Thieme chemistry journal awardees - Where are they now? Synthesis of (-)-cubebol by intramolecular cyclopropanation of a terminal epoxide

Article abstract of DOI:10.1055/s-0029-1217353

A synthesis of (-)-cubebol from l-menthone is described. The key step involves efficient (90%) and completely stereocontrolled intramolecular cyclopropanation of an unsaturated α-lithiated terminal epoxide. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217353

1730
LETTER
Thieme Chemistry Journal Awardees – Where Are They Now?
Synthesis of (–)-Cubebol by Intramolecular Cyclopropanation of a Terminal
Epoxide
(
–)-Cubebol by Cy
a
clopropana
v
tion of an U
n
i
satura
t
d
ed Epoxide M. Hodgson,* Saifullah Salik
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
Fax +44(1865)285002; E-mail: david.hodgson@chem.ox.ac.uk
Received 6 April 2009
Abstract: A synthesis of (–)-cubebol from l-menthone is described.
The key step involves efficient (90%) and completely stereocon-
trolled intramolecular cyclopropanation of an unsaturated a-lithiat-
ed terminal epoxide.
Key words: cubebol, intramolecular cyclopropanation, lithium
2,2,6,6-tetramethylpiperidide, epoxide, total synthesis
(–)-Cubebol (1; Scheme 1) is a naturally occurring ses-
quiterpene mainly found in cubeb oil from the berries of
Piper cubeba.1 Its use as a flavouring ingredient appeared
David M. Hodgson obtained his first degree in Chemistry at Bath
University. After a Ph.D. at Southampton University in the field of
natural product synthesis (with P. J. Parsons) and a research position
at Schering, he was appointed in 1990 to a lecturership at Reading
University. In 1995 he moved to the Chemistry Department at Oxford
University, where he is now a Professor of Chemistry. His research
in the patent literature in 2001.2 From a synthetic perspec-
tive the central challenge is efficient installation of the in-
ternal cyclopropane. Previous syntheses of (–)-cubebol
employ (R)-carvone (4) as starting material, with ketone 2
being a common late-stage intermediate. Syntheses from
the 1970s proceeded via intramolecular cyclopropanation
of unsaturated a-diazoketones (e.g., 3); however, yields
were moderate and diastereofacial selectivity was poor,
and in favour of the undesired isomer.1,3 More recently, in
2006, two independent syntheses of cubebol were report-
ed from Fürstner4 and from Fehr5 [in 14 and 13 steps,
respectively, from carvone (4)], where the key cyclopro-
panation step involved metal-catalysed isomerisation of
propargylic esters 5 (R = Me, t-Bu) and the facial selectiv-
ity was controlled by the configuration at the propargylic
stereocentre.
interests are broadly in the development and application of synthetic
methods.
Saifullah Salik studied chemistry at the University of Punjab, Paki-
stan. At Oxford, supported by an Overseas Scholarship from the HEC
in Pakistan, Saifullah is currently involved in the development and
application of cyclopropanation methodology using epoxides.
We have recently developed a practical methodology for
stereocontrolled intramolecular cyclopropanation involv-
ing a-lithiated terminal epoxides (e.g., 8, Scheme 2) to
give cyclopropyl alcohols (e.g., 9).6,7 In the present paper
we describe an application of this chemistry in the synthe-
sis of (–)-cubebol.
N
Li
(LTMP)
OH
O
OH
t-BuOMe
Li
O
O
O
O
7
8
9
2
N2
3
1
Scheme 2 Base-induced intramolecular cyclopropanation of a ter-
minal epoxide 7
O2CR
So as to examine this chemistry, the required epoxide 6
was prepared from commercially available l-menthone
[(10), also straightforwardly accessed by oxidation of
menthol],8 in five steps according to Scheme 3. Thus,
formylation of menthone under kinetically controlled
conditions9 gave hydroxymethylene ketone 11 (55%, S:R =
98:2 at C-6), which was reduced using LiAlH4 to give
allylic alcohol 1210,11 isolated as a single isomer (50%,
stereochemistry currently unknown at C-1) after chroma-
tography. Conversion to the allylic chloride 1312 (79%)
O
6
4
5
Scheme 1 Synthetic approaches to cubebol 1
SYNLETT 2009, No. 11, pp 1730–1732
Advanced online publication: 12.06.2009
DOI: 10.1055/s-0029-1217353; Art ID: S03609ST
© Georg Thieme Verlag Stuttgart · New York
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x
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LETTER
(–)-Cubebol by Cyclopropanation of an Unsaturated Epoxide
1731
LDA, then
TPAP
NMO
OH
LiAlH4
HCO2CH2CF3
LTMP
90%
6
Et2O
reflux, 12 h
50%
Et2O
–78 °C, 3 h
55%
1
O
O
OH
94%
OH
O
O
10
11
12
18
17
16
MsCl, Et3N, CH2Cl2
0 °C, 0.5 h
Scheme 5 Intramolecular cyclopropanation of epoxide 16
then LiCl, acetone
r.t., 12 h
In summary, we have reported a concise, 7–8 step synthe-
sis of (–)-cubebol from l-menthone, which highlights the
ability of lithiated epoxide methodology to efficiently cy-
clopropanate tethered alkenes bearing additional stereo-
centres. Importantly, the facial selectivity is not
influenced by the additional stereocentres, but rather is
determined solely by the epoxide stereochemistry.
