Asymmetric synthesis of 6′-hydroxyarenarol: The proposed biosynthetic precursor to popolohuanone E

Article abstract of DOI:10.1021/jo801404u

(Chemical Equation Presented) The first synthesis of (+)-6′- hydroxyarenarol 3, the proposed biogenetic precursor to popolohuanone E (1), is described. An enantioselective route to key iodide intermediate 12 has been developed allowing the asymmetric synt

Full text of DOI:10.1021/jo801404u

Asymmetric Synthesis of 6′-Hydroxyarenarol: The Proposed
Biosynthetic Precursor to Popolohuanone E
Rachel H. Munday, Ross M. Denton, and James C. Anderson*
School of Chemistry, UniVersity of Nottingham, Nottingham, NG7 2RD, United Kingdom
j.anderson@nottingham.ac.uk
ReceiVed June 27, 2008
The first synthesis of (+)-6′-hydroxyarenarol 3, the proposed biogenetic precursor to popolohuanone E
(1), is described. An enantioselective route to key iodide intermediate 12 has been developed allowing
the asymmetric synthesis of the known cis-decalin 22. Conditions which allow the removal of the methyl
ether protecting groups on the hydroxyarene leaving the exocyclic methylene moiety in tact have also
been developed to complete this synthesis.
Introduction
Popolohuanone E (1) is a marine natural product isolated from
the sponge Dysidea in 1990 as a dark purple solid (Figure 1).1
The molecule has a trihydroxylated dibenzofuran-1,4-dione core
to which are appended two identical cis-decalin units each
containing four contiguous stereocenters. Aside from its unique
structure, 1 demonstrates interesting biological activity being a
potent inhibitor of Topoisomerase II and showing selective
cytotoxicity against the A549 nonsmall human lung cancer cell
line.1
FIGURE 1. Popolohuanone E and related compounds.
Popolohuanone E and a related compound, arenarol (2),2
bearing the same sesquiterpene unit and also isolated from
Dysidea sp., have attracted much interest from the synthetic
community. There have been several reported syntheses of
arenarol, in both racemic3 and enantiopure form,4 including a
formal racemic synthesis published by our group.5 No total
synthesis of 1 has been published as yet, although Katoh et al.
very nearly achieved this goal in preparing 8-O-methylpopolo-
huanone E in 2001.6
For a number of years our group has been interested in
pursuing a total synthesis of 1, in particular, in testing the
biosynthetic hypothesis that popolohuanone E is derived from
oxidative dimerization of the, as yet unreported, 6′-hydroxyaren-
arol 3.1,7 This strategy is very efficient and especially appealing
for a total synthesis as the tricyclic core should be generated
without the need for protection on the hydroxyl groups. We
were keen to avoid the difficulties that Katoh et al. had
experienced when trying to deprotect the core of the molecule
in the latter stages of their synthesis. In 2005 we demonstrated
(1) Carney, J. R.; Scheuer, P. J. Tetrahedron Lett. 1993, 34, 3727. Popolohua
means purplish blue as the sea in Hawaiian.
(2) Arenarol (2) was first isolated from Dysidea arenaria in 1984 and
subsequently from a Fenestraspongia species, see:(a) Schmitz, F. J.; Lakshmi,
V.; Powell, D. R.; van der Helm, D. J. Org. Chem. 1984, 49, 241. (b) Carte, B.;
Rose, C. B.; Faulkner, D. J. J. Org. Chem. 1985, 50, 2785.
(3) Watson, A. T.; Park, D. F.; Wiemer, D. F.; Scott, W. J. J. Org. Chem.
1995, 60, 5102.
(4) Kawano, H.; Itoh, M.; Katoh, T.; Terashima, S. Tetrahedron Lett. 1997,
38, 7769.
(5) Anderson, J. C.; Pearson, D. P. J. Chem. Soc., Perkin Trans. 1 1998,
2023.
(6) Katoh, T.; Nakatani, M.; Shikita, S.; Sampe, R.; Ishiwata, A.; Ohmori,
O.; Nakamura, M.; Terishima, S. Org. Lett. 2001, 3, 2701.
(7) While 6′-hydroxyareranol has not been isolated the related compound
6′-hydroxyavarol the ∆3,4 isomer and C-5 epimer has been isolated from
Dysideacinerea: Hirsh, S.; Rudi, A.; Kashman, Y.; Loya, Y. J. Nat. Prod. 1991,
54, 92.
10.1021/jo801404u CCC: $40.75
Published on Web 09/18/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8033–8038 8033

Munday et al.
SCHEME 3. Asymmetric Synthesis of Alcohol 11
SCHEME 1. Model Study for Biosynthesis of 18
SCHEME 2. Initial Route to Key Iodide Intermediate 12
CBS reduction11 failed to give allylic alcohol 9 with an ee of
more than 50% despite extensive screening.12 That, coupled with
the instability of alcohol 9 due to its tendency to undergo
Peterson elimination, led us to develop an alternative route
utilizing a chiral auxiliary to introduce the methyl stereocenter
(Scheme 3).
Alkylation precursor 14 was formed from γ-butyrolactone
via acid 13.13 Asymmetric alkylation with the pseudoephedrine
auxiliary14 gave higher yield and ee than the Evans’ oxazoli-
dinone and allowed direct conversion to methyl ketone 16.15
Standard Wittig reaction failed to introduce the allyl silane
moiety directly therefore a four-step protocol was employed:
addition of vinyl magnesium bromide and isomerization of the
resulting tertiary allylic alcohol gave primary allylic alcohol
17.16 This was converted to allylic chloride 18 and the chloride
ion was displaced by using TMSLi, serendipitously also cleaving
the benzyl protecting group to give 11. Finally, the alcohol was
converted to the enantiomerically pure iodide under standard
conditions to give key intermediate 12.
