Synthesis of symmetrical carotenoids by a two-fold Stille reaction

Article abstract of DOI:10.1021/jo025727f

β-Carotene 1 and (3R,3′R)-zeaxanthin 2 have been stereoselectively prepared in a highly convergent fashion by a 2-fold Stille cross-coupling reaction. The C_12-pentaenylbis-stannane 8 is the central "lynchpin" that connects two units of the terminal C₁₄-iodides 9 and 17 to afford 1 and 2, respectively.

Full text of DOI:10.1021/jo025727f

C12 + C14 building principle, featuring a 2-fold Stille cross-
coupling of C12-bis-stannane 8 and C14-alkenyl iodides 9
and 17, yielding â-carotene 1 and (3R,3′R)-zeaxanthin 2,
respectively.
Syn th esis of Sym m etr ica l Ca r oten oid s by a
Tw o-F old Stille Rea ction
Bele´n Vaz, Rosana Alvarez, and Angel R. de Lera*
Pentaenylbis-stannane 8 was prepared by the modified
one-pot J ulia olefination6 that condensates two C6 frag-
ments, both derived from known stannyldienol 3.7 The
synthesis of the required C6-sulfone 6 started with the
treatment of 3 with 2-mercaptobenzothiazole under Mit-
sunobu conditions to afford benzothiazolyl sulfide 5 (96%
yield). Oxidation of the sulfide to the sulfone was trouble-
some, and under the best conditions [Mo7O24(NH4)6‚4H2O,
35% H2O2, EtOH, 25 °C]6 afforded 6 in moderate yields
(61%) together with 7 (31%), the protiodestannylation
product.8,9
Generation of the anion of sulfone 6 with NaHMDS at
-78 °C, followed by addition of 4,7a afforded with high
stereoselectivity in 83% yield symmetrical all-E-pentaene
8,10 the longest substituted conjugated bis-stannane yet
reported.
Departamento de Quı´mica Orga´nica, Facultad de Ciencias,
Universidade de Vigo. 36200 Vigo, Spain
qolera@uvigo.es
Received March 18, 2002
Abstr a ct: â-Carotene 1 and (3R,3′R)-zeaxanthin 2 have
been stereoselectively prepared in a highly convergent
fashion by a 2-fold Stille cross-coupling reaction. The C12
pentaenylbis-stannane 8 is the central “lynchpin” that
connects two units of the terminal C14-iodides 9 and 17 to
afford 1 and 2, respectively.
-
Carotenoids1 are highly conjugated polyenes that play
fundamental roles as photoprotective and antioxidation
agents and are dietary sources of vitamin A and other
naturally ocurring retinoids.2,3
The carotenoid polyenic chain has traditionally been
synthesized by consecutive or convergent double bond
forming strategies, commonly a Wittig reaction (or some
of its variants) or a J ulia-type olefination.1c These pro-
cedures generally afford mixtures of E/ Z geometric
isomers which are very difficult to separate.
The trisubstituted alkenyl iodides 911a and 17 were in
turn prepared by Negishi’s methodology,11 using the
zirconium-assisted methylalumination-iodination of the
precursor alkynes. The synthesis of dienyne 15 started
with the protection of enantiopure (R)-10 to 1112a followed
(5) For standard nomenclature and numbering of carotenoids, see
(a) IUPAC Commission on Nomenclature of Organic Chemistry and
the IUPAC-IUB Commission on Biochemical Nomenclature. Pure
Appl. Chem. 1975, 41, 407. (b) Weedon, B. C. L.; Moss, G. P. Structure
and Nomenclature, in ref 1a, chapter 3, p 27.
(6) (a) Baudin, J . B.; Hareau, G.; J ulia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175. (b) Bellingham, R.; J arowicki, K.; Kocienski, P.
J .; Martin, V. Synthesis 1996, 285. (c) Blakemore, P. R.; Kocienski, P.
J .; Marzcak, S.; Wicha, J . Synthesis 1999, 1209. (d) Blakemore, P. R.;
Kocienski, P. J .; Morley, A.; Muir, K. J . Chem. Soc., Perkin Trans. 1
1999, 955. (e) Drew, M. G. B.; Harwood: L. M.; J ahaus, A.; Robertson,
J .; Swallow, S. Synlett 1999, 185.
The alternative strategy featuring generation of single
bonds connecting Csp2 atoms has somehow been ne-
glected for this particular class of conjugated polyenes.
