An enantiospecific polyene cyclization initiated by an enantiomerically pure bromonium ion

Article abstract of DOI:10.1002/chir.22194

Dimethylaluminum triflate-mediated activation of tetrafluorobenzoates of enantiomerically pure bromohydrins results in enantiospecific polyene cyclizations. The initiation of cyclization by enantiomerically pure bromonium ions and subsequent propagation i

Full text of DOI:10.1002/chir.22194

CHIRALITY 25:692–700 (2013)
An Enantiospecific Polyene Cyclization Initiated by an
Enantiomerically Pure Bromonium Ion
1
1
2
1
D. CHRISTOPHER BRADDOCK, * JARED S. MARKLEW, KEVIN M. FOOTE, AND ANDREW J. P. WHITE
1
Department of Chemistry, Imperial College London, London, UK
2
AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK
ABSTRACT
Dimethylaluminum triflate-mediated activation of tetrafluorobenzoates of
enantiomerically pure bromohydrins results in enantiospecific polyene cyclizations. The initiation
of cyclization by enantiomerically pure bromonium ions and subsequent propagation is not subject
to catastrophic erosion of enantiomeric purity by any intramolecular or intermolecular bromonium
ion-to-alkene transfer. Chirality 25:692–700, 2013. © 2013 Wiley Periodicals, Inc.
KEY WORDS: bromonium ion; polyene cyclization; enantiospecific
INTRODUCTION
cyclization. In any initiation step, an enantiopure bromonium
ion must be formed regioselectively at the terminus alkene
of the polyene. Currently, there is no widely applicable
method for the formation of enantiopure bromonium ions
by direct bromination of a simple trisubstituted alkene (even
Since the advance of the Stork-Eschenmoser hypothesis,1–3
cation-initiated polyene cyclizations as inspired by the enzy-
matic conversions of squalene to hopene and oxidosqualene
to lanosterol have attracted much synthetic attention,4–6 with
before considering the required regioselectivity of
enantioselective variants now representing the state of the
the process).5
3–57
In the propagation step(s) intramolecular
7
–15
16–29
art.
With the continued isolation
of complex single en-
58,59
and/or intermolecular bromonium ion-to-alkene transfer
antiomer brominated (poly)cyclic terpenoid natural products
must be avoided, where Denmark et al. have recently demon-
strated that racemization of enantiopure bromonium ions via
bromonium ion-to-olefin transfer with an added alkene is
competitive with intermolecular capture by anionic nucleo-
philes.60 Since by definition a polyene cyclization substrate
will always contain alkene functional groups, it is not unrea-
sonable to ask if such asymmetric cyclizations are therefore
inherently compromised when not under enzymatic control.
Thus, methods for the initiation of polyene cyclizations with
enantiopure bromonium ions are required to be developed,
so that the extent of the racemization via either intramolecu-
lar or intermolecular bromonium ion-to-alkene transfer can
be assessed. An enantiomerically pure bromonium ion was
generated in the formation of a vicinal bromochloride in the
containing the signature a-bromo-b,b-dimethylcyclohexane
3
0–34
motif from marine sources,
a consensus has arisen that
nature employs enzyme-mediated bromonium ion initiated
asymmetric polyene cyclizations to so construct them
Fig. 1).35 While van Tamelen and Hessler demonstrated
36
(
the first direct brominative cyclization of polyene methyl
farnesate with NBS nearly 50 years ago, the products were
necessarily racemic and formed in very low yields (ca. 5%).
Over the next 30 years a number of other direct brominative
polyene cyclizations have further been reported using a
37–48
variety of (achiral) reagent-solvent combinations.
The
low yields generally obtained in these cyclizations must
arise in part from the requirement of the reagent to
react regioselectively with the olefin at the terminus of
the polyene chain. The recent introduction of the powerful
bromodiethylsulphonium bromopentachloroantimonate re-
agent, BDSB, by Snyder and co-workers now allows for
highly efficient bromonium ion initiated polyene cyclizations
to give bi- tri-, and even tetracyclic adducts, albeit still as
61
total synthesis of (+)-intricatetraol. Lewis acid-mediated
carbocyclizations of (racemic) 1,2-bromohydrins (3˚ alcohol
and/or esterified derivatives, 2˚ bromide) have been demon-
62–66
strated previously,
and a cyclization of an enantiopure
1
,2-bromohydrin (3˚ alcohol, 2˚ bromide) to an enantiopure
67
4
1–51,
1-bromo-2,2,4-trimethylcyclohexane has been reported, but
bromonium ions were not invoked. Herein, as an extension of
our previous work, we report the formation of an enantiopure
racemates.
reported
* Snyder and colleagues have also recently
two-step mimic for direct, asymmetric
a
bromonium-induced polyene cyclizations using a chiral Hg(II)
5
2
bromonium ion at the terminus of a polyene by suitable activa-
salt to mediate the initial cyclization. However, the demon-
stration of an enantiospecific, nonenzymatic-mediated, poly-
ene cyclization initiated by an enantiopure bromonium ion
tion of an enantiopure bromohydrin,6
8,69
thereby initiating
polyene cyclization to produce tricyclic carbocycles with the
characteristic a-bromo-b,b-dimethylcyclohexane motif of
†
remains unreported.
(
poly)cyclic naturally occurring terpenoids. Under these
In contemplating such an asymmetric bromonium ion-
initiated polyene cyclization, challenges in each of the funda-
mental steps of initiation and propagation arise (Fig. 2), and a
suitable group must also be chosen to terminate the polyene
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: We thank the EPSRC, Arrow Therapeutics and
AstraZeneca for a CASE award (to J. S. M.), and the EPSRC for further finan-
cial support; Contract grant number: EPSRC Grant no. EP/E058272/1.
*Chiral versions of BDSB are also reported in Ref. 50. However, no asym-
*
Correspondence to: D. Christopher Braddock, Department of Chemistry,
metric induction was observed in the cyclization of a representative polyene.
†
Imperial College London, South Kensington, London, SW7 2AZ, UK. E-mail:
c.braddock@imperial.ac.uk
Chiral phosphoramidites at stoichiometric loading have delivered high
enantiomeric excess for direct iodonium-induced polyene cyclizations
(
Received for publication 28 March 2013; Accepted 10 May 2013
DOI: 10.1002/chir.22194
Published online 26 July 2013 in Wiley Online Library
(wileyonlinelibrary.com).
up to 95% ee) using NIS as the electrophilic halide source. With NBS
as the halide source instead to effect a bromonium-ion induced cycliza-
tion, the asymmetric induction dropped off markedly (36% ee) (Ref. 10).
©
2013 Wiley Periodicals, Inc.

ENANTIOSPECIFIC BROMONIUM ION POLYENE CYCL.
693
high-performance liquid chromatography (HPLC) were HPLC grade
and used as received.
Experimental techniques. Reactions were carried out in oven-dried
glassware under an inert atmosphere of nitrogen, unless otherwise
stated. Air and moisture-sensitive reagents were transferred by syringe.
