Synthesis of methoxynor polyisoprenoid alcohols by alkylation of (3-methoxyallyl)lithium reagents

Article abstract of DOI:10.1135/cccc20020055

A series of six methyl enol ether analogs 8-13 of geraniol, (E,E)-farnesol, and (E,E,E)-geranyl-geraniol was synthesized from a group of three allylic methyl ethers and three allylic chlorides. Lithiation of the 1-methyl-, or 1-alkenylvinyl ethers with se

Full text of DOI:10.1135/cccc20020055

Methoxynor Polyisoprenoid Alcohols
55
SYNTHESIS OF METHOXYNOR POLYISOPRENOID ALCOHOLS
BY ALKYLATION OF (3-METHOXYALLYL)LITHIUM REAGENTS
a,+
a1,
Qingwu JIN and Robert M. COATES
*
a
Department of Chemistry, Roger Adams Laboratory, Box 40-5, University of Illinois,
600 South Mathews Avenue, Urbana, IL 61801, U.S.A.; e-mail: coates@scs.uiuc.edu
1
Received October 23, 2001
Accepted Jan uary 3, 2002
Dedicated to the memory of Dr Václav Černý.
A series of six m eth yl en ol eth er an alogs 8–13 of geran iol, (E,E)-farn esol, an d (E,E,E)-geran yl-
geran iol was syn th esized from a group of th ree allylic m eth yl eth ers an d th ree allylic ch lo-
rides. Lith iation of th e 1-m eth yl-, or 1-alken ylvin yl eth ers with sec-butyllith ium at –78 °C
followed by alkylation s of th e resultin g (Z)-(3-m eth oxyallyl)lith ium reagen ts afforded th e six
possible Z-con figured(tran s) m eth oxyn or polypren yl ben zyl eth ers bearin g th e m eth oxy
substituen t at th e in tern al an d term in al double bon ds with h igh Z/E ratios (5 : 1–31 : 1) an d
47–80% yields. Reductive cleavage of th e ben zyl groups with lith ium in liquid am m on ia
gave th e correspon din g m eth oxyn or polypren ols. 11-Meth oxy-18-n or an d 7-m eth oxy-19-n or
geran ylgeran iols (13 an d 12) were con verted to th e correspon din g diph osph ates, 7 an d 32,
by th e Poulter displacem en t m eth od. Th e stability of th e en ol eth er in 7 in aqueous solution
at pH 8 was verified by NMR an alyses. Th e diph osph ates of th e m eth oxyn or polypren ols
m ay prove useful as substrate an alogs for terpen e syn th ases to capture tran sien t in term edi-
ates in cyclization reaction s catalyzed by th ese en zym es.
Keyw ord s: Lith iation s; Allyllith ium reagen ts; Alkylation s; En ol eth ers; Terpen oids;
Isopren oids; Polyen es.
Th e cyclic structures com m on ly foun d in n aturally occurrin g isopren oid
n atural products are usually form ed by th e action of cyclase en zym es upon
on e m em ber of a sm all set of acyclic precursors: geran yl diph osph ate (GPP,
1) for m on oterpen es, (E,E)-farn esyl diph osph ate (FPP, 2) for sesquiterpen es,
(E,E,E)-geran ylgeran yl diph osph ate (GGPP, 3) for diterpen es, an d eith er
squalen e or (S)-2,3-oxidosqualen e for triterpen es1. Th e cyclization m ech a-
n ism s are th ough t to proceed th rough com plex, m ulti-step sequen ces in -
+
Curren t address: Early Process Research & Developm en t, Ph arm acia Corporation , 1510-91-1,
7000 Portage Road, Kalam azoo, MI 49001, U.S.A.; e-m ail: alan .q.jin @am .pn u.com
Collect. Czech. Chem. Commun. (Vol. 67) (2002)
doi:10.1135/cccc20020055

56
Jin, Coates:
volvin g h ypoth etical carbocation in term ediates, an d in som e cases,
th rough n eutral partially cyclized olefin or alcoh ol in term ediates wh ich
m ay or m ay n ot escape from th e active site of th e cyclase. Th e tran sien t ex-
isten ce of th e carbocation s alon g th e reaction path way an d th e in accessibil-
ity of en zym atically en closed terpen es or terpen ol in term ediates n ecessitate
th e use of in direct m eth ods to gain eviden ce about th e structure an d
stereoch em istry of th ese in term ediates. Th e in direct approach es used to
elucidate th e n ature of th ese in term ediates in clude (i) evaluation of in h ibi-
tors th at m im ic th e proposed structures2,3, (ii) disruption of th e cyclization
m ech an ism by use of substrate or in term ediate an alogs4, an d (iii) experi-
m en ts with m utan t form s of th e cyclases lackin g key residues n ecessary to
con vert th e in term ediate to th e fin al product2g,5
.
1, n = 2 (GPP)
2, n = 3 (FPP)
3, n = 4 (GGPP)
OPP
H
n
CH3
Som e types of an alogs utilized to derail th e cyclization m ech an ism s are
2,3-m eth an o- an d 6,7-dih ydro-GPP (refs4a,4b), 6,7-dih ydro- an d 13-m eth yl-
iden e-FPP (refs4c,4d), 8-oxo- an d 8-h ydroxy-17-n orcopalyl diph osph ate4e, as
well as oxa, deh ydro, m eth yliden e, an d oth er m odified form s of 2,3-oxido-
squalen e1d,3. A sign ifican t classic exam ple is th e en zym atic cyclization of
2,3-oxido-20-oxasqualen e to a n orprotosterol keton e product arisin g from
h ydrolysis of an oxo-carben ium ion in term ediate6. Th e discovery th at th e
n orprotosterol possessed th e un expected 13α,17α stereoch em istry con tra-
ven ed prediction s based on th e expected stereoch em ical preferen ce for
an tarafacial h ydride sh ifts durin g th e subsequen t backbon e rearran gem en ts.
H3C
11
H
H3C
H3C
12
11
+
TS
7
H
H
OPP
4A+
5
3
H
H
H3C
H3C
7
+
H
H
H
H
6
4B+
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Methoxynor Polyisoprenoid Alcohols
57
Our in terest in elucidatin g th e C-11 stereoch em istry of th e verticillen yl
carbocation in term ediate (4A+) form ed in th e first stage of th e cyclization
of 3 to taxadien e (6) catalyzed by taxadien e syn th ase7 (Sch em e 1) prom pted
con sideration of a sim ilar strategy. We proposed th at en zym e-catalyzed
cyclization of a GGPP an alog bearin g a m eth oxy substituen t at C-11 (7) in -
stead of th e m eth yl group would lead to an exocyclic oxo-carben ium ion
wh ich likely would un dergo h ydrolysis to a bicyclic product rath er th an
proton tran sfer an d furth er cyclization . Th e C-11 con figuration of th e re-
sultin g n orverticillon e sh ould reveal th e un kn own stereoch em istry of 4A+
an d provide furth er in sigh t in to th e rem arkable proton tran sfer th at con -
cludes th e n orm al cyclization m ech an ism leadin g to taxadien e7 (4A+ → 4B+).
Furth erm ore it seem ed likely th at oth er m eth oxyn or an alogs of 1–3 would
be useful tools for m ech an istic studies of oth er terpen e cyclases. In th is pa-
per we report syn th eses of th e six possible Z-con figured(tran s) m eth oxyn or
polypren ols 8–13 at th e rem ote double bon ds of geran iol, (E,E)-farn esol,
an d (E,E,E)-geran ylgeran iol by m ean s of alkylation s of (3-m eth oxyallyl)lith -
ium reagen ts, an d th e con version of 11-m eth oxy-18-n or an d 7-m eth oxy-
19-n or geran ylgeran iols (13 an d 12) to th e correspon din g diph osph ates (7
an d 32).
MeO
11
OPP
7
OH
R
OH
n
n
OMe
OMe
11, R = CH3, n = 1
12, R = 4-methylpent-3-enyl, n = 1
13, R = CH3, n = 2
8, n = 1
9, n = 2
10, n =3
Regio- an d stereoselective syn th esis of 1,2-disubstituted en ol eth ers h as
been accom plish ed by Horn er–Wadsworth –Em m on s con den sation s of
α-eth oxy(ph osph on o)acetate with aldeh ydes8a,8b, by base-catalyzed addi-
tion of m eth an ol to alkyn ylm eth yl sulfon es8c, by Tebbe olefin ation of es-
ters8d, by Wittig olefin ation s with m eth oxy substituted ylides8e, by sim ilar
Horn er–Wittig olefin ation with a dim eth ylallyloxy substituted ylide6, an d
by base-catalyzed isom erization γ-m eth oxy-α,β-un saturated sulfon es8f. It is
also kn own th at (Z)-(3-alkoxyallyl)lith ium reagen ts (h om oen olate an ion s)
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

58
Jin, Coates:
can be gen erated by lith iation of alkyl an d allyl trieth ylsilyl eth ers with
sec-butyllith ium at low tem peratures9. Recen tly m oderate to good yields of
α-alkylation s h ave been accom plish ed followin g tran sm etallation s to th e
correspon din g (3-alkoxyallyl)barium reagen ts10. We h ave foun d th at
1-alkylallyl m eth yl eth ers can be sim ilarly m etallated with sec-butyllith ium
an d th at th e resultin g (Z)-(3-m eth oxyallyl)lith ium reagen ts so form ed can
be alkylated with allylic ch lorides to form polyisopren oid ch ain s bearin g re-
m ote m eth oxy groups on th e term in al an d in tern al double bon ds.