Recently, however, Negishi and Zeng reported a stereo-
selective and highly efficient synthesis of carotenoids
using a Pd- and Zn-catalyzed cross-coupling of alkenyl
fragments. The nucleophile was generated by Al-Zn
transmetalation following zirconium-mediated methyl-
alumination of alkynes.4 Using two C5 and one C2 halides
as electrophiles, these C40 polyolefins were built by an
iterative sequence which displays a C14 + C5 + C2 + C5
+ C14 pattern.5
(7) (a) Yokakawa, F.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1993,
34, 6559. (b) Betzer, J .-F.; Delagoge, F.; Muller, B. Pancrazi, A.; Prunet,
J . J . Org. Chem. 1997, 62, 7768.
(8) Other experimental conditions proved unsuccessful. The use of
MCPBA in the presence of Na2CO3 or Et3N led to a mixture of products.
On the other hand, cat. TPAP/NMO in CH3CN (Guerlin, K. R.; Kende,
A. S. Tetrahedron Lett. 1993, 34, 5369) returned unreacted starting
material. The use of Oxone (Trost, B. M.; Curran, D. P. Tetrahedron
Lett. 1981, 22, 1287) in MeOH/H2O led to even greater amounts of 7.
In addition, no improvement was observed when the Mo(VI)-based
oxidant was slowly added to the solution of the sulfide in MeOH/H2O
or when base was added to neutralize the reaction medium.
(9) Sulfone 7 was obtained as an unseparable (HPLC) mixture of
E/Z isomers. Although we have not carried out detailed mechanistic
studies, the isolation of double bond isomers of 7 suggest the interven-
tion of a reversible allyl sulfoxide-allyl sulfenate rearrangement
following the initial oxidation of sulfide 5.
(10) For the use of other symmetrical bis-stannanes in organic
synthesis, see (a) (E,E)-1,4-bis(trimethylstannylbutadiene: Kiehl, A.;
Eberhardt, A.; Adams, M.; Enkelmann, V.; Mu¨llen, K. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 1588. Kiehl, A.; Eberhardt, A.; Mu¨llen, K.
Liebigs Ann. Chem. 1995, 223. (b) (E,E)-1,2-bis(tri-n-butylstannyl)-
ethylene: Nicolaou, K. C.; Chakraborty, T. K.; Piscopio, A. D.; Minowa,
N.; Bertinato, P. J . Am. Chem. Soc. 1993, 115, 4419. Panek, J . S.;
Masse, C. E. J . Org. Chem. 1997, 62, 8290. (c) (Z)-1,2-bis(tri-n-
butylstannyl)ethylene: Shair, M. D.; Yoon, T.; Danishefsky, S. J . J .
Org. Chem. 1994, 59, 3755.
We wish to report another stereocontrolled approach
to symmetrical carotenoids based on a convergent C14
+
* To whom correspondence should be addressed. Phone: 0034-986-
812316. Fax: 986-812556.
(1) For recent monographs, see (a) Britton, G.; Liaaen-J ensen, S.;
Pfander, H., Eds. Carotenoids. Part 1A. Isolation and Analysis;
Birkha¨user: Basel, 1995. (b) Britton, G.; Liaaen-J ensen, S.; Pfander,
H., Eds. Carotenoids. Part 1B. Spectroscopy; Birkha¨user: Basel, 1995.
(c) Britton, G.; Liaaen-J ensen, S.; Pfander, H., Eds. Carotenoids. Part
2. Synthesis; Birkha¨user: Basel, 1996.
(2) â-Carotene dioxygenases, enzymes that effect the centric cleavage
of â-carotene to retinal, have been characterized; see (a) Wyss, A.;
Wirtz, G.; Woggon, W.-D.; Brugger, R.; Wyss, M.; Friedlein, A.;
Bachmann, H.; Hunziker, W. Biochem. Biophys. Res. Commun. 2000,
271, 334. (b) von Linting, J .; Vogt, K. J . Biol. Chem. 2000, 275, 11915.
For a mechanistic proposal of the enzymatic reaction, see Leuenberger,
M. G.; Engeloch-J arret, C.; Woggon, W.-D. Angew. Chem., Int. Ed.
2001, 40, 2614.
(3) Vision is also believed to be affected by the intake of certain
hydroxylated carotenoids, such as zeaxanthin 2. Their suggested role
as optical filters and antioxidation agents is considered to help decrease
the risk of developing AMD (age-related macular degeneration), the
leading cause of blindness in elderly people; see Rando, R. R. Chem.
Biol. 1996, 3, 255.
(11) (a) Negishi, E.; King, A. O.; Klima, W. L. J . Org. Chem. 1980,
45, 2526. (b) Negishi, E.; Owczarczyk, Z. Tetrahedron Lett. 1991, 32,
6683. (c) Negishi, E. Tetrahedron 1995, 51, 2435.