With this in hand, methodology that had been used in the
racemic synthesis could be used without modification to generate
aldehyde 24.5,9 Vinyl bromide 19 and iodide 12 were coupled
and the ketal deprotected to give the precursor to the
Hosomi-Sakurai reaction. Treatment of 20 with Lewis acid in
the presence of MeSCH2Cl gave cis-decalin 21 as a single
diastereoisomer in 68% yield along with 9% of the proton
quenched product. Reduction of the sulfide, protection of the
ketone, and cleavage of the alkene then gave the desired
aldehyde 24, also an intermediate in Katoh’s synthesis.17
The next challenge was to construct the very sterically
hindered benzylic bond. From previous work we knew that this
this approach to be feasible, generating the dibenzofuran-1,4-
dione core from a model trihydroxyarene with a neopentyl group
in place of the decalin unit (Scheme 1).8 Treatment of
trihydroxyarene 4 with silica-supported FeCl3 effected oxidative
dimerization and further oxidation to the bisquinone 5. Subse-
quent biquinone rearrangement was brought about under very
mild conditions with use of K2CO3 in acetone to give the
tricyclic dibenzofuran-1,4-dione core of popolohuanone E 6.
In an analogous fashion we reasoned that oxidative coupling
of 3 followed by further oxidation would give a bisquinone that
could then undergo rearrangement to 1. To investigate this
hypothesis, we report the first asymmetric synthesis of 6′-
hydroxyarenarol.
Results and Discussion
Our initial studies focused on the asymmetric synthesis of
the cis-decalin unit. We envisaged this could be achieved by
modifying the route we had used from Tokoroyama9 in our
formal synthesis of (()-2.5 An asymmetric synthesis would
require generating iodide 12 in enantiomerically pure form. In
the literature racemic route, 12 had been generated from tiglic
aldehyde by using a Claisen rearrangement as a key step. A
route from tiglic acid was developed (Scheme 2), the success
of which required allylic alcohol 9 to be generated in enantio-
merically pure form and for chirality to be transferred through
the Claisen rearrangement. Although it was found that chirality
could be transferred exclusively through an Ireland Claisen
rearrangement10 this route eventually proved unsuccessful as
(11) (a) Corey, E. J.; Guzman-Perez, A.; Lazerwith, S. E. J. Am. Chem. Soc.
1997, 119, 11769. (b) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31,
611. (c) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1989, 30, 6275. (d) Helal,
C. J.; Magriotis, P. A.; Corey, E. J. J. Am. Chem. Soc. 1996, 118, 10938.
(12) Since our studies in this area CBS reduction on the same substrate with
SiMe2Ph instead of TMS has been successfully carried out albeit with 0.4 equiv
of CBS catalyst. Rodgen, S. A.; Schaus, S. E. Angew. Chem., Int. Ed. 2006, 45,
4929.
(13) Lafontaine, J. A.; Provencal, D. P.; Gardelli, C.; Leahy, J. W. J. Org.
Chem. 2003, 68, 4215.
(14) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(15) Enantiomeric purity measured by HPLC against a racemic standard,
i
using a Chiralcel OJ-H column of PrOH/hexane (2:98), 0.25 mL min-1. Rt: R
(minor) 75.1 min, S (major) 79.7 min. Absolute configuration was assumed from
(8) Anderson, J. C.; Denton, R. M.; Wilson, C. Org. Lett. 2005, 7, 123.
(9) Tokoroyama, T.; Tsukamoto, M.; Asada, T.; Iio, H. Tetrahedron Lett.
1987, 28, 6645.
the Myers mnemonic.14
(16) (a) Bellemin-Laponnaz, S.; Le Ny, J. P.; Osborn, J. A. Tetrahedron
Lett. 2000, 41, 1549. (b) Morrill, C.; Grubbs, R. H. J. Am. Chem. Soc. 2005,
127, 2842.
(10) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897.
8034 J. Org. Chem. Vol. 73, No. 20, 2008

Asymmetric Synthesis of 6′-Hydroxyarenarol
SCHEME 4. Synthesis of trimethyl-6′-hydroxyarenarol 28.
SCHEME 5. Deprotection of Model Compound 29
without double bond isomerization.20 Initial attempts focused
on thiolates and it was found that monodemethylation at C-221
could be achieved by using EtSNa in DMF at 110 °C in 86%
yield22 or Ph2PK in refluxing THF in an unoptimized yield of
63%. Any attempts to further deprotect this monodemethylated
compound were unsuccessful. Didemethylation to give 30 could
be effected by using PhSH and K2CO3 in NMP at 190 °C;
however, the 22% isolated yield would not be viable for use in
a synthesis. The suggested structure 30 is consistent with
literature precedence in that once the methyl ether at C-2 has
been removed21 and the hydroxyl protonated an intramolecular
hydrogen bond between this proton and the methoxy group at
C-3 can assist cleavage of the second methyl ether.23 In addition
the detection of an o-quinone possessing an OMe group from
the oxidation of 30 is also consistent with this assignment (vide
infra). It was eventually found that the same didemethylated
compound 30 could be obtained in an excellent yield of 90%
(along with 9% of compound having undergone didemethyla-
tion, presumably at C-221 and C-6), using Ph2PLi generated from
n-BuLi and an excess of Ph2PH. Prolonged exposure or
resubmission of the monomethylated compound to these condi-
tions did not result in the removal of the final methyl ether
protecting group. After much experimentation it was found that
30 could be converted to fully deprotected compound 33 by
using an oxidation-reduction protocol.24 Treatment of dihy-
droxyarene 30 with Salcomine/O2 resulted in formation of the
unstable o-quinone 31. This transformation could also be
facilitated with CAN and it was noted that if the reaction was
stirred for a longer period of time the o-quinone was completely
converted to another compound, which proved to be p-quinone
32. Direct reduction with Na2S2O4 gave model trihydroxyarene
33 in good overall yield over 3 steps with the exocyclic
methylene still intact (Scheme 5).
could be achieved in high yield by addition of an aryl lithium
to 24 provided the protecting groups on the hydroxyls were
small.5 Katoh had demonstrated that the resulting benzylic
alcohol could be deoxygenated in high yield using a modified
Barton procedure and we also found this to be more efficient
than direct hydrogenation.5 Therefore reaction of ortho-lithiated
1,2,5-trimethoxybenzene with aldehyde 24 gave benzylic alcohol
25 as a 6:1 inseparable mixture of diastereoisomers in excellent
yield and subsequent deoxygenation proceeded smoothly to give
26 (Scheme 4).
