The organoalkali route to vitamin A and β-carotene

Article abstract of DOI:10.1002/1099-0690(200110)2001:20<3903::AID-EJOC3903>3.0.CO;2-R

The reductive cleavage of methyl vinyl-β-ionyl ether (1) or the deprotonation of 3,2′,6′,6′-tetramethyl-5-(1-cyclohexenyl)-1, 3-pentadiene (2) gives rise to an organometallic C₁₅ species that combines selectively with a variety of electrophiles at the terminal chain position. Its reaction with aldehydes, however, is less clean. In particular, (E)-β-formyl-2-butenyl acetate gives the expected adduct 7a and, after dehydration, vitamin A acetate only in poor yield. The same is true for the analogous reaction with 2,7-dimethyl-2,4,6-octatriendial, which ultimately affords βcarotene. Vitamin A acetate can also be prepared, this time in moderate yield, by functionalization through consecutive deprotonation, borylation, oxidation and acetylation of a C₂₀ pentaene hydrocarbon having the required skeleton. Both the C₁₅ and the C₂₀ organometallic key intermediates adopt spontaneously a zigzag-like outstretched conformation which, upon electrophilic trapping, directly and exclusively leads to the all-(E) configuration.

Full text of DOI:10.1002/1099-0690(200110)2001:20<3903::AID-EJOC3903>3.0.CO;2-R

FULL PAPER
The Organoalkali Route to Vitamin A and β-Carotene
Günter Rauchschwalbe,[a] Armin Zellner,[a] and Manfred Schlosser*[a]
Keywords: Vitamins / Olioisoprenoids / Extensively delocalized organometallic intermediates / / Regioselectivity /
Stereoselectivity
The reductive cleavage of methyl vinyl-β-ionyl ether (1) or
triendial, which ultimately affords β-carotene. Vitamin A
the deprotonation of 3,2Ј,6Ј,6Ј-tetramethyl-5-(1-cyclohex- acetate can also be prepared, this time in moderate yield, by
enyl)-1,3-pentadiene (2) gives rise to an organometallic C15
species that combines selectively with a variety of elec-
functionalization through consecutive deprotonation, boryl-
ation, oxidation and acetylation of a C20 pentaene hydrocar-
trophiles at the terminal chain position. Its reaction with alde- bon having the required skeleton. Both the C15 and the C20
hydes, however, is less clean. In particular, (E)-β-formyl-2- organometallic key intermediates adopt spontaneously a zig-
butenyl acetate gives the expected adduct 7a and, after de- zag-like outstretched conformation which, upon electrophilic
hydration, vitamin A acetate only in poor yield. The same is trapping, directly and exclusively leads to the all-(E) config-
true for the analogous reaction with 2,7-dimethyl-2,4,6-octa- uration.
3-Methoxy-3-methyl-1-(2,6,6-trimethyl-1-cyclohexenyl)-
1,4-pentadiene (1), quantitatively obtained by the treatment
of vinyl-β-ionol with sodium hydride and methyl iodide in
tetrahydrofuran or with dimethyl sulfate in the presence of
sodium hydroxide under phase-transfer conditions, is read-
ily cleaved by lithium metal or sodium/potassium alloy. The
resulting heptatrienyl-type organometallic C15 entity[1Ϫ3]
can be trapped by standard electrophiles to afford, for ex-
ample, the hydrocarbon 3, the silane 4 or the alcohol 5. As
we have found more recently, the same C15 species can be
generated conveniently by the deprotonation of 3-methyl-5-
(2,6,6-trimethyl-1-cyclohexenyl)-1,3-pentadiene (2) with
sec-butyllithium or the superbasic mixture of butyllithium
and potassium tert-butoxide. The required triene is easily
prepared by a Wittig olefination of (E)-2-methyl-4-(2,6,6-
trimethyl-1-cyclohexenyl)-2-butenal,[4Ϫ5] the key building
block in the Isler/Hoffmann-LaRoche syntheses of vitamin
A[5Ϫ7] and β-carotene.[7Ϫ8]
(E)-3-Formyl-2-butenyl acetate is, along with vinyl-β-
ionol, the major component of the Pommer/BASF
route[9Ϫ10] to vitamin A. When this aldehyde was allowed
to react with the organometallic C15 species, regardless of
[a]
´
Section de Chimie (BCh), Universite,
1015 Lausanne, Switzerland
Fax: (internat.) ϩ41-21/692-3965
Eur. J. Org. Chem. 2001, 3903Ϫ3909
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/1020Ϫ3903 $ 17.50ϩ.50/0
3903

G. Rauchschwalbe, A. Zellner, M. Schlosser
FULL PAPER
whether it was generated from the ether 1 or the triene 2,
the adduct 7a was indeed obtained, although only in poor
yield (around 30%). Substantial amounts (20Ϫ25%) of the
ketone 6 and the hydrocarbon 3 invariably formed as by-
products. Obviously, the organometallic intermediate does
not discriminate sufficiently between the two functional
groups of the C5 electrophile. By attack of the ester function
and ensuing acetyl transfer, it forms the β,γ-unsaturated ke-
tone 6, and by deprotonation of the latter the hydrocarbon
3. The adduct 7a can be acetylated to give the diacetate
7b, hydrolyzed to afford the diol 7c and, with phosphorus
tribromide, it can be converted into the bromoester 8, which
can be dehydrobrominated in situ with 1,5-diazo-5-bicyclo-
[4.3.0]nonene to afford vitamin A acetate (9, 31%).
Aldehydes are known to lack regioselectivity when com-
bining with delocalized polar organometallics.[11Ϫ12] Pre-
sumably for this reason, even simple aldehydes harboring
no additional functional groups give only moderate yields.
Thus, the adducts 10 and 11 derived from tiglic aldehyde
and benzaldehyde are isolated in not more than 57% and
68% yield. The twofold reaction performed with terephthal
dehyde affords a still lower yield of the diol 12 (39%). The
product is presumably composed of a 1:1 meso/dl mixture
which apparently crystallizes as a molecular compound, as
evidenced by a narrow melting range (mp 35Ϫ37 °C).