79%
Mg, THF
CuI (10 mol%)
NaOH
Cl
MeOH
O
Cl
r.t., 1.5 h
82%
OH
O
(0.8 equiv)
–78 to 0 °C, 3 h
49%
Cl
6
14
13
Scheme 3 Synthesis of unsaturated terminal epoxide 6
Acknowledgment
and reaction of the derived Grignard reagent with com-
mercially available (R)-epichlorohydrin under copper
catalysis13 gave the chlorohydrin 14 (49%), which was
ring-closed to the desired epoxide 6 (82%).
We thank the Higher Education Commission of Pakistan for stu-
dentship support (to S.S.).
References and Notes
In the event, epoxide 6 underwent reaction with lithium
2,2,6,6-tetramethylpiperidide (LTMP, 2 equiv) to give a
single cyclopropyl alcohol 15 (90%, Scheme 4),14 which
was oxidised to pivotal ketone 2 (95%) using tetrapropyl-
ammonium perruthenate (TPAP; 5 mol%)–NMO (2
equiv). Cyclopropyl alcohol 15 could also be prepared
more directly13 from chlorohydrin 14 in 71% yield, using
n-BuLi (3.5 equiv) and 2,2,6,6-tetramethylpiperidine (2.5
equiv). Addition of methylcerium to ketone 2 according to
Fürstner4 and Fehr5 gave cubebol (1; 85%).
(1) Tanaka, A.; Tanaka, R.; Uda, H.; Yoshikoshi, A. J. Chem.
Soc., Perkin Trans. 1 1972, 1721.
(2) Velazco, M. I.; Wuensche, L.; Deladoey, P. US Patent,
6214788, 2001; Chem. Abstr. 2000, 133, 265959.
(3) (a) Torri, S.; Okamoto, T. Bull. Chem. Soc. Jpn. 1976, 49,
771. (b) See also: Piers, E.; Britton, R. W.; de Wall, W. Can.
J. Chem. 1971, 49, 12.
(4) Fürstner, A.; Hannen, P. Chem. Eur. J. 2006, 12, 3006.
(5) Fehr, C.; Galindo, J. Angew. Chem. Int. Ed. 2006, 45, 2901.
(6) (a) Hodgson, D. M.; Chung, Y. K.; Paris, J.-M. J. Am. Chem.
Soc. 2004, 126, 8664. (b) Hodgson, D. M.; Chung, Y. K.;
Nuzzo, I.; Freixas, G.; Kulikiewicz, K. K.; Cleator, E.; Paris,
J.-M. J. Am. Chem. Soc. 2007, 129, 4456.
TPAP, NMO
4 Å MS
(7) For a recent example in natural product synthesis, see:
Tashiro, T.; Mori, K. Tetrahedron: Asymmetry 2008, 19,
1215.
LTMP
t-BuOMe
0 °C to r.t., 20 h
90%
CH2Cl2
r.t., 1.5 h
95%
OH
O
(8) (a) Nwaukwa, S. O.; Keehn, P. M. Tetrahedron Lett. 1982,
23, 35. (b) Malkov, A. V.; Baxendale, I. R.; Bella, M.;
Langer, V.; Fawcett, J.; Russell, D. R.; Mansfield, D. J.;
Valko, M.; Kocovsky, P. Organometallics 2001, 20, 673.
(9) (a) Formylation using HCO2Et–NaH is known to lead to
cis-11 preferentially (S:R = 7:93 at C-6), see: Kashima, C.;
Miwa, Y.; Shibata, S.; Nakazono, H. J. Heterocycl. Chem.