Reaction temperatures other than room temperature were recorded as
aluminum alloy heating block, or bath temperatures. Concentrated under
reduced pressure refers to rotary evaporation. Brine refers to a saturated
aqueous solution of NaCl. Column chromatography was performed on sil-
ica gel, particle size 40-63 mm unless otherwise stated. Chiral HPLC was
performed on CHIRALCEL OJ or CHIRALPAK AD columns detecting
R
at 284 nm. Retention times (t ) are reported in minutes. Analytical thin-layer
chromatography (TLC) was performed on Kieselgel 60 F254 precoated alu-
minum-backed plates visualized by ultraviolet light (350 nm) and/or chem-
ical staining using potassium permanganate solution. Silver nitrate-doped
Fig. 1. Selected single enantiomer terpenoid natural products containing the
a-bromo-b,b-dimethylcyclohexane motif (highlighted in blue) considered to arise
via bromonium ion-initiated polyene cyclization.
silica gel was obtained after slurrying silica in aqueous AgNO
3
solution
-
1
(0.1 M, 4 mLg silica) and concentrating under reduced pressure
azeotroping with toluene until dryness.
Characterization. Fourier transform IR spectra were recorded neat
1
13
19
using an ATR-IR spectrometer. H, C and F NMR spectra were
recorded on Brüker AV400 and AV500 spectrometers at 400 MHz and
500 MHz, and 100 MHz and 125 MHz, and 377 (AV500 only) MHz, re-
spectively. Chemical shifts (d) are quoted in parts per million (ppm)
and are referenced to the residual solvent resonance. Coupling constants
(J) are quoted in Hertz (Hz). Low-resolution mass spectroscopy (MS) (EI,
CI), gas chromatography MS (GCMS), and high-resolution MS (HRMS)
were recorded by the Imperial College Department of Chemistry Mass
Spectrometry Service.
(
E)-1-(4,8-Dimethylnona-3,7-dienyl)-4-methoxybenzene (1). Pre-
49
pared according to a modified procedure of Snyder and Treitler. To a
stirred solution of geraniol (23 mL, 133 mmol) and pyridine (32 mL, 398
ꢀ
mmol) in diethyl ether (80 mL) at –15
C was added diethyl
chlorophosphate (29 mL, 199 mmol) and the mixture was allowed to
warm to room temperature over 5 h. The reaction mixture was quenched
with 1M aqueous HCl solution (250 mL), extracted with ethyl acetate
(
2ꢁ 250 mL), washed with saturated aqueous NaHCO
3
solution
Fig. 2. Challenges for enantiospecific polyene cyclization initiated by an
(
2ꢁ 250mL), brine (250 mL), dried over Na SO and concentrated under
2
4
enantiopure bromonium ion.
reduced pressure to give geranyl diethyl phosphate as a colorless oil
46 g) which was used directly without purification. To magnesium turn-
(
conditions—even with a necessarily present trisubstituted al-
kene in the cyclization substrates—the brominated tricyclic
carbocycles are isolated in high enantiomeric excess. Race-
mization via either intramolecular or intermolecular
bromonium ion-to-alkene transfer is evidently not in opera-
tion, and the cyclizations proceed enantiospecifically.
ings (7.6 g, 318 mmol) stirred in anhydrous THF (200 mL) was added a
portion of 4-methoxybenzyl chloride (2.0 mL, 15 mmol), where the
reaction could be started by gentle heating. Subsequently, a solution of
4-methoxybenzyl chloride (19.5 mL, 144 mmol) in anhydrous THF
(200 mL) was added dropwise over 1 h at such a rate as to maintain reflux.
After complete addition, reflux was continued for 2 h. The reaction mix-
ꢀ
ture was cooled to -40 C and added dropwise via cannula to a stirred so-
lution of geranyl diethyl phosphate (23 g, 80 mmol) in anhydrous THF
(250 mL) at -40 C and allowed to warm to room temperature over 16 h.
ꢀ
MATERIALS AND METHODS
General Experimental
The reaction mixture was quenched with saturated aqueous NH
tion (300 mL), extracted with diethyl ether (2ꢁ 300 mL), washed with sat-
urated aqueous NaHCO solution (300 mL), brine (300 mL), dried over
Na SO , concentrated under reduced pressure, and chromatographed
(0:1-1:3 CH Cl :PE) to afford the title compound 1 as a mixture of consti-
tutional isomers with branched diene 1a in 19:1 ratio (12.7 g, 49 mmol,
1%) as a colorless oil. A second run on the same scale afforded the title
product 1 as a mixture of constitutional isomers with 1a in ratio 35:1
14.0 g, 54 mmol, 68%). The purity of 1 could be increased to >98% by
4
Cl solu-
Reagents. 4-Methoxybenzyl chloride was prepared from 4-
methoxybenzyl alcohol according to a procedure by Yadav and col-
leagues. Bromodiethylsulphide pentachloroantimonybromide (BDSB)
3
7
0
2
4
5
1
2
2
was prepared according to the procedure by Snyder and Treitler.
Pyridine was distilled from CaH . Methanesulphonamide was purified
2
6
by recrystallization from EtOH. All other regents were obtained from
commercial sources and used as received.
(
fractional distillation of the combined diene mixtures (27 g, 26:1 1:1a).
Distillation (200 ˚C, 0.003 mmHg) collecting the fraction at 70 ˚C was
enriched in branched isomer 1a and the distillation residue was linear
Solvents. All reactions were carried out in anhydrous solvents unless
used in combination with H O. CH Cl , Et O, and THF were dried by
2 2 2 2
passing through a column of alumina beads. N-Methyl-2-pyrrolidone
was purified by distillation and stored over 4Å molecular sieves. All other
reaction solvents, extraction solvents, and chromatography eluents were
diene 1 (8.2 g, 32 mmol). Diene 1: R
2919, 2854, 1612, 1584 cm ; H NMR (400 MHz, CDCl
f
= 0.35 (15% CH
2
Cl
2
in PE); IR nmax
-
1 1
3
) d 7.17 (d, J = 8.5
Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 5.24 (t, J = 7.1 Hz, 1H), 5.19-5.13 (m, 1H),
3.82 (s, 3H), 2.60 (t, J= 7.8 Hz, 2H), 2.34 (q, J = 8.5 Hz, 2H), 2.17-2.02 (m, 4H),
used as received. MeOH and CH
AnalaR grade, and Et O, EtOAc, and petroleum ether 40-60 (referred
to as PE) were GPR grade. n-Hexane and i-PrOH for analytical
2 2
Cl were HiPerSolv grade, EtOH was
1
3
2
3
1.75 (s, 3H), 1.67 (s, 3H), 1.62 (s, 3H) ppm; C NMR (100 MHz, CDCl )
d 157.7, 135.7, 134.6, 131.3, 129.4, 124.4, 123.7, 113.7, 55.3, 39.8, 35.3, 30.2,
Chirality DOI 10.1002/chir

6
94
BRADDOCK ET AL.
+
+
+
2
6.8, 25.7, 17.7, 16.0 ppm; MS (CI ) m/z 276 [M+ NH
4
] ; HRMS (CI ) calcd.
Hz, 1H), 3.30 (d, J = 9.6 Hz, 1H), 3.29 (br s, 2H), 2.90 (ddd, J = 13.8, 8.8, 4.9
Hz, 1H), 2.65 (dt, J = 13.7, 8.2 Hz, 1H), 2.53 (br s, 1H), 2.20 (br s, 1H), 1.81-
1.56 (m, 5H), 1.48-1.37 (m, 1H), 1.21 (s, 3H), 1.17 (s, 3H), 1.13 (s, 3H) ppm;
+
for C18
H27O [M+ H] 259.2062. Found: 259.2050. An analytically pure sam-
ple of branched diene 1a could be obtained after silver nitrate-doped silica
gel chromatography (0:1-3:7 Et O:PE).