(12) (a) Yamamoto, Y.; Ito, M. J . Chem. Soc., Perkin Trans. 1 1993,
1599. (b) Yamano, Y.; Tode, C.; Ito, M. J . Chem. Soc., Perkin Trans. 1
1998, 2569. (c) Tode, C.; Yamano, Y.; Ito, M. J . Chem. Soc., Perkin
Trans. 1 2001, 3338.
(4) Zeng, F.; Negishi, E. Org. Lett. 2001, 3, 719.
10.1021/jo025727f CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/06/2002
5040
J . Org. Chem. 2002, 67, 5040-5043

SCHEME 1a
a
Reagents and reaction conditions: (a) SO3‚Py, Et3N, CH2Cl2/DMSO (1:1), 0 °C (96%), ref 7; (b) BTSH, DIAD, PPh3, THF, 0 f 25 °C
(93%); (c) Mo7O24(NH4)6‚4H2O, 35% H2O2, EtOH, 25 °C (6, 61%; 7, 31%); (d) i. NaHMDS, Et2O, -78 °C. ii. 4, THF, -78 f 25 °C (70%).
SCHEME 2a
by conversion of 11 to hydrazone 12. Oxidation of the
latter with iodine according to Barton’s procedure13
afforded cyclohexenyl iodide 13 in 80% overall yield. Heck
coupling of 13 with methyl vinyl ketone14 led in 90% yield
to 14.12b The one-pot, three-step procedure for converting
methyl ketones to terminal alkynes11 proceeded unevent-
fully to afford 15 in 67% yield, which was deprotected to
16 (96%). Alkyne 16 was finally converted to the trienyl
iodide 17 in 69% yield by the well-established protocol,
a procedure which also yielded trienyl iodide 9 from its
precursor dienyne as already described.11a
A comprehensive study of the Stille reaction15,16 was
carried out to optimize the stitching reaction of 8 and 9.
The best conditions found involve the use of 4 mol %
(PhCN)2PdCl2 as precatalyst in a THF/DMF mixture in
the presence of Hu¨nig’s base (3 equiv) and a trace amount
of the radical inhibitor BHT. Under these conditions, the
coupling of 8 and 9 required 12 h at room temperature,
affording â-carotene 1 in 73% yield. Farina’s conditions
[Pd2dba3, tris-phenylarsine, NMP]17 were also successful,
albeit the yield was lower. Other alternatives proved
unsatisfactory: Pd2dba3/tris-2-furylphosphine in DMF16
and (CH3CN)2PdCl2 in DMF15b led to product deteriora-
tion, whereas Pd2dba3/tris-2-furylphosphine in THF17
returned unreacted starting components at ambient
a
(13) Barton, D. H. R.; Bashiardes, G.; Fourrey, J .-L. Tetrahedron
1988, 44, 147.
Reagents and reaction conditions: (a) TBDMSCl, imidazol,
DMF, 25 °C (83%); (b) H2NNH2‚H2O, Et3N, EtOH, reflux; (c) I2,
DBN, Et2O (two steps, 80%); (d) Pd(PPh3)4 (cat.), MVK, Et3N,
DMF, 75 °C, 12 h (90%); (e) i. LDA, ClPO(OEt)2, -78 °C. ii. LDA,
0 f 25 °C (67%); (f) (nBu)4NF, THF, 25 °C (96%); (g) i. Me3Al,
Cp2ZrCl2, CH2Cl2, 25 °C, 12 h. ii. I2, THF, -40 °C (69%); (h) 9 or
17, (PhCN)2PdCl2 (cat.), (iPr)2NEt, BHT, THF/DMF (1:1), 25 °C
(1, 73%; 2, 46%).
(14) (a) Arcadi, A.; Marinelli, F.; Cacchi, S. J . Organomet. Chem.
1986, 312, C27. (b) Ito, M. Pure Appl. Chem. 1991, 63, 13.
(15) (a) Stille, J . K. Pure Appl. Chem. 1985, 57, 1771. (b) Stille, J .
K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (c) Farina, V. In
Comprehensive Organometallic Chemistry II; Abel, E. W.; Stone, F.
G. A.; Wilkinson, G., Eds.; Elsevier: Oxford, 1995; Vol. 12, chapter
3.4, p 161. (d) Farina, V. Pure Appl. Chem. 1996, 68, 73. (e) Farina,
V.; Roth, G. P. In Advances in Metal-Organic Chemistry; Liebeskind,
L. S., Ed.; J AI Press: New York, 1996; Vol. 5, p 1. (f) Farina, V.;
Krishnamurthy, V.; Scott, W. J . Organic Reactions; Paquette, L. A.,
Ed.; J ohn Wiley & Sons: New York, 1997; Vol. 50, chapter 1, p 1. (g)
Duncton, M. A. J .; Pattenden, G. J . Chem. Soc., Perkin Trans. 1 1999,
1235.
temperature. The optimized conditions described above
provided the more unstable (3R,3′R)-zeaxanthin 218 in
46% yield after purification by column chromatography.