Lithiations and Alkylations
R
OMe
OMe
15, R = CH3
16, R = 4-methyl-3-pentenyl
14
OBn
OBn
Cl
Cl
n
17
18, n = 1
19, n = 2
Allyl m eth yl eth ers 14–16, an d allylic ch lorides 17–19 were used as startin g
m aterials for syn th esis of th e six m eth oxyn or polyen yl ben zyl eth ers. Th e
kn own eth er 14 was prepared as described11a, an d th e un kn own eth ers 15
an d 16 were obtain ed by O-m eth ylation 11b,12 (NaH, CH3I, eth er) of th e cor-
respon din g allylic alcoh ols resultin g from vin yl Grign ard addition s to th e
precursor aldeh ydes13. Th e allylic ch lorides 17–19, all th ree of wh ich are
kn own 14–16, were prepared by E-selective Wittig olefin ation s to form th e
α,β-en oate esters17, AlH3 reduction s to th e allylic alcoh ols15,16, an d con ver-
sion to th e h alides by Meyers’ m eth od18 (MsCl, LiCl, collidin e, DMF).
Allylic eth ers 14 an d 15 were lith iated with lim itin g am oun ts of sec-BuLi
(0.75–0.80 equiv.) in THF (refs9b,9c), an d th e deproton ation s were foun d to
1
be com plete after 30 m in at –78 °C upon quen ch in g an d an alysis by H NMR
spectroscopy (Sch em es 2 an d 3). Th e allylic ch lorides (0.33–0.67 equiv.
with respect to sec-BuLi) were added as n eat oils at –78 °C. Th e yields based
on th e ch lorides ran ged from 47 (26) to 80% (23), an d Z/E ratios varied
from 5 : 1 (21) to 31 : 1 (28) (see Table I). It was foun d th at th e proportion
of th e ch loride used in th e alkylation affected both th e yield an d th e
stereoselectivity. For exam ple, durin g th e preparation of geran yl an alog 21,
use of 0.68 equivalen t of th e ch loride resulted in 35% yield an d 3.5 : 1 Z/E
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Methoxynor Polyisoprenoid Alcohols
59
OBn
7
OMe
17
21
s-BuLi,
THF
- 78oC
18
11
OBn
OBn
OMe
OMe
MeO
(Z)-20
Li
14
22
19
15
OMe
23
SCHEME 2
selectivity. Wh en 0.41 equivalen t of ch loride was used, th e yield in creased
to 71% an d th e selectivity im proved to 5 : 1. Alth ough th e lon ger ch ain
eth er 16 could n ot be lith iated un der th e sam e con dition s, upon addition
of TMEDA (1 equiv. with respect to sec-BuLi)19 th e m etallation proceeded
sm ooth ly at –78 °C with in 1 h , an d alkylation with 17 afforded 7-m eth oxy-
19-n or geran ylgeran yl eth er (27) with a typical 6 : 1 Z/E ratio in 51% yield.
TABLE I
Yields an d Z/E isom er ratios of m eth oxyn or polyen yl ben zyl eth ers from lith iation /alkyl-
ation s (Sch em es 2 an d 3), an d yields of m eth oxyn or polyen e alcoh ols from ben zyl eth er
cleavages
Startin g m aterials
Meth oxyn or ben zyl eth era
Meth oxyn or alcoh olb
allylic
eth er
allylic
ch loride
No.
Yield, %
Z/E ratioc
No.
Yield, %d
14
14
14
15
16
15
17
18
19
17
17
18
21
22
23
26
27
28
71
73
80
47
51
78
5 : 1
7 : 1
8
9
82
78
41
56
61
66
7 : 1
10
11
12
13
15 : 1
6 : 1e
31 : 1
a
Lith iation of allylic eth ers (s-BuLi, THF, –78 °C) followed by alkylation s with allylic ch lo-
b
c
rides at –78 °C. Ben zyl groups cleaved with Li in 3 : 2 NH3–THF (–78 °C). Determ in ed by
NMR in tegration after purification . In cludes 7–18% of E isom er presen t. TMEDA additive
was used.
d
e
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

60
Jin, Coates:
s-BuLi,
THF
R
R
- 78oC
MeO
MeO
24, R = CH3
Li
15, R = CH3
16, R = 4-methyl-3-pentenyl
25, R = 4-methyl-3-pentenyl
7
OBn
24
25
+
+
17
17
OMe
26
27
OBn
OBn
OMe
11
25
+
18
OMe
28
SCHEME 3
Purification s were carried out by silica gel ch rom atograph y with 2% Et3N
in th e eluen ts to rem ove th e large excess of m eth yl eth er startin g m aterial
an d oth er im purities6. In th e absen ce of th e Et3N additive, th e en ol eth ers
were foun d to decom pose durin g th e purification s. In som e cases un reacted
allylic ch loride startin g m aterial was also presen t, an d its separation from
th e en ol eth er product was difficult. Th is problem was solved by allowin g
th e ch loride to react with an am in e base (Et2NH, 5 equiv. relative to th e al-
lylic ch loride, DMF, room tem perature, 12 h ). Th e dieth ylam in e an d am in e
alkylation product were rem oved by fast extraction with ch illed, dilute 0.1
M HCl, after wh ich purification by ch rom atograph y gave th e pure en ol
eth ers free from th e ch loride con tam in an ts.
Th e Z/E isom er ratios were determ in ed after ch rom atograph ic purifi-
cation s by 1H NMR in tegration of eith er th e vin yl or m eth oxy proton s of
th e en ol eth er groups. Th e spectra were acquired in ben zen e-d6 in stead of
th e usual CDCl3 to avoid th e risk of isom er alteration or decom position
from traces of HCl often presen t in th e latter solven t. Un fortun ately, th e
spectra of th e crude products were too com plicated for reliable m easure-
m en t of th e sm all am oun ts of E isom ers owin g to th e presen ce of large
quan tities of th e allylic eth er startin g m aterials, m in or un iden tified prod-
ucts, an d in som e in stan ces un reacted ch loride. Alth ough th e isom ers ex-
h ibited very sim ilar ch rom atograph ic m obilities, th e possibility of sm all
ch an ges in th e ratios by in adverten t fraction ation durin g purification can -
n ot be excluded. Som e perturbation s of th e Z/E ratios by traces of HCl re-
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Methoxynor Polyisoprenoid Alcohols
61
leased from un reacted allylic ch lorides m igh t also h ave occurred durin g th e
reaction s or isolation procedures wh ich would in crease th e proportion of
th e presum ably m ore stable E isom er som ewh at. Despite th ese con cern s, re-
peated experim en ts with th e sam e com poun ds gave reason ably reproduc-
ible yields (±10%) an d selectivities.
Th e 1H NMR spectra of th e m ajor alkylation products all sh ow on e-
proton triplets (J = 7.0 Hz) at δ 4.3–4.5 ppm for th e vin yl proton on th e
en ol eth er double bon d, upfield (∆δ = –0.8 to –1.0 ppm ) from th e vin yl pro-
ton peaks at δ 5.1–5.3 ppm for th e oth er trisubstituted double bon ds in th e
polyen e ch ain s. Th e vin yl proton s of th e E isom ers reson ate som ewh at fur-
th er upfield at aroun d δ 4.3 ppm as a triplet (J = 7.1 Hz). Th e Z/E isom er ra-
tios were usually determ in ed by in tegration of th ese two en ol eth er vin yl
proton peaks; h owever, in som e cases m ore accurate estim ates were obtain -
ed from th e m eth oxy peak ratios. Th e peaks for th e CH2 proton s across th e
double bon d from th e m eth oxy group con sisten tly appeared as quartets at
δ 2.4 ppm (J = 7.4 Hz), down field from oth er CH2 proton s at δ 2.0–2.2 ppm .
OBn
17
OMe
(2E, 6Z)-21
s-BuLi
MeO
Li
(Z)-20
14
+
?
Li
17
OBn
MeO
MeO
(E)-20
(E, E)-21
SCHEME 4
Th e reason s for th e substan tial variation s in th e isom er ratios an d yields
are un clear at th is tim e. It seem s likely th at th e (Z)-(3-m eth oxyallyl)lith ium
in term ediates are th erm odyn am ically m ore stable th an th eir E isom ers, ow-
in g to stron g ch elation in th e form er. However, th e rates of th e reaction s
with th e allylic ch lorides m ay be quite differen t for th e two isom ers, an d
th e presum ably less stable E form m ay un dergo faster alkylation . On e possi-
ble m ech an ism an d explan ation for th e form ation of Z/E m ixtures is th at
(Z)- an d (E)-(3-m eth oxyallyl)lith ium s are form ed irreversibly in kin etically
con trolled reaction s with sec-butyllith ium (Sch em e 4). In th is scen ario th e
Z/E ratios of th e products would reflect th e ratios of th e isom eric lith ium
reagen ts presen t. However, it is also plausible th at th e (Z)- an d (E)-(3-
m eth oxyallyl)lith ium isom ers un dergo partial or com plete equilibration at
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

62
Jin, Coates:
–78 °C, an d a low proportion of th e (E)-(3-m eth oxyallyl)lith ium is in -
creased in th e product by a faster alkylation . Th us it seem s plausible th at
th e som ewh at h igh er ratios (7 : 1) of th e lon ger ch ain term in al m eth oxyn or
isom ers 22 an d 23 com pared to 21 (5 : 1) m igh t be attributed to som ewh at
faster alkylation s of (Z)-20 with ch lorides 18 an d 19, sin ce th e reactivity of
17 m igh t be depressed by th e in ductive in fluen ce of th e proxim al allylic
ben zyloxy group. However, th e presum ably less reactive 17 gave an en -
h an ced Z/E ratio (15 : 1) in th e alkylation of (Z)-24 (R = CH3) to form 26. In
th is case th e lon ger ch ain substituen t on th e (m eth oxyallyl)lith ium reagen t
(20, R = m eth yl vs 24, R = h om opren yl) m ay affect th e outcom e.