At this point we wanted to introduce the exocyclic methylene
as this would be more difficult once deprotection of the hydroxyl
groups had taken place. Ketal deprotection gave 27 and the
exocyclic double bond could be introduced by using Nysted’s
reagent in 75% yield. It was found to be crucial to add TiCl4
slowly as a solution in CH2Cl2 to avoid isomerization of the
double bond. While experiencing problems with this step it was
also discovered that the exocyclic methylene could be installed
by using an operationally much simpler Wittig reaction, using
t-BuOK to form the ylide and refluxing in toluene.18 This gave
a comparable yield and the use of basic conditions avoided any
possibility of double bond isomerization.
Application of the deprotection conditions developed in the
model system to trimethyl-6′-hydroxyarenarol 28 proceeded
presumably via the analogous diol 34 to accomplish the first
synthesis of (+)-6′-hydroxyarenarol (3) (Scheme 6).
In summary, the first synthesis of (+)-6′-hydroxyarenarol,
the proposed precursor of popolohuanone E in nature, has been
With trimethyl-6′-hydroxyarenarol 28 in hand all that was
needed to complete the synthesis of 3 was the removal of the
three methyl ether protecting groups. Standard Lewis acidic
conditions usually employed for the removal of phenolic methyl
ethers were thought to be unsuitable as they would result in
isomerization of the double bond to the more stable endocyclic
position. Therefore model compound 29 was synthesized19 to
find a strategy whereby deprotection could be accomplished
(20) It should be noted that all attempts to deprotect this model compound
with acetal, ketone, or protected alcohol in place of the exocyclic methylene
under Lewis acidic conditions (BBr3/TMSI) failed.22
(21) This is consistent with literature precedent for the demethylation of
phenols. Methyl ethers with two ortho-substituents have been shown to be
deprotected first: Lal, K.; Ghosh, S.; Salomon, R. G. J. Org. Chem. 1987, 52,
1072.
(22) Denton, R. M. Ph.D. Thesis, University of Nottingham, 2005.
(23) Chakraborti, A. K.; Sharma, L.; Nayak, M. K. J. Org. Chem. 2002, 67,
6406.
(17) [R]D +8.4 (c 0.81, CHCl3) [lit. [R]D +7.4 (c 1.01, CHCl3)]. The optical
rotation obtained was the same sign and within experimental error leading us to
believe that ee had not been eroded through the route.
(18) Stahl, P.; Kissau, L.; Mazitschek, R.; Huwe, A.; Furet, P.; Giannis, A.;
Waldmann, H. J. Am. Chem. Soc. 2001, 123, 11586.
(19) See the Supporting Information.
(24) A similar oxidation reduction protocol has been used previously: See
ref 3 and 4.
J. Org. Chem. Vol. 73, No. 20, 2008 8035

Munday et al.
SCHEME 6. Deprotection of 28 To Give 3
dropwise over 15 min and the mixture was warmed to 0 °C for 5
min and then recooled to -78 °C. A solution of pseudoephedrine
amide 14 (18.3 g, 53.7 mmol) in THF (160 mL) was added via
cannula over 30 min. The reaction mixture was stirred at -78 °C
for 1 h, 0 °C for 15 min, and rt for 5 min, then recooled to 0 °C
whereupon MeI (10.0 mL, 161 mmol) was added. The mixture was
stirred at 0 °C for 15 min and then quenched by the addition of
sat. aq NH4Cl. The mixture was partitioned between sat. aq NH4Cl
and EtOAc and the aqueous layer was separated and extracted with
EtOAc. The combined organics were washed with 1 M HCl, dried,
and concentrated in vacuo. Purification by flash column chroma-
tography (Et2O) gave alkylated product 15 (18.4 g, 96%) as a
colorless oil: IR νmax (thin film) 3380, 2933, 2869, 1615, 1453,
completed. The introduction of the key stereocenter in iodide
12 was introduced by using Myers ephedrine auxiliary enolate
alkylation methodology for use in the Tokoroyama route to
prepare enantiomerically pure decalin 22. Subsequent addition
of 1,2,5-trimethoxybenzene, functional group manipulations, and
a three-step deprotection of the phenolic methyl ethers led to
(+)-6′-hydroxyarenarol (3). Investigations toward the biomi-
metic total synthesis of popolohuanone E (1) have proven not
to be as straightforward as anticipated and work toward this
goal is ongoing.25
1
1089 cm-1; H NMR (1:3.1 rotamer ratio, asterix denotes signals
due to minor rotamer) δ 0.97* (3H, d, J ) 6.8 Hz), 1.04 (3H, d, J
) 6.8 Hz), 1.13 (3H, d, J ) 7.0 Hz), 1.17* (3H, d, J ) 6.7 Hz),
1.68 (1H, m), 2.01 (1H, m), 2.81 (3H, s, NMe), 2.93* (3H, s, NMe),
2.88-2.97 (1H, m, COCHMe), 3.43 (1H, m, CH2OBn), 3.51 (1H,
m), 4.24-4.44 (1H, m, NCHMe), 4.47 (2H, s, OCH2Ph), 4.53- 4.63
(1H, m, CHOH), 7.25-7.37 (10H, m); 13C NMR (asterix denotes
signals due to minor rotamer) δ 14.6 (CH3), 15.7* (CH3), 17.7
(CH3), 17.9* (CH3), 27.1* (CH), 27.4 (CH), 32.4* (CH3), 33.3
(CH3), 34.3 (CH2), 34.8* (CH2), 57.8 (CH), 68.1 (CH2), 68.2*
(CH2), 73.1 (CH2), 75.7* (CH), 76.5 (CH), 126.4 (CH), 127.1 (CH),
127.6 (CH), 127.7 (CH), 127.9 (CH), 128.4 (CH), 128.5 (CH), 128.5
(CH), 128.8 (CH), 138.5 (Cq), 142.6 (Cq), 177.9* (Cq), 178.9 (Cq);
m/z (ES) 356 (100%, M+) HRMS found 356.2207, C22H30NO3
requires 356.2226; [R]D +93.6 (c 1.88, CHCl3).