1
3
2
C NMR (100 MHz, CDCl
3
) d 157.8, 134.2, 129.4, 113.9, 78.9, 74.6,
+
7
3.2, 55.3, 50.7, 35.6, 33.6, 31.9, 26.5, 25.0, 23.3, 20.6 ppm; MS (CI , NH
3
)
+
+
+
(
R
E)-1-(2,6-Dimethyl-2-vinylhept-5-enyl)-4-methoxybenzene (1a).
m/z 344 [M+ NH
4
] ; HRMS (CI , NH
) calcd. for C18H O
3 31 5
[M+ H]
-1 1
f
= 0.35 (15% CH
2
Cl
) d 7.03 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H),
.76 (dd, J = 17.6, 10.8 Hz, 1H), 5.10-5.05 (m, 1H), 5.00 (dd, J = 10.8, 1.4
Hz, 1H), 4.82 (dd, J = 17.6, 1.4 Hz, 1H), 3.79 (s, 3H), 2.54 (m, 2H), 1.91
2
in PE); IR nmax 2920, 2854, 1612 cm ; H NMR
3
27.2171. Found: 327.2164. A reference sample of (ꢂ)-diol 3 was prepared
72
(400 MHz, CDCl
3
following a modified procedure of Warren and colleagues. To a solution
5
of potassium ferricyanide (383 mg, 1.16 mmol), potassium carbonate
(
(
2 4 2
161 mg, 1.16 mmol), K OsO .2H O (4 mg, 0.012 mmol), quinuclidine
(
(
1
q, J = 8.0 Hz, 2H), 1.67 (s, 3H), 1.58 (s, 3H), 1.37-1.25 (m, 2H), 0.94
s, 3H) ppm; C NMR (100 MHz, CDCl
30.6, 125.0, 112.9, 112.1, 55.2, 47.2, 40.8, 40.4, 25.7, 23.1, 21.9, 17.6
ppm; MS (CI ) m/z 276 [M + NH
1 mg, 0.012 mmol), and methanesulphonamide (37 mg, 0.39 mmol) in
13
) d 157.8, 146.6, 131.6, 131.0,
ꢀ
3
water (2.5 mL) and tert-butanol (2.5 mL) at 0 C was added olefin 1
(
100 mg, 0.39 mmol) and stirred vigorously for 2 h. The reaction mixture
was quenched with a saturated aqueous solution of sodium sulfite
10 mL), extracted with EtOAc (2ꢁ 20 mL), washed with brine (40 mL),
dried over Na SO concentrated under reduced pressure, and
+
+
+
4
] ; HRMS (CI ) calcd. for C18
H30NO
+
[
M + NH ] 276.2327. Found: 276.2328.
4
(
2
4
,
(
1
(
2R*,4aR*,10aS*)-2-Bromo-6-methoxy-1,1,4a-trimethyl-
,2,3,4,4a,9,10,10a-octahydrophenanthrene (2R*,4aR*,10aS*)-
2) by direct brominative cyclization of polyene 1 with BDSB. Bro-
mide (2R*,4aR*,10aS*)-2 was prepared by direct brominative cyclization
chromatographed (1:1-3:2 EtOAc:PE) to afford (ꢂ)-diol 3 (21 mg, 19%) as
a colorless oil. HPLC (CHIRALCEL OJ; 10% IPA in n-hexane; 1.0 mL/min)
t
R
= 16.5 min, 17.8 min.
4
9
of diene 1 using the method of Snyder and Treitler. To a stirred solution
(
-)-(S,E)-3-[-6-(4-Methoxyphenyl)-3-methylhex-3-enyl]-2,2-
ꢀ
of alkene 1 (100 mg, 0.39 mmol) in CH
quickly a solution of BDSB (213 mg, 0.39 mmol) in CH
stirred for 5 min. The reaction mixture was quenched with a 1:1 mixture
of 5% aqueous NaHCO and 5% aqueous Na SO solution (20 mL) and
stirred for 15 min before being poured into water (20 mL), extracted with
CH Cl SO , concentrated under reduced pres-
(2ꢁ 20 mL), dried over Na
sure, and chromatographed (PE) to afford bromide (2R*,4aR*,10aS*)-2
88 mg, 68%) as a white solid: m.p. 86-87 ˚C. R = 0.64 (40:60 CH Cl :PE);
IR nmax 2933, 2851, 1611 cm ; H NMR (400 MHz, CDCl ) d 7.00
d, J = 8.3 Hz, 1H,), 6.77 (d, J = 2.8 Hz, 1H), 6.71 (dd, J = 8.3, 2.8 Hz, 1H),
3
NO
2
(6 mL) at -25 C was added
73
dimethyloxirane (4). Using a modified procedure of Corey et al., to a
3
2
NO (2 mL) and
stirred solution of (R)-diol 3 (840 mg, 2.88 mmol) and pyridine (0.46 mL,
ꢀ
5
.75 mmol) in CH
Cl
2 2
(15 mL) at 0 C was added methanesulphonyl chlo-
3
2
3
ride (0.29 mL, 3.72 mmol). After 0.5 h the mixture was allowed to warm to
room temperature and stirred for 3 h. Additional pyridine (1.38 mL
2
2
2
4
17.7 mmol) was added and the reaction mixture stirred for 16 h. The reac-
tion mixture was poured into a suspension of K CO (6.63 g, 48 mmol) in
2
3
(
f
2
2
-
1
1
methanol (25 mL), stirred for 6 h, concentrated under reduced pressure,
3
diluted with water (50 mL), extracted with EtOAc (2ꢁ 50 mL), washed with
(
4
(
(
(
4 2 4
10% aqueous CuSO solution (100 mL), brine (100 mL), dried over Na SO ,
.07 (dd, J = 12.5, 4.1 Hz, 1H), 3.80 (s, 3H), 2.98-2.76 (m, 2H) 2.48-2.23
m, 3H), 1.98 (ddt, J= 13.4, 7.0, 2.2 Hz, 1H), 1.88-1.75 (m, 1H), 1.69-1.56
m, 1H), 1.48 (dd, J = 12.1, 2.2 Hz, 1H), 1.27 (s, 3H), 1.18 (s, 3H), 1.09
s, 3H) ppm; C NMR (100 MHz, CDCl
11.2, 110.2, 68.8, 55.3, 51.3, 40.1, 39.9, 38.1, 31.6, 30.6, 30.0, 24.8, 20.8,
) m/z 354, 356 [M + NH
4
calcd. for C18H29NO Br [M+ NH ]
CHIRALPAK AD; 1% IPA in n-hexane; 1.0 mL/min) t
concentrated under reduced pressure, and chromatographed (1:19-1:4
EtOAc:PE) to afford the title product (S)-4 (565 mg, 83%) as a colorless
24
1
3
oil: R
2
f
= 0.34 (1:9 EtOAc:PE); [a]
D
-2.5 (c 1.6, CH
2
Cl
2
); IR nmax 2958, 2925,
3
) d 157.8, 150.0, 129.9, 127.0,
-1 1
835, 1612, 1586 cm ; H NMR (400 MHz, CDCl
3
) d 7.13 (d, J = 8.6 Hz,
1
+
+
+
2H), 6.85 (d, J = 8.6 Hz, 2H), 5.26 (tq, J = 5.8, 1.5 Hz, 1H), 3.81 (s, 3H), 2.72
(app. t, J = 6.3 Hz, 1H), 2.62 (t, J = 7.5 Hz, 2H), 2.32 (app. q, J = 7.6 Hz, 2H),
18.3 ppm; MS (CI , NH
3
4
] ; HRMS (CI , NH
354.1433, found 354.1433. HPLC
= 4.9 min, 5.7 min.
