New Lewis-acidic molybdenum(II) and tungsten(II) catalysts for intramolecular carbonyl erie and prins reactions. Reversal of the stereoselectivity of cyclization of citronellal

Article abstract of DOI:10.1021/jo9821675

New Mo(II) complexes BnEt₃N+[Mo(CO)₄ClBr₂]^- (A) and Mo(CO)₅(OTf)₂ (B) and their W(II) congeners D and E have been developed as catalysts for the title reactions. Unlike other Lewis acids, the latter catalysts exhibit cis-stereoselectivity in the cyclization of citronellal (1 → 3 with A and 1 → 5 with B). Isotopic labeling allowed formulation of the reaction mechanism, according to which these complexes act as bulky Lewis acids, η¹- coordinated to the carbonyl oxygen. The stereochemistry appears to be controlled by the protruding ligand L(p), which dictates the boatlike transition state III. The kinetically formed cis-alkenol 3 can be equilibrated by [Mo(CO)₄Br₂]₂ (C) or ZnCl₂ to its trans-epimer 2 via a retro-ene reaction.

Full text of DOI:10.1021/jo9821675

J . Org. Chem. 1999, 64, 2765-2775
2765
New Lew is-Acid ic Molybd en u m (II) a n d Tu n gsten (II) Ca ta lysts for
In tr a m olecu la r Ca r bon yl En e a n d P r in s Rea ction s. Rever sa l of th e
Ster eoselectivity of Cycliza tion of Citr on ella l
Pavel Kocˇovsky´,*,† Ghafoor Ahmed,†,‡ J irˇ´ı Sˇrogl,†,§ Andrei V. Malkov,† and J ohn Steele|,
Department of Chemistry, University of Leicester, Leicester LE1 7RH, U.K., and Discovery Chemistry,
Pfizer Central Research, Sandwich, Kent CT13 9NJ , U.K.
Received October 28, 1998
New Mo(II) complexes BnEt3N+[Mo(CO)4ClBr2]- (A) and Mo(CO)5(OTf)2 (B) and their W(II)
congeners D and E have been developed as catalysts for the title reactions. Unlike other Lewis
acids, the latter catalysts exhibit cis-stereoselectivity in the cyclization of citronellal (1 f 3 with A
and 1 f 5 with B). Isotopic labeling allowed formulation of the reaction mechanism, according to
which these complexes act as bulky Lewis acids, η1-coordinated to the carbonyl oxygen. The
stereochemistry appears to be controlled by the protruding ligand Lp, which dictates the boatlike
transition state III. The kinetically formed cis-alkenol 3 can be equilibrated by [Mo(CO)4Br2]2 (C)
or ZnCl2 to its trans-epimer 2 via a retro-ene reaction.
Sch em e 1a
In tr od u ction
The ene reaction1 is a powerful synthetic tool for C-C
bond formation that allows construction of two vicinal
chiral centers. Like the Diels-Alder addition, it proceeds
thermally and can be accelerated by Lewis acids. Whereas
the intermolecular ene reaction is only successful in the
case of highly reactive substrates,1,2 its intramolecular
version has been extensively studied and developed into
a reliable methodology.1-3 Thus, for instance, citronellal
1a is readily cyclized in the presence of Lewis acids
(AlCl3, BF3, SbCl3, SbCl5, etc.; 0.1-1 equiv) to produce
mainly isopulegol 2, accompanied by its cis-diastereo-
isomer 3 (Scheme 1);3 the 2/3 ratios2,3 vary from 95:5 with
ZnI2 to 43:57 with SbCl5 (Table 1, entries 1-4).2-5
A
reversal in the sense of diastereoselectivity has been
observed (but not explained) for the stoichiometric reac-
tion with (Ph3P)3RhCl, which gave a 1:3 mixture of 2 and
* Correspondence author. E-mail: PK10@Le.ac.uk.
† University of Leicester.
‡ Current address: Oxford Asymmetry International PLC, Milton
Park, Abingdon OX1 45D, U.K.
a
A ) PhCH2(Et)3N+[Mo(CO)4ClBr2]-; B ) Mo(CO)5(OTf)5; C
§ Current address: Department of Chemistry, Emory University,
Atlanta, GA 30322.
) [Mo(CO)4Br2]2.
| Pfizer Central Research.
Current address: Medicinal Chemistry Department, Astra Charn-
wood, Loughborough LE11 5RH, U.K.
3 (entry 5).6,7 Herein, we report on new molybdenum(II)
and tungsten(II) catalysts, which favor formation of the
(1) For reviews, see: (a) Snider, B. B. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, U.K.,
1991; Vol. 2, pp 527-567. (b) Snider, B. B. In Ibid., Vol. 5, pp 1-27.
(c) Oppolzer, W. In Ibid., Vol. 5, pp 29-61. (d) Mikami, K.; Shimizu,
M. Chem. Rev. 1992, 92, 1021. (e) Mikami, K.; Terada, M.; Narisawa,
S.; Nakai, T. Synlett 1992, 255. (f) Snider, B. M. Acc. Chem. Res. 1980,
13, 426. (g) Trost, B. M. Acc. Chem. Res. 1990, 23, 34. For recent
synthetic applications, and detailed mechanistic studies, see, e.g.: (h)
Marshall, J . A.; Andersen, M. W. J . Org. Chem. 1992, 57, 5851. (i)
Marshall, J . A.; Andersen, M. W. J . Org. Chem. 1993, 58, 3912. (j)
Braddock, D. C.; Hii, K. K.; Brown, J . M. Angew. Chem. 1998, 37, 1720.
For a general overview, see: (k) Eliel, E. L.; Willen, S. H.; Mander, L.
N. Stereochemistry of Organic Compounds; J . Wiley & Sons: New York,
1994.
(4) The corresponding imines are cyclized by means of FeCl3 or TiCl4
to also afford trans-products; see ref 5b and: (a) Laschat, S.; Grel, M.
Angew. Chem., Int. Ed. Engl. 1994, 33, 458. (b) Temme, O.; Laschat,
S. J . Chem. Soc., Perkin Trans. 1 1995, 125. (c) Laschat, S.; Noe, R.;
Riedel, M.; Kru¨ger, C. Organometallics 1993, 12, 3738. For a remark-
ably efficient Lewis acid-catalyzed intramolecular imine-ene reaction
and its masterly application to the synthesis of (-)-perhydrohistrioni-
cotoxin, see: (d) Tanner, D.; Hagberg, L. Tetrahedron 1998, 54, 7907.