(3S)-5-Benzyloxy-3-methylpentan-2-one (16). To a solution of
pseudoephedrine amide 15 (18.4 g, 51.8 mmol) in THF (450 mL)
at -78 °C under N2 was added MeLi (1.6 M in Et2O; 78.0 mL,
124 mmol) over 30 min. The solution was warmed to 0 °C once
the addition was complete and stirred for 15 min at 0 °C. The
reaction was quenched by addition of i-Pr2NH (7.3 mL, 52 mmol)
and stirred at 0 °C for a further 15 min after which time a solution
of acetic acid in Et2O (20% v/v, 140 mL) was added. The reaction
mixture was diluted with Et2O and H2O and the layers separated.
The aqueous layer was extracted with Et2O and the combined
organics washed with sat. aq NaHCO3 and brine, dried, and
concentrated in vacuo. Purification by flash column chromatography
(20% EtOAc-petrol) gave ketone 16 (8.64 g, 81%, 90% ee by
HPLC15) as a colorless oil: IR νmax (thin film) 2932, 2859, 1710,
1454, 1361, 1099 cm-1; 1H NMR δ 1.11 (3H, d, J ) 7.1 Hz), 1.63
(1H, dq, J ) 14.1, 6.0 Hz), 2.03 (1H, m), 2.14 (3H, s), 2.74 (1H,
sex, J ) 6.9 Hz), 3.49 (2H, t, J ) 6.3 Hz), 4.47 (2H, s), 7.29-7.36
(5H, m); 13C NMR δ 16.5 (CH3), 28.4 (CH3), 32.8 (CH2), 44.1
(CH), 68.0 (CH2), 73.1 (CH2), 127.7 (CH), 127.7 (CH), 128.5 (CH),
138.4 (Cq), 212.5 (Cq); m/z (ES) 229 (100%, MNa+); HRMS found
229.1200, C13H18O2Na requires 229.1204. Anal. Calcd for
C13H18O2: C, 75.68; H 8.80. Found: C, 75.38; H, 8.67. [R]D +10.7
(c 0.98, CHCl3).
(4S)-6-Benzyloxy-3,4-dimethylhex-2-en-1-ol (17). A solution
of vinyl magnesium bromide (1 M in THF; 54 mL, 54 mmol) was
added dropwise over 25 min to methyl ketone 16 (5.58 g, 27.1
mmol) stirred in THF (200 mL) at -78 °C under N2. The reaction
mixture was warmed to rt and stirred for 4 h before sat. aq NH4Cl
was added and the layer separated. The aqueous layer was extracted
with Et2O, washed with brine, dried (MgSO4), and concentrated in
vacuo to give crude tertiary allylic alcohol (6.2 g).
A solution of Ph3SiOReO3 (0.67 g, 1.32 mmol) and N,O-
bis(trimethylsilyl)acetamide (7.8 mL, 32 mmol) were stirred in Et2O
(250 mL) at 0 °C under N2 for 10 min. A solution of crude tertiary
allylic alcohol (6.2 g, 26.5 mmol) in Et2O (60 mL + 20 mL wash)
was added rapidly via cannula. The reaction was allowed to stir
and warmed to rt for 14 h after which time Et3N (2.6 mL) was
added and the solvent was removed in vacuo. To the residue was
added MeOH (270 mL) and K2CO3 (7.3 g, 53 mmol) and the
mixture was stirred at rt for 3 h after which time sat. aq NH4Cl
was added. The layers were separated and the aqueous was extracted
Experimental Section
(S,S)-4-Benzyloxy-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-
methylbutyramide (14). To a solution of carboxylic acid 1313 (19.8
g, 102 mmol) in Et2O (750 mL) at rt under N2 was added Et3N
(14.3 mL, 102 mmol) and the mixture was stirred at rt for 15 min.
The solution was cooled to 0 °C and t-BuCOCl (12.6 mL, 102
mmol) was added. A thick white precipitate formed immediately.