Attem pts to syn th esize 28 by Horn er–Wittig olefin ation 6,8e an d by tan -
dem reduction -alkylation s of a 3-m eth oxyallyl sulfon e were un successful,
despite n um erous trial experim en ts (Sch em e 5). Lith iation of α-m eth oxy-
ph osph in e oxide 29 (i-Pr2NLi, THF, –78 °C) followed by reaction s with
ben zaldeh yde afforded com plex product m ixtures rath er th an th e expected
β-h ydroxy ph osph in e oxide diastereom ers 30 (refs6,8e). An oth er attractive
approach in volved reductive cleavage of 3-m eth oxyallyl p-tolyl sulfon e8f (31)
with lith ium n aph th alen ide wh ich seem ed likely to produce (3-m eth oxy-
allyl)lith ium 24. However, attem pts to obtain 28 from reduction s of 31
(C10H8-Li, THF, –78 °C) followed by addition of th e allylic brom ide corre-
spon din g to 18 (Br in place of Cl) were fruitless. Furth erm ore, th e likeli-
h ood of radical in term ediates in th e reductive lith iation was in dicated by
th e lack of deuterium in corporation in to th e reduction product after addi-
tion of D2O.
OH
1. i-Pr2NLi,
x
OMe
Ph
Ph
MeO P Ph
P
2. PhCHO
O
O
Ph
Ph
30
29
31
O
O
1. C10H8 Li+
x
-
S
p-Tol
28
OMe
2.
Br
R
SCHEME 5
Methoxynor Polyprenyl Alcohols and Diphosphates
Li/NH3 reduction s to rem ove th e ben zyl protectin g groups of 21–23 an d
26–28 were carried out at –78 °C with a large excess of th e m etal in a 3 : 2
m ixture of NH3 an d THF as solven t20 (Table I). Th e alcoh ol products 8–13
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Methoxynor Polyisoprenoid Alcohols
63
were purified by flash ch rom atograph y with 2% Et3N in th e eluen t. Th e
am oun t of E isom er presen t (7–18%) was estim ated as above by in tegration
1
of th e respective en ol eth er vin yl proton s in th e H NMR spectra, an d th e
E/Z ratios were essen tially th e sam e as th ose of th e ben zyl eth ers from
wh ich th ey were derived. Th e yields for th e reductive cleavages varied
widely from 41% of th e term in al m eth oxyn or diterpen e an alog 10 to 82%
of th e m on oterpen e derivative 8 (see Table I). 7- an d 11-Meth oxyn or
geran ylgeran iol (12 an d 13) were con verted to th e diph osph ates 32 an d 7
by form ation of th e correspon din g allylic ch lorides18 an d displacem en t
1
with in organ ic pyroph osph ate21 (Sch em e 6). Th e H NMR spectra sh owed a
vin yl proton peak at δ 4.5 ppm (t, J = 7.1 Hz), in dicatin g th at th e en ol eth er
was n ot h ydrolyzed durin g th e two-step procedures. 31P NMR spectra
sh owed two doublets at δ –8.55 an d –8.01 ppm (J = 19.5 Hz) diagn ostic for
m on oalkyl diph osph ates.
11
H3C
OH
7
CH3
OMe
CH3
CH3
(CH3)
(OMe)
13 (12)
1. MsCl, LiCl
2. (Bu4N+)3HP2O7
-3
H3C
OPP
CH3
OMe
CH3
CH3
(CH3)
(OMe)
7 (32)
SCHEME 6
Th e stability of diph osph ate 7 was evaluated at pH 8 in D2O solution
with ph osph ate buffer as a prelude to in cubation s with taxadien e syn th ase.
Th e solution was an alyzed in term itten tly by 1H (400 MHz) an d 31P NMR
(162 MHz) spectroscopy. After 24 h at room tem perature, th e triplet from
th e C-10 vin yl proton at δH 4.46 ppm an d th e two doublets from th e
diph osph ate at δP –5.4 an d –9.6 ppm in dicated th at th e sen sitive en ol eth er
was in tact. A prelim in ary in cubation of 7-OPP with recom bin an t taxadien e
syn th ase resulted in slow con version to a m ajor product (ca 50%) h avin g
GC reten tion tim e an d apparen t m olecular weigh t (GC/MS, m/z 274) appro-
priate for a n or diterpen e keton e (C19H32O) an d dem on strably differen t
th an h ydrolysis products arisin g from acid h ydrolysis of 7 followed by de-
h ydration 22,23
.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

64
Conclusion
Jin, Coates:
All tran s polyen e isopren oid alcoh ols bearin g m eth oxy groups in place of
m eth yl substituen ts on th e rem ote double bon ds are n ow available by se-
quen tial lith iation of allyl m eth yl eth ers 14–16, couplin g with allylic ch lo-
rides 17–19, an d ben zyl eth er cleavage. Th e stability of th e en ol eth er to
con dition s required for con version of th e correspon din g diph osph ates an d
to aqueous buffer at pH 8 in dicates th e poten tial utility of th ese m eth oxy-
n or an alogs of 1–3 as m ech an istic probes in terpen e syn th ase reaction s.
EXPERIMENTAL2f,18b
Com poun ds were n am ed in accordan ce with th e IUPAC con ven tion s24. Solven ts were dis-
tilled from th e in dicated dryin g agen ts prior to use: THF, dieth yl eth er, ben zen e (Na/ben zo-
ph en on e); CH2Cl2 (CaH2); h exan e, eth yl acetate (n on e). CH3CN, DMSO an d DMF were
distilled from P2O5, an d stored over 3 Å m olecular sieves. Et3N an d pyridin e were distilled
from CaH2, an d stored over KOH. CuI was purified as described by Kauffm an an d Teter25
.
Meth an esulfon yl ch loride was obtain ed from Aldrich Ch em ical Com pan y, an d distilled from
P2O5. Dih ydrogen disodium pyroph osph ate was obtain ed from Sigm a Ch em ical Com pan y,
an d was con verted to th e tetrabutylam m on ium salt accordin g to a procedure reported by
Poulter21. Most oth er reagen ts were purch ased from Aldrich Ch em ical Co., an d were used
with out furth er purification s. sec-BuLi (1.3 M solution in cycloh exan e) was obtain ed from
Aldrich , an d titrated before use26
.
Th e progress of all reaction s was m on itored by TLC un less stated oth erwise. TLC an alyses
were perform ed on plastic-backed Merck Kieselgel 60 F254 plate with visualization by UV
fluorescen ce at 254 n m , I2 stain in g, or ph osph om olybdic acid spray followed by develop-
m en t on a h ot plate at 120 °C.
GC an alyses were perform ed on a Sh im adzu GC-14A with a 30-m Restek Rtx-5 colum n .
GC/MS an alyses were con ducted with a Hewlett–Packard 5890A in strum en t GC/5970 with a
m ass selective detector (EI). Dowex AG 50W-X8 ion exch an ge resin (H+ form ) obtain ed from
BioRad was con verted to th e am m on ium form before each ch rom atograph y accordin g to a
publish ed procedure21. Cellulose TLC plates (Am erican Scien tific Products) were developed
with cellulose ch rom atograph y buffer. Cellulose ch rom atograph y was perform ed on
Wh atm an CF-11 fibrous cellulose21
.
Flash ch rom atograph y was perform ed accordin g to th e procedure of Still27 usin g Merck
0.040–0.063 m m silica gel. Ch rom atograph ic purification s of th e en ol eth er products were
carried out with eluen ts con tain in g 2% v/v Et3N. Th e en ol eth er products were stored at
–20 °C in h exan e con tain in g 1% Et3N. Sam ples for elem en tal an alyses were prepared by
flash ch rom atograph y followed by evacuation un der reduced pressure. Elem en tal an alyses
were perform ed by th e Microan alytical Laboratory at th e Un iversity of Illin ois. Th e purity of
all products was estim ated to be at least 90–95% by in spection an d in tegration of NMR spec-
tra an d/or GC an alyses.
1H NMR spectra were acquired on Un ity 400 or Un ity 500 spectrom eters at 400 or
500 MHz in CDCl3 or C6D6 with th e solven t as th e in tern al referen ce (δ(CHCl3) 7.26 or
δ(C6D5H) 7.15 ppm ). Couplin g pattern s were an alyzed as if first-order, an d th e couplin g
con stan ts reported (J, Hz) are th e correspon din g lin e spacin gs. Multiplets an d couplin g con -
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Methoxynor Polyisoprenoid Alcohols
65
stan ts design ated “apparen t” (app) m ay in fact be secon d-order in wh ich case th e data
sh ould be regarded as descriptive. 13C NMR spectra were recorded with th e Un ity 400 or 500
spectrom eter at 101 or 126 MHz in CDCl3 with CDCl3 as th e referen ce (δ(CDCl3) 77.0 ppm ).
