An efficient and convenient synthesis of enantiopure 4-(t-butyldimethylsilyloxy)-cyclohex-2-en-1-one: A formal synthesis of (±)-mesembranol

Article abstract of DOI:10.1016/S0040-4039(01)00481-6

Inexpensive enantiopure (+)-limonene oxide 1 is converted to 4-(R)-(t-butyldimethylsilyloxy)-cyclohex-2-en-1-one 2a. All isolated intermediates can be distilled obviating the need for chromatography. With 2a,b in hand, a formal synthesis of (±)-mesembrano

Full text of DOI:10.1016/S0040-4039(01)00481-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3673–3675
An efficient and convenient synthesis of enantiopure
4-(t-butyldimethylsilyloxy)-cyclohex-2-en-1-one: a formal
synthesis of ( )-mesembranol
Jerry B. Evarts, Jr. and Philip L. Fuchs*
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
Received 19 March 2001; revised 20 March 2001; accepted 21 March 2001
Abstract—Inexpensive enantiopure (+)-limonene oxide 1 is converted to 4-(R)-(t-butyldimethylsilyloxy)-cyclohex-2-en-1-one 2a.
All isolated intermediates can be distilled obviating the need for chromatography. With 2a,b in hand, a formal synthesis of
( )-mesembranol 17 using vinyl triflate methodology is high yielding. © 2001 Elsevier Science Ltd. All rights reserved.
OMe
Enantiopure pure 4-(t-butyldimethylsilyloxy)-cyclohex-
OMe
2-en-1-one 2a is a highly useful chiral building block.
OMe
Since the first reported synthesis of (S)-2a from
D
(−)-
O
quinic acid by Danishefsky in 1989, a number of alter-
native methods have been published.1 One report
derives its enantiopurity from chiral catalysis; however,
the cost of the preparation or purchase of sufficient
catalyst to produce multi-gram quantities of 2a is pro-
hibitive.2a Other reports are either low yielding or
involve lengthy synthesis or separations.2 In conjunc-
tion with our vinyl triflate projects, an efficient, inex-
pensive route to 2a has been developed.3 Using our
chiral vinyl triflate methodology,4 we also report a
formal synthesis of ( )-mesembranol (17) based on the
total synthesis reported by Ogawa (Fig. 1).5
O
N
OMe
H
HO
OTBS
OTBS
OH
17
1
16a
2a
(+)-limonene oxide
(±)-mesembranol
Figure 1.
and silylation under standard conditions furnish 4 in
74% yield after distillation (Scheme 1).
The key starting material, inexpensive (+)-limonene
oxide 1, is available as a 1:1 mixture of diastereomers.
Ozonolysis of the isopropenyl side-chain followed by
Baeyer–Villiger oxidation gives acetate 3 following a
slight modification of the Cain protocol.6 Hydrolysis
Regiospecific conversion of the epoxide mixture 4 to
allylic acetates 5 was achieved using diisobutylalu-
minum-diisopropylamine,7 followed by acylation of the
crude product in 94% yield. Elimination of acetate,
facilitated by catalytic palladium[0], yields diene 6 with-
O
O
O
AcO
EF
G
AB
CD
OAc
OTBS
OTBS
OTBS
4
5
6
1
3
Scheme 1. Conditions: A: a. O3, MeOH, CH2Cl2, b. Me2S; B: mCPBA (2.2 equiv.), CH2Cl2 25°C, 48 h; C: 10% aq. KOH, MeOH
25°C, 3 h; D: TBDMSCl, imidazole, DMF, 25°C, 3 h, distill, 74% from 1. E: (i-Pr)2NAl(i-Bu)2, benzene, 12 h, 0°C; F: Ac2O,
DMAP, Et3N, 2 h, 0–25°C, 94% crude; G: 2.5% Pd(PPh3)4, Et3N, dioxane, 5 h, reflux, distill 83%.