This mixture was warmed to rt and stirred for 1 h after which time
the mixture was recooled to 0 °C. To this mixture was added a
solution of (+)-pseudoephedrine (13.0 g, 78.7 mmol) and Et3N (11.0
mL, 78.7 mmol) in THF (190 mL + 20 mL wash) rapidly via
cannula. The mixture was stirred at 0 °C for 0.5 h, warmed to rt,
and stirred for a further 0.5 h after which time the excess anhydride
was quenched by addition of H2O. The organic layer was separated
and washed with sat. aq NaHCO3 and 1 M HCl, dried (MgSO4),
and concentrated in vacuo. Purification by flash column chroma-
tography (50% EtOAc-petrol) gave pseudoephedrine amide 12
(24.4 g, 91%) as a colorless oil: IR νmax (thin film) 3385, 2933,
1
2860, 1621 cm-1; H NMR (1:2.2 rotamer ratio, asterix denotes
signals due to minor rotamer) δ 0.98* (3H, d, J ) 6.8 Hz), 1.09
(3H, d, J ) 6.9 Hz), 1.92-2.04 (2H, m), 2.47 (1H, dt, J ) 7.4, 4.7
Hz), 2.34-2.64 (1H, m), 2.83 (3H, s), 2.91* (3H, s), 3.52 (2H, t,
J ) 6.0 Hz), 3.56* (2H, t, J ) 6.1 Hz), 4.05 (1H, m), 4.50 (2H, s),
4.52* (2H, s), 4.4-4.61 (1H, m), 7.28-7.38 (10H, m); 13C NMR
(asterix denotes signals due to minor rotamer) δ 14.4 (CH3),
15.3*(CH3), 25.2 (CH2), 25.5* (CH2), 30.2* (CH2), 30.8 (CH2),
26.8* (CH3), 32.6 (CH3), 58.3 (CH), 69.4 (CH2), 69.7* (CH2), 72.7
(CH2), 72.8 (CH2), 75.4* (CH), 76.4 (CH), 126.4 (CH), 126.9 (CH),
127.5 (CH), 127.6 (CH), 127.6 (CH), 127.7 (CH), 128.2 (CH), 128.3
(CH), 128.4 (CH), 128.6 (CH), 138.4 (Cq), 138.5* (Cq), 141.5*
(Cq), 142.4 (Cq), 173.8* (Cq), 175.0 (Cq); m/z (ES) 342 (100%,
M+); HRMS found 342.2052, C21H28NO3 requires 342.2069; [R]D
+75.9 (c 1.08, CHCl3).
(1S,2S,2′S)-4′-Benzyloxy-N-(2-hydroxy-1-methyl-2-phenylethyl)-
N-methyl-2′-methylbutyramide (15). To LiCl (15.9 g, 376 mmol),
flame dried under vacuum and cooled under an atmosphere of Ar,
was added THF (70 mL) and i-Pr2NH (17.0 mL, 121 mmol) and
the resulting suspension was stirred at -78 °C under N2. A solution
of n-BuLi (2.5 M in hexanes; 45.0 mL, 113 mmol) was added
(25) Trihydroxyarene 3 seems to be stable in air and in solution of a variety
of solvents (CDCl3, CH2Cl2, Et2O, EtOAc, MeCN). Subjection of 3 to the
oxidative dimerization conditions developed for model system 4 (Scheme 1)8
only resulted in oxidation to hydroxy p-quinone. Other preliminary experiments
with other oxidants, discredited on the model system 4, have unsurprisingly
proven unfruitful.
8036 J. Org. Chem. Vol. 73, No. 20, 2008

Asymmetric Synthesis of 6′-Hydroxyarenarol
with DCM. The combined organics were washed with brine (50
mL), dried (MgSO4), and concentrated in vacuo. Purification by
flash column chromatography (20% Et2O-petrol) gave allylic
alcohol 1726 (4.18 g, 66% over 2 steps) as a colorless oil as a 4:1
mixture of double bond isomers: IR νmax (thin film) 3392, 2930,
2869, 1454, 1102 cm-1; 1H NMR (only signals due to major isomer
quoted) δ 1.03 (3H, d, J ) 6.9 Hz), 1.60 (3H, s), 1.55-1.75 (2H,
m), 2.34 (1H, sex, J ) 7.2 Hz), 3.42 (2H, t, J ) 6.5 Hz), 4.14 (2H,
d, J ) 6.4 Hz), 4.47 (1H, d, J ) 12.0 Hz), 4.51 (1H, d, J ) 12.0
Hz), 5.42 (1H, tq, J ) 6.8, 0.7 Hz), 7.25-7.4 (5H, m); 13C NMR
δ 12.7 (CH3), 19.6 (CH3), 34.6 (CH2), 39.4 (CH), 59.4 (CH2), 68.7
(CH2), 73.0 (CH2), 123.4 (CH), 127.6 (CH), 127.8 (CH), 128.4
(CH), 138.7 (Cq), 143.1 (Cq); m/z (ES) 257 (70%, MNa+), 217
(100%, M+ - OH); HRMS found 257.1521, C15H22O2Na requires
257.1517; [R]D +15.8 (c 0.37, CHCl3).
warmed to -55 °C over 1 h after which time sat. aq NaS2O4 was
added and the reaction mixture warmed to rt. The layers were
separated and the aqueous phase was extracted with Et2O. The
combined organics were washed with brine, dried (MgSO4), and
concentrated in vacuo. The residue was purified by flash column
chromatography (20% Et2O-petrol) to yield the xanthates as a
yellow oil (81 mg). The xanthates were transferred to a Schlenk
flask under Ar and dried for 2 h under vacuum before toluene (5
mL) was added. To this solution was added Bu3SnH (0.17 mL,
0.62 mmol) and AIBN (2.5 mg, 15 µmol) and the mixture was
degassed by a freeze, pump, thaw procedure. The reaction mixture
was heated at 110 °C for 2 h, allowed to cool to rt, filtered, and
concentrated in vacuo. Purification by flash column chromatography
(gradient elution: petrol then 10% EtOAc-petrol) gave 26 (64 mg,
92% over 2 steps) as a colorless oil: IR νmax (thin film) 2937, 2835,
1484, 1463, 1090 cm-1; 1H NMR δ 0.83 (3H, d, J ) 6.6 Hz), 0.93
(3H, s), 1.20-1.42 (2H, m), 1.44 (3H, s), 1.45-1.74 (9H, m), 1.86
(1H, dt, J ) 14.0, 4.8 Hz), 2.62 (1H, d, J ) 13.1 Hz), 2.92 (1H, d,
J ) 13.1 Hz), 3.73 (3H, s), 3.75 (3H, s), 3.83 (3H, s), 3.91-3.93
(4H, m), 6.52 (1H, d, J ) 8.9 Hz), 6.73 (1H, d, J ) 8.9 Hz); 13C
NMR δ 18.6, 19.0, 22.8, 24.8, 28.6, 30.4, 30.8, 36.1, 36.4, 41.9,
43.0, 48.8, 55.3 (CH3), 56.2 (CH3), 60.0 (CH3), 64.5 (CH2), 64.6
(CH2), 104.7 (CH), 109.9 (CH), 114.5 (Cq), 124.1 (Cq), 147.1 (Cq),
149.6 (Cq), 153.5 (Cq); m/z (ES) 441 (100%, MNa+), 357 (25%),
181 (57%, C10H13O3+); HRMS found 441.2609, C25H38O5Na
requires 441.2617; [R]D +12.0 (c 0.40, CHCl3).