(16) For a comprehensive study of the application of the Stille cross-
coupling to the synthesis of retinoids, see (a) Dom´ınguez, B.; Iglesias,
B.; de Lera, A. R. Tetrahedron 1999, 55, 15071. (b) Dom´ınguez, B.;
Pazos, Y.; de Lera, A. R. J . Org. Chem. 2000, 65, 5917.
(18) Kakinuma, K.; Dekishima, Y.; Matsushima, Y.; Eguchi, T.;
Misawa, N.; Takagi, M.; Kuzuyama, T.; Seto, H. J . Am. Chem. Soc.
2001, 123, 1238.
(17) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585.
J . Org. Chem, Vol. 67, No. 14, 2002 5041

dried, and the solvent was removed. The residue was purified
by chromatography column (C-18 silica gel, 70:30 CH3CN/CH2-
Cl2) to afford 0.076 g (83%) of 8. 1H NMR (400 MHz, (CD3)2CO):
δ 6.79 (d, J ) 19.2 Hz, 2H), 6.73 (m, 2H), 6.46 (m, 2H), 6.41 (d,
J ) 19.2 Hz, 2H), 1.90 (s, 6H), 1.5-1.6 (m, 12H), 1.3-1.4 (m,
12H), 0.8-1.0 (m, 30H). 13C NMR (100 MHz, (CD3)2CO): δ 151.9,
138.4, 129.3, 127.4, 127.0, 29.8, 27.9, 14.0, 10.0, 8.3. UV
(MeOH): λmax 258, 340, 376. MS (FAB+): m/z (%) 680 (M+-Bu,
4), 179 (100). HRMS (FAB+): calcd for C36H69120Sn2 741.3443;
found 741.3444.
In summary, synthesis of the carotenoid polyene region
via σ bond construction has been achieved by a 2-fold
Stille cross-coupling of geometrically homogeneous cen-
tral lynchpin C12-bis-stannane 8 and two units of termi-
nal C14-alkenyl iodides. Work is in progress to develop
experimental conditions for monocoupling that could
extend the protocol to the preparation of nonsymmetrical
carotenoids.
(4R,6R)-4-(ter t-Bu t yld im et h ylsilyloxy)-2,2,6-t r im et h yl-
cycloh exa n -1-on e 11. To a solution of (4R,6R)-4-hydroxy-2,2,6-
trimethylcyclohexan-1-ona 10 (100 mg, 0.64 mmol) and imidazole
(109 mg, 1.6 mmol) in DMF (2 mL), at 0 °C, was added a solution
of TBDMSiCl (182 mg, 0.7 mmol) in DMF (2 mL). The reaction
was stirred for 6 h and then poured into H2O (10 mL) and
extracted with hexane (3×). The organic layers were washed
with H2O (5×), dried, and evaporated. The residue was purified
by chromatography (silica gel, 97:3 hexane/ethyl acetate) to
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es.16b (2E,4E)-1-(Ben -
zot h ia zol-2-yl)-su lfa n yl-5-(t r i-n -b u t ylst a n n yl)-3-m et h yl-
pen ta-2,4-dien e 5. To a solution of (2E,4E)-5-(tri-n-butylstannyl)-
2-methylpenta-2,4-dien-1-ol 3 (0.5 g, 1.29 mmol), 2-mercaptobenzo-
thiazol (0.32 g, 1.94 mmol), and Ph3P (0.55 g, 2.10 mmol) in THF
(8 mL), at 0 °C, was added diisopropyl azodicarboxylate (DIAD)
(0.38 mL, 1.94 mmol) in THF (3 mL). After the mixture was
stirred for 30 min, the solvent was removed and the residue was
purified by chromatography (C-18 silica gel, 85:15 CH3CN/CH2-
Cl2) to afford 0.64 g (93%) of 5. 1H NMR (400 MHz, C6D6): δ
7.96 (d, J ) 8.2 Hz, 1H), 7.27 (d, J ) 8.2 Hz, 1H), 7.13 (t, J )
7.3 Hz, 1H), 6.96 (t, J ) 7.6 Hz, 1H), 6.80 (d, J ) 19.3 Hz, 3J Sn-H
afford 143 mg (83%) of 11. [R]D -65.0 (c 0.55, MeOH).12a
20
(R)-ter t-Bu tyld im eth ylsilyl 3,5,5-Tr im eth yl-4-iod ocyclo-
