Selenium dioxide E-methyl oxidation of suitably protected geranyl derivatives - Synthesis of farnesyl mimics

Article abstract of DOI:10.1016/S0040-4039(01)00110-1

Difunctional allylic terpenes are important synthetic building blocks. Functionalisation of protected geranyl derivatives by SeO₂ provides a convenient route to such compounds. The effect of the geranyl protecting group on the oxidation of the

Full text of DOI:10.1016/S0040-4039(01)00110-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2205–2208
Selenium dioxide E-methyl oxidation of suitably protected
geranyl derivatives—synthesis of farnesyl mimics
Ian J. S. Fairlamb,† Julia M. Dickinson* and Mathew Pegg
Department of Chemistry and Materials, John Dalton Building, Manchester Metropolitan University, Chester Street,
Manchester M20 5GD, UK
Received 11 October 2000; revised 11 January 2001; accepted 17 January 2001
Abstract—Difunctional allylic terpenes are important synthetic building blocks. Functionalisation of protected geranyl derivatives
by SeO2 provides a convenient route to such compounds. The effect of the geranyl protecting group on the oxidation of the
terminal E-methyl group was systematically investigated. © 2001 Elsevier Science Ltd. All rights reserved.
The synthesis and biological evaluation of mimics of
farnesyl diphosphate (FPP) has attracted a considerable
amount of attention over the last 10 years, mainly as FPP
is used as a substrate by both Squalene synthase1 (SSase)
and Farnesyl-protein transferase2,3 (FPTase). Wiemer
of a range of farnesyl mimics (2).4 Intermediates, such as
1, have also been utilised in the synthesis of a large
number of natural products.5 Notable examples include
( )-tricyclohexaprenol6 4 and dl-Sirenin7 5 by Corey.
identified that di-functional terpene derivatives
1
The synthesis of di-functionalised derivatives 1 are syn-
thetically commonly approached via SeO2 oxidation of
(Scheme 1) are useful intermediates towards the synthesis
Scheme 1.
Scheme 2.
Keywords: allylic oxidation; selenium dioxide; protecting group.
* Corresponding author. E-mail: j.dickinson@mmu.ac.uk
† Present address: School of Chemistry, University of Bristol, Cantocks Close, Bristol, Avon, UK.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00110-1

2206
I. J. S. Fairlamb et al. / Tetrahedron Letters 42 (2001) 2205–2208
to proceed to completion.5b,10 A compromise of 5 mol%
SeO2 and 3.6 equiv. t-BuO2H led to complete consump-
tion of the acetate 6 starting material, giving the oxi-
dised products 16 and 17 in 52% yield.11 Reduction of
the crude mixture of 16 and 17 using NaBH4 gave pure
17 in 49% yield.12
protected geranyl derivatives (Scheme 2). A well-estab-
lished oxidation process, we herein report the effect of
the allylic protecting group on the ‘E-methyl selective’
allylic oxidation8 of suitably protected/derivatised ger-
anyl analogues.
Various derivatives of commercially available E-geran-
iol (R=OAc 6, O2CPh 7, O2CCH2Cl 8, OMe 9, OTB-
DMS 10, OTBDPS 11, OBn 12, OTHP 13, SO2Ph 14
and SO2Me 15) were synthesised by standard
procedures.
Yields from the oxidation of various geranyl analogues
are quite varied and we sought an explanation for this.
Wiemer4a reported low yields (15–40%) in the allylic
oxidation of 11, 12 and 13, which are all geranyl ethers.
In order to see whether there was a trend, i.e. a
contributing effect of the protecting group on the oxi-
dation process, the allylic oxidation of all the geranyl
analogues (7–15) was performed using the modified
Sharpless procedure11 (Table 1).
In our first oxidation of geranyl acetate 6, under Sharp-
less conditions (0.5 equiv. SeO2 and 2 equiv. t-BuO2H),
the reaction ran to completion after 8 hours, although
we noted that selenious by-products9 were formed and
present in small quantities even after purification by
distillation or chromatography. We also found that
trace amounts of selenium were still present after sev-
eral synthetic steps after the oxidation reaction. As
these types of compounds may be used as biological
probes or inhibitors, we considered it crucial that these
selenious by-products were minimised, allowing the
purification of ‘selenium-free’ products. For the oxida-
tion of 6, the use of lower molar quantities of SeO2,
typically 1–2 mol%, greatly reduced the selenium by-
products, although in our hands these reactions failed
It was immediately noticeable that the overall oxidation
yields of the esters (16–21) were significantly higher
(20–30% higher) than the ethers (22–31). This led us to
believe that the carbonyl function might be involved in
stabilising, through hydrogen bonding, the generally
accepted six-electron cyclic transition state13 (I, Fig. 1),
whereas the protected ethers weakly possess this ability
(compare II and III, Fig. 1). Marshall proposed that
oxidation of sulphone 14 was more selective than the
analogous oxidation of acetate 6.14 This is indeed the
Table 1.
Entry
R
Compounda
Yieldb (%)
Alcohol
Total yieldc (%)
Aldehyde
1
2
3
4
5
6
7
8
OCOCH3
OCOCH2Cl
OCOPh
OMed
16 and 17
18 and 19
20 and 21
22 and 23
24 and 25
26 and 27
28 and 29
30 and 31
32 and 33
34 and 35
37 and 38
9 (11)
0
43 (53)
43e
(38)
Nd
(26)
Nd
27
31
6
0
Nd
49, 59
43
54
19
31
28
24, 44
33
89, 90
82
38
(18)
Nd
(10)
Nd
22
9
86
91
Nd
OTBDMSe
OTBDPSd
OCH2Phe
OTHPd
9
10
11
SO2Ph
SO2Me
SPhd,f
a Compound numbering; aldehyde and alcohol, respectively.
b GC yields of aldehyde and alcohol in parenthesis.
c Isolated yields after NaBH4 reduction and purification by distillation or chromatography, selected cases are averages of several runs including
the best yield in bold.
d The aldehyde/alcohol ratio was not determined (nd).
e Similar selenium by-products observed by GC and 1H NMR, see Ref. 9.
f Ref. 5a, 20 mol% SeO2, 3.6 equiv. t-BuO2H, followed by LiAlH4 reduction.
Figure 1.