The C20 backbone of vitamin A can be assembled by con-
necting C15 ϩ C5 modules (‘‘Pommer pattern’’) or C14
ϩ
C6 modules (‘‘Isler pattern’’). To elaborate an organoalkali
version of the second option too, we have first combined
the organometallic C6 unit[12,14,15] generated from 3-methyl-
1,4-pentadiene with butyllithium, in the presence or absence
Despite the discouraging yield encountered with tereph- of potassium tert-butoxide, with the C14 aldehyde men-
thaldehyde, our organometallic C15 building block was al- tioned above. Burgess dehydration[13] of the resulting C20
lowed to react with another difunctional electrophile. The alcohol 15 (84%) gave the pentaene 16 (81%). The latter
addition to (2E,4E,6E)-2,7-dimethyl-2,4,6-octatrienedial af- was converted into pure all-trans vitamin A acetate (9; 41%)
forded the diol 13 (39%). Dehydration of the latter using by the consecutive treatment with lithium diisopropylamide,
Burgess’ reagent [(methoxycarbonylsulfamoyl)triethylam- fluorodimethoxyborane, hydrogen peroxide and acetic acid
monium hydroxide][13] afforded β-carotene (14) in 32% yield anhydride. No trace of stereoisomers was detected by chro-
(relative to the dialdehyde).
matography.
3904
Eur. J. Org. Chem. 2001, 3903Ϫ3909

The Organoalkali Route to Vitamin A and β-Carotene
FULL PAPER
and -potassiums carrying branching alkyl groups at the
anti-nodal positions exhibit a marked tendency to adopt a
W-shaped (zigzag-like) structure, with a maximally out-
stretched geometry.[2,15] This gives rise to all-(E) configura-
tions upon electrophilic trapping.
The heptatrienyl type C15 and the undecapentadienyl
type C20 species clearly follow this trend and favor the zig-
zag-like outstretched conformation. After electrophilic in-
terception, the all-(E) isomers were found exclusively. Thus,
these organometallic intermediates offer effortless and
spontaneous stereoselectivity.
Experimental Section
General: For standard procedures and abbreviations, see an earlier
publication from this laboratory.[25] 1H and 13C NMR spectra were
recorded at 400 and 101 MHz, respectively, all samples being dis-
solved in deuterochloroform. The DEPT[26] sequence was employed
to corroborate critical structure assignments.
2-[(1E)-3-Methoxy-3-methyl-1,4-pentadienyl]-1,3,3-trimethyl-
cyclohexene (1): (E)-3-methyl-1-(2,6,6-trimethyl-1-cyclohexenyl)-
1,4-pentadien-3-ol[27Ϫ29] (26 mL, 22 g, 0.10 mol) in tetrahydrofuran
(25 mL) was added dropwise, in the course of 15 min., to a suspen-
sion of sodium hydride (7.2 g, 0.30 mol) in tetrahydrofuran (25 mL)
containing methyl iodide (9.4 mL, 21 g, 0.15 mol) with vigorous
stirring. As soon as the gas evolution had ceased the mixture was
heated under reflux (ഠ75 °C) for 1 h. Upon distillation a colorless
liquid was collected; bp 143Ϫ145 °C/8 Torr; n2D0 ϭ 1.4901; yield
22.1 g (94%). Ϫ 1H NMR: δ ϭ 6.04 (d, J ϭ 16.4 Hz, 1 H), 5.91
(dd, J ϭ 17.6, 10.8 Hz, 1 H), 5.42 (d, J ϭ 16.3, 1 H), 5.23 (d, J ϭ
17.6, 1 H), 5.17 (d, J ϭ 10.8 Hz, 1 H), 3.24 (s, 3 H), 1.98 (t, J ϭ
6.1 Hz, 2 H), 1.68 (s, 3 H), 1.6 (m, 2 H), 1.5 (m, 2 H), 1.40 (s, 3
H), 1.00 (s, 3 H). Ϫ 13C NMR: δ ϭ 142.1 (CH), 137.2 (C), 136.5
(CH), 128.2 (CH), 128.0 (C), 114.2 (CH2), 78.2 (C), 50.8 (CH3,
39.4 (CH3), 33.9 (C), 32.5 (CH2), 28.8 (CH3), 23.8 (CH3), 21.4
(CH3), 19.2 (CH2). Ϫ MS: m/z (%) ϭ 234 (56), [Mϩ], 219 (29), 203
(65), 133 (43), 119 (100), 105 (83), 85 (34). Ϫ C16H26O (234.38):
The new routes leading to vitamin A and β-carotene are
compromised by moderate or even poor yields. For this calcd. C 81.99, H 11.18; found C 82.05, H 11.08.
reason, they have little chance of competing with optimized
1,3,3-Trimethyl-2-[(2E)-3-methyl-2,4-pentadienyl]cyclohexene
(2):
The ‘‘instant ylide’’[30Ϫ31] mixture of methyltriphenylphosphonium
bromide (89 g, 0.25 mol) and sodium amide (9.8 g, 0.25 mol) was
suspended in diethyl ether (0.15 L). After 45 min. of vigorous stir-
ring, (E)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexenyl)-2-butenal[4Ϫ5]
(57 mL, 52 g, 0.25 mol) was added. After a further 45 min. the
mixture was poured into ice-cold hexanes (0.50 L). The solution
was decanted from the pasty precipitate and filtered through kiesel-
guhr (diatomite). Distillation gave a colorless liquid; bp 90Ϫ92 °C/
1 Torr (ref.:[32] bp 60Ϫ62 °C/0.1 Torr); n2D0 ϭ 1.5141; yield 44.0 g
(87%). Ϫ 1H NMR: δ ϭ 6.37 (dd, J ϭ 17.5, 10.9 Hz, 1 H), 5.35
(t, J ϭ 6.6 Hz, 1 H), 5.08 (d, J ϭ 17.5 Hz, 1 H), 4.91 (d, J ϭ
10.9 Hz, 1 H), 2.86 (d, J ϭ 6.5 Hz, 2 H), 1.94 (t, J ϭ 6.2 Hz, 2 H),
1.79 (s, 3 H), 1.66 (m, 2 H), 1.55 (s, 3 H), 1.4 (m, 2 H), 0.98 (s, 6
H). Ϫ 13C NMR: δ ϭ 141.6 (CH), 136.1 (C), 134.4 (CH), 132.5
(C), 128.1 (C), 109.8 (CH2), 39.7 (CH2), 34.5 (C), 32.8 (CH2), 28.2
(CH3), 27.5 (CH2), 19.7 (CH3), 19.5 (CH2), 11.7 (CH3). Ϫ MS:
m/z (%) ϭ 204 (12) [Mϩ], 133 (41), 119 (100), 105 (75), 93 (79),
81 (63).