For recent reviews, see: (e) Borzilleri, R. M.; Weinreb, S. M. Synthesis
1995, 347. (f) Laschat, S. Liebigs Ann./ Recueil 1997, 1.
(5) Chiral Zn and Ti complexes exhibit trans-diastereoselectivity
with high enantiocontrol: (a) Sakane, S.; Maruoka, K.; Yamamoto, H.
Tetrahedron Lett. 1985, 26, 5535. (b) Sakane, S.; Maruoka, K.;
Yamamoto, H. Tetrahedron 1986, 42, 2203. (c) Mikami, K.; Terada,
M.; Sawa, E.; Nakai, T. Tetrahedron Lett. 1991, 32, 6571. (d) Mikami,
K.; Terada, M.; Motoyama, Y.; Nakai, T. Tetrahedron: Asymmetry 1991,
2, 643.
(2) (a) Aggarwal, V. K.; Vennall, G. P.; Davey, P. N.; Newman, C.
Tetrahedron Lett. 1998, 39, 1997 and references therein. (b) Gao, Y.;
Lane-Bell, P.; Vederas, J . C. J . Org. Chem. 1998, 63, 2133. (c) Evans,
D. E.; Burgey, C. S.; Paras, N. A.; Vojkovsky´, T.; Tregay, S. W. J . Am.
Chem. Soc. 1998, 120, 5824.
(3) Nakatani, Y.; Kawashima, K. Synthesis 1978, 147.
10.1021/jo9821675 CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/20/1999

2766 J . Org. Chem., Vol. 64, No. 8, 1999
Kocˇovsky´ et al.
substitution10,12,14 and other tranformations.8 Further
investigation has now revealed their catalytic effect in
the intramolecular ene-type reactions. Thus, complex A
(5 mol %) was found to catalyze the cyclization of (()-1a
in dry DME (rt (room temperature), 24 h), affording a
mixture of 2 and 3 in a 25:75 ratio (entry 6), from which
neoisopulegol 315 was isolated in 68% yield.16 When
carried out in CH2Cl2, the reaction was complete in 8 h
(rt) and gave a 40:60 mixture of 2 and 3 (entry 7). The
tungsten congener D9 exhibited similar reactivity, giving
2 and 3 in a 24:76 ratio in DME (entry 8). By contrast,
complex B (5 mol %) in wet DME preferentially produced
diol 5 (73%),17 again with a relatively high cis-stereo-
selectivity (4/5 ) 20:80; entry 9), and its tungsten
analogue E11 gave the same products (4/5 ) 44:56; entry
10).18,19 Finally, a dramatic solvent effect was observed
for catalyst C: whereas in DME a 55:45 mixture of 2 and
3 (entry 11) was formed (rt, 8 h), the reaction carried out
in CH2Cl2 was complete in 5 min(!) and gave preferen-
tially the trans- rather than cis-product (2/3 ) 82:18;
entry 12), suggesting a change of mechanism. Interest-
ingly, when the pure cis-product 3 was exposed to catalyst
C in CH2Cl2, it was rapidly converted into a 90:10
mixture of 2 and 3 (rt, 30 min) and similar isomerization
was then observed for ZnCl2 and other Lewis acids.20 This
behavior indicates that the cis-isomer 3 results from a
kinetically controlled reaction and can be equilibrated to
the thermodynamically more stable trans-isomer 2 under
the reaction conditions, which may, at least partly, take
account for the differences in the stereochemistry of
cyclization of 1 when various Lewis acids are employed
(vide supra3). Although a standard axial-equatorial
alcohol equilibration1k 3 f 2 can, a priori, rationalize this
isomerization, we have been able to show that this is not
the case since other axial alcohols, such as 5R-cholestan-
3R-ol, are not equilibrated to their equatorial isomers
under the same conditions. Therefore, a different mech-
Ta ble 1. Ster eoch em istr y of th e Ca r bon yl En e/
P r in s-Typ e Cycliza tion of 1, 9, a n d 10 w ith Lew is-Acid
Ca ta lystsa
starting
ratio
entry compd
catalyst
solvent
C6H6
C6H6
C6H6
products trans:cis
b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
9
ZnI2
2 + 3
2 + 3
95:5c
d
d
SbCl3
SbCl5
71:29c
43:57c
80:20e
1:3g
2 + 3
(TfO)3Sce
CH2Cl2
2 + 3
(Ph3P)3RhClf CHCl3
2 + 3
A
A
D
B
DME
2 + 3
25:75h
40:60h
24:76h
20:80h
44:56h
55:45h
82:18h
91:9h
CH2Cl2
DME
2 + 3
2 + 3
DME, H2Oi
DME, H2Oi
DME
4 + 5
E
4 + 5
Cj
Ck
A
B
2 + 3
CH2Cl2
DME
DME
2 + 3
11 + 12
11 + 12
11 + 12
9
10
90:10h
36:64h
A
DME
a
At rt for 24 h with 5 mol % of the catalyst unless stated
otherwise. b 1 equiv, 5-10 °C, 15 min. c See ref 3. 10 mol %. e See
d
refs 2a and 55. f 1 equiv, rt, 15 h. See ref 6. Established by 1H
g
h
i
j
k
NMR. 1-2% H2O. 8 h. 5 min.
Ch a r t 1
cis-hydroxyalkene 3 or the cis-diol 5 as a result of the
carbonyl ene or Prins reaction, respectively.
Resu lts a n d Discu ssion
Ca r bon yl En e- a n d P r in s-Typ e Cycliza tion of
Citr on ella l. Recently, we have described the utilization
of molybdenum(II) and tungsten(II) complexes A,8,9 B,10,11
C,12,13 D,9 and E10,11 (Chart 1) as catalysts in allylic
(14) (a) Malkov, A. V.; Baxendale, I. R.; Mansfield, D. J .; Kocˇovsky´,
P. J . Org. Chem. 1999, 64, 2737-2750. (b) Malkov, A. V.; Davis, S. L.;
Baxendale, I. R.; Mitchell, W. L.; Kocˇovsky´, P. J . Org. Chem. 1999,
64, 2751-2764.