3
)
7
9
+
2
.24-2.06 (m, 2H), 1.78-1.62 (m, 2H), 1.61 (s, 3H) 1.33 (s, 3H) 1.29 (s, 3H)
(
R
13
ppm; C NMR (100 MHz, CDCl
3
) d 157.7, 134.8, 134.3, 129.3, 124.3,
+
113.7, 64.1, 58.3, 55.2, 36.3, 35.1, 30.2, 27.5, 24.9, 18.8, 16.0 ppm; MS (CI ,
(
(
+)-(R,E)-9-(4-Methoxyphenyl)-2,6-dimethylnon-6-ene-2,3-diol
71
+
+
+
3 4 3 18 27 2
NH ) m/z 292 [M + NH ] ; HRMS (CI , NH ) calcd. for C H O [M+ H]
3). According to the method of Sharpless, to a stirred solution of
-
1
275.2011, found 275.2011.
AD-mix b (22.3 g, 1.4 gmmol ) and methanesulphonamide (1.5 g,
ꢀ
1
6 mmol) in water (40 mL) and tert-butanol (40 mL) at 0 C was added
alkene 1 (4.1 g, 16 mmol). The reaction mixture was stirred vigorously
for 16 h, quenched with saturated aqueous sodium sulfite solution
(
(
6
-)-(S,E)-2-Bromo-9-(4-methoxyphenyl)-2,6-dimethylnon-6-en-3-ol
5a) and (+)-(R,E)-3-bromo-9-(4-methoxyphenyl)-2,6-dimethylnon-
-en-2-ol (5b). Following the method of Couladouros and Vidali,67 to a
(
(
50 mL), extracted with EtOAc (2ꢁ 100 mL), washed with brine
solution of (S)-epoxide 4 (200 mg, 0.73 mmol) in N-methyl-2-pyrrolidone
0.22 mL) was added LiBr (99 mg, 0.95 mmol) and PPTS (183 mg,
.73 mmol) and stirred at room temperature for 4 h. The reaction was
quenched with saturated aqueous NaHCO solution (15 mL), extracted with
SO , concen-
100 mL), dried over Na SO , concentrated under reduced pressure,
2
4
(
0
and chromatographed (1:1-3:2 EtOAc:PE) to afford first unreacted diene
(1.64 g, 6.3 mmol, 40%), the title product 3 (1.16 g, 4.3 mmol, 27%, 67%
based on recovered starting material) as a colorless oil, and tetraol 3a
1
3
EtOAc (2ꢁ 15 mL), washed with brine (30 mL), dried over Na
2
4
(
1.27 g, 3.9 mmol, 24%) as a white solid. Diol 3: R = 0.42 (1:1 EtOAc:
f
2
4
-
1
trated under reduced pressure, and chromatographed (1:9-1:4 EtOAc:PE)
PE); [a]
D
= +12.3 (c 1.9, CH
2 2
Cl ); IR nmax 3600-3100, 2931, 2858, cm ;
1
to yield first (E)-9-(4-methoxyphenyl)-2,6-dimethylnon-6-en-3-one (10 mg,
H NMR (400 MHz, CDCl
3
) d 7.13 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6
Hz, 2H), 5.26 (br t, J = 7.1 Hz, 1H), 3.81 (s, 3H), 3.32 (dd, J = 10.5. 2.0
Hz, 1H), 2.63 (t, J = 7.6 Hz, 2H), 2.38-2.19 (m, 3H), 2.15-2.01 (m, 3H),
.64-1.55 (m, 1H) 1.60 (s, 3H), 1.44 (m, 1H), 1.21 (s, 3H), 1.18 (s, 3H)
ppm; C NMR (100 MHz, CDCl
5%) as a colorless oil, second bromohydrin 5a (66 mg, 25%) as a colorless
oil, and third, bromohydrin 5b (119 mg, 46%) as a colorless oil.
2
4
Bromohydrin 5a: R
max 3600-3200, 2958, 2926, 2855, 2835, 1612 cm ; H NMR (400 MHz,
CDCl ) d 7.14 (d, J = 8.6 Hz, 2H), 6.86 (d, J= 8.6 Hz, 2H), 5.27 (tq, J = 6.8,
.4 Hz, 1H), 3.82 (s, 3H), 3.40 (dd, J= 10.1, 3.0 Hz, 1H), 2.63 (t, J = 7.5 Hz
f D 2 2
= 0.32 (1:9 EtOAc:PE); [a] -10.6 (c 1.3, CH Cl ); IR
1
-1 1
13
n
3
) d 157.7, 135.5, 134.4, 129.4, 124.5,
1
13.7, 78.1, 73.0, 55.3, 36.7, 35.1, 30.1, 29.6, 26.4, 23.2, 15.9 ppm; MS
3
+
+
+
1
2
1
(
CI , NH
3
)
m/z 310 [M + NH
4
] ; HRMS (CI , NH
] 310.2382. Found: 310.2384; HPLC (CHIRALCEL
OJ; 10% IPA in n-hexane; 1.0 mL/min) t = 16.2 min (major), 18.2 min
minor) – e.r. 99:1. In a run using AD - mix a, (S)-diol ent-3 was obtained:
3
) calcd. for
+
H), 2.37-2.25 (m, 3H), 2.17-2.05 (m, 2H), 1.82 (s, 3H), 1.81-1.72 (m, 1H),
18 3 4
C H32NO [M + NH
.75 (s, 3H), 1.59 (s, 3H), 1.49 (dddd, J = 14.0, 10.3, 8.8, 5.2 Hz, 1H) ppm;
R
1
3
C NMR (100 MHz, CDCl
3
) d 157.7, 135.1, 134.4, 129.4, 124.6, 113.7,
(
[
+
2
4
7
9.0, 75.4, 55.3, 36.4, 35.1, 31.1, 30.1 (ꢁ2), 28.9, 16.0 ppm; MS (CI , NH
3
)
79
2
a]
D
= - 5.9 (c 1.0, CH
2 2
Cl ); HPLC (CHIRALCEL OJ; 10% IPA in n-hexane;
= 15.9 min (minor), 17.1 min (major) – e.r. 6:94.
+
+
m/z 374, 372 [M+ NH
4
] ; HRMS (CI , NH
3
) calcd. for C18H31NO
Br
= 0.24 (1:9
+35.1 (c 1.3, CH ); IR nmax 3600-3250, 2925, 2854,
3
1612 cm ; H NMR (400 MHz, CDCl ) d 7.13 (d, J= 8.6 Hz, 2H), 6.86
1.0 mL/min) t
R
+
[M+ NH
4
]
372.1538, found 372.1538. Bromohydrin 5b: R
f
2
4
(
+)-(3R,6R,7R)-2,6-Dimethyl-9-(4-methoxyphenyl)nonane-2,3,6,7-
tetraol (3a). m.p. 130-131˚C. [a]
EtOH:PE); IR nmax 3600-3100, 2972, 2952 cm ; H NMR (400 MHz, CDCl
d 7.16 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 3.81 (s, 3H), 3.41 (d, J = 9.6
EtOAc:PE); [a]
D
2 2
Cl
2
4
-1 1
D
= +20.0 (c 1.0, EtOH); R
f
= 0.28 (1:1
-1 1
3
)
(d, J= 8.6 Hz, 2H), 5.29 (t, J= 7.3 Hz, 1H), 3.95 (dd, J= 11.6, 1.9 Hz, 1H),
3.82 (s, 3H), 2.63 (td, J= 7.4, 3.4 Hz, 2H), 2.39-2.27 (m, 3H), 2.24 (s, 1H),
Chirality DOI 10.1002/chir

ENANTIOSPECIFIC BROMONIUM ION POLYENE CYCL.
