On the selective reduction of the distal olefin in geraniol and farnesol derivatives

Article abstract of DOI:10.1016/S0040-4039(03)01047-5

The selective reduction of the distal olefin of many types of terpenoid-based natural products has been commonly approached using gaseous HCl in CH₂Cl₂. We herein present evidence that this method is inefficient and produces many side products, whose formation, in our hands, was difficult to avoid (over several reaction runs). A more efficient procedure for geranyl acetate using 1 equiv. of TiCl₄ in CH₂Cl₂ at -78°C is reported.

Full text of DOI:10.1016/S0040-4039(03)01047-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4539–4542
On the selective reduction of the distal olefin in geraniol and
farnesol derivatives
Alexandre Demotie, Ian J. S. Fairlamb* and Sally K. Radford
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 3 March 2003; revised 7 April 2003; accepted 17 April 2003
Abstract—The selective reduction of the distal olefin of many types of terpenoid-based natural products has been commonly
approached using gaseous HCl in CH2Cl2. We herein present evidence that this method is inefficient and produces many side
products, whose formation, in our hands, was difficult to avoid (over several reaction runs). A more efficient procedure for geranyl
acetate using 1 equiv. of TiCl4 in CH2Cl2 at −78°C is reported. © 2003 Elsevier Science Ltd. All rights reserved.
The polyprenols (isoprenoids) comprise of a vast array
of natural products, whose selectivity and activity vary
via small changes in structure: (i) by the length of their
hydrophobic moiety (acyclic or cyclic); (ii) specific posi-
tion and stereochemistry of an olefinic bond; (iii) by
selective reduction of an olefinic bond. Isoprenoids are
ation inhibitors that specifically inhibit PFTase2—a
target for chemotherapeutic intervention. We have a
specific interest in the design of new PFTase inhibitors.3
Efficient syntheses for both 6,7-dihydrogeraniol and
10,11-dihydrofarnesol derivatives were sought after to
evaluate the effectiveness of our newly proposed cyclic
FDP analogues.4 6,7-Dihydrogeraniol derivatives have
also been employed in mechanistic studies involving the
transition metal catalysed (Pd, Pt, and Ru) cycloiso-
merisation of terpenoid-based 1,6-enynes (1“2).5
Indeed this area inadvertently links directly to our
efforts to obtain novel cyclopentene FDP analogues.
known to play
a central role in cellular lipid
metabolism, e.g. geranyl diphosphate (GDP) and farne-
syl diphosphate (FDP) (Fig. 1). Small changes in the
structures (i, ii or iii) of GDP and FDP have yielded a
plethora of analogues that have been used in enzyme
mechanism and inhibition studies. FDP is required, as a
substrate, by a number of enzymes, in particular,
protein farnesyl transferase (PFTase).1 Great interest
has been attached to the development of protein prenyl-
The catalytic hydrogenation of geranyl derivatives
occurs preferentially at the proximal olefin.6 Selective
hydrogenation of the distal olefin in such derivatives is
rare.7 The seemingly most efficient method has been the
electrophilic attack of HCl on distal trisubstituted dou-
ble bonds, followed by dehalogenation using either
Zn(BH4)2/Et2O/cyclohexene/40°C or n-Bu3SnH/AIBN/
benzene/75°C (3“4“5, Scheme 1).
In 1986, Julia8 reported extensive details of this reaction
sequence, although the exact procedure given for 3“4
was brief (Scheme 2). It became clear after our first two
attempts, that the reaction between HCl and 3 in
CH2Cl2 at −78°C is not facile. Indeed in our hands
several side products9 (6–8), formed in minor amounts
prior to our work, are simultaneously obtained in vary-
ing quantities that encumbers the facile purification of
4. Herein we report details of our attempts at repeating
this reaction. A more efficient procedure for the addi-
tion of HCl to the distal olefin of 3 using TiCl4 in
CH2Cl2 at −78°C, followed by a H2O quench, which
Figure 1. (a) GDP and FDP analogues. (b) Cycloisomerisa-
tion of terpenoid 1,6-enynes.