(15) Identical with the known compound: (a) Shishibori, T. Bull.
Chem. Soc. J pn. 1968, 41, 1170. (b) Burkard, S.; Looser, M.; Borsch-
berg, H.-J . Helv. Chim. Acta 1988, 71, 209.
(6) (a) Sakai, K.; Oda, O. Tetrahedron Lett. 1972, 4375. (b) Funa-
koshi, K.; Togo, N.; Sakai, K. Tetrahedron Lett. 1989, 30, 1095. (c) Koga,
I.; Funakoshi, K.; Matsuda, A.; Sakai, K. Tetrahedron: Asymmetry
1993, 4, 1857.
(7) PCC also mediates the cyclization; however, the product is
instantaneously oxidized by the reagent, so that the stereochemistry
of the ring closure cannot be determined: Corey, E. J .; Ensley, H. E.
Suggs, J . W. J . Org. Chem. 1976, 41, 380.
(8) Sˇrogl, J .; Kocˇovsky´, P. Tetrahedron Lett. 1992, 33, 5991.
(9) The complex A was prepared from PhCH2(Et)3N+[Mo(CO)5Cl]-
on bromination; see ref 8 and: (a) Ganorkar, M. C.; Stiddard, M. H.
B. J . Chem. Soc. 1965, 3494. (b) Abel, E. W.; Butler, I. S.; Red, J . G.
J . Chem. Soc. 1964, 2068. Alternatively, A was also obtained on the
reaction of [Mo(CO)4Br2]2 (C)13 with PhCH2(Et3)N+Cl-. The tungsten
analogue D was prepared according to the former protocol.
(10) (a) Dvorˇa´kova´, H.; Dvorˇa´k, D.; Sˇrogl, J .; Kocˇovsky´, P. Tetrahe-
dron Lett. 1995, 35, 6351. (b) Malkov, A. V.; Baxendale, I. R.; Mansfield,
D. J .; Kocˇovsky´, P. Tetrahedron Lett. 1997, 38, 4895.
(16) All yields refer to isolated (preparative) yields. Diastereoiso-
meric ratios were determined by integration of suitable signals in the
1H NMR spectra of the crude product mixtures with usual accuracy
(g(2%).
(17) The diol 5 is a plant growth inhibitor, originally isolated from
Eucalyptus citriodora: Nishimura, H.; Nakamura, T.; Mizutani, J .
Phytochem. 1984, 23, 2777.
(18) A facile, though less stereoselective, formation of the corre-
sponding cyclopentane derivatives from 2,6-dimethyl-5-hepten-1-al has
also been observed.
(19) Similar Cp2Ti(PMe3)2-catalyzed cyclizations of 6-hepten-2-one
and its congeners, leading to cis-disubstituted cyclopentanes, have
recently been reported; attempted construction of cyclohexane homo-
logues was, however, unsuccessful: (a) Kablaoui, N. M.; Buchwald, S.
L. J . Am. Chem. Soc. 1995, 117, 6785. (b) Kablaoui, N. M.; Buchwald,
S. L. J . Am. Chem. Soc. 1996, 118, 3182. (c) Kablaoui, N. M.; Hicks, F.
A.; Buchwald, S. L. J . Am. Chem. Soc. 1996, 118, 5818. (d) Kablaoui,
N. M.; Hicks, F. A.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119, 4424.
(e) Crowe, W. E.; Rachita, M. J . J . Am. Chem. Soc. 1995, 117, 6787. (f)
Crowe, W. E.; Vu, A. T. J . Am. Chem. Soc. 1996, 118, 1557. (g) Crowe,
W. E.; Vu, A. T. J . Am. Chem. Soc. 1996, 118, 5508. See also: (h)
Okamoto, S.; Kasatkin, A.; Zubaidha, P. K.; Sato, F. J . Am. Chem.
Soc. 1996, 118, 2208. (i) Taber, D. F.; Wang, Y. Tetrahedron Lett. 1995,
36, 6639. For a review on analogous cyclization of dienes, see: (j)
Buchwald, S. L.; Nielsen, R. B. Chem. Rev. 1988, 88, 1047. For related
titanocene-catalyzed ene-type cycloisomerization of enynes and di-
enynes, see: (k) Sturla, S. J .; Kablaoui, N. M.; Buchwald, S. L. J . Am.
Chem. Soc. 1999, 121, 1976.
(11) (a) The complex B was generated in situ from PhCH2(Et)3N+-
[Mo(CO)5Cl]- via a redox reaction with CF3SO3Ag (3 equiv) at room
temperature in DME. Its tungsten congener E was generated in an
analogous way: (b) Abbott, A. P.; Malkov, A. V.; Zimmermann, N.;
Raynor, J . B.; Ahmed, G.; Steele, J .; Kocˇovsky´, P. Organometallics
1997, 16, 3690. See also ref 14a.
(12) Malkov, A. V.; Davis, S. L.; Mitchell, W. L.; Kocˇovsky´, P.
Tetrahedron Lett. 1997, 38, 4899.
(13) The complex C was prepared by titration of Mo(CO)6 with Br2
(1 equiv) at -78 °C in a noncoordinating solvent, such as CH2Cl2: (a)
Bowden, J . A.; Colton, R. Aust. J . Chem. 1968, 21, 2657. (b) Cotton, F.
A.; Falvello, L. R.; Meadows, J . H. Inorg. Chem. 1985, 24, 514. (c)
Cotton, F. A.; Poli, R. Inorg. Chem. 1987, 26, 1514. See also ref 14a.
(20) On the other hand, exposing 3 to either A or B (rt, g48 h)
proved to have practically no effect, except a slow, partial decomposi-
tion/elimination.

