5.90 (1H, dq, J 15.4, 1.7, CH=CHCH3), 6.80 (1H, q, J 1.8,
C(3)H), 7.05 (1H, dq, J 15.4, 6.9, CH=CHCH3), 7.32-7.60 (9H, m, aryl-H); δC (125 MHz; CDCl3) 4.4
(Si(CH2CH3)3), 6.6 (Si(CH2CH3)3), 18.0 (CH=CHCH3), 42.8 (C(6)H), 50.3 (C(5)H), 60.3 (C(7)H2), 72.8
(C(4)H), 122.2 (CH=CHCH3), 127.1, 127.2, 127.3, 128.4, 128.8 & 133.5 (aryl-CH, aryl-C & C(2) (some
signals coincident)), 145.4 (CH=CHCH3), 150.0 (C(3)H), 165.9 (C=O, ester), 196.7 (C=O, ketone); m/z
(+ES) 499 ([M+Na]+, 100%); (Found 499.2283, C29H36O4NaSi ([M+Na]+) requires 499.2281).
((1S,6R)-6-hydroxy-3-oxo-1,2,3,6-tetrahydro-[1,1':4',1''-terphenyl]-4-yl)methyl (E)-but-2-enoate (22f)
A solution of crotonate ester 26f (26 mg, 0.09 mmol) in TFA:H2O (7:1, 0.5 mL) was stirred at room
temperature for 30 minutes. The solvents were removed in vacuo to give a colourless oil which was purified
by flash silica chromatography (ethyl acetate:40-60 petroleum ether, 1:3), to furnish hybrid analogue 22f as a
white film (10 mg, 53%). [α]D -38.5 (c 0.6 in CH2Cl2); νmax (film)/cm-1 3407 br (O-H), 3020w (C-H),
24
2958s (C-H), 1720s (C=O, ester), 1685s (C=O, ketone); δH (500 MHz; CDCl3) 1.92 (3H, dd, J 6.9, 1.8,
CH=CHCH3), 2.76–2.83 (2H, m, C(6)H2), 3.31 (1H, td, J 10.1, 7.9, C(5)H), 4.76 (1H, br d, J 10.1, C(4)H),
4.88 (1H, dt, J 14.4, 1.7, C(7)HaHb), 4.94 (1H, dt, J 14.4, 1.7, CHaHb), 5.92 (1H, dq, J 15.4, 1.8,
CH=CHCH3), 6.98 (1H, q, J 1.7, C(3)H), 7.06 (1H, dq, J 15.4, 6.9, CH=CHCH3), 7.27-7.32 (3H, m, aryl-H),
7.38 (2H, t, J 7.9, aryl-H), 7.50-7.58 (4H, m, aryl-H); δC (125 MHz; CDCl3) 18.1 (CH=CHCH3), 43.2
(C(6)H2), 50.3 (C(5)H), 60.2 (C(7)H2), 71.9 (C(4)H), 122.2 (CH=CHCH3), 127.1, 127.5, 127.9, 128.1 &
128.9 (aryl-CH), 134.3, 138.2, 140.4 & 141.0 (aryl-C and C(2)), 145.7 (CH=CHCH3), 148.1 (C(3)H), 165.9
(C=O, ester), 196.2 (C=O, ketone); m/z (+ES) 385 ([M+Na]+, 100 %).
5. References and Notes
1) Takeuchi, T.; Chimura, H.; Hamada, M.; Umezawa, H.; Yoshioka, O.; Oguchi, N.; Takahashi, Y.;
Matsuda, A. J. Antibiot. 1975, 28, 737.
2) Bohlmann, F.; Zdero, C.; Ramachandran Nair, A.G. Phytochemistry 1979, 18, 1062.
3) McNally, M.; Capon, J. R. J. Nat. Prod. 2001, 64, 645.
4) Collu, F.; Bonsignore, L.; Casu, M.; Floris, C.; Gertsch, J.; Cottiglia, F. Bioorg. Med. Chem. Lett. 2008,
18, 1559.
5) Aghil, O.; Bibby, M. C.; Carrington, S. J.; Double, J.; Douglas, K. T.; Phillips, R. M.; Shing, T. K. M.
Anti-Cancer Drug Design 1992, 7, 67.
6) a) Arthurs, C.L.; Raftery, J.; Whitby, H.L.; Whitehead, R.C.; Wind, N.S.; Stratford, I.J. Bioorg. Med.
Chem. Lett. 2007, 17, 5974; b) Arthurs, C. L.; Wind, N. S.; Whitehead, R. C.; Stratford, I. J. Bioorg. Med.