* Corresponding author. Tel.: +44(0)1904-434091; fax: +44(0)1904-
432516; e-mail: ijsf1@york.ac.uk
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01047-5

4540
A. Demotie et al. / Tetrahedron Letters 44 (2003) 4539–4542
presence of several components: 3 (54%), 4 (27%), 6
(14%), 7 (3%) and 8 (2%). Indeed, after 1 h, no further
consumption of the starting material 3 was seen by GC,
thus HCl gas was again bubbled through at a slow rate
over 0.5 h. After a reaction time of 2 h, GC analysis
confirmed complete loss of 3. The proportion of the
products 4, 6, 7 and 8 were 58, 28, 9 and 5%, respec-
tively.10 We repeated the reaction several times and
observed a similar trend, although the proportions of 4,
6, 7 and 8 varied slightly between runs. We obtained 4
in an isolated yield of 42% after high vacuum distilla-
tion, which was shown to be 86% pure by 1H NMR; the
remaining impurities 6, 7 and 8 could be separated by
careful chromatography. If one changes the solvent to
diethyl ether11 an improvement is seen. Thus reaction of
3 with dry HCl gas at −78°C provides 4 in 68% yield,
accompanied by 6 in 5% yield. The dehalogenation of 4
was straight forward using n-Bu3SnH and AIBN in
refluxing benzene, affording 5 in 93% yield.
Scheme 1. Selective reduction of the distal olefin in geranyl
acetate 3. i. HCl (g), dry CH2Cl2, −78°C; ii. Zn(BH4)2 or
n-Bu3SnH, AIBN.
The HCl procedure is poor for the demanding selectiv-
ity required by farnesyl acetate (Scheme 3). Julia
reported that the dichlorinated compound 118 is the
major product under the standard conditions, accom-
panied by 12 and 13, including cyclised derivatives. We
can confirm these results, although we have been
unable to determine the structures of the cyclised mate-
rial. It should be noted that we failed to detect com-
pound 10.
Scheme 2. Addition of HCl to geranyl acetate 3: i. HCl (g),
CH2Cl2, −78°C, 2 h.
It is quite apparent that the HCl procedure is problem-
atic and as we required large quantities of 5, we sought
a reliable method for the synthesis of 4.
Selective TiCl4 addition to the distal olefin: Our initial
idea for adopting TiCl4 for electrophilic addition on the
distal olefin came from a recent report by Vidari and
co-workers12 on a TiCl4 promoted reaction of alde-
hydes with 1,5-dienyl allyl silanes. In two separate
reactions, they isolated two products where chlorine
had been added to the distal olefin (10–14% yields). We
were encouraged by this and felt that a direct reaction
of 3 with TiCl4 (2 equiv.) in CH2Cl2 at −78°C would
provide a good yield of 4 (Scheme 4). In this reaction
we found that 4 was produced in 45% yield, accompa-
nied by two other products, 6 and 8 in 17 and 5%
yields, respectively.13 We then decided to investigate the
effect of adding varying quantities of TiCl4 (Table 1).
Scheme 3. Addition of HCl to farnesyl acetate 9: i. HCl (g),
dry CH2Cl2, −78°C, 2 h.
gives 4 reproducibly in >92% yields (after distillation),
is reported.
On the gaseous HCl procedure. In our first reaction,
compound 3 in CH2Cl2 was cooled to −78°C and then
saturated with a slow passage of dry HCl gas (from a
lecture cylinder fitted with
a pressure regulator)
through a fine pipette over 0.5 h. Analysis by GC
(sample quenched with water, neutralised with sat.
NaHCO3 and extracted into diethyl ether) showed the
Scheme 4.

A. Demotie et al. / Tetrahedron Letters 44 (2003) 4539–4542
Table 2. Effect of protecting groupa
4541
Table 1. Effect of TiCl4 equiv. on addition to geranyl
acetate 3a
TiCl4 (equiv.)
Yields (%)
4
6
8
4
2
1
12
45
96
47
0
42
17
2
<1
0
23
5
0
0
0
0.5b
0.25c
a Conditions: CH2Cl2, N2, −78°C, 0.25 h, 92% purity by 1H NMR.
b Unreacted 3 was recovered (34%).
c No products were formed after 0.25 h (98% recovered 3).
Entry
X
Yieldb (%)
The employment of 4 equiv. of TiCl4 resulted in
increased quantities of 6 and 8. The reaction of 3 with
1 equiv. of TiCl4 gave 4 in essentially quantitiative
yield. It should be noted that leaving the reaction for
longer than 0.25 h resulted in the production of other
side products (cyclisation, dimerisation or polymerisa-
tion products). It is our finding that this reaction (1
equiv. of TiCl4) is complete in ca. 2 min. Further
reducing the TiCl4 equiv. to 0.5 or 0.25 resulted in
incomplete reaction.