695
2
.15 (dt, J = 14.9, 8.2 Hz, 1H), 1.97 (dtd, J = 16.2, 8.0, 1.8 Hz, 1H), 1.85-1.74 two exocyclic alkenes (6 mg, 19%) as a colorless oil, R = 0.39 (1:4 CH Cl :
f 2 2
1
3
(
(
m, 1H), 1.56 (s, 3H), 1.354 (s, 3H), 1.347 (s, 3H) ppm; C NMR
100 MHz, CDCl ) d 157.7, 134.3, 133.7, 129.4, 125.5, 113.7, 72.5, 70.8,
PE), and second bromides (2R,4aR,10aS)-2 and (2R,4aS,10aR)-2 as an in-
3
separable mixture of diastereoisomers (d.r. 3:1, 8 mg, 25%) as a white solid:
m.p. 92-93 ˚C; R = 0.64 (40:60 CH Cl :PE). The major diastereoisomer
f 2 2
+
5
3
3
5.3, 38.2, 35.1, 31.8, 30.2, 26.6, 25.9 15.8 ppm; MS (CI , NH
72 [M + NH
72.1538, found 372.1540.
3
) m/z 374,
+
+
79
2
+
4
] ; HRMS (CI , NH
3
) calcd. for C18
H
31NO
Br [M+ NH
4
]
(2R,4aR,10aS)-2 was identical to that produced in the BDSB mediated
cyclization of polyene 1, and the minor diastereoisomer (2R,4aS,10aR)-2
1
was identified in the mixture by its characteristic H NMR signal at 4.42
1
13
(-)-(S,E)-2-Bromo-9-(4-methoxyphenyl)-2,6-dimethylnon-6-en-3-yl
(1H, CHBr) ppm as a broad singlet (see SI 11 for H and C NMR spectra).
1
2
,3,4,5-tetrafluorobenzoate (6a). Using the method of Neises and
Data for (2R,4aS,10aR)-2 [as 1:3 mixture with bromide (2R,4aR,10aS)-2]: H
7
4
Steglich, to a stirred solution of secondary alcohol 5a (380 mg,
.07 mmol) in CH Cl (7.5 mL) was added 2,3,4,5-tetrafluorobenzoic acid
3
NMR (400 MHz; CDCl ) d 7.01 (d, J= 8.3 Hz, 1H,), 6.84 (d, J= 2.8 Hz, 1H),
1
2
2
6.71 (dd, J= 8.3, 2.8 Hz, 1H), 4.42 (br s, 1H), 3.81 (s, 3H), 2.94-2.75 (m, 2H),
2.42-2.38 (m, 1H), 2.21-2.06 (m, 3H), 1.89 (dd, J= 12.4, 2.5 Hz, 1H), 1.82-1.67
(
(
228 mg, 1.18 mmol), DMAP (39 mg, 0.321 mmol, 30 mol%) and DCC
287 mg, 1.39 mmol). After 4 h the reaction mixture was filtered through
13
(m, 2H), 1.22 (s, 3H), 1.12 (s, 6H) ppm; C NMR (100 MHz, CDCl
3
)
a silica plug eluting with Et
chromatographed (0:1-3:17 Et
a (520 mg, 92%) as a colorless oil. R
2
O, concentrated under reduced pressure, and
O:PE) to afford bromo tetrafluorobenzoate
= 0.34 (5:95 EtOAc:PE);
); IR nmax 2935, 2861, 2362, 2344, 1729 cm ;
) d 7.69 (dddd, J= 10.3, 8.3, 6.0, 2.4 Hz, 1H), 7.13
d 157.8, 150.5, 129.8, 127.1, 111.0, 110.0, 69.1, 55.3, 43.5, 38.4, 37.8, 33.4,
+
+
32.9, 29.1, 28.7, 25.5, 22.2, 18.5 ppm; GCMS (EI ) m/z 337, 335 [M - H] .
The diastereoisomers were inseparable by standard column chromatog-
raphy on silica gel, but could be separated by preparative HPLC (Prep Si;
2
6
f
2
4
-1
[
a]
D
-22.0 (c 1.1, CH
H NMR (400 MHz, CDCl
d, J= 8.5 Hz, 2H), 6.85 (d, J= 8.6 Hz, 2H), 5.27 (d, J=9.9 Hz 1H),
.22 (t, J= 7.0 Hz, 1H), 3.82 (s, 3H), 2.61 (app. t, J= 7.7 Hz, 2H), 2.37-2.19
m, 2H), 2.10-2.03 (m, 3H) 1.99-1.85 (m, 1H), 1.83 (s, 3H), 1.82 (s, 3H)
2
Cl
2
1
n-hexane;
[(2R,4aR,10aS)-2]. Bromide (2R,4aR,10aS)-2: [a]
HPLC (CHIRALPAK AD; 1% IPA in n-hexane; 1.0 mL/min) t
5
mL/min)
t = 145 min [(2R,4aS,10aR)-2], 165 min
R
3
24
{
(
5
(
D
-100 (c 0.04, CH
2
Cl
2
) ;
R
= 4.7
D
2
4
min (minor), 5.4 min (major), e.r. 98:2. Bromide (2R,4aS,10aR)-2: [a]
-43
; HPLC (CHIRALPAK AD; 1% IPA in n-hexane;
= 4.7 min (major), 6.1 min (minor), e.r. 98:2. Cyclization
of secondary bromide 6b (135 mg, 0.254 mmol) was conducted as above
using 2.5 equivalents of Me AlOTf to afford first monocycles 7 as an
inseparable mixture of at least two endocyclic and two exocyclic alkenes
(21 mg, 25%) as a colorless oil, R = 0.39 (1:4 CH Cl :PE), and second
1
3
{
1.58 (s, 3H) ppm; C NMR (100 MHz, CDCl
3
) d 161.5, 157.7, 148.0 (dddd,
(c 0.01, CH
2 2
Cl )
J= 262, 11, 3, 1 Hz), 146.6 (dddd, J = 249, 10, 4, 2 Hz), 143.6 (dddd, J = 262, 17,
3, 3 Hz), 141.4 (dddd, J = 255, 17, 12, 3 Hz) 134.3, 134.0, 129.4, 125.1, 114.7
m), 113.7, 113.4 (dd, J = 21, 3 Hz), 81.5, 65.8, 55.2, 36.0, 35.0, 30.44, 30.35,
1.0 mL/min) t
R
1
(
2
1
9
30.15, 29.3, 15.9 ppm; F NMR (377 MHz, CDCl
3
) d -153.1 (t, J = 20 Hz,
+
1
F), -147.0 (m, 1F), -137.6 (m, 1F), -133.6 (m, 1F) ppm; MS (CI , NH
3
)
f
2
2
+
+
79
3
+
m/z 548, 546 [M + NH
5
4
] ; HRMS (EI ) calcd. for C25
H
27
O
BrF
4
[M]
bromides (2R,4aR,10aS)-2 and (2R,4aS,10aR)-2 as an inseparable
mixture of diastereoisomers (d.r. 3:1, 30 mg, 35%) as a white solid. The
diastereomers were separated by preparative HPLC (Prep Si; n-hexane;
30.1080, found 530.1080.