22

Chem. Lett. 2007, 17, 553; c) Arthurs, C. L.; Lingley, K. F.; Piacenti, M.; Stratford, I. J.; Tatic, T.;
ACCEPTED MANUSCRIPT
Whitehead, R.C.; Wind, N. S. Tetrahedron Lett. 2008, 49, 2410; d) Arthurs, C. L.; Morris, G.A.; Piacenti,
M.; Pritchard, R.G.; Stratford, I. J.; Tatic, T.; Whitehead, R.C.; Williams, K.F.; Wind, N.S. Tetrahedron
2010, 66, 9049; e) Christou, S.; Ozturk, E.; Pritchard, R.G.; Quayle, P.; Stratford, I.J.; Whitehead, R.C.;
Williams, K.F. Bioorg. Med. Chem. Lett. 2013, 23, 5066.
7) Barros, M.T.; Maycock, C.D.; Ventura, M.R. J. Org. Chem., 1997, 62, 3984.
8) Ohnemüller, U.K.; Nising, C.F.; Encinas, A.; Bräse, S. Synthesis 2007, 14, 2175.
9) Isobe, M.; Kondo, S.; Nagasawa, N.; Goto, T. Chem. Lett. 1977, 679.
10) a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229; b) Itooka, R.; Iguchi, Y.,
Miyaura, N. J. Org. Chem. 2003, 68, 6000.
11) Crystal data for 10f: C24H26O3, M=362.45, space group P212121, a=5.9418(2), b=8.6600(3),
c=36.2709(11) Å, U=1866.36(11) Å3, dcalcd=1.290 Mg/m3. Intensity data were collected using a Bruker
X8 Prospector diffractometer; 14846 reflections were collected, of which 2685 were unique including 969
Friedel pairs, Rint= 0.0447. Data processing was carried out using Bruker SAINT and the structure was
solved by direct methods using SHELXS97. All non-hydrogen atoms were refined anisotropically, and
hydrogens were included in calculated positions, using the riding method. Refinement on F2 was carried out
using SHELXL97. Final wR2=0.0913 for all data and R1=0.0417 for data with I>2σ(I). All calculations
were carried out using the WinGX package. Crystallographic data (excluding structure factors) have been
deposited in the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 950707.
Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK [fax: +44 1223 336033 or email: deposit@ccdc.cam.ac.uk].
12) Audia, J.E.; Boisvert, L.; Patten, A.D.; Villalobos, A.; Danishefsky, S.J. J. Org. Chem., 1989, 54, 3738.
13) a) Gatri, R.; El Gaied, M.M. Tetrahedron Lett., 2002, 43, 7835; b) Luo, S.; Wang, P.G.; Cheng, J.-P. J.
Org. Chem., 2004, 69, 555.
14) Prolonged exposure of the conjugate adducts to aqueous NaOH resulted in a unexpected dimerization of
the initially formed γ-hydroxyenones to give perhydrodibenzofuranones: Christou, S.; Edwards, A.C.;
Pritchard, R.G.; Quayle, P.; Stratford, I.J.; Whitehead, R.C. Synlett, 2014, 1263.
15) a) Porzelle, A.; Williams, C.M.; Schwartz, B.D.; Gentle, I.R. Synlett 2005, 2923; b) Schwartz, B.D.;
Porzelle, A.; Jack, K.S.; Faber, J.M.; Gentle, I.R.; Williams, C.M. Adv. Synth. Catal. 2009, 351, 1148.
16) miLogP
values
were
calculated
using
the
molinspiration
WEB
resource:
http://www.molinspiration.com/cgi-bin/properties.
17) Carmichael, J.; DeGraff, W.G.; Gazdar, A.F.; Minna, J.D.; Mitchell, J.B. Cancer Res. 1987, 47, 936.
18) a) Hamilton, D. S.; Ding, Z.; Ganem, B.; Creighton, D. J. Org. Lett. 2002, 4, 1209; b) Hamilton, D. S.;
Zhang, X.; Ding, Z.; Hubatsch, I.; Mannervik, B.; Houk, K. N.; Ganem, B.; Creighton, D. J. J. Am. Chem.
Soc. 2003, 125, 15049.
19) Endo, K.; Hikino, H. Can. J. Chem. 1984, 62, 2011.
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20) Chen, Y-Q.; Shen, Y-H.; Su, Y-Q.; Kong, L-Y.; Zhang, W-D. Chem. Biodivers. 2009, 6, 779.
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