Catalysts for Carbonyl Ene and Prins Reactions
J . Org. Chem., Vol. 64, No. 8, 1999 2767
Sch em e 2
Sch em e 3
(67%).27-30 Deprotection of the latter product (17 f 18;
p-TsOH, MeOH, rt, 7 h; 89%), followed by Collins
oxidation, afforded the required aldehyde 9 (59%). Simi-
lar strategy was applied to the synthesis of the (Z)-isomer
10: aldehyde 135b was converted in two steps into the
propargylic derivative 19 (81%),31 whose hydrogenation
on Lindlar catalyst gave (Z)-ester 20 (99%). Diisobutyl-
aluminum hydride reduction of the latter ester (20 f 21;
84%), followed by acetylation (Ac2O, pyridine, rt), gave
allylic acetate 22 (91%), which was converted into allyl-
silane 23 on treatment with (PhMe2Si)2CuLi (75%).26
Deprotection of the latter compound (p-TsOH, MeOH, rt;
95%), followed by Collins oxidation of the resulting
alcohol 24, afforded the desired aldehyde 10 (63%).
Surprisingly, 3-methylcitronellal (6) reacted very slug-
gishly with our catalysts (∼10% conversion over 48 h in
DME)32 and cis- and trans-6-octen-1-al (7, 8) proved inert
to both A and B although their ready cyclization with
standard Lewis acids has been reported.33 On the other
hand, trans-allylsilane 9 reacted readily in the presence
of either catalyst in DME, affording mixtures of the
expected trans- and cis-products 11 and 12 (91:9 with A
and 90:10 with B; entries 13 and 14). The cis-configured
allylsilane 10 afforded the same product mixture with
the ratio reverted in favor of cis-isomer 12 (64:36; entry
15), indicating the dominant control of the reaction
stereochemistry exercised by the silane group rather that
the catalyst.30,34
anism must be operating in this system and the retro-
ene reaction appears to be the most likely one.21
Ca r bon yl En e- a n d P r in s-Typ e Cycliza tion of
Citr on ella l Con gen er s. To shed more light on the
preferred formation of the cis-configured products on
cyclization of citronellal, we prepared a series of related
substrates 6-10, whose cyclization in the presence of
standard Lewis acids has been described previously. The
methyl analogue 6 was readily obtained on cuprate
addition to citral,5a,b and the two “demethyl” analogues
of citronellal, i.e., trans- and cis-6-octen-1-al (722,23 and
8),22a,23 were synthesized using known methods. The
synthesis of (E)- and (Z)-allylsilanes 9 and 10 commenced
with the protected hydroxy aldehyde 13, available in two
steps from 1,6-hexanediol (Scheme 2). Wittig olefination
of 13 with Ph3PdCHCO2Et (80 °C, 3 h) afforded the R,â-
unsaturated ester 14 (89%; E/Z ) 96:4),24 whose reduc-
tion with diisobutylaluminum hydride in toluene (-20
°C, 25 min) furnished allylic alcohol 15 (90%).24a,b,25
Acetate 16, obtained from the latter alcohol (Ac2O,
pyridine, rt, overnight; 93%), was treated with (PhMe2-
Si)2CuLi (THF, -60 °C, 12 h)26 to give allylsilane 17
Oth er Ca r bon yl En e-Typ e Cycliza tion s. Cycliza-
tion of 2535 (Scheme 3) is known to produce 26 on
thermolysis,35a,b and traditional Lewis acid catalysis
proceeded in a similar way.1f With our catalyst A, it
afforded a mixture of regioisomers 26 and 27 in an 81:
19 ratio (rt, 48 h), whereas B gave the same isomers in
(27) For analogous Me3Si derivatives, see refs 28 and 29; for related
Bu3Sn derivatives, see ref 30.
(28) Tietze, L. F.; Whu¨sch, J . R. Synthesis 1990, 985.
(29) Tietze, L. F.; Schu¨nke, C. Angew. Chem., Int. Ed. Engl. 1995,
34, 1731.
(30) Keck, G. E.; Dougherty, S. M.; Savin, K. A. J . Am. Chem. Soc.
1995, 117, 6210.
(31) Ma, D.; Lu, X. Tetrahedron 1990, 46, 6319.
(32) With standard Lewis acids, 6 reacts readily to afford the
(21) For a review on retro-ene reaction, see: Ripoll, J .-L.; Vale´e, Y.
Synthesis 1993, 659.
(22) (a) Marvell, E. N.; Rusay, R. J . Org. Chem. 1977, 42, 3336. (b)
Melnick, M. J .; Freyer, A. J .; Weinreb, S. M. Tetrahedron Lett. 1988,
29, 3891.
(23) (a) Denmark, S. E.; Dappen, M. S.; Cramer, C. J . J . Am. Chem.
Soc. 1986, 108, 1306. (b) Denmark, S. E.; Moon, Y.-C.; Cramer, C. J .;
Dappen, M. S.; Senanayake, C. B. W. Tetrahedron 1990, 46, 7373.
(24) (a) Baldwin, S. W.; Wilson, J . D.; Aube´, J . J . Org. Chem. 1985,
50, 4432. (b) Clasby, M. C.; Craig, D.; Slawin, A. M. Z.; White, A. J . P.;
Williams, D. J . Tetrahedron 1995, 51, 1509. (c) Craig, D.; Geach, N. J .
Tetrahedron: Asymmetry 1991, 2, 1177.
(25) (a) Patterson, J . W. Synthesis 1985, 337. (b) Martin, V. S.; Ode,
J . M.; Palazon, J . M.; Soler, M. H. Tetrahedron: Asymmetry 1992, 3,
573.
corresponding trans-product.5
(33) Related cyclizations with MeAlCl2 have been shown to lead
preferentially to the trans-isomer, whereas Me2AlCl tends to prefer
the corresponding cis-isomer, which has been interpreted in terms of
the differences in the relative strength of the two Lewis acids
employed: (a) Snider, B. B.; Karras, M.; Price, R. T.; Rodini, D. J . J .
Org. Chem. 1982, 47, 4538. For further examples of application of Me2-
AlCl, see: (b) J ohnson, M. I.; Kwass, J . A.; Beal, R. B.; Snider, B. B. J .
Org. Chem. 1987, 52, 5419. (c) Robertson, J .; O′Connor, G.; Middleton,
D. S. Tetrahedron Lett. 1996, 37, 3411.
(34) (a) Denmark, S. E.; Almstead, N. G. J . Org. Chem. 1994, 59,
5130. (b) Denmark, S. E.; Hosoi, S. J . Org. Chem. 1994, 59, 5133.