h ex-3-en -1-yl Eth er 13. To a solution of (4R,6R)-4-(tert-bu-
tyldimethylsilyloxy)-2,2,6-trimethylcyclohexan-1-one 11 (0.50 g,
1.28 mmol) in ethanol (3.5 mL) at 25 °C, were added H2NNH2‚
H2O (1.6 mL, 33.13 mmol) and Et3N (0.39 mL, 2.78 mmol). After
the mixture was stirred for 24 h at 100 °C, the solvent was
removed and the residue was taken in Et2O (4 mL) and washed
with brine (3×). The aqueous layers were extracted with Et2O
(4×), and the organic extracts were dried over Na2SO4 and
concentrated. To a solution of the residue in Et2O (7.5 mL) and
DBN (2.06 mL, 16.65 mmol) was added a solution of iodine (0.99
g, 3.88 mmol) in Et2O (7.5 mL). After the mixture was stirred
for 15 min, an aqueous saturated NaHCO3 solution was added,
the layers were separated, the organic layer was dried over Na2-
SO4, and the solvent was removed. A solution of the residue in
C6H6 (7.5 mL) was treated with DBN (5 mL). After the mixture
was stirred for 2.5 h, it was poured into Et2O and washed with
aqueous Na2S2O3 (3×), and the organic layer was dried and
evaporated. The residue was purified by chromatography (silica
2
) 31.6 Hz, 1H), 6.45 (d, J ) 19.3 Hz, J Sn-H ) 33.8 Hz, 1H),
5.79 (t, J ) 7.9 Hz, 1H), 4.10 (d, J ) 7.9 Hz, 2H), 1.81 (s, 3H),
1.7-1.6 (m, 6H), 1.5-1.3 (m, 6H), 1.3-1.0 (m, 15H). 13C NMR
(100 MHz, C6D6): δ 166.5, 153.9, 150.5, 140.0, 135.9, 128.3,
126.2, 125.6, 124.3, 121.8, 121.2, 31.9, 29.5, 27.7, 13.9, 11.9, 9.8.
MS (FAB+): m/z (%) 538 (M++2, 24), 537 (M++1, 16), 536 (M+,
22), 177 (100). HMRS (FAB+): calcd for C25H40NS2118Sn,
536.1604; found, 536.1618.
(2E,4E)-1-((Ben zoth iazol-2-yl)su lfon yl)-5-(tr i-n -bu tylstan -
n yl)-3-m eth ylp en ta -2,4-d ien e 6. To a solution of (2E,4E)-1-
((benzothiazol-2-yl)sulfanyl)-5-(tri-n-butylstannyl)-3-methylpenta-
2,4-diene 5 (0.15 g, 0.28 mmol) in EtOH (3 mL), at 25 °C, was
added a solution of Mo7O24(NH4)6‚4H2O (0.74 g, 0.06 mmol) in
H2O2 (35% in H2O, 2.4 mL, 27.96 mmol). After the mixture was
stirred at room temperature for 30 min, aqueous NH4Cl solution
was added, the mixture was extracted with Et2O (3×) and the
organic extracts were washed with water (3×), dried over Na2-
SO4 and the solvent was evaporated. The residue was purified
by chromatography (Al2O3, 90:10 hexane/ethyl acetate) to afford
0.097 g (61%) of 6 and 0.024 g (31%) of 7. Data for 6: 1H NMR
(400 MHz, C6D6): δ 7.98 (d, J ) 8.0 Hz, 1H), 7.0-7.1 (m, 2H),
gel, hexane) to afford 0.563 g (80%) of 13. [R]D -29.9 (c 1.79,
20
MeOH). 1H NMR (400 MHz, CDCl3): δ 3.8-3.9 (m, 1H), 2.28
(dd, J ) 5.6, 2.2 Hz, 1H), 2.24 (dd, J ) 5.6, 2.2 Hz, 1H), 1.9-1.8
(1H, m), 1.86 (s, 3H), 1.64 (dd, J ) 12.1, 11.9 Hz, 1H), 1.11 (s,
3H), 1.08 (s, 3H), 0.87 (s, 9H), 0.05 (s, 6H). 13C NMR (100 MHz,
CDCl3): δ 135.1, 115.7, 65.1, 46.4, 42.9, 41.4, 34.5, 30.7, 29.3,
25.9, -4.7. MS (EI+): m/z (%) 380 (M+, 1), 323 (M+ - tBu, 32),
267 (100). HRMS (EI+): calcd for C15H29IOSi 380.1032; found,
380.1022.