industrial processes. Although some critical steps could be
improved significantly, the disappointing regioselectivity of
the delocalized polar organometallic species towards alde-
hydes will always remain a serious handicap that is tough
to control or to compensate for. Regiochemical unreliability
is a problem that only afflicts reactions driven by an elec-
tron flow from charge-excess to slightly electrophilic cen-
ters. In contrast, only the terminal positions are linked to-
gether when olefins become attached to delocalized cations,
for example to the carbenium-oxonium ions acting as the
key intermediates in enamine condensations of the Müller-
Cunradi and Pieroh type,[16Ϫ20] or their modern dienether
extensions.[21Ϫ24]
The singular and most fascinating feature of polar
pentadienyl-, heptatrienyl- and nonatetraenylmetal com-
pounds is their stereochemical behavior. Whereas penta-
dienylpotassium and 2,4-dialkyl-substituted congeners coil
up in tetrahydrofuran solution to form a U-shaped (horse-
1,3,3-Trimethyl-2-[(1E,3E)-3-methyl-1,3-pentadienyl]cyclohexene
shoe-like) open-sandwich structure, pentadienyllithiums (3): Butyllithium (25 mmol) in hexanes (20 mL) and (E)-3-methyl-
Eur. J. Org. Chem. 2001, 3903Ϫ3909 3905

G. Rauchschwalbe, A. Zellner, M. Schlosser
FULL PAPER
5-(2,6,6-trimethyl-1-cyclohexenyl)-1,3-pentadiene (2; 5.4 mL, 5.1 g, biphenyl/lithium (1:1) adduct (hydrobiphenylyllithium, 50 mmol) in
25 mmol) were added consecutively to a suspension of potassium
tetrahydrofuran (0.10 L) was added dropwise to ether 1 (5.8 g,
tert-butoxide (2.8 g, 25 mmol) in hexanes (25 mL). After 1 h of vig- 25 mmol) in tetrahydrofuran (25 mL). At the end of the addition
orous stirring at 25 °C, the solvent was stripped off and replaced
the bluish-green color persisted, but disappeared as soon as the
by precooled (Ϫ75 °C) tetrahydrofuran (50 mL). The red solution solution was treated, still at Ϫ75 °C, with (E)-4-acetoxy-2-methyl-
was then immediately treated with a precooled (Ϫ75 °C) solution
of hydrogen chloride (25 mmol) in diethyl ether (10 mL). The mix-
2-butenal[39Ϫ43] (3.3 mL, 3.6 g, 15 mmol) and, 15 min. later, with
acetic acid anhydride (4.7 mL, 5.1 g, 50 mmol). Chromatography
ture was absorbed on silica gel (10 mL) and the powder, when dry, on thoroughly degassed (ultrasound!) and nitrogen-saturated silica
poured on top of a column filled with more silica gel (0.25 L). gel (0.30 L) in the dark, using degassed eluents with progressively
Elution with a 1:4 (v/v) mixture of diethyl ether and hexane, fol-
increasing polarity (diethyl ether/hexanes mixture varying from 0:1
lowed by distillation, afforded a colorless liquid; bp 90Ϫ91 °C/ over 1:4 to 1:2) enabled the isolation, along with other products
0.5 Torr (ref.:[33] bp 70Ϫ75 °C/0.1 Torr); n2D0 ϭ 1.4611; yield 3.7 g
(e.g., 31% of hydrocarbon 3), of the diacetate 7b as a yellowish
(73%). Ϫ H NMR: δ ϭ 6.03 (d, J ϭ 16.6 Hz, 1 H), 5.98 (d, J ϭ liquid; m.p. Ϫ34 to Ϫ32 °C; n2D0 ϭ 1.5651; yield 3.1 g (32%). Ϫ H
16.6 Hz, 1 H), 5.51 (q, J ϭ 7.0 Hz, 1 H), 2.01 (t, J ϭ 8.8 Hz, 2 H), NMR: δ ϭ 6.03 (d, J ϭ 16.4 Hz, 1 H), 5.98 (d, J ϭ 16.4 Hz, 1 H),
1.80 (s, 3 H), 1.77 (d, J ϭ 7.0 Hz, 3 H), 1.70 (s, 3 H), 1.6 (m, 2 H), 5.59 (t, J ϭ 6.9 Hz, 1 H), 5.28 (t, J ϭ 7.2 Hz, 1 H), 5.19 (t, J ϭ
1.5 (m, 2 H), 1.03 (s, 6 H). Ϫ 13C NMR: δ ϭ 137.9 (C), 137.9 6.6 Hz, 1 H), 4.62 (d, J ϭ 6.9 Hz, 2 H), 2.55 (dt, J ϭ 15.1, 7.2 Hz,
1
1
(CH), 134.9 (C), 128.2 (C), 125.3 (CH), 124.0, CH), 39.7 (CH2),
1 H), 2.46 (dt, J ϭ 15.1, 6.6 Hz, 1 H), 2.05 (s, 3 H), 2.04 (s, 3 H),
34.4 (C), 33.1 (CH2), 29.1 (CH3), 21.6 (CH3), 19.4 (CH2), 13.8 1.99 (t, J ϭ 6.2 Hz, 2 H), 1.78 (s, 3 H), 1.71 (s, 3 H), 1.67 (s, 3 H),
(CH3), 11.9 (CH3). Ϫ MS: m/z (%) ϭ 204 (16) [Mϩ ϩ H], 204 (13) 1.6 (m, 2 H), 1.4 (m, 2 H), 1.01 (s, 6 H). Ϫ 13C NMR: δ ϭ 170.8
[Mϩ], 189 (9), 133 (44), 119 (100).