(35) (a) Albisetti, C. J .; Fisher, N. G.; Hogsed, M. J .; J oyce, R. M. J .
Am. Chem. Soc. 1956, 78, 2637. (b) Viola, A.; Iorio, E. J .; Chen, K. K.;
Glover, G. M.; Nayak, U.; Kocien´ski, J . P. J . Am. Chem. Soc. 1967, 89,
3462. (b) Wilson, R. M.; Rekers, J . W.; Packard, A. B.; Elder, R. C. J .
Am. Chem. Soc. 1980, 102, 1633.
(26) For a review on the synthesis of allylisilanes, see: Sarkar, T.
K. Synthesis 1990, 969 and 1101.

2768 J . Org. Chem., Vol. 64, No. 8, 1999
Kocˇovsky´ et al.
Sch em e 4a
La belin g Exp er im en ts. Since the above consider-
ations call for isotopic labeling, both (E)- and (Z)-isomers
of d3-labeled citronellal (()-1b and (()-1c were synthe-
sized in a stereospecific manner, starting from the
protected aldehyde 37, readily obtained from the benzyl
ether of citronellol via ozonization (Scheme 5).38 Wittig
olefination of the latter aldehyde with Ph3PdC(Me)CO2-
Et (CH2Cl2, 40 °C, 4 h) proceeded in a remarkably
stereoselective manner,39 affording the conjugated ester
38 (93%)40 as a 98:2 E/Z mixture. Reduction of the latter
ester with LiAlD4 afforded d2-labeled alcohol 3941 (89%;
g98% of d2), which on chlorination with N-chlorosuccin-
imide and Me2S (CH2Cl2, 0 °C, 5 h)42 afforded allylic
chloride 4043 (92%). Reduction of 40 with LiAlD4 (Et2O,
reflux for 6 h) gave the d3-derivative 4144 (97%; g98% of
d2), whose debenzylation with Li in liquid ammonia (41
f 42; 91%),38,44 followed by Swern oxidation provided (E)-
citronellal-d3 (1b) (98%; g97% of d3).
A prerequisite for the synthesis of the (Z)-isomer 1c
was a stereoselective access to the (Z)-isomer of ester 38,
which would allow us to employ the same strategy for
the isotopic labeling. After considering the suitability of
several approaches, we chose one that relies on depro-
tonation of the intermediate in Wittig olefination.45
According to this strategy, aldehyde 37 was treated with
the ylide obtained from Ph3P+CH2CH3 Br- and n-BuLi
(THF, -78 °C, 5 min). The betaine intermediate thus
generated was deprotonated with 1 equiv of n-BuLi (THF,
-78 to 0 °C), and the resulting anion was treated with
paraformaldehyde (0 °C, 1 h, then rt, 10 h)45 to afford
allylic alcohol 43 (45%) as a 93:7 mixture of (Z) and (E)
isomers.46 The latter allylic alcohol was first oxidized with
MnO2 to the corresponding aldehyde (0 °C, 30 min; 98%),
which was then treated with MnO2, NaCN, and AcOH
in MeOH (rt, 12 h); in this mixture, the in situ generated
cyanohydrin was oxidized by the present MnO2 to the
corresponding R-ketoacid nitrile,47 methanolysis of which
gave rise to the required (Z)-ester 44 (48%). Reduction
of 44 with LiAlD4 followed by replacement of the allylic
hydroxyl with chlorine42 (44 f 45 f 46) and another
reduction with LiAlD4 afforded d3-derivative 47 (88%
a
a , R ) CH3; b, R ) CD3.
a 7:93 ratio (rt, 30 min). The former isomer 26 is
apparently a kinetic product as it can be equilibrated on
action of complex B (to give an ∼1:9 26/27 mixture). The
analogue 2836 has been reported to produce a 2:3 mixture
of 29 and 30 on reaction with Me3SiCl and Mg in THF;36
with A or B, mixtures of 29 and 30 were formed in 83:17
(rt, 48 h) and 45:55 (rt, 30 min) ratios, respectively.
Again, 29 could be equilibrated in the presence of complex
B to produce a ∼1:1 29/30 mixture.
This behavior suggests that our Mo(II) and W(II)
complexes would catalyze cyclization of only those alk-
enals that are capable of fair stabilization of a positive
charge, e.g., by geminal alkyl groups, as in 1, 25, and
28, or owing to the â-stabilizing effect of silicon,34 as in 9
and 10. Other potential substrates, such as 7 and 8,
lacking these effects, are inert. Hence, the transition state
must have a substantial carbocationic character,33 with
the charge developed on the sp2 carbon (e.g., C-7 in 1).
Mech a n istic Con sid er a tion s. Several mechanisms
can be proposed to rationalize the cyclization of 1
(Scheme 4). Since the reaction gives rise either to an
olefin (3) or a tertiary alcohol (5), carbocation 32 can be
envisaged as an intermediate. Alternatively, concerted
or semiconcerted processes, involving 31 or 33, can also
be considered. However, the striking preference for the
cis-products seems to suggest a template effect, i.e., the
C-C bond formation occurring in the coordination sphere
of the metal (34 f 35 or 36),37 followed by â-elimination
(35 f 3) or hydration (36 f 5). In the former reaction,
the required â-H would be available from either methyl
group (35), so that the elimination step may not be
selective. By contrast, the hydration (via 36) should be
stereospecific; i.e., the reaction should proceed as an
overall syn-addition across the CdC bond. Similar con-
siderations can be applied to the other pathways: thus,
an overall anti-addition would result if the reaction
proceeded via 33, whereas a lack of, or little, stereodif-
ferentiation can be assumed for capture of the carbocation
32; the ene product could be formed by a regioselective
deprotonation via 31.
(38) (a) Overman, L. E.; J acobsen, E. J . J . Am. Chem. Soc. 1982,
104, 7225. (b) Kim, M. Y.; Starrett, J . E.; Weinreb, S. M. J . Org. Chem.
1981, 46, 5383. (c) Breitenbach, R.; Chiu, K.-F.; Massett, S. S.; Meltz,
H.; Muritiashan, C. W. Tetrahedron: Asymmetry 1996, 7, 435.
(39) Coates, R. M.; Ley, D. A.; Cavender, P. L. J . Org. Chem. 1978,
43, 4915.