* Corresponding author. Fax: +1 765 494 7679; e-mail: pfuchs@purdue.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00481-6

3674
J. B. E6arts, Jr., P. L. Fuchs / Tetrahedron Letters 42 (2001) 3673–3675
O
OTf
O
O
O
J
K
H
I
O
O
OR
OR
OR
OTBS
OTBS
OTBS
2a, R = TBS
2b, R = MOM
8a,b
9a,b
6
7
2a
Scheme 2. Conditions: H: trifluorodimethyldioxirane, gener-
ated in situ9 plus 20% THF, 0°C, 7 h; I: 1% solid HIO4, 1
equiv. NaIO4, 1:1 t-BuOH:H2O, plus 20% THF, 3 h, 25°C,
83%.
Scheme 3. Conditions: J: TBHP, 2.5% Triton B, benzene,
5°C, 2 h, 8a 85%, 8b 83%; K: pyr-NTf2, LDA, THF, −78 to
25°C, 8 h, 9a 86%, 9b 55%.
OMe
OMe
OMe
OMe
OMe
OMe
OTf
OTf
N
L
M
ref 4
ref 4
H
O
MeHN
HO
HO
OR
OR
OMOM
OH
OR
9a,b
13a,b
3a,b
15
17
(±)-mesembranol
Scheme 4. Conditions: L: BH3, THF 0°C 2 h, 13a,b 88%; M: Me3Sn-Ar, 2.5% Pd2dba3, ZnCl2, AsPPh3, NMP, 25°C, 1 h, 3a 83%,
Ar-B(OH)2, 2.5% Pd(PPh3)4, LiCl, 2 M Na2CO3, DME, 50°C 45 min, 3b 86%.
out any competitive aromatization in 83% yield. Filtra-
tion through silica is necessary to remove palladium
before distillation (Scheme 2).8
References
1. Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.;
Danishefsky, S. J. J. Org. Chem. 1989, 54, 3738–3740.
2. (a) Ogasawara, K.; Kurihara, Y.; Hiroya, K. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2287; (b) Bruckner, R.;
Gebauer, O. Liebigs. Ann. 1996, 1559; (c) Winterfeldt, E.;
Brunjes, R.; Tilstam, U. Chem. Ber. 1991, 124, 1677; (d)
Carreno, M. C.; Garcia Ruano, J. L.; Garrido, M.; Pilar
Ruiz, M.; Solladie, G. Tetrahedron Lett. 1990, 46, 6653;
(e) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport,
A. T.; Cuccia, L. A. J. Org. Chem. 1991, 56, 2656.
3. Both (R)- and (S)-limonene oxide is commercially avail-
able, normally at equal cost, allowing an effective means
of preparing either enantiomer of 2a.
Regioselective oxidative cleavage is accomplished by
first epoxidizing the exo-olefin of 6 to give 7, followed
by treatment with HIO4/NaIO4 to leave 2a in 83% yield
after silica gel chromatography.10 These reactions are
readily scaled and are regularly performed in our labo-
ratories to give ]20 g of 2a. Purification of intermedi-
ates 4 and 6 is accomplished with distillation, while
silica chromatography is normally used to isolate 2a.
The yield over the three isolations is 48%, 97.8% ee
(Scheme 3).11,12
With 2a,b in hand, a formal synthesis of ( )-mesembra-
nol (17) was straightforward. Stereoselective epoxida-
tion of enone 2a,b provides 8a,b with >20:1 selectivity.13
Trapping the enolate from 8b as vinyl triflate affords 9b
in only 55% yield; however, 8a nicely furnishes 8a in
86% (Scheme 4).14
4. (a) Hentemann, M. F.; Fuchs, P. L. Tetrahedron Lett.
1999, 40, 2699; (b) Evarts, J. B.; Fuchs, P. L. Tetrahedron
Lett. 1999, 40, 2703.
5. Chida, N.; Sugihara, K.; Amano, S.; Ogawa, S. J. Chem.
Soc., Perkin Trans. 1 1997, 275.
6. Cane, D. E.; Yang, G.; Coates, R. M.; Pyun, H.; Hohn,
T. M. J. Org. Chem. 1992, 57, 3454. No purifications are
used in the synthesis of 4. Attempts to follow the
Schreiber protocol, Schreiber, S. L.; Liew, W. F. Tetra-
hedron Lett. 1983, 24, 2363–2366, of a one-pot conversion
of an isopropenyl side-chain to an acetate invariably lead
to large amounts of ketone with this substrate.