4
6
14
1
2
3
4
5
6
7
8
9
OAc
96
94
41
25
12
0
2
3
39
12
18
0
0
OCOtBu
OCOPh
SO2Me
SO2Phc
OBnd
OMed
OHe
0
17
19
–
54
48
0
0
0
0
0
>45
64
Bre
0
The identity of the intermediate titanium species is
unknown. However, we observed an intense red colour,
produced after complete addition of TiCl4 (1 equiv.).
Addition of 0.5 equiv. of TiCl4 gives only a yellow
colour.
a Conditions: dry CH2Cl2, N2, −78°C, 0.25 h.
b Isolated yields after distillation and/or flash chromatography.
c Extensive decomposition.
d Polymerisation.
e Decomposition and polymerisation.
We have established that quenching the reaction with
deuterium oxide results in deuterium incorporation at
the C-6 position to give 6-[2H]-4 in 90% yield ({1H}2H
For those geranyl derivatives containing OBn, OMe,
OH and Br substituents (3f–i) only cyclised material
2
NMR, 76 MHz, l 1.67, 73% H incorporation).14
1
could be detected (entries 6–9, Table 2). The H NMR
spectra of the products from these reactions again
In order to investigate the scope of this reaction we
decided to change the C1-substituent (Table 2) to see if
the standard procedure15 was general. Previous results
have shown that the C1-substituent can have a marked
effect on the yields obtained in SeO2/tBuO2H E-selec-
tive oxidations of the terminal methyl group at the
distal olefin in a variety of geranyl derivatives.16
showed the disappearance of both proximal and distal
1
olefins, however the H integrals suggest that extensive
polymerisation had taken place, particularly where X=
OH (3h) and Br (3i) (entries 8 and 9, Table 2).
In a recent report, Jones et al. have shown that TiCl4
catalyses phosphoryl transfer to a variety of alcohols.17
It was noted that geraniol 3h, a particularly activated
alcohol, decomposes under the reaction conditions (2
mol% TiCl4, 1.5 equiv. (PhO)3P(O)Cl and 1.5 equiv.
Et3N in THF). Indeed it is our finding that the reaction
of 0.25 equiv. TiCl4 with 3h results in rapid cyclisation/
polymerisation/decomposition. It is clear that certain
types of C1-substituents trigger this process, although
the exact mechanism remains unknown at the current
time.
We encountered no problems changing the substituent
to pivaloate (3b“4b, entry 2, Table 2). However on
shifting to the benzyloxycarbonyl substituent (3c“4c,
entry 3, Table 2) 4c was isolated in 41% yield, accompa-
nied by 6 in 39% and the cyclised material 14c in 17%
yield. It was subsequently found that an excess of TiCl4
(2 equiv.) provides 14c as the major identifiable product
in 34%, accompanied by polymerisation and decompo-
1
sition. The H NMR spectra of the mixture of products
obtained from this reaction was complex, but it did
demonstrate that both the distal and proximal olefins
had been lost. The sulphone substituents facilitate some
selective addition although the yields of the desired
products are low with dramatic decomposition
observed for the SO2Ph substituent (entries 4 and 5,
Table 2).
In order to see whether we could improve on the
selectivity observed for the addition of HCl to farnesyl
acetate, we attempted to mono-chlorinate 9 using our
TiCl4 mediated procedure. However, competing cyclisa-
tion reactions thwarted our attempts. This is not sur-
prising given the propensity for isoprenoids to undergo
rapid cyclisation reactions in cellular biosynthesis.

4542
A. Demotie et al. / Tetrahedron Letters 44 (2003) 4539–4542
In conclusion we have illustrated that the direct HCl
addition to 3 is problematic and the production of
chlorinated side products hampers the yield and purifi-
cation of the desired product 4. Our TiCl4 mediated
procedure overcomes this limitation. It was shown that
the use of 1 equiv. of TiCl4 and a reaction time of <0.25
h is crucial for obtaining a high yield of 4. It was
however somewhat disappointing to discover that the
generality of the reaction could not be extended to
include a range of C1 substituents. On the other hand it
is clear that this could be exploited in the future.
Mueller, T. J. Am. Chem. Soc. 1991, 113, 636. For
excellent overviews of the area, see: (c) Lloyd-Jones, G.
C. Org. Biomol. Chem. 2003, 1, 215; (d) Aubert, C.;
Buisine, O.; Malacria, M. Chem. Rev. 2002, 102, 813 and
references cited therein.