2002, 39, 1235. (b) For kinetic formylation, see: Zayia,
G. H. Org. Lett. 1999, 1, 989.
15
6
MeLi, CeCl3
OH
THF
–78 °C, 1 h
85%
O
1
2
(10) (a) Dreiding, A. S.; Hartman, J. A. J. Am. Chem. Soc. 1953,
75, 939. (b) Searles, S. Jr.; Mortensen, H. E. J. Org. Chem.
1962, 27, 1979. (c) Vig, O. P.; Bhatia, M. S.; Verma, A. K.;
Matta, K. L. J. Indian Chem. Soc. 1970, 47, 277.
Scheme 4 Synthesis of (–)-cubebol (1)
It was established that the configuration at the epoxide
was the sole factor determining face selectivity in the
above cyclopropanation, by reaction of epoxide 16 [pre-
pared in an identical manner to epoxide 6 from allylic
chloride 13, but using (S)-epichlorohydrin] with LTMP,
which gave cyclopropyl alcohol 1715 (90%, Scheme 5).
The presence of the i-Pr group on the same face of the al-
kene which undergoes cyclopropanation did not reduce
the efficiency of this transformation. The corresponding
ketone 18, prepared using TPAP–NMO as earlier, gave
data in full accord with that reported by Fürstner.4
(11) Characterisation Data for (3R,6S)-6-Isopropyl-3-methyl-
2-methylenecyclohexanol (12): [a]D25 –100.9 (c = 1.42,
CHCl3). IR: 3480 (br), 3067 (w), 2958 (s), 2933 (s), 2870
(m), 1644 (w), 1475 (w), 1450 (w), 1029 (m), 948 (m), 905
(s) cm–1. 1H NMR (400 MHz, CDCl3): d = 5.02 (d, J = 1.0
Hz, 1 H, =CH2), 4.73 (d, J = 1.5 Hz, 1 H, CH2), 3.83 (br s, 1
H, CHOH), 2.20–2.29 (m, 1 H, CHMe2), 1.94–2.03 (m, 1 H,
CHMe), 1.79–1.84 (m, 1 H, H-4a), 1.62–1.71 (m, 1 H,
H-5a), 1.56 (d, J = 5.5, 1 H, OH), 1.17–1.29 (m, 2 H, H-5b,
H-6), 1.09 (d, J = 6.5 Hz, 3 H, CHMe), 0.95–1.02 (m, 1 H,
H-4b), 0.93 (d, J = 7.0 Hz, 3 H, Me of CHMe2), 0.87 (d, J =
7.0 Hz, 3 H, Me of CHMe2). 13C NMR (100 MHz, CDCl3):
Synlett 2009, No. 11, 1730–1732 © Thieme Stuttgart · New York

1732
D. M. Hodgson, S. Salik
LETTER
d = 156.9 (=C), 100.6 (=CH2), 74.3 (COH), 51.9 (C-6), 36.7
(CHMe), 35.9 (C-4), 26.5 (CHMe2), 23.0 (C-5), 20.9 (Me of
CHMe2), 18.1 (CHMe), 15.8 (Me of CHMe2). MS (CI+):
m/z (%) = 152 (11), 151 (100), 150 (4). HRMS (CI): m/z
[M – OH]+ calcd for C11H19: 151.1487; found: 151.1488.
Hz, 1 H, OH), 1.02–1.09 (m, 1 H, H-7), 1.00 (d, J = 6.5 Hz,
3 H, CHMe), 0.91–0.93 (m, 1 H, H-5), 0.91 (d, J = 7.0 Hz, 3
H, Me of CHMe2), 0.87 (d, J = 7.0 Hz, 3 H, Me of CHMe2),
0.82–0.85 (m, 1 H, H-8b), 0.52–0.60 (m, 1 H, H-9b), 0.38 (t,
J = 3.0 Hz, 1 H, H-6). 13C NMR (100 MHz, CDCl3): d = 75.1
(C-4), 44.1 (C-7), 35.5 (C-5), 34.5 (C-1), 33.5 (C-10), 31.6
(C-3), 31.4 (C-9), 29.9 (CHMe2), 28.6 (C-2), 26.5 (C-8),
24.5 (C-6), 20.0 (CHMe), 19.6 (Me of CHMe2), 19.1 (Me of
CHMe2). MS (CI+): m/z (%) = 208 (10) [M]+, 191 (100) [M
– OH]+. HRMS (CI): m/z [M – OH]+ calcd for C14H23:
191.1800; found: 191.1811.