5
[
mL/min)
(2R,4aR,10aS)-2]. Bromide (2R,4aR,10aS)-2: HPLC (CHIRALPAK AD; 1%
IPA in n-hexane; 1.0 mL/min) t = 4.7 min (minor), 5.4 min (major), e.r.
R
t = 145 min and [(2R,4aS,10aR)-2] and 165 min
(
+)-(R,E)-3-Bromo-9-(4-methoxyphenyl)-2,6-dimethylnon-6-en-2-yl
2
,3,4,5-tetrafluorobenzoate (6b). Using the method of Neises and
7
4
Steglich, to a stirred solution of tertiary alcohol 5b (350 mg, 0.99 mmol)
in CH Cl (7.5 mL) was added 2,3,4,5-tetrafluorobenzoic acid
383 mg, 1.97 mmol), DMAP (36 mg, 0.30 mmol, 30 mol%), and DCC
R
98:2. Bromide (2R,4aS,10aR)-2: HPLC (CHIRALPAK AD; 1% IPA in n-hexane;
2
2
1.0 mL/min) t = 4.7 min (major), 6.1 min (minor), e.r. 98:2.
R
(
(
(
610 mg, 2.96 mmol). After 16 h further 2,3,4,5-tetrafluorobenzoic acid
191 mg, 0.98 mmol), DMAP (36 mg, 0.30 mmol, 30 mol%), and DCC (305
(-)-(4aS,10aS)- and (+)-(4aS,10aS)-6-methoxy-1,1,4a-trimethyl-
1,2,3,4,4a,9,10,10a -octahydrophenanthrenes (8) from reduction
of a 3:1 mixture of (-)-(2R,4aR,10aS)- and (-)-(2R,4aS,10aR)-
2-Bromo-6-methoxy-1,1,4a-trimethyl-1,2,3,4,4a,9,10,
10a-octahydrophenanthrenes (2). Using the method of Chatgilialoglu
mg, 1.48 mmol) was added and stirred for 5 h, passed through a plug of sil-
ica, and chromatographed (0:1-2:3 CH Cl :PE) to afford tetrafluorobenzoate
ester 6b (316 mg, 60%) as a colorless oil. R
14.4 (c 1.4, CH Cl ); IR nmax 2931, 2858, 2362, 1719 cm ; H NMR
400 MHz, CDCl ) d 7.66-7.56 (m, 1H), 7.15 (d, J = 8.6 Hz, 2H), 6.85
2
2
2
4
f
= 0.3 (5:95 EtOAc:PE); [a]
D
-1 1
+
2
2
7
5
(
(
(
3
and colleagues,
to a stirred solution of (2R,4aR,10aS)-2 and
d, J = 8.6 Hz, 2H), 5.34 (t, 6.80 Hz, 1H), 4.54 (dd, J = 11.5, 1.9 Hz, 1H), 3.81
s, 3H), 2.66 (t, J = 7.6 Hz, 2H), 2.44-2.26 (m, 3H) 2.21 (dt, J= 13.8, 8.0 Hz,
(2R,4aS,10aR)-2 (d.r. 3:1, 15 mg, 45 mmol) in toluene (2 mL) was added
tris(trimethylsilyl)silane (16.5 mL, 53 mmol) and azobisisobutyronitrile
(0.73 mg, 40 mmol) and heated to 90 C for 2 h. The mixture was allowed
ꢀ
1
H), 2.09-2.00 (m, 1H) 1.94-1.85 (m, 1H) 1.79 (s, 3H), 1.76 (s, 3H), 1.60
1
3
(s, 3H) ppm; C NMR (125 MHz, CDCl
3
) d 160.5, 157.7, 147.8 (dddd,
to cool, concentrated under reduced pressure, and chromatographed
J= 262, 11, 4, 2 Hz), 146.4 (dddd, J= 249, 10, 4, 2 Hz), 143.4 (dddd, J = 262,
(0:1-3:7 CH
2 2
Cl :PE) to give trans-decalin 8 (5 mg, 43%) as a single diastereo-
24
1
1
3
7, 13, 3 Hz), 141.3 (dddd, J = 255, 17, 12, 3 Hz), 134.3, 133.6, 129.3, 125.7,
isomer as a colorless oil. R
f
= 0.42 (20:80 CH
); lit. (4aS,10aS)-8 [a] +64.0 (c 1.0, CHCl
2852, 1686, 1609 cm ; H NMR (500 MHz, CDCl
3
2
Cl
2
:PE); [a]
); IR nmax 2997, 2924,
) d 6.96 (d, J = 8.3 Hz,
D
-23.0 (c 0.26,
7
6
16.0 (m), 113.6, 113.2 (dd, J= 21, 2 Hz), 86.2, 61.6, 55.2, 37.8, 35.0, 31.5,
CH Cl
2 2
D
3
19
-1 1
0.2, 24.1, 23.3, 15.8 ppm; F NMR (377 MHz, CDCl
3
) d -153.5 (t, J= 20
Hz, 1F), -147.7 (tt, J= 19, 8 Hz, 1F), -138.0 (dt, J= 22, 12 Hz, 1F), -134.5
1H), 6.81 (d, J = 2.7 Hz, 1H), 6.66 (dd, J= 8.3, 2.7 Hz, 1H), 3.78 (s, 3H), 2.88
(ddd, J = 16.8, 6.9, 1.3 Hz, 1H), 2.78 (ddd, J= 16.8, 11.2, 7.4 Hz, 1H), 2.24
(br d, J = 12.6 Hz, 1H), 1.86 (dddd, J = 13.3, 7.5, 2.0, 2.0 Hz, 1H), 1.80-1.57
+
+
+
(
m, 1F) ppm; MS (CI , NH ) m/z 548, 546 [M + NH ] ; HRMS (EI ) calcd.
3
4
79 +
3 4
for C25H27NO BrF [M] 530.1080, found 530.1082.
(m, 3H), 1.48 (br d, J = 13.2 Hz, 1H), 1.41 (td, J = 13.1, 3.7 Hz, 1H), 1.32
(
1
-)-(2R,4aR,10aS)- and (-)-(2R,4aS,10aR)-2-Bromo-6-methoxy-
,1,4a-trimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrenes (2)
(dd, J = 12.5, 2.3 Hz, 1H), 1.23 (dd, J= 13.7, 4.0 Hz, 1H), 1.21 (s, 3H), 0.97
(s, 3H), 0.95 (s, 3H) ppm; C NMR (100 MHz, CDCl ) d 157.6, 151.5,
3
1
3
from cyclization of bromotetrafluorobenzoates 6a and 6b. Cyclization
of tertiary bromide 6a: To a stirred solution of Me Al (2M in hexanes,
(2 mL) at –78 C was added a solution
of trifluoromethanesulphonic acid (43 mL, 0.5 mmol) in CH Cl (4 mL)
and stirred at –78 C for 0.5 h and 0 C for 0.5 h. The white suspension
of Me AlOTf was recooled to –78 ˚C and solution of bromo
tetrafluorobenzoate 6a (50 mg, 0.292 mmol) in CH Cl (2 mL) was added
129.7, 127.5, 110.7, 110.2, 55.3, 50.3, 41.7, 38.8, 38.0, 33.5, 33.3, 29.6, 24.8,
+
+
+
21.7, 19.3, 19.1 ppm; MS (CI , NH
3
) m/z 259 [M + H] ; HRMS (CI , NH
3
)
3
+
ꢀ
0
.25 mL, 0.5 mmol) in CH
Cl
2 2
calcd. for C18
H
27O [M + H] 259.2062, found 259.2071. HPLC (CHIRALPAK
AD; 1% IPA in n-hexane; 1.0 mL/min) t
4.72 min [(4aR,10aR)-8], e.r. 25:75.