(C), 170.0 (C), 138.4 (C), 137.7 (C), 137.4 (CH), 136.4 (C), 128.5
(C), 125.1 (CH), 124.5 (CH), 121.4 (CH), 77.5 (CH), 60.6 (CH2),
39.4 (CH2), 34.0 (C), 32.7 (CH2), 31.7 (CH2), 28.7 (CH3), 21.6
(CH3), 21.1 (CH3), 20.9 (CH3), 19.2 (CH2), 12.6 (CH3), 12.3 (CH3).
Ϫ MS: m/z (%) ϭ 388 (2) [Mϩ], 328 (23), 253 (27), 203 (52), 119
(100), 105 (87), 83 (53). Ϫ C24H36O4 (388.54): calcd. C 74.19, H
9.34; found C 74.12, H 9.50.
[(2E,4E)-3-Methyl-5-(2,6,6-trimethyl-1-cyclohexenyl)-2,4-penta-
dienyl]trimethylsilane (4): An analogous reaction was quenched
with chlorotrimethylsilane (3.2 mL, 2.7 g, 25 mmol) to give a color-
less liquid; bp 114Ϫ115 °C/0.1 Torr (ref.:[34] bp 110 °C/0.4 Torr);
n2D0 ϭ 1.5617; yield 4.9 g (71%). Ϫ 1H NMR: δ ϭ 6.04 (d, J ϭ
16.3 Hz, 1 H), 5.89 (d, J ϭ 16.3 Hz, 1 H), 5.49 (t, J ϭ 8.9 Hz, 1
H), 2.01 (t, J ϭ 6.6 Hz, 2 H), 1.74 (s, 3 H), 1.71 (s, 3 H), 1.6 (m, 2
H), 1.5 (m, 2 H), 1.03 (s, 6 H), 0.02 (s, 9 H). Ϫ 13C NMR: δ ϭ
138.3 (CH), 138.0 (C), 131.9 (C). 127.8 (C), 127.5 (CH), 122.5
(CH), 122.1 (CH), 39.5 (CH2), 34.2 (C), 32.9 (CH2), 29.3 (CH3),
21.5 (CH3), 19.9 (CH2), 19.3 (CH2), 12.0 (CH3), Ϫ1.6 (CH3).
Virtually the same result was found when the organometallic C15
intermediate was generated from the triene 2 (25 mmol) by reaction
with butyllithium activated with potassium tert-butoxide (as de-
scribed for the preparation of the hydrocarbon 3) rather than by
the biphenyl/lithium-promoted reductive cleavage of ether 1 (see
above).
(2E,4E)-3-Methyl-5-(2,6,6-trimethyl-1-cyclohexenyl)-2,4-pentadien-
1-ol (5): An analogous reaction, performed as described above (see
preparation of hydrocarbon 3), was terminated by the consecutive
addition of fluorodimethoxyborane diethyl etherate[35Ϫ36] (7.5 mL,
6.6 g, 40 mmol), 30% aqueous hydrogen peroxide (4.0 mL,
40 mmol) and a 3.0  aqueous solution (15 mL) of sodium hydrox-
ide (45 mmol). After stirring for 1 h at 25 °C, the product was isol-
ated by chromatography (support: silica gel; eluent: diethyl ether
and hexanes in a 2:3 ratio) and distillation as a colorless liquid; bp
(2E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2,6,8-
nonatriene-1,4-diol (7c): A reaction mixture was prepared in the
same way as above but, after the addition of acetic acid anhydride,
it was treated with ammonium dihydrogen phosphate (25 g, 0.21
mol) in water (50 mL) for 1 h at 25 °C and then with sodium hydro-
gen sulfite (5.0 g, 48 mmol) for 15 min. The organic layer obtained
after extraction under nitrogen with diethyl ether (3 ϫ 25 mL) and
washing with brine (3 ϫ 25 mL), was concentrated and submitted
to chromatography on degassed silica gel (0.25 L) applying a hex-
anes Ǟ diethyl ether gradient for the elution. The products were
collected in this order: hydrocarbon 3 (1.0 g, 20%), biphenyl (7.7 g,
132Ϫ134 °C/0.1 Torr (ref.:[37] bp 140Ϫ145 °C/0.3 Torr); n2D0
ϭ
1
1.4756; yield 3.0 g (54%). Ϫ H NMR: δ ϭ 6.15 (d, J ϭ 16.1 Hz,
1 H), 6.04 (d, J ϭ 16.1 Hz, 1 H), 5.63 (t, J ϭ 7.0 Hz, 1 H), 4.31
(d, J ϭ 7.0 Hz, 2 H), 2.01 (t, J ϭ 6.2 Hz, 2 H), 1.86 (s, 3 H), 1.69
(s, 3 H), 1.6 (m, 2 H), 1.5 (m, 2 H), 1.01 (s, 3 H). Ϫ 13C NMR:
δ ϭ 137.8 (C), 137.2 (CH), 136.7 (C), 129.0 (C), 128.7 (CH), 126.9
(CH), 59.3 (CH2), 39.5 (CH2), 34.2 (C), 32.9 (CH2), 28.9 (CH3),
21.7 (CH3), 19.4 (CH2), 12.4 (CH3). Ϫ MS: m/z (%) ϭ 220 (8)
[Mϩ], 203 (7), 159 (5), 133 (16), 119 (100), 105 (38), 91 (21), 77 (11).
98%),
(4E,6E)-5-methyl-7-(2,6,6-trimethyl-1-cyclohexenyl)-4,6-
heptadien-2-one (6, see above; 1.4 g, 22%) and diol (6c; 2.1 g, 28%).
The latter product, a yellow oil, was purified by crystallization from
pentane; m.p. 69.0Ϫ71.5 °C; yield 2.0 g (26%). Ϫ 1H NMR: δ ϭ
6.05 (s, 2 H), 5.68 (t, J ϭ 7.0 Hz, 1 H), 5.35 (t, J ϭ 7.5 Hz, 1 H),
4.17 (d, J ϭ 7.0 Hz, 2 H), 4.06 (t, J ϭ 7.0 Hz, 1 H), 3.05 (s, 1 H),
2.41 (t, J ϭ 7.0 Hz, 2 H), 1.8 (m, 15 H), 1.0 (s, 6 H). Ϫ MS: m/z
(%) ϭ 304 (2) [Mϩ], 66 (100). Ϫ C20H32O2 (304.47): calcd. C 79.90,
H 10.59; found C 79.11, H 10.66.