I. J. S. Fairlamb et al. / Tetrahedron Letters 42 (2001) 2205–2208
2207
Scheme 3.
case and we were able to produce 33 in 90% yield. This
lends credibility to the idea that the oxygens, in this
case of the SꢀO function, are able to hydrogen bond
within the transition state (IV, Fig. 1).
References
1. For two excellent reviews in this area, see: (a) Nadin,
A.; Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996,
35, 1622; (b) Biller, S. A. Curr. Pharm. Des. 1996, 2, 1.
2. (a) Bhide, R. S.; Patel, D. V.; Patel, M. M.; Robinson,
S. P.; Hunihan, L. W.; Gordon, E. M. Biorg. Med.
Chem. Lett. 1994, 4, 2107; (b) Clarke, S. Ann. Rev.
Biochem. 1992, 61, 355; (c) Schafer, W. R.; Rine, J. Ann.
Rev. Genet. 1992, 30, 209; (d) Omer, C. A.; Gibbs, J. B.
Mol. Microbiol. 1994, 11, 219; (e) Casey, P. J.; Seabra,
M. C. J. Biol. Chem. 1996, 271, 5289.
Oxidation of methylsulphone 15 proceeded equally well
in 82% yield. Interestingly, the oxidation of thiophenyl
geranyl derivative (R=SPh, 36) is reported to give
significantly lower yields of the alcohol product 38. The
results presented here therefore demonstrate that the
CꢀO and SꢀO functions might be involved in stabilising
the intermediate transition state structures.
3. Barbacid, M. Ann. Rev. Biochem. 1987, 56, 779.
4. (a) Mechelke, M.; Wiemer, D. F. Tetrahedron Lett.
1998, 39, 783; (b) Mechelke, M.; Wiemer, D. F. J. Org.
Chem. 1999, 64, 4821; (c) Mechelke, M. F. Ph.D. Thesis.
‘Heads and Tails’. The Design and Synthesis of Novel
RAS Farnesyl Protein Transferase Inhibitors, The Uni-
versity of Iowa, USA, 1998.
5. (a) Dauben, W. G.; Saugier, R. K.; Fleischhauer, I. J.
Org. Chem. 1985, 50, 3767; (b) Yue, X.; Lan, J.; Li, J.;
Liu, Z.; Lin, Y. Tetrahedron 1999, 40, 133; (c) Corey, E.
J.; Tius, M. A.; Das, J. J. Am. Chem. Soc. 1980, 102,
1742; (d) Corey, E. J.; Burk, M. Tetrahedron Lett. 1987,
28, 6413; (e) Corey, E. J.; Reid, J. G.; Myers, A. G.;
Hahl, R. W. J. Am. Chem. Soc. 1987, 109, 918.
As we were ultimately interested in the synthesis of
farnesyl mimics, it was rationalised that sulphone 33
would serve as an ideal template in which various
terminal isoprene mimics could be introduced. It has
also been reported that similar SO2R moieties can act
as a biological mimic of the diphosphate group.15 The
protected sulphone derivative 39 was synthesised from
the corresponding alcohol 33 in quantitative yield
(Scheme 3). To our delight we were able to displace the
allylic tetrahydropyranyl moiety to give 40 and 41 in an
SN2 fashion using aryl Gringard reagents in the pres-
ence of copper(I)iodide (CuI) in satisfactory yields (40–
50%), using the conditions described by Wiemer.4a–c
Benzoylation of 33 to give 42 in 57% yield was also
possible using standard conditions.
6. (a) Corey, E. J.; Burk, R. M. Tetrahedron Lett. 1987,
28, 6413; (b) Corey, E. J.; Reid, J. G.; Myers, A. G.;
Hahl, R. W. J. Am. Chem. Soc. 1987, 109, 918.
7. Corey, E. J.; Achiwa, K.; Katzenellenbogen, J. A. J.
Am. Chem. Soc. 1969, 91, 4318.
In conclusion, the oxidation of suitably functionalised
and protected geranyl derivatives with the SeO2/
tBuO2H system, originally developed by Sharpless,8 has
been systematically investigated. The chosen protecting
group clearly influences the oxidation process. Further
studies on the oxidation of smaller tri-substituted iso-
prenes and the biological activities of the farnesol ana-
logues will be reported in due course.
8. Sharpless, K. B.; Umbreit, M. A. J. Am. Chem. Soc.
1977, 99, 5526 and references cited therein.
9. 2-(2%-Acetoxy-1%-hydroxyethyl)-5-isopropenyl-2-methylse-
lenolane was observed by GC–MS (m/z M+=291) and
1H NMR of a crude mixture containing several side
products. Similar side products have been observed:
Moiseenkov, A. M.; Grigor’eva, N. Ya.; Lozanova, A.
V. Dokl. Chem. (Engl. Transl.) 1986, 289, 251. Dokl.
Akad. Nauk SSSR Ser. Khim. 1986, 289, 114.
Acknowledgements
10. (a) Sen, E. S.; Ewing, G. J. J. Org. Chem. 1997, 62,
3529; (b) Spencer, T. A.; Onofrey, T. J.; Cann, R. O.;
Russell, J. S.; Lee, L. E.; Blanchard, D. E.; Castro, A.;
Gu, P.; Jiang, G.; Schechter, I. J. Org. Chem. 1999, 64,
807.
I.J.S.F. thanks the Manchester Metropolitan University
for a Ph.D. studentship. We would like to thank Pro-
fessor David F. Wiemer (University of Iowa, USA) for
valuable insights into the CuI mediated Grignard cou-
pling reactions.