31P NMR spectra were obtain ed with th e Un ity 400 at 162 MHz in CD3OD or D2O with 85%
H3PO4 as th e extern al referen ce (δ(H3PO4) 0.00 ppm ). IR spectra (waven um bers in cm –1
)
were recorded on a Mattson Galaxy Series 5000 FT-IR spectrom eter as n eat liquids on NaCl
plates.
3-Meth oxybut-1-en e (14)
Th e literature procedure11a (but-3-en -2-ol, NaH, Me2SO4, o-xylen e, 140 °C, 23 h ) afforded
.
6.4 g (48%), b.p. 49–56 °C. Th e 1H NMR data m atch ed th e publish ed values28 1H NMR
(CDCl3, 500 MHz): 1.23 d, 3 H, J = 6.4 (CH3); 3.27 s, 3 H (OCH3); 3.70 quin tet, 1 H, J = 6.6
(CHOCH3); 5.14 app ddd, 1 H, Japp = 10.2, 1.6, 0.7 (H-1); 5.18 app ddd, 1 H, Japp = 17.2, 1.6,
1.1 (H-1); 5.70 ddd, 1 H, J = 17.4, 10.2, 7.3 (H-2).
5-Meth ylh ex-4-en al
A solution of 2-m eth ylbut-3-en -2-ol (10.9 g, 0.13 m ol), eth yl vin yl eth er (20.0 g, 0.28 m ol),
an d H3PO4 (85% in H2O, 6 drops) was h eated for 4 h at 150 °C in a sealed tube29. Th e solu-
tion was allowed to cool to room tem perature, an d Et3N (1 m l) was added. Distillation at
96–126 °C (40 torr) afforded 14.0 g of a yellow oil th at was a 1 : 1.77 m ixture of th e alde-
h yde an d its dieth yl acetal accordin g to NMR an alysis. Th e oil (7.0 g) was dissolved in ace-
ton e (150 m l) an d H2O (2.2 g, 0.12 m ol), an d Am berlyst-15 sulfon ic acid resin (1.5 g) was
added. Th e suspen sion was stirred at room tem perature for 2 h an d filtered. Con cen tration
of th e filtrate an d distillation at reduced pressure gave th e kn own aldeh yde29 as a colorless
oil: yield 3.21 g (52%), b.p. 78–79 °C (35 torr) [ref.29 b.p. 90 °C (100 torr)]. Th e followin g
1H NMR data are con sisten t with th e reported values30 1H NMR (CDCl3, 400 MHz): 1.60 s,
.
3 H (CH3); 1.61 s, 3 H (CH3); 2.30 q, 2 H, J = 7.2 (CH2); 2.45 t, 2 H, J = 7.2 (CH2); 5.09 t of
quin tets, J = 7.6, 1.3 (vin yl H); 9.75 t, 1 H, J = 1.7 (CHO).
7-Meth ylocta-1,6-dien -3-ol
Th e procedure by Gadwood for a differen t com poun d was followed13 to prepare th e kn own
alcoh ol31. A solution of vin ylm agn esium brom ide (1.0 M in THF, 100 m l) in THF (60 m l)
was stirred an d cooled at 0 °C as th e aldeh yde (7.1 g, 40 m m ol) in THF (40 m l) was added
over 1 h . After an addition al 2 h , saturated NH4Cl (10 m l) was added, an d th e solven t was
rem oved by sim ple distillation . Saturated NH4Cl (100 m l) an d H2O (100 m l) were added,
an d th e product was extracted with Et2O (3 × 100 m l). Th e com bin ed eth ereal extracts were
wash ed with saturated NaHCO3 (1 × 60 m l) an d saturated NaCl (1 × 60 m l). Dryin g (an h y-
drous Na2SO4), evaporation un der reduced pressure, an d purification by flash ch rom atogra-
ph y (30% EtOAc in h exan e) gave th e title alcoh ol as a yellow oil (3.6 g, 69%). Th e followin g
1H NMR data are con sisten t with th e reported values32 1H NMR (CDCl3, 400 MHz): 1.54 m ,
.
2 H (CH2); 1.59 s, 3 H (CH3); 1.67 d, 3 H, J = 0.7 (CH3); 1.80 s, 1 H (OH); 2.06 q, 2 H, J = 7.4
(CH2); 4.08 q, 1 H, J = 6.4 (CHOH); 5.08 app d of quin tets, 1 H, Japp = 10.4, 1.4 (H-1);
5.12 app d of quin tets, 1 H, Japp = 7.3, 1.3 (H-6); 5.20 dt, 1 H, J = 17.2, 1.4 (H-1); 5.85 ddd,
1 H, J = 17.0, 10.4, 6.0 (H-2). 13C NMR (CDCl3, 126 MHz): 17.7, 24.0, 25.7, 37.0, 72.8,
114.5, 123.9, 132.2, 141.2.
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Jin, Coates:
3-Meth oxy-7-m eth ylocta-1,6-dien e (15)11b
Th e reaction was carried out accordin g to a literature procedure for a differen t com poun d12
.
MeI (1.82 g, 12.8 m m ol) was added to a suspen sion of NaH (616 m g, 12.8 m m ol) in a solu-
tion of th e precedin g alcoh ol (900 m g, 6.42 m m ol) in Et2O (25 m l). Th e suspen sion was
stirred for 18 h at room tem perature, water (30 m l) was added, an d th e product was ex-
tracted with Et2O (3 × 30 m l). Th e com bin ed eth ereal extracts were wash ed with saturated
NaCl (1 × 20 m l), dried (an h ydrous Na2SO4), an d con cen trated un der reduced pressure to
give a dark green oil (1.61 g). Purification by flash ch rom atograph y (3% Et2O in pen tan e) af-
forded eth er 15 as a ligh t yellow oil: yield 72 m g (76%). IR (n eat): 2 931, 1 449, 1 107.
1H NMR (CDCl3, 400 MHz): 1.37 dddd, 1 H, J = 13.4, 8.3, 7.3, 6.1 (CH2); 1.53–1.57 m , 1 H
(CH2); 1.50 s, 3 H (CH3); 1.59 d, 3 H, J = 1.0 (CH3); 1.93 sextet, 2 H, J = 8.0 (CH2); 3.16 s,
3 H (OCH3); 3.39 q, 1 H, J = 6.9 (CHOMe); 5.00 app t of quin tets, 1 H, Japp = 7.3, 1.3 (H-1);
5.07 app ddd, 1 H, Japp = 9.3, 2.0, 0.7 (H-1); 5.10 m , 1 H (H-6); 5.55 ddd, 1 H, J = 16.8, 10.7,
7.6 (H-2). 13C NMR (CDCl3, 101 MHz): 17.5, 23.6, 25.5, 35.3, 55.9, 82.2, 116.8, 123.9, 131.6,
138.7. MS (m/z, rel.%): low resolution EI: 154 (<0.4) [M+], 104.1 (37), 89 (10), 73.1 (100),
59.0 (55); low resolution CI: (CH4) 131.1 (19), 105.1 (15), 73.0 (6.0), 59.0 (100).
(E)-5,9-Dim eth yldeca-4,8-dien al
Th e reduction was carried out accordin g to th e procedure of Szan tay et al. for a differen t
com poun d33. To a solution of eth yl (E)-5,9-dim eth yldeca-4,8-dien oate34 (1.0 g, 4.5 m m ol) in
h exan e (35 m l) at –78 °C was added diisobutylalum in um h ydride (1.0 M in h exan e, 5.8 m l).
After 2 h at –78 °C, MeOH (2 m l) was added, an d th e solution was allowed to warm to room
tem perature. Saturated aqueous potassium , sodium tartrate solution (35 m l) was added, an d
th e aqueous layer was extracted with h exan e (1 × 35 m l). Th e h exan e layer wash ed with sat-
urated. NaCl (1 × 25 m l), dried (an h ydrous Na2SO4), an d con cen trated. Purification by flash
ch rom atograph y (5% EtOAc in h exan e) gave 0.68 g (84%) of th e kn own dien al as a colorless
.
oil. Th e followin g 1H NMR data agree with th e values reported by Poulter35 1H NMR
(CDCl3, 400 MHz): 1.59 s, 3 H (CH3); 1.61 s, 3 H (CH3); 1.67 s, 3 H (CH3); 1.93–2.09 m , 4 H
(CH2); 2.32 q, 2 H, J = 7.0 (CH2); 2.46 td, 2 H, J = 6.8, 1.0 (CH2); 5.08 m , 2 H (vin yl H);
9.76 t, 1 H, J = 1.7 (CHO).
(E)-7,11-Dim eth yldodeca-1,6,10-trien -3-ol
Reaction of th e precedin g dien al (0.67 g, 3.7 m m ol) an d vin ylm agn esium brom ide accordin g
to th e procedure described above with 5-m eth ylh ex-4-en al gave 583 m g (69%) of th e kn own
alcoh ol36 prepared by a ph otoch em ical m eth od. Th e 1H NMR data correspon ded well with
.
th e literature values36 1H NMR (CDCl3, 400 MHz): 1.56 m , 2 H (CH2); 1.59 s, 3 H (CH3);
1.60 s, 3 H (CH3); 1.67 s, 3 H (CH3); 1.95–2.11 m , 6 H (CH2); 4.10 q, 1 H, J = 6.3 (CHOH);
5.08 m , 1 H (vin yl H); 5.10 app d of quin tets, 1 H, Japp = 10.5, 1.3 (vin yl H); 5.13 app t of
sextets, 1 H, Japp = 7.1, 1.2 (vin yl H); 5.21 dt, 1 H, J = 17.1, 1.5 (vin yl H); 5.86 ddd, 1 H, J =
17.1, 10.5, 6.1 (vin yl H). 13C NMR (CDCl3, 101 MHz): 15.9, 17.6, 23.7, 25.6, 26.5, 36.8,
39.6, 72.7, 114.4, 123.6, 124.1, 131.3, 135.6, 141.0.