NOESY[38] cross peaks between δ ϭ 4.31 and 1.86 and δ ϭ 6.04
and 5.63 corroborated the assigned (E,E) configuration.
(4E,6E)-5-Methyl-7-(2,6,6-trimethyl-1-cyclohexenyl)-4,6-heptatrien-
2-one (6): An analogous reaction was carried out with acetyl chlor-
ide (25 mL, 28 g, 35 mmol; inverse addition). The product was isol-
ated by distillation as a colorless liquid; bp 131Ϫ133 °C/1 Torr;
yield 4.2 g (68%). Ϫ 1H NMR: δ ϭ 6.08 (s, 2 H), 5.63 (t, J ϭ
7.0 Hz, 1 H), 3.33 (d, J ϭ 7.0 Hz, 2 H), 2.10 (s, 3 H), 1.7 (m, 12
H), 1.00 (s, 6 H). Ϫ MS: m/z (%) ϭ 146 [Mϩ], 43 (100). Ϫ C17H26O
(246.39): calcd. C 82.87, H 10.64; found C 82.94, H 10.99.
(2E,6E,8E)-4-Hydroxy-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclo-
hexenyl)-2,6,8-nonatriene Acetate (7a): The reaction was repeated
as described above (see the preparation of diacetate 7b) but, after
the addition of the aldehyde, the mixture was treated with acetic
acid (2.9 mL, 3.1 g, 50 mmol) rather than with its anhydride. Elu-
tion from silica gel with a 1:4 (v/v) mixture of diethyl ether and
hexanes afforded an almost colorless oil; m.p. Ϫ27 to Ϫ25 °C; yield
1
2.4 g (28%). Ϫ H NMR: δ ϭ 6.04 (s, 2 H), 5.63 (t, J ϭ 6.9 Hz, 1
(2E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2,6,8- H), 5.39 (t, J ϭ 7.2 Hz, 1 H), 4.65 (d, J ϭ 6.9 Hz, 2 H), 4.12 (t,
nonatriene-1,4-diyl Diacetate (7b): At Ϫ75 °C, a 0.5  solution of
J ϭ 6.3 Hz, 1 H), 2.44 (t, J ϭ 6.9 Hz, 2 H), 2.06 (s, 3 H), 2.00 (t,
Eur. J. Org. Chem. 2001, 3903Ϫ3909
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The Organoalkali Route to Vitamin A and β-Carotene
FULL PAPER
J ϭ 6.3 Hz, 2 H), 1.82 (s, 3 H), 1.79 (s, 3 H), 1.69 (s, 3 H), 1.6 (m, (3E,5E)-4-Methyl-1-phenyl-6-(2,6,6-trimethyl-1-cyclohexenyl)-3,5-
2 H), 1.5 (m, 2 H), 1.01 (s, 6 H). Ϫ 13C NMR: δ ϭ 170.9 (C), 142.6 hexadien-1-ol (11): This reaction was performed as above but with
(C), 137.6 (C), 137.4 (CH), 136.4 (C), 128.3 (C), 125.9 (CH), 124.9 benzaldehyde (2.5 mL, 2.6 g, 25 mmol) instead of tiglic aldehyde;
1
(CH), 119.3 (CH), 75.9 (CH), 60.7 (CH2), 39.3 (CH2), 34.0 (CH2), m.p. Ϫ49 to Ϫ47 °C; n2D0 ϭ 1.4619; yield 5.3 g (68%). Ϫ H NMR:
33.9 (C), 32.7 (CH2), 28.6 (CH3), 21.4 (CH3), 20.7 (CH3), 19.0
δ ϭ 7.4 (m, 4 H), 7.3 (m, 1 H), 6.03 (s, 2 H), 5.46 (dd, J ϭ 7.9,
(CH2), 12.2 (CH3), 12.1 (CH3). Ϫ MS: m/z (%) ϭ 304 (5) [Mϩ], 6.6 Hz, 1 H), 4.77 (ddd, J ϭ 7.9, 6.6, 3.3 Hz, 1 H), 2.68 (dt, J ϭ
203 (58), 119 (100), 105 (78), 83 (68). Ϫ C22H34O3 (346.51): calcd. 14.6, 7.9 Hz, 1 H), 2.59 (dt, J ϭ 14.6, 6.6 Hz, 1 H), 2.02 (d, J ϭ
C 76.26, H 9.89; found C 75.62, H 9.92.
3.3 Hz, 1 H), 2.01 (t, J ϭ 6.2 Hz, 2 H), 1.79 (s, 3 H), 1.70 (s, 3 H),
1.6 (m, 2 H), 1.5 (m, 2 H), 1.02 (s, 3 H). Ϫ 13C NMR: δ ϭ 144.0
(C), 137.6 (C), 137.4 (CH), 136.8 (C), 128.8 (C), 127.3 (CH), 125.9
(CH), 125.6 (CH), 125.1 (CH), 73.9 (CH), 39.4 (CH2), 38.3 (CH2),
34.0 (C), 32.6 (CH2), 28.8 (CH3), 21.6 (CH3), 19.3 (CH2), 12.5
(CH3). Ϫ MS: m/z (%) ϭ 310 (12), 293 (7), 204 (55), 189 (14), 173
(5), 147 (11), 133 (36), 119 (99), 105 (100), 91 (39), 77 (62). Ϫ
C22H30O (314.48): calcd. C 85.11, H 9.74; found C 85.04, H 9.81.
(2E,6E,8E)-4-Bromo-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclo-
hexenyl)-2,6,8-nonatrienyl acetate (8): At Ϫ75 °C, phosphorus tri-
bromide (0.95 mL, 2.7 g, 10 mmol) was added to a solution of the
hydroxyacetate 7a (3.5 g, 10 mmol) in dichloromethane (20 mL).