2208
I. J. S. Fairlamb et al. / Tetrahedron Letters 42 (2001) 2205–2208
11. Modified Sharpless procedure (taken from Ref. 8): A
stirred mixture containing t-BuO2H (8.27 g, 3.6 equiv.),
SeO2 (0.14 g, 5 mol%) and 4-hydroxybenzoic acid (0.35 g,
10mol%) in CH2Cl2 (70mL) was allowed to stir for 1
hour, then compound 6 (5.0 g, 1 equiv.) in CH2Cl2 (20
mL) was added dropwise at 0°C and stirred overnight.
The mixture was concentrated in vacuo and taken up in
diethyl ether (100 mL), and washed successively with 20%
aqueous sodium sulphite (2×50 mL) and water (1×50
mL), dried over anhydrous MgSO4 and concentrated in
vacuo to afford a light green oil, which was purified by
flash chromatography. Elution with hexane–diethyl ether
(4:1, v/v) gave aldehyde 16 as a light green oil (0.48 g,
9.2%), followed by the alcohol 17 as a clearer green oil
(2.33 g, 43.1%). NaBH4 reduction: The crude mixture was
taken up in ethanol (50 mL) and stirred at 0°C. NaBH4
(0.97 g, 25.5 mmol, 1 equiv.) was added in small portions
over 20 minutes. After 1 hour the reaction was quenched
with saturated aqueous ammonium chloride (50 mL) and
extracted with diethyl ether (3×100 mL). The combined
organic extracts were washed with water (2×100 mL),
dried over anhydrous MgSO4 and concentrated in vacuo
to give the alcohol 17 as a green oil.
12. The overall yield is an average of eight runs on large and
small scale; best yield 59%, lowest yield 42%. Reported
yields vary between 40 and 76%, depending on the SeO2
loading and accounting for recovered/recycled starting
material.
13. Here it is assumed that the active acid catalyst is a
selenous half ester (t-BuOSeO2H), see: (a) Stephenson,
L.; Speth, S. J. Org. Chem. 1979, 44, 4683; (b) Woggon,
W. D.; Ruther, F.; Egli, H. Chem. Commun. 1980, 706.
During the submission of this article it was reported that
SeO2 is the most favourable oxidant species (based on
theoretical calculations and experimental results). How-
ever, the formation of t-BuOSeO2H could not be pre-
cluded and is therefore likely to be present under any
reaction conditions where t-BuOH is present; Singleton,
D. A.; Hang, C. J. Org. Chem. 2000, 65, 7554.
14. (a) Marshall, J. A.; Andrews, R. C. J. Org. Chem. 1985,
50, 1602; (b) Marshall, J. A.; Lebreton, J. J. Org. Chem.
1988, 53, 4108.
15. Traxler, P. M.; Wacker, O.; Bach, H. L.; Geissler, J. F.;
Kump, W.; Meyer, T.; Regenass, U.; Roesel, J. L.;
Lydon, N. J. Med. Chem. 1991, 34, 2328.
.