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Methoxynor Polyisoprenoid Alcohols
67
(E)-3-Meth oxy-7,11-dim eth yldodeca-1,6,10-trien e (16)
Th e m eth ylation of th e precedin g alcoh ol (491 m g, 2.36 m m ol) was carried out as described
for 15 to give allylic eth er 16 as a ligh t yellow oil: yield 562 m g (100%). 1H NMR (CDCl3,
400 MHz): 1.47 dddd, 1 H, J = 13.4, 11.1, 6.8, 4.9 (CH2); 1.63 m , 1 H (CH2); 1.59 s, 3 H
(CH3); 1.60 s, 3 H (CH3); 1.68 s, 3 H (CH3); 1.95–2.10 m , 6 H (CH2); 3.26 s, 3 H (OCH3);
3.49 q, 1 H, J = 7.0 (CHOCH3); 5.06–5.13 m , 2 H (vin yl H); 5.17 ddd, 1 H, J = 12.2, 1.7, 0.7
(vin yl H); 5.20 br d, 1 H, J = 3.9 (vin yl H); 5.65 ddd, 1 H, J = 17.1, 10.5, 7.6 (vin yl H).
13C NMR (CDCl3, 101 MHz): 15.8, 17.6, 23.5, 25.6, 26.5, 35.2, 39.6, 56.0, 82.2, 116.9, 123.8,
124.2, 131.2, 135.3, 138.7. MS (m/z, rel.%): low resolution EI: 222.2 (0.4) [M+], 207.2 (2.5),
147.1 (18), 121.1 (34), 105.1 (16), 93.1 (75), 79.1 (52), 69.1 (100), 55.1 (32); h igh resolution EI:
calculated for C15H26O 222.198366, foun d 222.199191.
(E)-4-(Ben zyloxy)-1-ch loro-2-m eth ylbut-2-en e (17)
Th e con version to ch loride was carried out accordin g to Meyers’ procedure18 (see also proce-
dure for preparation of 32 below). Th e 1H NMR data agree with th e values reported by
Hayash i14. A solution of (E)-4-(ben zyloxy)-2-m eth ylbut-2-en -1-ol37 (400 m g, 2.08 m m ol),
LiCl (441 m g, 10.4 m m ol), an d collidin e (2.0 g, 16.6 m m ol) in DMF (40 m l) was stirred an d
cooled at 0 °C as CH3SO2Cl (715 m g, 6.24 m m ol) was added. After 1.5 h at 0 °C, ice-water
(35 m l) was added, an d th e product was isolated by extraction with cold pen tan e (3 ×
35 m l). Th e com bin ed organ ic extracts were wash ed with saturated Cu(NO3)2 (1 × 100 m l
an d 3 × 25 m l), saturated NaCl (1 × 25 m l), saturated NaHCO3 (1 × 25 m l), an d saturated
NaCl (1 × 25 m l). Dryin g (an h ydrous Na2SO4), an d evaporation gave 17 as a yellow oil: yield
338 m g (77%). 1H NMR (C6D6, 400 MHz): 1.40 d, 3 H, J = 1.0 (CH3); 3.54 s, 3 H (CH2);
3.73 dd, 2 H, J = 6.3, 0.7 (CH2); 4.22 s, 2 H (CH2); 5.50 app t of sextet, 1 H, Japp = 6.1, 1.2
(vin yl H); 7.03–7.26 m , 5 H (aryl H). 13C NMR (CDCl3, 101 MHz): 13.8, 50.8, 65.9, 71.8,
126.9, 127.2, 127.3, 128.1, 134.2, 138.5.
(E,E)-8-Ben zyloxy-1-ch loro-2,6-dim eth ylocta-2,6-dien e (18)
Th e precedin g procedure for 17 usin g (E,E)-8-ben zyloxy-2,6-dim eth ylocta-2,6-dien -1-ol15
(240 m g, 0.92 m m ol) gave 267 m g (quan titative) of th e kn own ch loride15 18 as a yellow oil.
.
Th e 1H NMR data agree with th e values reported15 1H NMR (C6D6, 400 MHz): 1.38 s, 3 H
(CH3); 1.49 d, 3 H, J = 0.7 (CH3); 1.79–1.92 m , 4 H (CH2); 3.63 s, 2 H (CH2); 3.92 dd, 2 H,
J = 6.3, 0.5 (CH2); 4.34 s, 2 H (CH2); 5.17 td, 1 H, J = 6.3, 0.7 (vin yl H); 5.42 app t of sextet,
1 H, Japp = 6.6, 1.2 (vin yl H); 7.03–7.31 m , 5 H (aryl H). 13C NMR (CDCl3, 101 MHz): 13.5,
15.9, 25.9, 38.4, 51.7, 66.3, 71.5, 122.0, 127.1, 127.3, 128.0, 129.6, 131.6, 138.0, 139.0.
(E,E,E)-12-Ben zyloxy-1-ch loro-2,6,10-trim eth yldodeca-2,6,10-trien e (19)
Reaction of (E,E,E)-12-ben zyloxy-2,6,10-trim eth yldodeca-2,6,10-trien -1-ol16 (400 m g,
1.22 m m ol) as described for 17 an d 18 gave th e kn own 16 19 (400 m g, 95%) as a ligh t yellow
.
oil. Th e followin g 1H NMR data m atch th e literature values16 1H NMR (C6D6, 500 MHz):
1.45 s, 3 H (CH3); 1.47 s, 3 H (CH3); 1.53 s, 3 H (CH3); 1.85–2.02 m , 6 H (CH2); 2.08 q, 2 H,
J = 7.2 (CH2); 3.68 s, 2 H (CH2); 3.96 d, 2 H, J = 6.4 (CH2); 4.36 s, 2 H (CH2); 5.11 td, 1 H,
J = 6.8, 1.1 (vin yl H); 5.24 t, 1 H, J = 6.6 (vin yl H); 5.53 td, 1 H, J = 6.6, 1.3 (vin yl H);
7.04–7.32 m , 5 H (aryl H).
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Jin, Coates:
Represen tative Procedure for Lith iation /Alkylation of 1-Alkylallyl Meth yl Eth ers
(2E,6E,10Z)-1-Benzyloxy-11-methoxy-3,7,15-trimethylhexadeca-2,6,10,14-tetraene (28). Th e
lith iation step was carried out accordin g to th e procedure by Still an d McDon ald for differ-
en t com poun ds9b,9c. A solution of eth er 15 (144 m g, 0.93 m m ol) in THF (1 m l) was stirred
an d cooled at –78 °C as sec-BuLi (1.3 M in cycloh exan e, 0.54 m l, 0.70 m m ol) was added. Af-
ter 20 m in , ch loride 18 (130 m g, 0.47 m m ol) was added dropwise to th e oran ge solution ,
an d th e ligh t yellow solution was stirred at –78 °C for 40 m in . MeOH (4 drops) was added,
an d th e solution was allowed to warm to room tem perature. After addition of H2O (20 m l),
th e product was extracted with Et2O (3 × 20 m l). Th e com bin ed eth ereal extracts were
wash ed with saturated NaCl (1 × 20 m l), dried (an h ydrous Na2SO4), an d con cen trated un der
reduced pressure to give a colorless oil (275 m g). Purification by flash ch rom atograph y (2%
Et3N in h exan e) gave en ol eth er 28 (145 m g, 78%) as a colorless oil. Th e E/Z ratio (31 : 1)
was estim ated from th e in tegral ratio of th e en ol eth er vin yl proton triplet (δ 4.56) an d a
weak peak at δ 4.22 attributed to th e E isom er. Th e product was stored in h exan e con tain in g
1% Et3N, an d storage of th e n eat oil was avoided. TLC RF 0.37 (10% EtOAc in h exan e). IR
(n eat): 2 923, 1 675, 1 454, 1 070. 1H NMR (C6D6, 500 MHz): 1.46 s, 3 H (CH3); 1.51 s, 3 H
(CH3); 1.56 s, 3 H (CH3); 1.62 d, 3 H, J = 1.1 (CH3); 2.01 q, 2 H, J = 7.5 (CH2); 2.05–2.14 m ,
6 H (CH2); 2.17 q, 2 H, J = 7.5 (CH2); 2.38 q, 2 H, J = 7.4 (CH2); 3.25 s, 3 H (OCH3); 3.96 dd,
2 H, J = 6.6, 0.5 (OCH2); 4.36 s, 2 H (CH2Ph ); 4.56 t, 1 H, J = 7.0 (vin yl H); 5.18 app t of
quin tet, 1 H, Japp = 7.0, 1.4 (vin yl H); 5.23 tq, 1 H, J = 7.0, 1.3 (vin yl H); 5.53 tq, 1 H, J =
6.6, 1.3 (vin yl H); 7.04–7.16 m , 3 H (aryl H); 7.30–7.33 m , 2 H (aryl H). 13C NMR (C6D6,
126 MHz): 15.7, 16.1, 17.4, 23.6, 25.5, 26.1, 26.4, 31.5, 39.6, 40.2, 55.6, 66.5, 71.5, 109.1,
121.8, 124.03, 124.05, 127.2, 128.2, 131.3, 135.1, 139.0, 139.3, 154.9. MS: low resolution EI:
m/z 396.5 [M+]; h igh resolution EI: calculated for C27H40O2 396.302831, foun d 396.302424.