(3S)-(6-Chloro-3,4-dimethylhex-4-enyloxymethyl)benzene
(18). To a stirred solution of N-chlorosuccinimide (1.18 g, 8.83
mmol) in CH2Cl2 (40 mL) at 0 °C under N2 was added Me2S (0.71
mL, 9.6 mmol) dropwise and the resulting white suspension was
cooled to -20 °C. Allylic alcohol 17 (1.88 g, 0.803 mmol) in
CH2Cl2 (8 mL) was added dropwise via cannula over 10 min. The
reaction mixture was stirred at 0 °C for 1 h after which time it was
poured onto ice cold brine and the layers separated. The aqueous
layer was extracted with CH2Cl2 and the combined organics washed
with brine, dried (MgSO4), and concentrated in vacuo to give allylic
chloride 18 (2.01 g, 99%) as a yellow oil: IR νmax (thin film) 2960,
1
2930, 2859, 1656, 1453, 1104, 697 cm-1; H NMR (only signals
(4aR,5S,6R,8aS)-5-[(2,3,6-Trimethoxyphenyl)methyl]-5,6,8a-
trimethyldecahydronaphthalen-1(2H)-one (27). To a solution of
ketal 24 (126 mg, 0.301 mmol) in THF (4 mL) was added 1 M
HCl (4 mL) and the reaction was stirred vigorously at rt for 4.5 h
until TLC analysis showed complete consumption of starting
material. The layers were separated and the aqueous extracted with
Et2O (3 × 2 mL). The combined organics were washed with brine
(4 mL), dried (MgSO4), and concentrated in vacuo to give ketone
due to major isomer quoted) δ 1.03 (3H, d, J ) 6.9 Hz), 1.6-1.75
(2H, m), 1.66 (3H, s), 2.33-2.34 (1H, sex, J ) 7.2 Hz), 3.41 (2H,
m), 4.09 (2H, d, J ) 8.0 Hz), 4.49 (2H, s), 5.48 (1H, t, J ) 7.9
Hz), 7.25-7.40 (5H, m); 13C NMR δ 12.4 (CH3), 19.3 (CH3), 34.7
(CH2), 39.3 (CH), 41.1 (CH2), 68.5 (CH2), 73.2 (CH2), 120.3 (CH),
127.6 (CH), 127.8 (CH), 128.4 (CH), 138.7 (Cq), 146.3 (Cq); m/z
(ES) 217 (80%, M+ - Cl); HRMS found 217.1583, C15H21O
requires 217.1592; [R]D +7.3 (c 0.44, CHCl3).
275 (109 mg, 96%) as a very viscous colorless oil: H NMR δ
1
(3S)-(E,Z)-3,4-Dimethyl-6-trimethylsilylhex-4-en-1-ol (11). To
a solution of hexamethyldisilane (0.75 mL, 3.7 mmol) in HMPA
(3 mL) at 0 °C under N2 was added MeLi (1.5 M in Et2O as a
complex with LiBr; 1.95 mL, 2.93 mmol). The reaction mixture
was stirred at 0 °C for 15 min whereupon THF (15 mL) was added
rapidly and the solution immediately cooled to -78 °C. Allyl
chloride 18 (98 mg, 0.39 mmol) in THF (4 mL) was added dropwise
via cannula over 5 min. The reaction was allowed to stir and
warmed slowly to rt o/n. The reaction mixture was poured onto
petrol and sat. aq NH4Cl. The layers were separated and the organics
washed with H2O and brine, filtered through a silica plug, and
concentrated in vacuo. Purification by flash column chromatography
(10% Et2O-petrol) gave alcohol 115 (75 mg, 96%) as a colorless
oil: [R]D +8.3 (c 1.26, CHCl3).
(4S)-(6-Iodo-3,4-dimethylhex-2-enyl)trimethylsilane (12). To
a solution of alcohol 11 (0.404 g, 2.02 mmol) in MeCN (35 mL)
at 0 °C under N2 was added imidazole (0.18 g, 2.6 mmol) and
PPh3 (0.69 g, 2.6 mmol). Solid iodine (0.62 g, 2.4 mmol) was added
in small portions over 30 min and the reaction stirred at rt for 3 h
before being poured onto 0.5 M HCl and the layers separated. The
aqueous was extracted with Et2O and the combined organics washed
with Na2S2O3 and brine, dried (MgSO4), and concentrated in vacuo.
Purification by flash column chromatography (petrol) gave iodide
125 (0.54 g, 87%) as a colorless oil: [R]D +22.6 (c 0.495, CHCl3).