The mixture was allowed to warm to 25 °C before it was poured
onto ice (25 g). The organic layer was decanted, washed with brine
(25 mL), dried and the solvents were evaporated. The dark-green
residue (3.2 g, crude) proved to be too unstable to be purified.
1,4-Phenylenebis-1,1Ј-[(3E,5E)-4-methyl-6-(2,6,6-trimethyl-1-cyclo-
hexenyl)-3,5-hexadien-1-ol] (12): This reaction was performed as
above but with terephthaldehyde (1.6 g, 12 mmol) instead of tiglic
(2E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2,4,6,8-
nonatetraenyl Acetate (vitamin A acetate, 9): At Ϫ75 °C, 1,5-diaza-
5-bicyclo[4.3.0]nonene (‘‘DBN’’, 2.4 mL, 2.5 g, 20 mmol) was ad-
ded to a solution of the crude bromo compound 8 (see above) dis-
solved in hexanes (50 mL). After 6 h at 25 °C, the mixture was
absorbed on degassed alumina (0.35 L, Brockmann activity I) and
eluted in the dark with diethyl ether and hexanes in a volume ratio
of 1:9. The yellowish oil obtained was crystallized from pentanes;
colorless needles; m.p. 54Ϫ56 °C (ref.:[6,44] m.p. 57Ϫ58 °C); yield
1
aldehyde; colorless pillars; m.p. 35Ϫ36 °C; yield 3.2 g (49%). Ϫ H
NMR: δ ϭ 7.38 (s, 2 H), 6.04 (s, 2 H), 5.46 (t, J ϭ 7.2 Hz, 1 H),
4.8 (m, 1 H), 2.68 (dt, J ϭ 14.9, 7.2 Hz, 1 H), 2.59 (dt, J ϭ 14.9,
5.9 Hz, 1 H), 2.01 (t, J ϭ 6.0 Hz, 2 H), 1.99 (d, J ϭ 3.4 Hz, 1 H),
1.80 (s, 3 H), 1.69 (s, 3 H), 1.6 (m, 2 H), 1.5 (m, 2 H), 1.02 (s, 6
H). Ϫ 13C NMR: δ ϭ 143.5 (C), 137.5 (C), 137.2 (CH), 137.1 (C),
128.5 (C), 125.9 (CH), 125.8 (CH), 125.4 (CH), 73.9 (CH), 39.6
(CH2), 38.4 (CH2), 34.2 (C), 32.6 (CH3), 28.9 (CH3), 21.7 (CH3),
19.3 (CH2), 12.6 (CH3). Ϫ C38H54O2 (542.84): calcd. C 84.04, H
10.03; found C 83.91, H 9.87.
1
1.0 g (31%). Ϫ H NMR: δ ϭ 6.65 (dd, J ϭ 15.1, 11.4 Hz, 1 H),
6.29 (d, J ϭ 15.1 Hz, 1 H), 6.19 (d, J ϭ 15.8 Hz, 1 H), 6.13 (d, J ϭ
15.8 Hz, 1 H), 6.09 (d, J ϭ 11.4 Hz, 1 H), 5.62 (t, J ϭ 7.3 Hz, 1
H), 4.74 (d, J ϭ 7.3 Hz, 2 H), 2.08 (s, 3 H), 2.02 (t, J ϭ 6.2 Hz, 2
H), 1.97 (s, 3 H), 1.90 (s, 3 H), 1.72 (s, 3 H), 1.6 (m, 2 H), 1.5 (m,
2 H), 1.03 (s, 6 H). Ϫ 13C NMR: δ ϭ 171.3 (C), 139.2 (CH), 137.7
(C), 137.5 (CH, 136.5 (CH), 135.7 (C), 129.3 (C), 127.0 (CH), 125.8
(C), 124.4 (CH), 61.3 (CH2), 39.6 (CH2), 34.2 (C), 33.1 (CH2), 29.0
(CH3), 21.6 (CH2), 21.0 (CH3), 19.2 (CH2), 12.6 (CH3). Ϫ MS: m/
z (%) ϭ 328 (65) [Mϩ], 269 (100), 253 (53), 119 (36), 105 (51),
91 (45).
(1E,3E,7E,9E,11E,15E,17E)-3,7,12,16-Tetraamethyl-1,18-bis(2,6,6-
trimethyl-1-cyclohexenyl)-1,3,7,9,11,15,17-octadecaheptaene-6,13-
diyl diacetate (13): This reaction was performed as above but with
(2E,4E,6E)-2,7-dimethyl-2,4,6-octatrienedial[45Ϫ47] (2.0 g, 12 mmol)
instead of tiglic aldehyde. However, instead of being hydrolyzed,
the adduct was treated at Ϫ75 °C with acetic acid anhydride
(4.7 mL, 5.1 g, 50 mmol). Elution from alumina (0.30 L,
Brockmann activity I) with a 2:3 (v/v) mixture of diethyl ether and
hexanes afforded a faintly yellowish oil; m.p. Ϫ18 to Ϫ15 °C; nD20
ϭ
(2E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2,6,8-
nonatrien-4-ol (10): The triene 2 (5.4 mL, 5.1 g, 25 mmol) was
treated with butyllithium in the presence of potassium tert-butoxide
as described previously (see the preparation of the hydrocarbon
3). (E)-2-Methyl-2-butenal (tiglic aldehyde; 2.4 mL, 2.1 g, 25 mmol)
was added to the solution of the organometallic intermediate in
neat tetrahydrofuran (50 mL) cooled to Ϫ75 °C. After warming to
25 °C, the reaction mixture was neutralized with a saturated aque-
ous solution of ammonium chloride (50 mL) and exhaustively ex-
tracted with diethyl ether (5 ϫ 20 mL). The combined organic
layers were dried, concentrated and absorbed on silica gel (50 mL).