R
= 4.12 min [(4aS,10aS)-8],
2
2
ꢀ
ꢀ
2
a
2
2
RESULTS AND DISCUSSION
ꢀ
dropwise at –78 C. The reaction was allowed to warm to room temperature
over 16 h, quenched with aqueous HCl solution (1M, 10 mL), extracted with
49
Polyene 1 (Fig. 3) was selected as the basic carbon
framework for our investigations, with the enantiopure
CH
10 mL) and brine (10 mL), dried over Na
pressure, and chromatographed (0:1-3:7 CH
monocycles 7 as an inseparable mixture of at least two endocyclic and
2 2
Cl
(2ꢁ 10 mL), washed with saturated aqueous NaHCO
SO , concentrated under reduced
Cl :PE) to afford first
3
solution
(
2
4
{
2
2
The concentration of this solution is very dilute and the absolute magni-
tude of this measurement is liable to a large error.
Chirality DOI 10.1002/chir

6
96
BRADDOCK ET AL.
Fig. 3. Polyene 1 and isomer 1a.
Fig. 4. The crystal structure of (2R*,4aR*,10aS*)-2. Crystallographic data
for the structure reported in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre (CCDC 928846.). Copies of the data
can be obtained, free of charge, on application to the Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, United Kingdom (Fax: 44-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk).
Scheme 1. BDSB mediated cyclization of polyene 1 into racemic tricyclic
bromide (2R*,4aR*,10aS*)-2.
bromonium ion to be formed on the terminus alkene, the sec-
ond, internal alkene acting as the propagating olefin, and the
polyene cyclization to be terminated by the aromatic nucleus.
Diene 1 could be prepared by the palladium(0) catalyzed cou-
pling of p-methoxybenzyl magnesium chloride with geranyl
bromide,77 but in our hands variable and significant quanti-
ties of the inseparable branched regioisomer 1a were also
Scheme 2. Asymmetric dihydroxylation of diene 1.
††
enantioselectivity (R)-3; e.r. 99:1) along with unavoidable
formation of tetraol (3R,6R,7R)-3a (Scheme 2). The absolute
configuration of diol (R)-3 was assigned on the basis of the
}
observed. The noncatalyzed coupling of the same Grignard
reagent with geranyl diethyl phosphate as described by
7
1,79
4
9
}
Sharpless mnemonic.
specifically into epoxide (S)-4 by the Corey et al. method,
followed by stereospecific (but non-regioselective) epoxide
Diol (R)-3 was converted stereo-
Synder gave significantly improved regioselectivity. The
73
49
direct action of BDSB on diene 1 as described by Synder
gave racemic tricyclic bromide (2R*,4aR*,10aS*)-2
Scheme 1) in good yield as a single diastereoisomer, which
55
ring-opening by bromide anion providing the separable
regioisomeric bromohydrins (S)-5a and (R)-5b (Scheme 3).
The regioisomeric bromohydrins (S)-5a and (R)-5b were
assigned on the basis of their distinctive chemical shifts at
.40 and 3.95 ppm in their H NMR spectra, respectively,
(
in our hands proved to be crystalline. Single crystal x-ray de-
termination (Fig. 4) of tricyclic bromide (2R*,4aR*,10aS*)-2
confirms the formation of the two six-membered carbocyclic
rings as a trans-fused decalin ring system, and also the equa-
torial positioning of the bromine atom.
1
3
where two regioisomeric bromohydrins of a trisubstituted
alkene were previously distinguished unambiguously by bro-
mide induced 13C isotopic shifts.
69–78
To the end of generating enantiopure bromohydrins,
69
high purity diene 1** was first dihydroxylated using AD-
71
In our previous work with non-alkene-containing sub-
strates,69 and on the basis of an earlier observation where
we had observed the spontaneous formation of a bromonium
ion from a 1-bromo-2-tetrafluorobenzoate on standing,80
enantiopure bromonium ions had been generated by
first converting enantiopure bromohydrins into 2,3,4,5-
tetrafluorobenzoates, followed by activation with catalytic
amounts of triflic acid. While we were confident that the cor-
responding tetrafluorobenzoates of bromohydrins (S)-5a and
mix b in good regioselectivity to give diol (R)-3, in excellent
}
In multiple runs the ratio of 1:1a was found to vary unpredictably from
3
5:1 to 10:1. The two isomers could not be separated by simple column
chromatography.
}
In two 80 mmol batch reactions, the ratio of 1:1a was determined to be
9:1 and 35:1. Analytically pure 1a could be obtained from silver nitrate-
1
doped silica gel column chromatography. The purity of 1 could be im-
proved to >98% by a fractional distillation process (see Experimental).
(
R)-5b could be synthesized, the presence of the acid-sensi-
*
*
High purity diene 1 free from branched 1a was found to be essential for
tive trisubstituted alkenes in these substrates would render
the use of triflic acid to subsequently generate bromonium
ions undoubtedly problematic. Nevertheless, knowing that a
suitable Lewis acid should offer an alternative activation
mode, tetrafluorobenzoates (S)-6a (92%) and (R)-6b (60%)
subsequent HPLC enantiomeric excess determination of products. The
branched isomers were inseparable at all stages of the subsequent syn-
thesis and overlapped and/or obscured the minor and/or major enantio-
mer signal in the HPLC analyses. This was especially problematic since
the asymmetric dihydroxylation of diene 1 is so highly enantioselective
(
99:1 e.r.), and therefore high purity was required for accurate ee assess-
(
Fig. 5) were prepared from alcohols (S)-5a and (R)-5b,
ment. Moreover, in dihydroxylation runs using lower purity diene 1, the
branched isomer actually accumulated (e.g., in multiple runs using dienes
74
respectively, by Steglich esterification
with 2,3,4,5-
1
:1a in a 13:1 ratio, the ratio of linear diol 3 to its inseparable branched
tetrafluorobenzoic acid. On activation—and stereospecific
diol counterpart was 5:1). Evidently, while could be further
3
dihydroxylated to tetraol 3a thus depleting the amount of 3, the terminal
alkene of the branched isomer diol was more resistant to further
dihydroxylation.
†
†
The enantiomeric purity was assayed by chiral HPLC methods (see
Supporting Information).
Chirality DOI 10.1002/chir

ENANTIOSPECIFIC BROMONIUM ION POLYENE CYCL.