Regioselective 1,5-hydride addition to 9a,b with BH3
giving 13a,b sets the stage for coupling.15 Treatment of
13a with veratrole boronic acid under Suzuki condi-
tions provides 3a in 86% yield. Similarly, treatment of
mono-protected diol 13b with trimethylstannyl vera-
trole under Stille conditions affords coupled product
3b, the Ogawa intermediate, in 83% yield.
7. Yasuda, A.; Tanaka, S.; Oshima, K.; Yamamoto, H.;
Nozaki, H. J. Am. Chem. Soc. 1974, 96, 6513.
8. Without careful removal of the palladium catalyst, distil-
lation of the diene results in aromatization to toluene.
However, 20 g of product can be filtered through 1/2 inch
of silica, eluting with hexane.
Acknowledgements
J.E. thanks Eastmann Kodak for fellowship support.

J. B. E6arts, Jr., P. L. Fuchs / Tetrahedron Letters 42 (2001) 3673–3675
3675
9. Yang, D.; Wong, M. K.; Yip, Y. C. J. Org. Chem. 1995,
60, 3887.
10. On a larger scale, 2a can be distilled (>90% purity by
GC). Danishefsky, S. J.; Simoneau, B. J. Am. Chem. Soc.
1989, 111, 2599.
a short path distillation apparatus and the volume was
reduced by half. The remaining volume was filtered
through a short plug of silica to remove the catalyst. The
diene was then fractionally distilled through a 15 cm
vigreux column, 48°C at 0.03 torr. 19.1 g (81%); [h]D (c
0.10, CHCl3)=+98.80; 1H NMR (CDCl3): l 6.19 (dd,
J=0.9 Hz, 10 Hz, 1H), 5.76 (d, J=10 Hz, 1H), 4.85 (s,
2H), 4.38 (m, 1H), 2.52 (dt, J=5 Hz, 15 Hz, 1H), 2.32
(m, 1H), 1.93 (m, 1H), 1.79 (m, 1H), 0.94 (s, 9H), 0.132
(s, 3H) 0.126 (s, 3H).
11. Compound 4: 52.6 g of (+)-limonene oxide 1 was submit-
ted to the conditions in Ref. 5 and used crude. Crude 3
was added to 700 mL of methanol/water (10:1). 50% w/v
aq. KOH (5 mL) was added dropwise to the stirred
solution cooled in a 25°C water bath. After 3 h, the
volume was reduced by half. Brine was added and the
mixture was extracted with CH2Cl2. The aqueous layer
was continuously extracted into CH2Cl2 for 24 h. The
combined organic layers were dried with MgSO4 and
concentrated. The residue was added to 200 mL of dry
DMF and 2.5 equiv. imidazole (59 g, 0.85 mol). TBSCl
(0.5 equiv.) was added to a stirred solution cooled in a
25°C water bath. The reaction was allowed to stir for 2 h
after which more TBSCl, in 5% increments, was added
until TLC indicated the reaction complete. The reaction
was partitioned between ether and water. The organic
layer was washed with water, sat. LiCl (to remove trace
DMF) dried with MgSO4 and concentrated. The clear
liquid was fractionally distilled under aspirator pressure;
fractions between 110 and 126°C, which were collected
and combined yielding 61.4 g, 74%, averaging 93% each
step of the operation. 1H NMR (CDCl3): two
diastereomers l 3.85 (m, 1H), 3.58 (m, 1H), 2.98 (d,
J=4.11 Hz, 1H), 2.89 (d, J=5.34 Hz, 1H), 2.5–1.9 (m,
4H), 1.90–1.65 (m, 4H), 1.65–1.38 (m, 4H), 1.34 (s, 3H),
1.32 (s, 3H), 0.9 (18H), 0.06 (12H).
Compound 2a: Diene 6 (12.3 g, 54.8 mmol) was dissolved
in 110 mL of MeCN/THF (8:2). Aqueous EDTA (90 mL
4×10−4 M) was added. NaHCO3 (23 g, 0.273 mol) was
added and a −78°C dry ice condenser affixed. The solu-
tion was cooled to 0°C and 3 mL CH3COCF3 (Aldrich,
used as received) was added. Oxone (16.8 g, 27.3 mmol)
was added in small portions to the stirring solution over
20 min. After 1 h, a second 3 mL portion of CH3COCF3
was added. After 6 h, water was added and the solution
was extracted into CH2Cl2. The solvent was removed and
the residue dissolved in t-BuOH/H2O/THF (45:45:10).