1
1.5721; yield 3.2 g (41%). Ϫ H NMR: δ ϭ 6.4 (m, 1 H), 6.1 (m, 1
H), 6.03 (d, J ϭ 16.8 Hz, 1 H), 5.98 (d, J ϭ 16.8 Hz, 1 H), 5.28 (t,
J ϭ 6.8 Hz, 1 H), 5.22 (d, J ϭ 6.8 Hz, 1 H), 2.58 (dt, J ϭ 15.2,
7.5 Hz, 1 H), 2.47 (dt, J ϭ 15.2, 6.8 Hz, 1 H), 2.06 (s, 3 H), 1.99
(t, J ϭ 6.0 Hz, 2 H), 1.80 (s, 6 H), 1.68 (s, 3 H), 1.6 (m, 2 H), 1.5
(m, 2 H), 1.00 (s, 6 H). Ϫ C44H64O4 (656.99): calcd. C 80.44, H
9.82; found C 80.51, H 9.91.
all-(E)-1,1Ј-(3,7,12,16-Tetramethyl-1,3,5,7,9,11,13,15,17-octa-
decanonaene-1,18-diyl)bis(2,6,6-trimethylcyclohexene) [β,β-carotene;
When dry, the powder was poured on top of a column filled with 14]: The reaction was performed as described in the preceding para-
more silica gel (0.30 L) and eluted with a 2:3 (v/v) mixture of di- graph, the only difference being that acetic acid anhydride was re-
ethyl ether and hexanes to collect a yellowish oil; m.p. Ϫ38 to Ϫ36 placed by triethyl(methoxycarbonylsulfamoyl)ammonium hydrox-
°C; nD20 ϭ 1.5153; yield 4.1 g (57%). Ϫ 1H NMR: δ ϭ 6.03 (s, 1 H), ide[13] (7.1 g, 30 mmol). After 1 h at 25 °C, the mixture was poured
5.53 (q, J ϭ 6.9 Hz, 1 H), 5.39 (dd, J ϭ 7.4, 6.3 Hz, 1 H), 4.08 (dd, into water (0.25 L) and extracted with hexanes (5 ϫ 25 mL). The
J ϭ 7.4, 6.3 Hz, 1 H), 2.47 (dt, J ϭ 15.1, 7.4 Hz, 1 H), 2.38 (dt, combined organic layers were dried and the solvents evaporated.
J ϭ 15.1, 6.3 Hz, 1 H), 2.01 (t, J ϭ 6.3 Hz, 2 H), 1.83 (s, 3 H), Chromatography (same conditions as above) of the residue in the
1.69 (s, 3 H), 1.69 (s, 3 H), 1.66 (d, J ϭ 6.9 Hz, 3 H), 1.6 (m, 2 H), dark and with strict exclusion of air gave a viscous, dark colored
1.5 (m, 2 H), 1.02 (s, 6 H). Ϫ 13C NMR: δ ϭ 137.6 (C), 137.5 oil that crystallized from a mixture of methanol and hexane as
(CH), 137.4 (C), 136.3 (C), 128.3 (C), 127.0 (CH), 125.7 (CH), violet platelets; m.p. 184Ϫ186 °C (dec.; ref.:[48] m.p. 182.0Ϫ182.5
1
120.7 (CH), 77.1 (CH), 39.7 (CH2), 34.5 (CH2), 34.3 (C), 32.9 °C); yield 2.3 g (36%). Ϫ H NMR: δ ϭ 6.6 (m, 2 H), 6.34 (d, J ϭ
(CH2), 28.9 (CH3), 21.6 (CH3), 19.4 (CH2), 13.2 (CH3), 12.7 (CH3), 14.6 Hz, 1 H), 6.3 (m, 1 H), 6.2 (m, 3 H), 2.04 (t, J ϭ 6.3 Hz, 2
11.4 (CH3). Ϫ MS: m/z (%) ϭ 271 (6), 204 (62), 189 (15), 147 (14), H), 1.73 (s, 3 H), 1.99 (s, 6 H), 1.6 (m, 2 H), 1.5 (m, 2 H), 1.05 (s,
133 (37), 119 (100), 105 (60), 91 (33), 85 (57). Ϫ C20H32O (288.47): 6 H). Ϫ 13C NMR: δ ϭ 138.8 (CH), 138.0 (C), 137.3 (CH), 136.4
calcd. C 83.27, H 11.18; found C 83.70, H 11.17.
(C), 136.0 (C), 132.4 (CH), 130.8 (CH), 130.0 (CH), 129.3 (C),
Eur. J. Org. Chem. 2001, 3903Ϫ3909
3907

G. Rauchschwalbe, A. Zellner, M. Schlosser
126.7 (CH), 125.1 (CH), 39.8 (CH2), 34.4 (C), 33.2 (CH2), 29.0 25 °C before being saturated with sodium chloride. The organic
FULL PAPER
(CH3), 21.7 (CH3), 19.4 (CH2), 12.8 (CH3).
layer was then decanted and the solvents evaporated. The residue
was dissolved in dichloromethane (50 mL) and pyridine (50 mL),
treated with acetyl chloride (3.6 mL, 3.9 g, 50 mmol) and kept 3 h
at 25 °C. The mixture was poured into ice-water (0.10 kg), the or-
ganic phase was decanted and the aqueous phase extracted with
dichloromethane (3 ϫ 30 mL). The combined organic layers were
washed with brine (2 ϫ 25 mL), concentrated and eluted in the
dark from degassed alumina (0.30 L, Brockmann grade I) with di-
ethyl ether/hexanes in the volume ratio of 1:9. The product, a
slightly yellowish oil, became colorless upon crystallization from
pentanes at Ϫ20 °C and exhibited the same physical and spectral
properties as specified above; yield 3.4 g (41%).
(2E,6E)-3,7-Dimethyl-1-(2,6,6-trimethyl-1-cyclohexenyl)-2,6,8-nona-
trien-4-ol (15): Potassium tert-butoxide (11 g, 0.10 mol) was added
to
a solution of butyllithium (0.10 mol) and 3-methyl-1,4-
pentadiene (12 mL, 8.2 g, 0.10 mol) in hexanes (0.20 L) at 0 °C.