697
†
†
(
2R,4aR,10aS)-2 (e.r. 98:2) was provided as a 3:1 mixture
with diastereomeric enantiopure bromide (2R,4aS,10aR)-2
†
†,†††
{{{ }}}
(
e.r. 98:2),
along with monocyclization adducts 7.,
The relative configuration of (2R,4aR,10aS)-2 had already
been established by x-ray crystallography (Fig. 4) from
direct BDSB mediated cyclization of polyene 1 (Scheme 1),
and the assignment of absolute configuration follows from
an R-configured bromonium ion. The relative configuration
of (2R,4aS,10aR)-2 was established by (Me Si) SiH mediated
3
3
dehalogenation of a 3:1 mixture of (2R,4aR,10aS)-2 and
2R,4aS,10aR)-2 diastereomers with essentially quantitative
(
conversion (43% isolated yield) to give a single diastereomeric
trans-decalin 8 (Scheme 5). The observed 3:1 e.r. for trans-
decalin 8 allows assignment of the absolute configurations
as (4aR,10aR)-8 and (4aS,10aS)-8 from (2R,4aR,10aS)-2 and
Scheme 3. Synthesis of enantiopure bromohydrins (S)-5a and (R)-5b.
(
2R,4aS,10aR)-2, respectively. The absolute configurations
were confirmed by comparison of the negative sign of optical
rotation for the 3:1 enantiomeric mixture of (4aR,10aR)-
displacement of the activated leaving group by neighboring
group participation of the bromide—each of (S)-6a and (R)-6b
should re-converge on the same R-configured enantiomerically
pure bromonium ion A (Fig. 5).
8
and (4aS,10aS)-8 with the rotation already reported for
76
(
+)-(4aS,10aS)-8.
Evidently, the bromonium ion initiated cyclizations de-
Attempted bromonium ion initiated cyclization of (S)-6a or
6
9
scribed herein (Scheme 4) are proceeding enantiospecifically
(
R)-6b with catalytic quantities of triflic acid, led, as pre-
,
68 }}}****
via enantiomerically pure bromonium ions
without
dicted (vide supra), to extensive decomposition, and previous
attempts to generate bromonium ions from vicinal bromo
problematic intramolecular or intermolecular bromonium
53
ion-to-alkene transfer. We invoke a chair-like conformation
tetrafluorobenzoates of trisubstituted alkenes by solvolysis
were unsuccessful69 and not pursued in this study. Lewis acid
C in the cyclization leading to (2R,4aR,10aS)-2, and a boat-like
conformation B in the cyclization leading to (2R,4aS,10aR)-2
activation was then explored, where the use of alkyl alumi-
num reagents as Lewis acids that lead to rigorously proton-
(
Fig. 6), each with the same absolute configuration of the
}
}}****
81
bromonium ion (R-configured).
free solutions was expected to be beneficial (oxophilic
Lewis acid metal halides were rejected as potential mediators
of the cyclization on the basis that hydrohalic acids would be
generated during the course of the reaction), and preliminary
CONCLUSION
In conclusion, we have demonstrated the first
enantiospecific polyene cyclizations initiated by enantiopure
bromonium ions. We have identified the stoichiometric use
of dimethylaluminum triflate to activate tetrafluorobenzoates
of enantiopure bromohydrins to initiate such processes,
where other Lewis and Brönsted acids fail. Notably, under
studies with stoichiometric quantities of Yb(OTf) and/or Eu
3
(
fod) in CH Cl or chlorobenzene were ineffective in initiat-
3 2 2
ing the cyclization even at elevated temperatures and/or
under microwave irradiation. The use of stoichiometric quan-
tities of trimethylaluminum to mediate the cyclization was
found to be ineffective, leading to decomposition of both of
the substrates (S)-6a or (R)-6b. Some cyclization adduct
was observed using dimethylaluminum chloride as the Lewis
acid activator, but a bromochloride was also observed as
the major product, where intermolecular attack of any
incipient bromonium ion by anionic chloride from the
†††
The two diastereoisomers were not separable by column chromatogra-
phy, but could be separated by preparative HPLC. This enabled the enan-
tiomeric purity of each to be established without interference from the
other (see Supporting Information).
{
{{
{
{
A mixture of inseparable monocyclisation adducts 7 could be isolated
Lewis acid is evidently competing. The use of the Lewis
by column chromatography after cyclization. Inspection of the alkene re-
acid dimethylaluminum triflate, incorporating the non-
1
gion of the H NMR spectrum reveals two monocycles with exocyclic
82
nucleophilic triflate anion—first reported in the 1980s and
H
methylene groups [d 5.03 (s, 1H), 4.79 (s, 1H), and 4.90 (s, 1H), 4.17
8
3
only infrequently employed —on either bromide (S)-6a
(s, 1H) in a 3:1 ratio respectively] and two monocycles with endocyclic tri-
}
}
}}
H
substituted alkenes [d 5.27 (br s, 1H), and 5.20 (br s, 1H) in a 3:1 ratio,
(
5 eq. Me AlOTf) or (R)-6b (2.5 eq. Me AlOTf) led to
2 2
respectively]. The endocyclic:exocyclic alkenes ratio is 1.5:1.
clean and complete conversion of substrates into cyclization
adducts (Scheme 4). *** In both cases, enantiopure bromide
}}}
Attempts to convert the isolated monocyclic alkene mixture 7 into tricy-
}}
clic adducts 2 with chlorosulphonic acid in nitromethane as previously
demonstrated by Sakakura et al. (Ref. 10) in a similar system, led instead
to extensive decomposition.
{
{
From a run using 131 mg of a mixture of 6a and 6b (1:2) 9 mg of cycli-
}
}}
zation adducts 2 (d.r. 3:1) were isolated after extensive column chroma-
The exact structure of a “bromonium ion” of an alkene will depend
tography. A noncyclized bromochloride (24 mg) was obtained with a
strongly on the substitution pattern of the alkene, the solvent, and its
counterion. It is understood that a cyclic bromonium ion and an open b-
bromocarbocation represent the two extremes of a spectrum of ionic in-
termediates that are possible.
characteristic mass spectrometry isotope pattern of 390 (82%), 392
+
(
100%), 394 (49%) (M + NH
The use of less equivalents of Me AlOTf led to incomplete consumption
2
4
) .
}}
*
***
of starting tetrafluorobenzoates. Evidently the 2˚ benzoate 6a is less read-
ily activated than the 3˚ benzoate 6b.
The enantiospecific cyclization of tertiary bromide (S)-6a requires the
intermediacy of an R-configured enantiomerically pure bromonium ion by
stereospecific NGP displacement of the tetrafluorobenzoate group,
whereas cyclization of secondary bromide (R)-6b may proceed instead di-
rectly via a tertiary carbocation. The near identical product distributions
}
}
The use of MeAl(OTf)
2 3 2 2
as prepared from Me Al and 2TfOH in CH Cl
led to decomposition of the substrates.
*
**
1
Inspection of the H NMR spectrum of the crude reaction mixtures
show that all starting material has cleanly been converted to product.
The relatively low isolated yields (scheme 4) reflect the difficult chro-
matographic purification/separation of these non-polar compounds.
for each substrate as observed by inspection of the crude reaction mix-
1
tures by H NMR implicate a single common intermediate viz. a
bromonium ion.
Chirality DOI 10.1002/chir

6
98
BRADDOCK ET AL.
the reported cyclization conditions, any intramolecular or
intermolecular bromonium ion-to-alkene transfer is evidently
not in operation. Further work will require the identification
of other Lewis acid-leaving group combinations to improve
overall yields of polycyclic products and to expand the sub-
strate scope.
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