NaIO4 (12.0 g, 56.3 mol) was added and the reaction was
stirred at 25°C with a water bath. HIO4 (100 mg) was
added. After 3 h, water was added and the solution
extracted into ether. The organic layer was washed with
brine, dried with MgSO4, and concentrated. Flash chro-
matography (4:1 hex–EtOAc) afforded 10.4 g (83%) of a
clear colorless oil. Enone 2a can also be distilled. Bp
120–122°C (5 mmHg); HPLC Chiracel OD (97:3 hex-
ane:i-PrOH) 97.8% ee; [h]D (c 0.04, CHCl3)=+103.76; 1H
NMR (CDCl3): l 6.84 (dm, J=10.2, 1H), 5.93 (dm,
J=10.2 Hz, 1H), 4.54 (m, 1H), 2.59 (dt, J=4.7 Hz, 16.8
Hz, 1H), 2.36 (dq, J=4.7 Hz, 12.8 Hz, 16.8 Hz, 1H), 2.23
(m, 1H), 2.01 (m, 1H), 0.94 (s, 9H), 0.148 (s, 3H) 0.139 (s,
3H). More detailed experiments as well as 13C data and
mass spectra are available from the author.
Compound 5: Neat (i-Bu)2AlCl (87.3 mL, 0.447 mol) was
slowly added over 1 h at −78°C to freshly prepared LDA
(0.447 mol) in benzene, followed by stirring for 4 addi-
tional hours at 0°C. Epoxide 4 (27.1 g, 0.112 mol)
dissolved in 30 mL anhydrous benzene was added via
cannula over 1 h. After 12 h at 25°C, the reaction was
carefully poured into an ice/5% HCl solution and diluted
with CH2Cl2. The organic layer was separated and dried
with MgSO4. Et3N (17.0 g, 0.168 mol) and DMAP (cat.)
(0.5 g) are added to the 0°C organic solution. Ac2O (11.4
g, 0.112 mol) was added dropwise over 2 min. The cold
bath was removed and the reaction was stirred for 5 h.
The reaction was poured into water and washed with 5%
HCl, brine, and dried with MgSO4. The solvent was
removed leaving 29.9 g (94%) of a pale yellow oil that
was directly used in the next step. 1H NMR (CDCl3): two
diastereomers: l 5.53 (dd, J=4.42 Hz, 8.24 Hz, 1H), 5.19
(m, 1H), 4.80–4.82 (d, 4H), 4.16 (m, 1H), 3.85 (m, 1H),
2.55–2.16 (m, 4H), 2.13 (s, 3H), 2.09 (s, 3H), 2.09–1.30
(m, 8H), 0.9 (18H), 0.06 (12H).
12. Racemic 2a was synthesized as a standard for HPLC
analysis. The ee was determined by HPLC: ChiralCel OD
25 cm with 5 cm guard column (97:3, hexane:i-PrOH, 1
mL/min), (S)-enantiomer 6.1 min, (R)-enantiomer 6.7
min. (R)-Limonene oxide, purchased from Aldrich is
reported as 98.5% ee.
13. Enone 2b was used in racemic form.
14. Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33,
6299.
15. Hydride addition to epoxyvinyl triflates can be com-
pletely regiospecifically controlled. Addition of DIBAL-H
to compound 10 regiospecifically yields the 1,3-reduction
product 11. BH3 in contrast yields the complimentary
1,5-reduction adduct 12.
Compound 6: 5 (29.9 g, 0.105 mol) was dissolved in 150
mL of anhydrous, degassed, 1,4-dioxane in a flame dried
flask equipped with a reflux condenser. Et3N (13.5 g,
0.133 mol) and Pd(PPh3)4 (3 g, 2.6 mmol, 2.4%) was
added. Under positive pressure of argon, the reaction was
heated to reflux for 6 h. The condenser was replaced with
OTf
OTf
OTf
BH3,THF
88%
DIBALH
toluene
46%
O
HO
HO
11
10
12
.