(40) Kocien´ski, P. J .; Pritchard, M.; Wadman, S. N.; Whitby, R. J .;
Yeates, C. L. J . Chem. Soc., Perkin Trans. 1 1992, 1, 3419.
(41) For the unlabeled product, see: (a) Umemura, T.; Mori, K.
Agric. Biol. Chem. 1987, 51, 217. (b) Phandis, A. P.; Sinha, B.; Nanda,
B.; Patwardhan, S. A.; Rao, J . V.; Sharma, R. N. Monatsh. Chem. 1989,
120, 581.
(42) For the method, see: Corey, E. J .; Kim, C. U.; Takeda, M.
Tetrahedron Lett. 1972, 4339.
(43) For the unlabeled product, see ref 41a and the following: Mori,
K.; Umemura, T. Tetrahedron Lett. 1981, 22, 4429.
(44) For the unlabeled product, see refs 38a,b and the following:
Patel, D. V.; Van Middlesworth, F.; Donaubauer, J .; Gannett, P.; Sih,
C. J . J . Am. Chem. Soc. 1986, 108, 4603.
(45) For the method, see: (a) Corey, E. J .; Yamamoto, H. J . Am.
Chem. Soc. 1970, 92, 226. (b) Corey, E. J .; Yamamoto, H.; Herron, D.
K.; Achiwa, K. J . Am. Chem. Soc. 1970, 92, 6635. (c) Corey, E. J .;
Yamamoto, H. J . Am. Chem. Soc. 1970, 92, 6637. (d) Schlosser, M.;
Christmann, K.-F. J ustus Liebigs Ann. Chem. 1967, 708, 1. (e)
Schlosser, M.; Christmann, K.-F.; P´ıskala, A. Chem. Ber. 1970, 103,
2814.
(36) Ikeda, T.; Yue, S.; Hutchinson, C. R. J . Org. Chem. 1985, 50,
5193.
(37) Related C-C bond forming cyclizations with the prerequisite
coordination of CdO and CdC to a transition metal have been reported
for Rh, W, and Ti. Rh: (a) Fairlie, D. P.; Bosnich, B. Organometallics
1988, 7, 936. (b) Fairlie, D. P.; Bosnich, B. Organometallics 1988, 7,
946. W: (c) Bryan, J . C.; Arterbun, J . B.; Cook, G. K.; Mayer, J . M.
Organometallics 1992, 11, 3956. Ti: refs 19a-h. For stable complexes
having CdO and CdC coordinated to Mo(0) or W(0), see, e.g.: (d) King,
R. B. J . Organomet. Chem. 1967, 8, 139. (e) Schmidt, T.; Kru¨ger, C.;
Betz, P. J . Organomet. Chem. 1991, 402, 97.
(46) Allylic oxidation in these and related systems is less selective:
(a) Bhalerao, U. T.; Rapoport, H. J . Am. Chem. Soc. 1971, 93, 4835.
(b) McMurry, J . E.; Kocˇovsky´, P. Tetrahedron Lett. 1984, 25, 4187.
(47) For the method, see: Corey, E. J .; Katzenellenbogen, J . A.;
Gilman, N. W.; Roman, S.; Erickson, B. W. J . Am. Chem. Soc. 1968,
90, 5618.

Catalysts for Carbonyl Ene and Prins Reactions
J . Org. Chem., Vol. 64, No. 8, 1999 2769
Sch em e 5
Sch em e 7
tially reduced in the spectrum of 49b (giving, again, an
85:15 epimeric ratio). Therefore, the configuration at C-8
in 49b and, consequently, in 5b must be (S*) as shown
(for the main epimer). The configuration at C-8 of the
trans-diol 4b, arising as the minor product, was estab-
lished in the same way, i.e., via comparison of the 1H
NMR spectra of the corresponding carbonates 51a ,b: in
the spectrum of 51a , signals for the geminal methyls
appeared at 1.30 (axial CH3) and 1.37 (equatorial CH3)
ppm, respectively, as revealed by an NOE effect of the
former with 3-H (dt at 4.13 ppm); in the spectrum of 51b,
the signal at 1.30 ppm was substantially reduced. These
results are consistent with the preferential anti-addition
across the CdC bond (1 f 33 f 5 for the major product
and 1 f 50 f 4 for its isomer), i.e., with the Prins
reaction mechanism.
In light of the mechanism of the Prins-type cyclization
1 f 5 discused above, formation of the ene-type product
3 from 1, catalyzed by A (Scheme 4), can be viewed as
proceeding via 31 (rather than 35). In the case of 1b, the
elimination occurs from CH3 and CD3 in a 70:30 ratio
(i.e., preferentially via 31b), as revealed by the relative
intensities of the signals corresponding to the vinylic and
Sch em e 6a
1
CHOH protons in the H NMR spectrum of the product.
This ratio mainly reflects the kinetic isotope effect as
shown by comparison with the reactivity of the (Z)-isomer
1c, which gave a 64:36 mixture. With less bulky reagents,
a proton is known to be removed selectively from MeE (1
f 2).5b
In the case of substrates 25 and 28 (Schemes 3 and 7),
the proton abstraction is fairly regioselective, preferen-
tially giving the expected products of formal ene reaction
26 and 29, respectively, on treatment with A. In fact,
Marshall has shown by stereospecific deuteration that
cyclization of 25 with traditional Lewis acids occurs with
a 95:5 preference for the intramolecular proton transfer
(via 25A).1h Formation of 29 from 28 in the presence of
catalyst A also suggests an intramolecular abstraction,
namely that of an axial proton (28A), favored over the
equatorial deprotonation as a manifestation of the ste-
reoelectronic effect. By contrast, catalysis with complex
B led mainly to the regioisomers 27 and 30, respectively,
which can be attributed to isomerization of the kinetic
products 26 and 29. Control experiments lend credence
to this rationalization as both 26 and 29 can be equili-
brated on treatment with catalyst B (vide supra).