Represen tative Procedure for Rem oval of Allylic Ch loride by Reaction with Dieth ylam in e
If NMR an d/or TLC an alyses sh owed th at allylic ch loride was presen t in th e crude alkylation
product m ixture, it was rem oved by reaction with dieth ylam in e. For exam ple, th e crude oil
(120 m g) was dissolved in 1 m l of DMF con tain in g 0.10 m l of dieth ylam in e. Th e solution
was stirred for 15 h at room tem perature, an d diluted with cold h exan e (30 m l). After
wash es with cold 0.1 M HCl (3 × 10 m l) an d saturated NaHCO3 (1 × 10 m l), th e organ ic
layer was dried (an h ydrous Na2SO4) an d con cen trated to give a yellow oil (93 m g).
Th e startin g m aterials, yields, an d product data for th e followin g en ol eth ers prepared by
th e represen tative procedure above are presen ted in an abbreviated form at below. Th e Z/E
isom er ratios were determ in ed as described in th e text an d collected in Table I.
(2E,6Z)-1-Benzyloxy-7-methoxy-3-methylocta-2,6-diene (21). Allyl eth er 14 (90 m g,
1.04 m m ol), 1.3 M sec-BuLi (0.60 m l, 0.78 m m ol), an d ch loride 17 (67 m g, 0.32 m m ol); yield
59 m g (71%) of 21, Z/E 5 : 1, TLC RF 0.23 (10% EtOAc in h exan e). For C17H24O2 (260.3) cal-
culated: 78.42% C, 9.29% H; foun d: 78.37% C, 9.37% H. IR (n eat): 2 931, 1 677, 1 452,
1 070. 1H NMR (C6D6, 400 MHz): 1.50 s, 3 H (CH3); 1.53 d, 3 H, J = 1.2 (CH3); 2.06 t, 2 H,
J = 7.6 (CH2); 2.36 qd, 2 H, J = 7.4, 1.0 (CH2); 3.14 s, 3 H (OCH3); 3.96 dd, 2 H, J = 6.6, 0.5
(OCH2); 4.35 s, 2 H (CH2Ph ); 4.36 td, 1 H, J = 6.8, 1.0 (vin yl H); 5.57 tq, 1 H, J = 6.6, 1.2
(vin yl H); 7.03–7.16 m , 3 H (aryl H); 7.29–7.33 m , 2 H (aryl H). 13C NMR (C6D6, 126 MHz):
16.0, 17.0, 23.1, 39.8, 54.7, 66.5, 71.4, 107.2, 121.7, 127.1, 128.1, 139.24, 139.32, 151.0. MS:
low resolution EI: m/z 260.3 [M+]; h igh resolution EI: calculated for C17H24O2 260.177630,
foun d 260.178248.
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Methoxynor Polyisoprenoid Alcohols
69
(2E,6E,10Z)-1-Benzyloxy-11-methoxy-3,7-dimethyldodeca-2,6,10-triene (22). Allyl eth er 14
(74 m g, 0.86 m m ol), 1.3 sec-BuLi (0.50 m l, 0.65 m m ol), an d ch loride 18 (120 m g,
M
0.43 m m ol); yield 103 m g (73%) of 22, TLC RF 0.32 (10% EtOAc in h exan e). IR (n eat):
2 931, 1 680, 1 452, 1 069, 734, 696. 1H NMR (C6D6, 400 MHz): 1.45 s, 3 H (CH3); 1.56 s,
3 H (CH3); 1.57 s, 3 H (CH3); 2.00 q, 2 H, J = 8.1 (CH2); 2.07–2.14 m , 4 H (CH2); 2.40 q, 2 H,
J = 7.6 (CH2); 3.16 s, 3 H (OCH3); 3.96 d, 2 H, J = 6.6 (OCH2); 4.36 s, 2 H (CH2Ph ); 4.43 td,
1 H, J = 7.1, 1.0 (vin yl H); 5.23 td, 1 H, J = 6.8, 1.2 (vin yl H); 5.52 tq, 1 H, J = 6.6, 0.8 (vi-
n yl H); 7.03–7.17 m , 3 H (aryl H); 7.29–7.33 m , 2 H (aryl H). 13C NMR (C6D6, 101 MHz):
15.7, 16.1, 17.0, 23.5, 26.3, 39.6, 40.1, 54.7, 66.5, 71.5, 107.6, 121.8, 123.9, 127.2, 127.5,
128.2, 135.2, 139.0, 139.3, 150.7. MS: low resolution EI: m/z 328.4 [M+]; h igh resolution EI:
calculated for C22H32O2 328.240231, foun d 328.240138.
(2E,6E,10E,14Z)-1-Benzyloxy-15-methoxy-3,7,11-trimethylhexadeca-2,6,10,14-tetraene (23).
Allyl eth er 14 (80 m g, 0.93 m m ol), 1.2 M sec-BuLi (0.58 m l, 0.70 m m ol), an d ch loride 19
(80 m g, 0.23 m m ol); yield 74 m g (80%) of 23, TLC RF 0.35 (10% EtOAc in h exan e). For
C
27H40O2 (399.6) calculated: 81.77% C, 10.17% H; foun d: 81.68% C, 10.11% H. IR (n eat):
2 932, 1 679, 1 452, 1 382, 1 070. 1H NMR (C6D6, 500 MHz): 1.47 s, 3 H (CH3); 1.53 s, 3 H
(CH3); 1.57 d, 3 H, J = 1.1 (CH3); 1.60 s, 3 H (CH3); 1.97–2.18 m , 10 H (CH2); 2.41 qd, 2 H,
J = 7.4, 1.1 (CH2); 3.17 s, 3 H (OCH3); 3.97 d, 2 H, J = 6.2 (CH2O); 4.36 s, 2 H (CH2Ph );
4.44 td, 1 H, J = 7.0, 0.9 (vin yl H); 5.19 td, 1 H, J = 7.0, 1.3 (vin yl H); 5.28 td, 1 H, J = 7.1,
1.1 (vin yl H); 5.53 td, 1 H, J = 6.6, 1.3 (vin yl H); 7.04–7.16 m , 3 H (aryl H); 7.29–7.33 m ,
2 H (aryl H). 13C NMR (C6D6, 126 MHz): 15.70, 15.75, 16.1, 17.0, 23.5, 26.3, 26.7, 39.6,
39.8, 40.1, 46.2, 54.7, 66.5, 71.5, 107.7, 121.8, 124.0, 124.3, 127.2, 128.2, 134.9, 135.0,
139.0, 139.2, 150.7.
(2E,6Z)-1-Benzyloxy-7-methoxy-3,11-dimethyldodeca-2,6,10-triene (26). Allyl eth er 15
(130 m g, 0.84 m m ol), 1.3
M sec-BuLi (0.49 m l, 0.63 m m ol), an d ch loride 17 (71 m g,
0.34 m m ol); yield 52 m g (47%) of 26, TLC RF 0.38 (10% EtOAc in h exan e). For C22H32O2
(328.5) calculated: 80.44% C, 9.82% H; foun d: 80.30% C, 9.85% H. IR (n eat): 2 919, 1 675,
1 452, 1 071, 737, 696. 1H NMR (C6D6, 400 MHz): 1.50 s, 3 H (CH3); 1.62 d, 3 H, J = 0.5
(CH3); 2.02–2.08 m , 4 H (CH2); 2.16 q, 2 H, J = 7.2 (CH2); 2.35 q, 2 H, J = 7.4 (CH2); 3.22 s,
3 H (OCH3); 3.97 d, 2 H, J = 6.6 (OCH2); 4.36 s, 2 H (CH2Ph ); 4.51 t, 1 H, J = 7.1 (vin yl H);
5.16 t of quin tet, 1 H, Japp = 6.8, 1.4 (vin yl H); 5.56 tq, 1 H, J = 6.6, 1.2 (vin yl H); 7.03–7.17 m ,
3 H (aryl H); 7.28–7.32 m , 2 H (aryl H). 13C NMR (C6D6, 101 MHz): 15.9, 17.2, 23.1, 25.3,
25.9, 31.3, 39.8, 55.4, 66.4, 71.4, 108.5, 121.7, 123.8, 127.0, 127.3, 128.0, 131.2, 138.9,
139.1, 154.9.