2
6.92 (t, J ) 7.1 Hz, 1H), 6.68 (d, J ) 19.3 Hz, J Sn-H ) 31.4 Hz,
1H), 6.38 (d, J ) 19.3 Hz, 3J Sn-H ) 32.7 Hz, 1H), 5.55 (t, J ) 8.0
Hz, 1H), 4.11 (d, J ) 8.0 Hz, 2H), 1.6-1.8 (m, 6H), 1.66 (s, 3H),
1.2-1.4 (m, 6H), 0.8-1.0 (m, 15H). 13C NMR (100 MHz, (CD3)2-
CO): δ 151.0, 146.4, 138.8, 132.3, 130.0, 129.8, 129.7, 126.9,
124.8, 117.1, 56.5, 29.7, 28.9, 20.1, 14.9, 11.0. MS (FAB+): m/z
[(R,E)-4-(ter t-Bu tyld im eth ylsilyloxy)-2,6,6-tr im eth ylcy-
cloh ex-1-en -1-yl]bu t-3-en -2-on e 14. To a solution of (R)-(tert-
butyldimethylsilyl) 3,5,5-trimethyl-4-iodocyclohex-3-en-1-yl ether
13 (0.80 g, 2.21 mmol) in DMF (40 mL) was added Pd(PPh3)4
(0.24 g, 0.21 mmol), and the mixture was degassed by the
freeze-thaw method (three cycles). MVK (0.53 mL, 6.31 mmol)
and Et3N (0.88 mL, 6.31 mmol) were then added, and the
reaction was heated to 75 °C for 13 h. The mixture was diluted
with tBuOMe (50 mL), washed with 1% HCl, and extracted with
tBuOMe (3×). The combined organic layers were washed with
aqueous NaHCO3 (3×) and dried (Na2SO4), and the solvent was
removed. The resulting oil was purified by chromatography
(silica gel, 90:10 hexane/AcOEt) affording 615 mg (90%) of 14.12b
(R,E)-ter t-Bu tyld im eth ylsilyl 4-(Bu t-1-en -3-yn -1-yl)-3,5,5-
tr im eth ylcycloh ex-3-en -1-yl Eth er 15. A solution of LDA was
prepared by addition of nBuLi (1.67 M, 1.2 mL, 2.00 mmol) to a
solution of (iPr)2NH (0.28 mL, 2.00 mmol) in THF (5.5 mL). After
30 min at 0 °C, the mixture was cooled to -78 °C and a solution
of [(R,E)-4-tert-butyldimethylsilyloxy-2,6,6-trimethylcyclohex-1-
en-1-yl]but-3-en-2-one 14 (0.615 g, 1.91 mmol) in THF (2 mL)
was added via cannula. The mixture was stirred for 1.5 h at
-78 °C, ClPO(OEt)2 (0.288 mL, 2.00 mmol) was added, and the
resulting mixture was stirred for 3 h at room temperature. In a
separate flask, a solution of LDA was prepared with (iPr)2NH
(0.60 mL, 4.29 mmol) and nBuLi (1.67 M, 2.6 mL, 4.29 mmol)
in THF (11 mL), at 0 °C. To this was added the reaction mixture
(%) 567 (M+, 10), 177 (100). HRMS (FAB+): calcd for C25H39
-
NO2S2118Sn, 567.1581; found 567.1596. Data for 7 (major
isomer): 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J ) 8.2 Hz, 1H),
8.01 (d, J ) 8.1 Hz, 1H), 7.6-7.7 (m, 2H), 6.34 (dd, J ) 17.4,
10.7 Hz, 1H), 5.52 (t, J ) 8.1 Hz, 1H), 5.21 (d, J ) 17.4 Hz, 1H),
5.10 (d, J ) 10.7 Hz, 1H), 4.38 (d, J ) 8.1 Hz, 2H), 1.69 (s, 3H).
13C NMR (100 MHz, C6D6): δ 165.7, 152.7, 144.1, 139.5, 137.2,
128.0, 127.5, 125.4, 122.3, 115.4, 114.6, 54.9, 12.2. MS (FAB+):
m/z (%) 279 (M+, 6), 200 (100). HRMS (FAB+): calcd for C13H13
NO2S2 279.0388; found 279.0387.