Mech a n istic Ep ilogu e. These experiments indicate
that all the complexes A-E act as Lewis acids. In accord
with the behavior of other catalysts of this class, A-E
can be assumed to operate via the corresponding η1-
complexes with the usual trans-geometry30,34,49 of the Cd
O bond (Chart 2). Two chairlike transition states trans-
TSq I and cis-TSq II and a boatlike cis-TSq III, all with
a
a , R ) CH3; b, R ) CD3.
overall), whose deprotection (Li, NH3; 84%) followed by
Swern oxidation led to (Z)-citronellal-d3 (1c) (92%; g97%
of d3).
Treatment of 1b with B (5 mol %) in wet DME afforded
the expected 1:4 mixture of trans- and cis-diols 4b and
5b; the latter diol proved to be an 85:15 mixture of the
C-8 epimers48 (Scheme 6). To determine the configuration
at C-8 of 5b, the latter product was converted into the
anancomeric carbonate 49b on reaction with phosgene
1
(COCl2, toluene, pyridine, 0 °C, 15 min, 93%). In the H
NMR spectrum of its nondeuterated congener 49a ,
prepared from 5a in the same manner, the geminal
methyls appeared as singlets at 1.38 (equatorial CH3) and
1.51 (axial CH3) ppm, respectively. The latter group
exhibited a significant NOE with 3-H (d at 4.85) in the
spectrum of 49a , and the same effect was observed for
49b. Furthermore, the singlet at 1.38 ppm was substan-
(49) (a) Denmark, S. E.; Weber, E. J .; Wilson, T. M.; Wilson, T. M.
Tetrahedron 1989, 45, 1053. See also: (b) Thiyagarayan, B.; Michal-
czyk, L.; Bollinger, J . C.; Huffman, J . C.; Bruno, J . W. Organometallics
1996, 15, 1989 and references therein. (c) Seebach, D.; Golin´ski, J . Helv.
Chim. Acta 1981, 64, 1413.
(48) The epimeric ratio was determined by integration of the geminal
CH3 signals in the 1H NMR spectrum.

2770 J . Org. Chem., Vol. 64, No. 8, 1999
Kocˇovsky´ et al.
the preferred synclinal disposition of the π-systems,49 can
be envisioned.50 In trans-TSq I, a severe repulsive inter-
action can be identified between the proximal ligand Lp
and the geminal methyl groups MeE and MeZ;51 note that
Lp cannot be easily relieved from its wedged-in position
by rocking (see the arrows). The cis-TSq II is not free of
steric congestion either although the repulsive interaction
between Lp and MeZ can partly be released by bending,
as suggested by the arrows. In the instance of 6 (R )
Me), the additional methyl group would impose a 1,3-
diaxial interaction with the O[M] group (II), which can
account for the lack of reactivity of 6. However, the cis-
TSq II still seems to be too congested due to the clash
between MeZ and Lp. A third possibility is the boatlike
TSq III, in which the latter obstacle is avoided. Inspection
of this model shows the methyl group of 1 (R ) H) in an
equatorial position, whereas in the case of 6 (R ) Me)
the additional methyl has to assume an inconvenient
axial position so that this model can also rationalize the
lack of the accelerating effect of the geminal dimethyl.
The boatlike TSq III gains further credence from a recent
study by Brown,1j who has demonstrated by isotopic
labeling that, while sterically nondemanding Lewis acids
(e.g., Me2AlCl) react via a chairlike TSq, extremely bulky
Lewis acids, such as Yamamoto’s MABR, tend to prefer
a boatlike TSq (rather than the originally proposed52
“open” mechanism) if this is the best way to avoid
unfavorable steric interactions between the substituents
and the metal ligands. We believe that our complexes A,
B, D, and E belong to this category owing to Lp.53
(E)-Allylsilane 9, lacking the MeZ group, is readily
cyclized to give the trans-product 11, presumably via a
trans-TSq similar to I. On the other hand, (Z)-allylsilane
10, lacking the MeE group, was found to produce mainly
the cis-isomer 12, presumably via a cis-TSq similar to II.
Apparently, the reactivity of these activated ene sub-
strates is mainly controlled by the secondary orbital
interaction as proposed by Denmark.34,49a
It may be argued that the stereochemistry of the
cyclization is dependent on the strength of the Lewis acid
employed and, consequently, on the magnitude of the
charge being developed in the transition structures. The
negative oxygen would then stabilize the partial positive
charge on the olefinic component.54 However, the latter
stabilization can apply to all synclinal arrangements in
Ch a r t 2a
a
R ) H or CH3; L ) CO or Br.
the transition states I-III so that this effect alone can
hardly be responsible for the observed variations. More-
over, the 43:57 trans/cis ratio (Table 1, entry 3) obtained
with SbCl5 (itself a strong Lewis acid)3 demonstrates the
importance of the steric effects and so does the recent
report by Brown on the boatlike transition state (vide
supra).1j Finally, comparison of the Mo(II) complexes A
and B with C lends further credence to the steric
argument: while A and B carry strongly coordinating
ligands, of which one can easily assume the role of the
protruding Lp (Chart 2), C is known to shed one or two
of its CO ligands in weakly coordinating solvents (pre-
sumably due to the trans-effect of the bromine atoms),
such as THF.13 Hence, complex C may actually lose its
Lp ligand and, as a result, can be anticipated to behave
similarly to the sterically less demanding Lewis acids,
i.e., to produce trans-isomer preferentially. The experi-
mental results (vide supra) are fully compatible with this
hypothesis. Therefore, it can be concluded that the degree
of congestion in the transition states I-III, which is
dependent on the Lewis acid employed, is the main factor
controlling the stereochemistry of the ene-type cyclization
rather than the strength of the Lewis acid: whereas the
bulky Rh(I)6 and our Mo(II) and W(II) complexes appear
to favor cis-TSq III, the relatively small reagents (ZnCl2,
AlCl3, BF3, etc.3), lacking the protruding Lp-type ligand,
prefer trans-TSq I, and SbCl5 (hexacoordinate!)3 shows
slight preference for the cis-isomer. Particularly convinc-
ing is the comparison between SbCl3 and SbCl5, where
the shift from trans- to cis-product is notable (compare
entries 2 and 3 in Table 1).55 The retro-ene equilibration
(vide supra) may further contribute to the usually
observed preference for 2 in the case of strong Lewis
acids.
(50) The highest observed trans/cis ratio 20:80 corresponds to ∼1
kcal‚mol-1 energy difference between I and II/III (at room tempera-
ture).