(2E,6Z,10E)-1-Benzyloxy-7-methoxy-3,11,15-trimethylhexadeca-2,6,10,14-tetraene (27). A liter-
ature procedure19 for lith iation in th e presen ce of TMEDA was followed. A solution of
TMEDA (84 m g, 0.72 m m ol) in THF (1 m l) was stirred an d cooled at –78 °C as 1.3 M sec-BuLi
(0.55 m l, 0.72 m m ol) was added. After 5 m in , allyl eth er 16 (200 m g, 0.90 m m ol) in THF
(1 m l) was added dropwise. After 1 h at –78 °C, ch loride 17 (95 m g, 0.45 m m ol) was added,
th e solution was stirred at –78 °C for 1 h , an d m eth an ol (4 drops) was added. Isolation of
th e product as described above for 28 in cludin g an addition al extraction with cold 0.1
M
HCl to rem ove TMEDA an d ch rom atograph ic purification gave 91 m g (51%) of 27, TLC RF
0.40 (10% EtOAc in h exan e). IR (n eat): 2 926, 1 675, 1 454, 1 068, 734, 696. 1H NMR (C6D6,
500 MHz): 1.51 s, 3 H (CH3); 1.52 s, 3 H (CH3); 1.54 s, 3 H (CH3); 1.64 s, 3 H (CH3);
2.02–2.22 m , 10 H (CH2); 2.36 q, 2 H, J = 7.4 (CH2); 3.23 s, 3 H (OCH3); 3.97 d, 2 H, J = 4.3
(OCH2); 4.36 s, 2 H (CH2Ph ); 4.52 t, 1 H, J = 7.1 (vin yl H); 5.21 m , 2 H (vin yl H); 5.57 tq,
1 H, J = 6.5, 1.0 (vin yl H); 7.03–7.17 m , 3 H (aryl H); 7.29–7.32 m , 2 H (aryl H). 13C NMR
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Jin, Coates:
(C6D6, 126 MHz): 15.7, 16.0, 17.4, 23.3, 25.5, 26.0, 26.8, 31.4, 39.8, 39.9, 55.5, 66.6, 71.5,
108.7, 121.8, 123.9, 124.6, 127.2, 128.0, 128.2, 130.8, 135.2, 139.1, 139.3, 155.1. MS: low
resolution EI: m/z 396.5 [M+]; h igh resolution EI: calculated for C27H40O2 396.302831, foun d
396.303311.
Represen tative Procedure for Cleavage of Ben zyl Eth ers with Li/NH3
(2E,6Z)-7-Methoxy-3-methylocta-2,6-dien-1-ol (8) A literature procedure20 for an alogs of
geran ylgeran yl ben zyl eth er was followed. A solution of ben zyl eth er 21 (89 m g, 0.34 m m ol)
in THF (6 m l) an d NH3 (9 m l) was stirred an d cooled at –78 °C as Li pieces (47 m g,
6.84 m m ol) were added. After 30 m in at –78 °C, h ex-3-yn e (1 m l) followed by MeOH (2 m l)
were added, an d th e wh ite suspen sion was allowed to warm to room tem perature. Saturated
NaHCO3 (5 m l) was added, an d th e THF solven t was evaporated un der reduced pressure. Sat-
urated NaHCO3 (15 m l) was added to th e residue, an d th e product was extracted with Et2O
(3 × 20 m l). Th e com bin ed eth ereal extracts were wash ed with saturated NaCl (3 × 20 m l),
dried (an h ydrous Na2SO4) an d evaporated. Purification of th e rem ain in g yellow oil (62 m g)
by flash ch rom atograph y (2% Et3N an d 20% EtOAc in h exan e) gave 48 m g (82%) of 8, Z/E
4.3 : 1, TLC RF 0.22 (30% EtOAc in h exan e). For C10H18O2 (170.3) calculated: 70.55% C,
10.66% H; foun d: 70.22% C, 10.71% H. IR (n eat) 3 376, 2 938, 1 675, 1 452, 1 380. 1H NMR
(C6D6, 400 MHz): 1.17 br s, 1 H (OH); 1.48 s, 3 H (CH3); 1.54 d, 3 H, J = 1.0 (CH3); 2.01 t,
2 H, J = 7.6 (CH2); 2.32 qd, 2 H, J = 7.5, 1.2 (CH2); 3.15 s, 3 H (OCH3); 3.97 dd, 2 H, J = 6.6,
0.5 (CH2OH); 4.36 td, 1 H, J = 7.1, 1.0 (vin yl H); 5.41 app t of sextet, 1 H, Japp = 6.7, 1.2
(vin yl H). 13C NMR (C6D6, 101 MHz): 15.6, 16.8, 23.0, 39.6, 54.5, 58.8, 107.1, 124.3, 137.8,
150.8.
Th e followin g ben zyl eth er cleavages were carried out accordin g to th e represen tative pro-
cedure described above. Th e iden tity an d am oun ts of ben zyl eth er startin g m aterials an d
product data are presen ted in abbreviated form at.
(2E,6E,10Z)-11-Methoxy-3,7-dimethyldodeca-2,6,10-trien-1-ol (9). Eth er 22 (79 m g,
0.24 m m ol); yield 45 m g (78%), Z/ E 6 : 1, TLC RF 0.33 (30% EtOAc in h exan e). For
C
15H26O2 (238.4) calculated: 75.58% C, 10.99% H; foun d: 75.73% C, 10.86% H. IR (n eat):
3 345, 2 921, 1 677, 1 451. 1H NMR (C6D6, 400 MHz): 1.06 br s, 1 H (OH); 1.43 s, 3 H
(CH3); 1.57 s, 6 H (CH3); 1.92–1.97 m , 2 H (CH2); 2.04–2.12 m , 4 H (CH2); 2.38 q, 2 H, J =
7.4 (CH2); 3.17 s, 3 H (OCH3); 3.97 d, 2 H, J = 6.6 (CH2OH); 4.42 td, 1 H, J = 7.0, 1.0 (vin yl
H); 5.21 app t of sextet, 1 H, Japp = 7.1, 1.2 (vin yl H); 5.37 app t of sextet, 1 H, Japp = 6.6, 1.2
(vin yl H). 13C NMR (C6D6, 101 MHz): 15.6, 15.7, 16.9, 23.4, 26.2, 39.4, 39.9, 54.6, 58.8,
107.5, 123.8, 124.4, 135.0, 137.6, 150.6.
(2E,6E,10E,14Z)-15-Methoxy-3,7,11-trimethylhexadeca-2,6,10,14-tetraen-1-ol (10). Eth er 23
(44 m g, 0. 11 m m ol); yield 14 m g (41%), Z/E 7 : 1, TLC RF 0.27 (30% EtOAc in h exan e). For
C
20H34O2 (306.5) calculated: 78.38% C, 11.18% H; foun d: 78.26% C, 11.09% H. IR (n eat):
3 327, 2 931, 1 678, 1 449, 1 380. 1H NMR (C6D6, 400 MHz): 0.55–0.70 br s, 1 H (OH); 1.43 s,
3 H (CH3); 1.53 s, 3 H (CH3); 1.57 d, 3 H, J = 1.2 (CH3); 1.60 s, 3 H (CH3); 1.93–1.99 m , 2 H
(CH2); 2.02–2.19 m , 8 H (CH2); 2.41 q, 2 H, J = 7.4 (CH2); 3.17 s, 3 H (OCH3); 3.94 d, 2 H, J =
6.6 (CH2OH); 4.44 td, 1 H, J = 7.1, 1.0 (vin yl H); 5.18 td, 1 H, J = 7.0, 1.2 (vin yl H); 5.28 td,
1 H, J = 6.8, 1.2 (vin yl H); 5.36 td, 1 H, J = 6.7, 1.2 (vin yl H). 13C NMR (C6D6, 101 MHz):
15.6, 15.7, 16.9, 23.4, 26.2, 26.6, 39.4, 39.7, 40.0, 54.6, 58.9, 107.5, 123.9, 124.1, 124.4,
134.8, 137.6, 150.6.
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Methoxynor Polyisoprenoid Alcohols
71
(2E,6Z)-7-Methoxy-3,11-dimethyldodeca-2,6,10-trien-1-ol (11). Eth er 26 (52 m g, 0.16 m m ol);
yield 21 m g (56%), Z/E 12 : 1, TLC RF 0.33 (30% EtOAc in h exan e). For C15H26O2 (238.4)
calculated: 75.58% C, 10.99% H; foun d: 75.54% C, 10.92% H. IR (n eat): 3 356, 2 931, 1 672,
1 448, 1 376. 1H NMR (C6D6, 400 MHz): 0.73 br s, 1 H (OH); 1.47 s, 3 H (CH3); 1.51 s, 3 H
(CH3); 1.63 d, 3 H, J = 1.0 (CH3); 1.98–2.07 m , 4 H (CH2); 2.16 q, 2 H, J = 7.6 (CH2); 2.31 q,
2 H, J = 7.5 (CH2); 3.23 s, 3 H (OCH3); 3.95 d, 2 H, J = 6.6 (CH2OH); 4.50 t, 1 H, J = 7.1
(vin yl H); 5.17 t of quin , 1 H, J = 7.0, 1.3 (vin yl H); 5.40 t of sextet, 1 H, J = 6.7, 1.2 (vin yl
H). 13C NMR (C6D6, 101 MHz): 15.6, 17.2, 23.2, 25.3, 25.9, 31.3, 39.7, 55.4, 58.8, 108.6,
123.8, 124.4, 131.2, 137.8, 154.9.
(2E,6Z,10E)-7-Methoxy-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol (12). Eth er 27
(81 m g, 0.20 m m ol); yield 38 m g (61%), Z/E ≈13 : 1, TLC RF 0.32 (30% EtOAc in h exan e).