(4aR,5S,6R,8aS)-5-[(2,3,6-Trimethoxyphenyl)methyl]-5,6,8a-
trimethyldecahydronaphthalene-1-spiro-2′-(1′,3′-dioxolane)
(26). To a solution of alcohol 25 (72 mg, 0.17 mmol) in THF (5
mL) under N2 at -78 °C was added NaHMDS (2 M in THF; 0.26
mL, 52 mmol). The reaction mixture was stirred at -78 °C for 30
min after which time CS2 (66 µL, 1.1 mmol) was added and the
reaction warmed to -55 °C over 1 h. The reaction was cooled to
-78 °C and MeI (34 µL, 0.55 mmol) was added and the reaction
0.82 (3H, s, CMe), 0.88 (3H, d, J ) 6.0 Hz, CHMe), 1.18 (3H, s,
CMe), 1.20-1.40 (5H, m), 1.80-2.20 (7H, m), 2.65 (1H, d, J )
13.4 Hz, CH2Ar), 2.73 (1H, d, J ) 13.4 Hz, CH2Ar), 3.74 (3H, s,
OMe), 3.75 (3H, s, OMe), 3.84 (3H, s, OMe), 6.53 (1H, d, J ) 8.9
Hz, ArH), 6.75 (1H, d, J ) 8.9 Hz, ArH); 13C NMR δ 17.8 (CH3),
18.8 (CH3), 21.3 (CH2), 24.6 (CH2), 28.4 (CH2), 30.8 (CH3), 34.6
(CH2), 34.7 (CH2), 36.5 (CH2), 38.9 (CH), 44.2 (Cq), 48.4 (Cq),
51.8 (CH), 55.3 (CH3), 56.1 (CH3), 60.0 (CH3), 104.7 (CH), 110.0
(CH), 123.1 (Cq), 147.0 (Cq), 149.6 (Cq), 153.3 (Cq), 217.8 (Cq);
[R]D +21.0 (c 0.78, CHCl3).
(4aR,5S,6R,8aS)-5-[(2,3,6-Trimethoxyphenyl)methyl]-1-methy-
lene-5,6,8a-trimethyldecahydronaphthalene (28). Nysted’s re-
agent (20% wt in THF; 0.14 mL, 74 µmol) was added to ketone
27 (7.9 mg, 21 µmol) stirred in CH2Cl2 (1 mL) at -78 °C under
N2. To this was added TiCl4 (1 M in DCM; 63 µL, 63 µmol)
dropwise over 5 min. The solution was stirred at -78 °C for a
further 30 min and then stirred at rt o/n. Et3N (0.1 mL) was added
in one portion and the solution was stirred for 10 min before being
passed through a celite plug, eluting with EtOAc, and concentrated
in vacuo. Purification by flash column chromatography (10%
Et2O-petrol) gave 285 (5.9 mg, 75%) as a colorless oil: 1H NMR
δ 0.87 (3H, d, J ) 6.1 Hz, CHMe), 0.89 (3H, s, CMe), 1.05 (3H,
s, CMe), 1.15-1.66 (3H, m), 1.50-1.68 (2H, m), 1.69-1.97 (4H,
m), 1.99-2.06 (1H, m), 2.10 (1H, dd, J ) 13.9, 5.2 Hz), 2.43 (1H,
dt, J ) 13.5, 6.6 Hz), 2.62 (1H, d, J ) 13.3 Hz, CH2Ar), 2.70 (1H,
d, J ) 13.3 Hz, CH2Ar), 3.73 (3H, s, OMe), 3.74 (3H, s, OMe),
3.83 (3H, s, OMe), 4.66 (1H, s, CdCH2), 4.69 (1H, s, CdCH2),
6.52 (1H, d, J ) 8.9 Hz, ArH), 6.74 (1H, d, J ) 8.9 Hz, ArH);
[R]D +24.6 (c 0.56, CHCl3).
Or to a suspension of t-BuOK (53 mg, 0.48 mmol) in benzene
(1.5 mL) at rt under Ar was added MePPh3Br (170 mg, 0.48 mmol)
and the resulting white suspension was heated at reflux for 1 h to
give a yellow solution. After cooling to rt the solvent was taken
off under reduced pressure (under Ar) and the residue dried under
(26) Tokoroyama, T.; Aoto, T. J. Org. Chem. 1998, 63, 4151.
J. Org. Chem. Vol. 73, No. 20, 2008 8037

Munday et al.
vacuum for 30 min. The residue was dissolved in toluene (2 mL)
and ketone 27 (8.9 mg, 24 µmol) in toluene (1 mL) was added via
cannula. The reaction mixture was heated at reflux o/n, cooled to
rt, and diluted with H2O (4 mL) and Et2O (2 mL). The layers were
separated and the aqueous extracted with Et2O (3 × 2 mL). The
combined organics were dried (MgSO4) and concentrated in vacuo.
Purification by flash column chromatography (5% Et2O-petrol)
gave alkene 28 (6.5 mg, 73%) as a colorless oil. Data were as above.