-
(1E ,3E ,5E ,7E ,9E )-1,10-Bis(t r i-n -b u t ylst a n n yl)-3,8-d i-
m eth yld eca -1,3,5,7,9-p en ta en e 8. To a solution of (2E,4E)-1-
((benzothiazol-2-yl)sulfonyl)-5-(tri-n-butylstannyl)-3-methylpenta-
2,4-diene 6 (0.071 g, 0.25 mmol) in THF (4 mL), at -78 °C, was
added NaHMDS (1 M in THF, 0.23 mL, 0.23 mmol), and the
mixture was stirred for 45 min. A solution of (2E,4E)-5-(tri-n-
butylstannyl)-2-methylpenta-2,4-dien-1-al 4 (0.072 g, 0.19 mmol)
in THF (4 mL) was added, and the reaction was allowed to reach
ambient temperature very slowly for 12 h. Aqueous 1 M NaOH
(5 mL) and tBuMeO (10 mL) were added. The layers were
separated, and the aqueous layer was extracted with tBuMeO
(3×). The organic extracts were washed with brine (3×) and
5042 J . Org. Chem., Vol. 67, No. 14, 2002

obtained above, and the resulting solution was stirred at room
temperature for 13 h. After cooling the reaction mixture to 0
°C, H2O was slowly added, followed by extraction with tBuOMe
(3×). The combined organic layers were washed with 1 M HCl
(3×), H2O (3×), and aqueous saturated NaHCO3 solution (3×)
and dried, and the solvent was evaporated. The resulting oil was
(dd, J ) 17.0, 9.6 Hz, 1H), 1.84 (s, 3H), 1.7-1.6 (m, 1H), 1.57 (s,
3H), 1.42 (t, J ) 11.8 Hz, 1H), 0.97 (s, 6H). 13C NMR (100 MHz,
C6D6): δ 145.4, 137.2, 134.9, 127.4, 127.0, 83.2, 64.6, 48.6, 42.7,
36.9, 30.3, 28.7, 21.6, 19.9. IR (NaCl): ν 3600-3100 cm-1. MS
(EI+): m/z (%) 332 (M+, 100). HRMS (EI+): calcd for C14H21IO
332.0637; found, 332.0637.
purified by cromatography (silica gel, 95:5 hexane/AcOEt), to
(3R,3′R)-Zea xa n th in 2. Gen er a l P r oced u r e for Stille
Cr oss-Cou p lin g. To a solution of (R)-4-[(E,E)-4-iodo-3-methyl-
but-1,3-dien-1-yl]-3,5,5-trimethylcyclohex-3-en-1-ol 17 (0.023 g,
0.069 mmol) and (PhCN)2PdCl2 (3.0 mg, 0.008 mmol) in DMF
(1.2 mL) was added a solution of (1E,3E,5E,7E,9E)-1,10-bis(tri-
n-butylstannyl)-3,8-dimethyldeca-1,3,5,7,9-pentaene 8 (0.019 g,
0.026 mmol) in THF (1.2 mL), followed by (iPr)2NEt (0.027 mL,
0.158 mmol) and one drop of a diluted BHT solution. The
reaction was stirred at room temperature in the dark for 16 h
and then poured into aqueous KF solution. The mixture was
extracted with CH2Cl2 (3×), the organic layers were washed with
H2O (3×) and dried, and the solvent was evaporated. The residue
was purified by chromatography (neutral alumina Act. II,
gradient 100 CH2Cl2 f 97:3 CH2Cl2:MeOH) and recrystallization
(mp 158-162 °C, hexane/AcOEt) to afford 6 mg (46%) of 2. 1H
NMR (400 MHz, CDCl3): δ 6.7-6.6 (m, 4H), 6.35 (d, J ) 15.0
Hz, 2H), 6.25 (d, J ) 5.9 Hz, 2H), 6.14 (d, J ) 12.5 Hz, 2H),
6.2-6.1 (m, 4H), 4.1-4.0 (m, 2H), 2.37 (dd, J ) 16.5, 5.2 Hz,
2H), 2.1-2.0 (m, 2H), 1.97 (s, 12H), 1.8-1.7 (m, 2H), 1.7 (s, 6H),
1.6-1.4 (m, 2H), 1.07 (s, 12H). MS (FAB+): m/z (%) 568 (M+,
45), 154 (100). HRMS (FAB+): calcd for C40H57O2 569.4359;
found, 569.4361.1b,18
1
afford 0.37 g (67%) of 15. [R]D -28.3 (c 0.17, MeOH). H NMR
24
(400 MHz, CDCl3): δ 6.57 (d, J ) 16.5 Hz, 1H), 5.38 (dd, J )
16.4, 2.1 Hz, 1H), 3.9-3.8 (m, 1H), 2.87 (d, J ) 2.2 Hz, 1H),
2.17 (dd, J ) 17.5, 5.7 Hz, 1H), 2.00 (dd, J ) 17.3, 9.5 Hz, 1H),
1.66 (s, 3H), 1.6-1.5 (m, 1H), 1.4-1.3 (m, 1H), 0.99 (s, 3H), 0.98
(s, 3H), 0.84 (s, 9H), 0.01 (s, 6H). 13C NMR (100 MHz, CDCl3):
δ 142.2, 136.3, 129.4, 111.5, 83.1, 65.3, 48.7, 43.0, 36.8, 30.0 28.4,
25.9, 21.4, 18.2, -4.6. IR (NaCl): ν 3314, 2100 cm-1. MS (EI+):
m/z (%) 304 (M+, 7), 191 (100). HRMS (EI+): calcd for C19H32
-
OSi 304.2222; found, 304.2226.