For C20H34O2 (306.5) calculated: 78.38% C, 11.18% H; foun d: 78.30% C, 11.19% H. IR
(n eat): 3 385, 2 924, 1 675, 1 444. 1H NMR (C6D6, 400 MHz): 0.61 s, 1 H (OH); 1.47 s, 3 H
(CH3); 1.52 s, 3 H (CH3); 1.55 s, 3 H (CH3); 1.64 d, 3 H, J = 0.7 (CH3); 1.98–2.22 m , 10 H
(CH2); 2.32 q, 2 H, J = 7.4 (CH2); 3.23 s, 3 H (OCH3); 3.95 d, 2 H, J = 6.8 (CH2OH); 4.51 t,
1 H, J = 7.2 (vin yl H); 5.21 m , 2 H (vin yl H); 5.40 t of sextet, 1 H, J = 6.6, 1.3 (vin yl H).
13C NMR (C6D6, 101 MHz): 15.61, 15.63, 17.2, 23.2, 25.4, 25.8, 26.7, 31.3, 39.7, 55.4, 58.8,
108.6, 123.6, 124.4, 130.7, 135.1, 137.8, 154.9.
(2E,6E,10Z)-11-Methoxy-3,7,15-trimethylhexadeca-2,6,10,14-tetraen-1-ol (13). Eth er 28
(69 m g, 0.17 m m ol); yield 35 m g (66%), Z/E 10 : 1, TLC RF 0.35 (30% EtOAc in h exan e). For
C
20H34O2 (306.5) calculated: 78.38% C, 11.18% H; foun d: 77.99% C, 11.21% H. IR (n eat):
3 333, 2 931, 1 672, 1 444, 1 382. 1H NMR (C6D6, 500 MHz): 0.76 s, 1 H (OH); 1.43 s, 3 H
(CH3); 1.51 s, 3 H (CH3); 1.57 s, 3 H (CH3); 1.62 s, 3 H (CH3); 1.95 quin , 2 H, J = 7.6 (CH2);
2.04–2.11 m , 4 H (CH2); 2.16 quin , 2 H, J = 7.4 (CH2); 2.37 q, 2 H, J = 7.4 (CH2); 3.26 s, 3 H
(OCH3); 3.95 d, 2 H, J = 6.5 (CH2OH); 4.56 t, 1 H, J = 7.0 (vin yl H); 5.15–5.24 m , 2 H (vin yl
H); 5.36 tq, 1 H, J = 6.6, 1.3 (vin yl H). 13C NMR (C6D6, 126, MHz): 15.7, 15.8, 17.4, 23.7,
25.5, 26.1, 26.3, 31.5, 39.5, 40.1, 55.6, 59.0, 109.2, 124.0, 124.6, 131.3, 135.0, 137.8, 154.9.
Triam m on ium (2E,6Z,10E)-7-Meth oxy-3,11,15-trim eth ylh exadeca-2,6,10,14-tetraen -1-yl
Diph osph ate (32)
Con version to th e ch loride an d diph osph ate form ation were carried out accordin g to th e
procedures of Meyers18a an d Poulter21 (see also ref.18b). A solution of alcoh ol 12 (13 m g,
0.0424 m m ol), LiCl (18 m g, 0.42 m m ol), an d collidin e (51 m g, 0.42 m m ol) in DMF (1 m l)
was stirred an d cooled at 0 °C as m eth an esulfon yl ch loride (15 m g, 0.13 m m ol) was added.
After 1 h at 0 °C, ice-water (10 m l) was added, an d th e aqueous layer was extracted with
cold pen tan e (3 × 10 m l). Th e com bin ed organ ic extracts were wash ed with saturated
Cu(NO3)2 (1 × 15 m l, th en 3 × 5 m l), saturated NaCl (1 × 10 m l), an d saturated NaHCO3
(1 × 10 m l). Dryin g (an h ydrous Na2SO4), an d evaporation gave th e correspon din g ch loride
as a ligh t yellow oil (12 m g, 100%). A solution of th e ch loride in CH3CN (0.5 m l) con tain -
in g 3 Å m olecular sieve powder (100 m g) an d tetrabutylam m on ium pyroph osph ate (83 m g,
0.0923 m m ol) was stirred at room tem perature for 16 h . Th e solids were filtered off an d
wash ed with CH3CN (20 m l). Th e filtrate was wash ed with pen tan e (3 × 10 m l), an d th e
CH3CN layer was evaporated un der reduced pressure to give th e diph osph ate (105 m g). Ion
exch an ge ch rom atograph y (20 m l resin , 20 m l ion exch an ge buffer) an d lyoph ilization of
th e eluate gave a wh ite solid (42 m g) wh ich was purified by cellulose ch rom atograph y
(40 m l of cellulose, cellulose ch rom atograph y buffer) to give 11 m g (52%) of 32 as a wh ite
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

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Jin, Coates:
solid, TLC RF 0.67 (cellulose TLC, cellulose buffer). 1H NMR (D2O + EDTA, 400 MHz): 1.41 s,
6 H (CH3); 1.48 s, 3 H (CH3); 1.51 s, 3 H (CH3); 1.78–2.02 m , 10 H (CH2); 2.37 m , 2 H
(CH2); 3.35 s, 3 H (OCH3); 4.27 t, 2 H, J = 6.5 (CH2O); 4.46 t, 1 H, J = 7.1 (vin yl H); 4.97 m ,
2 H (vin yl H); 5.25 t, 1 H, J = 6.8 (vin yl H). 31P NMR (D2O, 162 MHz): –9.67 d, J = 22.0;
–5.75 d, J = 22.0.
Tris(tetrabutylam m on ium ) (2E,6E,10Z)-11-Meth oxy-3,7,15-trim eth ylh exadeca-
2,6,10,14-tetraen -1-yl Diph osph ate (7)
Th e sam e procedure described above for con version of 12 to th e correspon din g ch loride
with 13 (14 m g, 4.57 · 10–5 m ol), LiCl (19 m g, 4.57 · 10–4 m ol), collidin e (55 m g, 4.57 · 10–5
m ol), an d CH3SO2Cl (16 m g, 1.37 · 10–4 m ol) gave 15 m g (100%) of (2E,6E,10Z)-1-ch loro-
11-m eth oxy-3,7,15-trim eth ylh exadeca-2,6,10,14-tetraen e as a yellow oil. Th e ch loride
was dissolved in CH3CN (0.5 m l), an d tetrabutylam m on ium pyroph osph ate (89 m g,
0.0914 m m ol) an d 3 Å m olecular sieve powder (100 m g) were added. After 15 h at room
tem perature, th e suspen sion was filtered an d wash ed with CH3CN (20 m l). Th e filtrate was
wash ed with pen tan e (3 × 10 m l), an d th e CH3CN layer was evaporated to give 148 m g of
diph osph ate product as tetrabutylam m on ium salts. 31P NMR an alysis sh owed th at it was a
0.94 : 1.00 m ixture of 7 an d in organ ic pyroph osph ate. 1H NMR (CD3OD, 400 MHz): 1.02 t,
36 H, J = 7.3 (CH3); 1.42 sextet, 24 H, J = 7.4 (CH2); 1.66 m , 24 H (CH2); 3.23 m , 24 H,
(CH2); 4.48 t, 1 H, J = 7.1 (vin yl H); 4.57 t, 2 H, J = 6.2 (CH2); 5.12 m , 1 H (vin yl H);
5.44 m , 1 H (vin yl H). 31P NMR (CD3OD, 162 MHz): –8.55 d, J = 19.5; –8.01 d, J = 19.5;
–6.04 s (PPi).
Th e stability of diph osph ate 7 was evaluated at pH 8 in aqueous solution with ph osph ate
buffer as a prelude for in cubation s with taxadien e syn th ase. Stock solution s of 0.1 M NaOH
an d 0.1 M KH2PO4 solution s were prepared by dissolvin g 0.4 g of NaOH in 100 m l of D2O
an d 1.36 g of KH2PO4 in 100 m l of D2O. Th e pH 8 buffer was prepared by m ixin g 0.1
M
NaOH (4.7 m l) an d 0.1 M KH2PO4 (5.0 m l) an d addin g 0.3 m l of D2O (ref.38). A solution of
10 m g of 7 in th e buffer (0.6 m l) was an alyzed by 1H an d 31P NMR (400 an d 162 MHz) spec-
troscopy. After 24 h at room tem perature, th e triplet (J = 7.2 Hz, vin yl H) at δH 4.46 ppm
(1H NMR) an d th e two doublets at δP –5.4 an d –9.6 ppm (J = 22.0 Hz) in dicated th at th e
en ol eth er was n ot h ydrolyzed. Th e sen sitivity of 7 to h ydrolysis was revealed in an oth er
stability test. Th e diph osph ate (10 m g) was dissolved in 10 m l of pH 8 buffer in H2O (10 m l)
prepared in th e sam e way as th e D2O buffer. After 20 h at room tem perature, th e water was
rem oved by rotary evaporation , an d th e rem ain in g oil (116 m g) was dissolved in CD3OD
an d an alyzed by 1H an d 31P NMR spectroscopy. Th e absen ce of th e expected triplet for th e
en ol eth er vin yl H (δH 4.4–4.6 ppm ) an d th e disappearan ce of th e two doublets at δP –4.2
an d –7.4 ppm (J = 18.3 Hz) in dicated com plete h ydrolysis of th e en ol eth er. It seem s likely
th at th e pH dropped below 8 durin g an d/or after th e evaporation .
The authors are grateful to the U.S. National Institutes of Health for financial support (GM 13956)
and to A. Jin for MS data for ethers 15 and 16.
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Methoxynor Polyisoprenoid Alcohols
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