complete conversion of the original orange spot to a yellow spot
(Rf 0.74). The reaction mixture was partitioned between H2O (10
mL) and Et2O (10 mL) and the phases separated. The aqueous phase
was extracted with Et2O (10 mL) and the combined organics washed
with brine (10 mL), dried (MgSO4), and concentrated in vacuo to
give the crude p-quinone. The residue was dissolved in Et2O (20
mL) and shaken with a solution of Na2S2O4 (0.5 g) in H2O (20
mL) in a separating funnel for 10 min until the organic layer had
turned from yellow to colorless and TLC analysis showed complete
consumption of starting material. The layers were separated and
the organic layer was washed with H2O (10 mL) and brine (10
mL), dried (MgSO4), and concentrated in vacuo. Purification by
flash column chromatography (25% EtOAc-petrol) gave triol 3
(18.2 mg, 58% from 34) as a yellow oil: IR νmax (CHCl3) 3603
(OH), 3544 (OH), 2933 (CH), 2870 (CH), 1632, 1487, 1461, 1110
(4aR,5S,6R,8aS)-6-Methoxy-1-(1,2,4a-trimethyl-5-methylene
decahydronaphthalen-1-ylmethyl)benzene-2,3-diol (34). To a
solution of diphenylphosphine (0.46 mL, 0.27 mmol) in THF (5
mL) under Ar at 0 °C was added n-BuLi (2.5 M in hexanes; 0.96
mL, 0.24 mmol) dropwise. The reaction was stirred at rt for
30 min after which time arene 28 (49.6 mg, 0.133 mmol) in THF
(1 mL + 0.5 mL wash) was added via cannula. The reaction mixture
was heated at reflux o/n, allowed to cool to rt, and H2O (5 mL)
was added. The layers were separated and the aqueous layer was
extracted with Et2O (3 × 3 mL). The combined organics were
washed with H2O (5 mL) and brine (5 mL), dried (MgSO4), and
concentrated in vacuo. Purification by flash column chromatography
(gradient elution: 10% EtOAc-petrol then 20%) gave diol 34 (32.7
mg, 71%) as a colorless oil; IR νmax (CHCl3) 3601 (OH), 3547
1
cm-1; H NMR δ 0.93 (3H, d, J ) 5.6 Hz, CHMe), 0.96 (3H, s,
CMe), 1.10 (3H, s, CMe), 1.20-1.32 (2H, m), 1.49-1.56 (3H, m),
1.60-1.78 (2H, m), 1.90-2.09 (3H, m), 2.13 (1H, dd, J ) 13.7,
5.2 Hz), 2.45 (1H, td, J ) 13.6, 6.6 Hz), 2.65 (1H, d, J ) 14.5 Hz,
CH2Ar), 2.70 (1H, d, J ) 14.5 Hz, CH2Ar), 4.51 (1H, s, OH), 4.69
(1H, s, CdCH2), 4.72 (1H, s, CdCH2), 5.46 (1H, s, OH), 6.22
(1H, d, J ) 8.5 Hz, ArH), 6.62 (1H, d, J ) 8.5 Hz, ArH); 13C
NMR δ 18.3 (CH3), 18.9 (CH3), 23.0 (CH2), 25.2 (CH2), 28.2 (CH2),
32.1 (CH2), 33.2 (CH3), 35.8 (CH2), 37.7 (CH2), 39.7 (Cq), 40.0
(CH), 44.5 (Cq), 49.2 (CH), 105.9 (CH2), 106.1 (CH), 113.3 (CH),
114.6 (Cq), 136.6 (Cq), 144.9 (Cq), 149.9 (Cq), 153.5 (Cq); m/z
(EI+) 330 (6%, M+), 191 (68%, M+ - C7H7O3), 149 (100%);
HRMS found 330.2189, C21H30O3 requires 330.2195; [R]D +34.8
(c 0.27, CHCl3).
1
(OH), 2931 (CH), 1489, 1463, 1083 cm-1; H NMR δ 0.91 (3H,
d, J ) 6.0 Hz, CHMe), 0.92 (3H, s, CMe), 1.07 (3H, s, CMe),
1.18-1.28 (2H, m), 1.48 (2H, m), 1.60-1.68 (1H, m), 1.71-2.01
(4H, m), 2.03-2.16 (2H, m), 2.45 (1H, td, J ) 13.6, 7.2 Hz), 2.65
(1H, d, J ) 14.0 Hz, CH2Ar), 2.71 (1H, d, J ) 14.0 Hz, CH2Ar),
3.71 (3H, s, OMe), 4.68 (1H, s, CdCH2), 4.71 (1H, s, CdCH2),
6.27 (1H, d, J ) 8.7 Hz, ArH), 6.70 (1H, d, J ) 8.7 Hz, ArH); 13
C
NMR δ 18.4 (CH3), 19.0 (CH3), 23.0 (CH2), 25.3 (CH2), 28.2 (CH2),
30.4 (Cq), 32.2 (CH2), 33.2 (CH3), 35.0 (CH2), 37.7 (CH2), 39.6
(CH), 44.5 (Cq), 48.8 (CH), 55.2 (CH3), 101.3 (CH), 105.7 (CH2),
112.5 (CH), 116.1 (Cq), 125.6 (Cq), 137.2 (Cq), 144.7 (Cq), 153.8
(Cq); m/z (EI+) 344 (7%, M+), 154 (100%, C8H10O3+); HRMS
found 344.2355, C22H32O3 requires 344.2351; [R]D +30.4 (c 0.67,
CHCl3).
6′-Hydroxyarenarol (3). A solution of CAN (131 mg, 0.238
mmol) in MeCN:H2O (2 mL:1 mL) was added fast dropwise to
diol 35 (32.7 mg, 95.1 µmol) in MeCN:H2O (4 mL:2 mL) at 0 °C
to give a dark red solution. TLC analysis after 5 min showed
complete consumption of starting material to an orange spot (Rf
0.28, 30% EtOAc-petrol) (o-quinone). After a further 30 min the
ice bath was removed and the reaction stirred at rt for a further 3 h
until the solution had lightened to yellow and TLC analysis showed
Acknowledgment. We thank the EPSRC, GSK, and Pfizer
Central Research for funding, Dr. N. Parr and Dr J. Åhmen for
helpful discussions, Mr. T. Hollingworth and Mr. D. Hooper
for providing mass spectra, and Dr T. Liu for microanalytical
data.
Supporting Information Available: General experimental
details, experimental procedures, and data for compounds 7-11,
25, and 29-33, optical rotation data for 20-24, and copies of
1H and 13C NMR spectra for 3, 7-12, 14-18, 25-28, and
30-34. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO801404U
8038 J. Org. Chem. Vol. 73, No. 20, 2008