(R)-4-[(E)-Bu t-1-en -3-yn -1-yl]-3,5,5-tr im eth ylcycloh ex-3-
en -1-ol 16. To a solution of (R,E)-tert-butyldimethylsilyl 4-(but-
1-en-3-yn-1-yl)-3,5,5-trimethylcyclohex-3-en-1-yl ether 15 (0.066
g, 0.22 mmol) in THF (2.2 mL) was added (nBu)4NF (1.0 M in
THF, 0.32 mL, 0.32 mmol), and the mixture was stirred for 2.5
h at room temperature. It was poured over aqueous satured
NaHCO3 solution, extracted with tBuOMe (3×), and dried
(NaSO4), and the solvent was evaporated. The residue was
purified by chromatography (silica gel, 80:20 hexane/AcOEt),
affording 0.041 g (96%) of 16. [R]D -94.6 (c 0.66, MeOH). 1H
24
NMR (400 MHz, CDCl3): δ 6.60 (d, J ) 16.4 Hz, 1H), 5.42 (dd,
J ) 16.4, 2.1 Hz, 1H), 3.9-3.8 (m, 1H), 2.92 (d, J ) 2.2 Hz, 1H),
2.35 (dd, J ) 17.1, 5.5 Hz, 1H), 2.0-1.9 (m, 1H), 1.71 (s, 3H),
1.8-1.7 (m, 1H), 1.5-1.4 (m, 1H), 1.04 (s, 6H). 13C NMR (100
MHz, CDCl3): δ 141.9, 136.5, 128.7, 111.8, 82.9, 77.4, 64.8, 48.3,
â,â-Ca r oten e 1. Following the general procedure for Stille
cross-coupling, the title compound was obtained in 73% yield
after purification by chromatography (neutral alumina Act II,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 6.7-6.6 (m, 4H), 6.29
(d, J ) 14.9 Hz, 2H), 6.2-5.9 (m, 8H), 1.96 (t, J ) 5.7 Hz, 4H),
1.91 (s, 6H), 1.66 (s, 6H), 1.6-1.5 (m, 8H), 1.20 (s, 6H), 0.97 (s,
12H). MS (EI+): m/z (%) 536 (M+, 56), 69 (100). HRMS (EI+):
calcd for C40H56 536.4382; found, 536.4386.4
42.4, 36.8, 29.7, 28.5, 21.3. IR (NaCl):ν 3600-3100, 2099 cm-1
.
MS (FAB+): m/z (%) 191 (M+, 100). HRMS (FAB+): calcd for
C
13H19O 191.1436; found, 191.1431.
(R)-4-[(E,E)-4-Iod o-3-m et h ylb u t -1,3-d ien -1-yl]-3,5,5-t r i-
m eth ylcycloh ex-3-en -1-ol 17. To a solution of Cp2ZrCl2 (0.081
g, 0.28 mmol) in CH2Cl2 (1 mL), at 0 °C, were sequentially added
Me3Al (0.080 mL, 0.83 mmol) and a solution of (R)-4-[(E)-but-
1-en-3-yn-1-yl]-3,5,5-trimethylcyclohex-3-en-1-ol 16 (0.053 g, 0.28
mmol) in CH2Cl2 (1 mL). After the reaction mixture was stirred
for 12 h at room temperature, it was cooled to -40 °C and a
solution of iodine (0.21 g, 0.83 mmol) in THF (1.5 mL) was added.
After addition of THF/H2O (1:1, v/v) the mixture was extracted
with tBuOMe (3×), the extracts were dried, and the solvent was
evaporated. The residue was purified by cromatography (silica
Ack n ow led gm en t. We thank Xunta de Galicia
(Grant PGIDT99 PX30105B) and MCYT (Grant SAF98-
0143, FPU fellowship to B. Vaz) for financial support,
and Dr. Michelangelo Scalone (F. Hoffman-La Roche,
Basel) for a generous gift of starting material (R)-10.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic char-
acterization and copies of 1H NMR/13C NMR spectra of the
compounds described in the text. This material is available
free of charge via the Internet at http://pubs.acs.org.
gel, 80:20 hexane/AcOEt) affording 0.064 g (69%) of 17. [R]D
22
1
-105.8 (c 0.135, MeOH). H NMR (400 MHz, C6D6): δ 6.1-5.9
(m, 3H), 3.9-3.8 (m, 1H), 2.20 (dd, J ) 17.0, 5.5 Hz, 1H), 1.94
J O025727F
J . Org. Chem, Vol. 67, No. 14, 2002 5043