The suspension was stirred vigorously for 45 min. The solvent was
stripped off under reduced pressure and replaced by precooled
(Ϫ75 °C) tetrahydrofuran (0.25 L). (E)-2-Methyl-4-(2,6,6-trimethyl-
1-cyclohexenyl)-2-butenal (22 mL, 21 g, 0.10 mol) was added drop-
wise in the course of 5 min. After 15 min. at Ϫ75 °C, the mixture
was allowed to reach 25 °C before being poured into a saturated
aqueous solution (0.25 L) of ammonium chloride. The product was
extracted with diethyl ether (3 ϫ 0.10 L) and absorbed on silica gel
(50 mL). When dry, the powder was added to a column filled with
more silica (0.50 L) and eluted with a 1:4 (v/v) mixture of diethyl
ether and hexane to afford a colorless, viscous oil; m.p. Ϫ41 to Ϫ38
°C; bp 168Ϫ170 °C/0.1 Torr; yield 24 g (84%). Ϫ 1H NMR: δ ϭ
6.34 (d, J ϭ 17.5, 10.7 Hz, 1 H), 5.42 (t, J ϭ 7.4 Hz, 1 H), 5.26 (t,
J ϭ 7.3 Hz, 1 H), 5.11 (d, J ϭ 17.5 Hz, 1 H), 4.95 (d, J ϭ 10.7 Hz,
1 H), 4.07 (t, J ϭ 6.8 Hz, 1 H), 2.73 (d, J ϭ 6.2 Hz, 2 H), 2.5 (m,
1 H), 2.4 (m, 1 H), 1.93 (t, J ϭ 6.2 Hz, 2 H), 1.77 (s, 3 H), 1.68 (s,
3 H), 1.6 (m, 2 H), 1.53 (s, 3 H), 1.4 (m, 2 H), 0.98 (s, 3 H), 0.96
(s, 3 H). Ϫ 13C NMR: δ ϭ 141.1 (CH), 136.3 (C), 135.8 (C), 134.8
(C), 128.6 (CH), 128.3 (CH), 127.8 (C), 110.9 (CH2), 77.3 (CH),
39.1 (CH2), 34.2 (C), 33.5 (CH2), 32.3 (CH2), 27.8 (CH3), 27.7
(CH3), 26.4 (CH2), 19.4 (CH3), 19.2 (CH2), 11.8 (CH3), 11.3 (CH3).
Ϫ MS: m/z (%) ϭ 288 (1) [Mϩ], 271 (7), 207 (37), 189 (22), 163 (10),
119 (89), 95 (83), 81 (100). Ϫ C20H32O (288.47): calcd. C 83.27, H
11.18; found C 82.93, H 10.82.
Acknowledgments
This work was financially supported by the Schweizerische Na-
tionalfonds zur Förderung der wissenschaftlichen Forschung, Bern
(grants 2-293-74, 2-467-75 and 20-49Ј307-96). The authors are in-
debted to Hoffmann-LaRoche, Basel, for complementary sponsor-
ship. Stimulating discussions with Drs. H. J. Mayer, U. Hengartner,
R. K. Müller and, in particular, A. Rüttimann were much appreci-
ated.
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1,3,3-Trimethyl-2-[(2E,4E,6E)-3,7-dimethyl-2,4,6,8-nona-
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14 g, 50 mmol) in tetrahydrofuran (50 mL) was added dropwise, in
the course of 15 min., to a solution of triethyl(methoxycarbonyl-
sulfamoyl)ammonium hydroxide[13] (13 g, 55 mmol) in tetrahy-
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into water (0.25 L). The product was extracted with diethyl ether
(3 ϫ 50 mL) before being purified by chromatography on alumina
(0.50 L, Brockmann grade I), with pentane as the eluent, and distil-
lation to afford a viscous colorless oil; m.p. Ϫ8 to Ϫ6 °C; bp
138Ϫ139 °C/0.1 Torr; yield 10.4 g (81%). Ϫ 1H NMR: δ ϭ 6.44
(dd, J ϭ 15.1, 11.1 Hz, 1 H), 6.43 (dd, J ϭ 17.2, 10.6 Hz, 1 H),
6.30 (d, J ϭ 15.1 Hz, 1 H), 6.11 (d, J ϭ 11.1 Hz, 1 H), 5.39 (t, J ϭ
6.8 Hz, 1 H), 5.18 (d, J ϭ 17.2 Hz, 1 H), 5.03 (d, J ϭ 10.6 Hz, 1
H), 2.86 (d, J ϭ 6.8 Hz, 2 H), 1.95 (t, J ϭ 6.4 Hz, 2 H), 1.89 (s, 3
H), 1.85 (s, 3 H), 1.6 (m, 2 H), 1.53 (s, 3 H), 1.4 (m, 2 H), 0.97 (s,
6 H). Ϫ 13C NMR: δ ϭ 141.3 (CH), 138.7 (CH), 136.0 (C), 135.2
(CH), 134.0 (C), 132.6 (C), 132.0 (CH), 128.0 (C), 121.9 (CH),
111.5 (CH2), 39.7 (CH2), 34.9 C), 32.8 (CH2), 28.2 (CH3), 27.8
(CH2), 19.7 (CH2), 19.5 (CH2), 12.5 (CH3), 12.0 (CH3). Ϫ MS: m/
z (%) ϭ 271 (100) [Mϩ ϩ H], 255 (27), 133 (44), 119 (72), 105 (51),
91 (50), 81 (28). Ϫ C20H30 (270.46): calcd. C 88.82, H 11.18; found
C 88.62, H 11.27.
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25 mmol), hexamethylphosphoric triamide (10 mL) and triene 16
(6.1 g, 25 mmol) were added consecutively to butyllithium
(25 mmol) in tetrahydrofuran (0.10 L) and hexanes (20 mL). After
15 h at Ϫ75 °C, the mixture was treated with fluorodimethoxybo-
rane diethyl etherate[35Ϫ36] (7.5 mL, 6.6 g, 40 mmol) and, 5 min.
later, with a 30% aqueous solution (8.0 mL) of hydrogen peroxide
(80 mmol) followed by a 3.0  aqueous solution (30 mL) of sodium
hydroxide (90 mmol). The mixture was stirred vigorously for 2 h at
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3908
Eur. J. Org. Chem. 2001, 3903Ϫ3909

The Organoalkali Route to Vitamin A and β-Carotene
FULL PAPER
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Received April 27, 2001
[O01208]
Eur. J. Org. Chem. 2001, 3903Ϫ3909
3909