6. Kuno, H.; Takahashi, K.; Shibagaki, M.; Matsushita, H.
Bull. Chem. Soc. Jpn. 1989, 62, 3779.
7. Geranyl trimethylsilane and geranyl isopropyldimethylsi-
lane are exceptions, with selective hydrogenation occur-
ing at the distal double bond. See: Calas, R.; Pillot, J. P.;
Dunogue`s, J. C. R. Acad. Sci. Paris 1981, 282, 669.
8. Julia, M.; Roy, P. Tetrahedron 1986, 42, 4991.
9. A 72% isolated yield of 4 after distillation was reported in
Ref. 8. Several products were isolated in very minor
quantities when the crude product was purified via flash
chromatography: 3,7-dichloro-3,7-dimethyl-1-octyl ace-
tate 7, 1,7-dichloro-3,7-dimethyl-2E-octene 6 and 1,3,7-
trichloro-3,7-dimethyloctane 8.
Overall we believe that researchers in two very different
fields: (1) design of terpenoid mimetics for enzyme
inhibition/mechanistic studies; (2) identification of new
selective transition metal catalysts for 1,6-enyne
cycloisomerisation, will benefit from an efficient synthe-
sis of 6,7-dihydrogeranyl acetate 5 and associated
derivatives.
10. The characterisation data (1H, 13C NMR and CI-MS) for
products 4–8 agreed with that given in Ref. 8.
11. The selective addition of HCl to the distal olefin of
several geranyl derivatives in diethyl ether was reported
some 13 years prior to the publication by Julia (Ref. 8).
See: (a) Kahovcova, J. Collect. Czech. Chem. Commun.
1973, 38, 765. Use of acetic acid as a solvent represents
the first report of selective addition of HCl to 3 to give 4
in 46% yield. See: (b) Brieger, G. J. Am. Chem. Soc. 1963,
85, 3783. No side products were reported in this reaction.
Our attempts at this reaction and careful analysis of the
1H NMR of the crude material show that chloride 6 is a
side-product in this reaction (23% yield). Protonation of
the acetate is expected where HCl or acetic acid is present
in excess, thus creating a better leaving group for dis-
placement by chloride. Selected data for compound 4: lH
Acknowledgements
The authors are very grateful to Professor Marc Julia
(Ecole Normale Supe´rieure (Paris), France) for provid-
´
ing useful advice and suggestions regarding the HCl
procedure. We thank Dr. Simon Jones (University of
Newcastle, UK) for discussion on the phosphoryl trans-
fer reaction catalysed by TiCl4. I.J.S.F. is grateful to the
University of York for an Innovation and Research
Priming Fund grant. The Department of Chemistry
(York) is thanked for funding and for facilitating a
summer project for S.K.R. The ERASMUS scheme is
thanked for funding for A.D.
3
4
(270 MHz, CDCl3) 5.29 (1H, tq, JHH=7.02, JHH=1.2,
C2-H), 4.57 (2H, d, 3JHH=7.02, C1-H2), 2.05 (3H, s,
OCOCH3), 1.99 (2H, br m, C4-H2), 1.67 (2H, br s,
C6-H2), 1.56–1.63 (11H, br m, C5-H2, 3×CH3). MS (CI)
m/z 252 (MH+NH3, 37Cl, 23%), 250 (MH+NH3, 35Cl,
69%), 214 (22%), 154 (36%), 137 (100%), 121 (12%), 81
(22%).
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13. Side-product 7 was not observed using this procedure.
2
14. The H incorporation was calculated from the CI-MS of
deuterated-4 and non-deuterated-4.
15. Typical TiCl4 procedure: Geranyl acetate (1 equiv.) in dry
CH2Cl2 was stirred at −78°C for 2 min under an atmo-
sphere of argon. TiCl4 (1 equiv.) was added directly via
syringe over 1 min. The mixture was stirred for 2 min and
then quenched by careful addition of water and allowed
to warm to 0–5°C (slowly turns to a white colour). The
organic layer was separated and the aqueous phase
extracted with CH2Cl2 (×2). The combined organic
extracts were washed with water (×1) and then brine (×1),
dried (MgSO4) and concentrated in vacuo to give a crude
oil which was subjected to flash chromatography (elution
with diethyl ether/hexane (19:1, v/v) to give a clear oil.
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drogeranyl(proparyl)malonate. See: (a) Trost, B. M.;
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