(12) Gu, Y.; Snider, B. B. Org. Lett. 2003, 5, 4385.
(13) Hodgson, D. M.; Chung, Y. K.; Paris, J.-M. Synthesis 2005,
2264.
(14) (1R,4R,5R,6R,7S,10R)-7-Isopropyl-10-methyltricyclo-
[4.4.0.01,5]decan-4-ol (15): n-BuLi (1.6 M in hexanes, 3.75
mL, 6.0 mmol) was added to a stirred solution of 2,2,6,6-
tetramethylpiperidine (1.0 mL, 6.0 mmol) in t-BuOMe (30
mL) at –78 °C. The resulting pale yellow solution of LTMP
was stirred at r.t. for 15 min and then cooled to 0 °C in an ice-
bath. To a stirred solution of epoxide 6 (593 mg, 2.85 mmol)
in t-BuOMe (14 mL) at 0 °C was added the above LTMP
solution dropwise via a cannula over 3 h. The reaction
mixture was stirred at r.t. for 17 h, then MeOH (3 mL) was
added, the mixture was evaporated under reduced pressure
and the residue dry-loaded onto a small amount of SiO2 and
purified by column chromatography (SiO2, gradient elution,
20–35% Et2O–PE) to give a white solid, cyclopropyl alcohol
15 (534 mg, 90%); Rf 0.4 (40% Et2O–PE); mp 74–76 °C;
[a]D25 –10.7 (c = 0.33, CHCl3). IR: 3608 (w), 3447 (br), 3018
(m), 2958 (m), 2928 (m), 2870 (m), 1385 (w), 1371 (w),
1216 (s) cm–1. 1H NMR (400 MHz, CDCl3): d = 4.22 (br s, 1
H, CHOH), 2.00–2.07 (m, 1 H, H-2a,), 1.79–1.88 (m, 1 H,
H-10), 1.60–1.65 (m, 1 H, H-9a), 1.50–1.59 (m, 2 H, CHMe2,
H-3a), 1.38–1.45 (m, 3 H, H-2b, H-3b, H-8a), 1.20 (d, J = 4.5
(15) Characterisation data for (1S,4S,5S,6S,7S,10R)-7-Isopropyl-
10-methyltricyclo[4.4.0.01,5]decan-4-ol (17): [a]D25 +28.0
(c = 1.0, CHCl3). IR: 3310 (br), 2954 (s), 2971 (s), 1470 (m),
1443 (w), 1383 (w), 1327 (w), 1057 (w), 974 (s) cm–1.
1H NMR (400 MHz, CDCl3): d = 4.21 (d, J = 5.0 Hz, 1 H,
CHOH), 1.95–2.03 (m, 1 H, H-2a), 1.88–1.94 (m, 1 H, H-
10), 1.69–1.72 (m, 1 H, H-3a), 1.46–1.62 (m, 3 H, H-7, H-
8a, H-9a), 1.32–1.43 (m, 3 H, CHMe2, H-2b, H-3b), 1.08 (d,
J = 7.0 Hz, 3 H, CHMe), 1.01 (d, J = 3.5 Hz, 1 H, H-5), 0.92
(d, J = 6.5 Hz, 3 H, Me of CHMe2), 0.89 (d, J = 6.5 Hz, 3 H,
Me of CHMe2), 0.86–0.88 (m, 1 H, H-9b), 0.71–0.84 (m, 1
H, H-8b), 0.68 (t, J = 4.2, 1 H, H-6). 13C NMR (100 MHz,
CDCl3): d = 75.6 (C-4), 40.3 (C-7), 33.2 (C-10), 33.0 (C-3),
32.9 (C-5), 32.4 (C-1), 31.5 (C-2), 31.2 (CHMe2), 28.6 (C-
9), 23.55 (C-6), 23.5 (C-8), 20.8 (Me of CHMe2), 20.7 (Me
of CHMe2), 20.5 (CHMe). MS (CI+): m/z (%) = 193 (1), 192
(13), 191 (100) [M – OH]+, 190 (26), 189 (37). HRMS (CI):
m/z [M – OH]+ calcd for C14H23: 191.1800; found: 191.1806.
Synlett 2009, No. 11, 1730–1732 © Thieme Stuttgart · New York