(51) Similar steric effect of a protruding CO ligand has been reported
for the Diels-Alder addition of dienes to vinylmetallocarbenes, where
it attenuates the secondary orbital interactions: Powers, T. S.; J iang,
W. Q.; Su, J .; Wulff, W. D. J . Am. Chem. Soc. 1997, 119, 6438-6439.
(52) (a) Maruoka, K.; Ooi, T.; Yamamoto, H. J . Am. Chem. Soc. 1990,
112, 9011. (b) Maruoka, K.; Saito, S.; Ooi, T.; Yamamoto, H. Synlett
1991, 579. (c) Ooi, T.; Maruoka, K.; Yamamoto, H. Tetrahedron 1994,
50, 6505.
(53) (a) In the case of transition metals, alternative η2-coordination
to CdO cannot be, a priori, ruled out, although group 6 complexes, as
a rule, prefer η1-coordination. Inspection of the corresponding models
for transition states with η2-coordination shows much less dramatic
differences than those identified for I-III (i.e., with η1-coordination).
(b) For an excellent review on the modes of coordination of carbonyl
groups to various transition metals (i.e., η1 vs η2), see: Shambayati,
S.; Crowe, W, E.; Schreiber, S. L. Angew. Chem., Int. Ed. Engl. 1990,
29, 256. (c) For recent, clear-cut examples of η1 vs η2 coordination of
an aldehyde group, see: Lenges, C. P.; Brookhart, M.; White, P. S.
Angew. Chem., Int. Ed. 1999, 38, 552.
Con clu sion s
In conclusion, we have designed new Mo(II) catalysts
A-C, which induce intramolecular cyclization of olefinic
(54) This effect has been proposed to rationalize the predominant
formation of the cis-product on cyclization cyclization of citronellal in
micelles: Clark, B. C., J r.; Chamblee, T.; Iacobucci, G. A. J . Org. Chem.
1984, 49, 4557.
(55) Preferential formation of the trans-isomer (2/3 ) 80:20 at room
temperature and 94:6 at -78 °C) has recently been reported for
(TfO)3Sc in CH2Cl2;2a we have observed an 80:20 ratio with (TfO)3Yb
(rt, CH2Cl2).

Catalysts for Carbonyl Ene and Prins Reactions
J . Org. Chem., Vol. 64, No. 8, 1999 2771
with ether and worked up. The crude product, which was a
1:4 mixture of 4a and 5a , as determined by 1H NMR, was
chromatographed on a column of silica gel (20 g) using a
petroleum ether-ether mixture (2:1) to furnish the cis-diol 5a
(163 mg, 73%): mp 78-81 °C (lit.15,17,56,57 mp 73-74 °C or 81-
82 °C); IR ν(OH) 3480 and 3610 cm-1; 1H NMR δ 0.89 (d, J )
6.2 Hz, 3 H, CH3CH), 1.24 (3 H, pro-S*-CH3), 1.37 (s, 3 H, pro-
R*-CH3), 1.60-1.90 (m, 6 H), 2.95-3.40 (br s, 2 H), 4.42 (br d,
J ) 2.5 Hz, 1 H, CHOH); 13C NMR δ 20.24 (t), 22.18 (q), 25.56
(d), 28.76 (q), 28.88 (q), 34.83 (t), 42.46 (t), 48.23 (d), 67.98 (d),
73.20 (s); HRMS (EI) m/z 154.135 82 (calcd for C10H18O,
154.135 77; M•+ - H2O). Continued elution afforded a more
polar fraction, identified as the trans-diol 4a (20 mg; 9%): mp
59-60 °C (petroleum ether) (lit.15,56,57 mp 60-61 °C or 77-78
°C); IR ν(OH) 3480, 3600 cm-1; 1H NMR δ 0.92 (d, J ) 6.5 Hz,
3 H, CH3CH), 1.23 (s, 6 H, CMe2), 1.25-2.05 (m, 8 H), 3.72
(dt, J ) 10.5 and 4.3 Hz, 1 H, CHOH), 3.88 (br s, 2 H, 2 ×
OH); 13C NMR δ 22.03 (q), 23.75 (q), 27.15 (t), 30.13 (q), 31.41
(d), 34.59 (t), 44.65 (t), 53.46 (d), 72.95 (d), 75.12 (s).
aldehydes. In the case of citronellal (1) as a prototype
substrate, preferential formation of the kinetic products
with the cis-configuration at the newly formed chiral
centers was observed. These catalysts are more efficient
than those in existence (e5 mol % is sufficient) and can
be tuned to drive the reaction either toward the ene- or
Prins-type product (3 or 5). Our experiments shed light
on the mechanism and show that formation of a cis-
product in reactions such as these may not always involve
a C-C bond formation occurring on the metal template.
Moreover, the crucial role of the protruding ligand Lp on
the stereochemical outcome has been demonstrated; in
conjunction with Wulff’s report,51 it appears that these
effects play a more important role in the reactivity of
transition metal complexes than previously realized.
Finally, the switch from the chairlike to the boatlike1j
mechanism (III) can be a viable option. In view of the
crowded TSq, asymmetric induction due to a chiral ligand
effect can be envisioned.
(E)-[8,8,8-2H3]-3,7-d im eth yl-6-octen -1-a l (1b). To a solu-
tion of oxalyl chloride (351 mg, 2.77 mmol) in CH2Cl2 (19 mL)
was added dropwise a solution of DMSO (433 mg, 5.54 mmol)
in CH2Cl2 (1.6 mL) at -78 °C, and the resulting solution was
stirred at -78 °C for 5 min. A solution of the alcohol 42 (410
mg, 2.57 mmol) in CH2Cl2 (1.6 mL) was then added at the same
temperature. After 15 min, Et3N (1.8 mL, 13 mmol) was added
and the mixture was allowed to warm to room temperature,
stirred for 30 min, and then poured into 1 M HCl. The product
was extracted with CH2Cl2, the organic layer was dried with
MgSO4, and the solvent was evaporated. The residue was
flash-chromatographed on silica gel (10 g) with a petroleum
ether-ether mixture (9:1) to afford 1b (395 mg; 98%) as a
Exp er im en ta l Section
Gen er a l P r oced u r e. Melting points were determined on
a Kofler block and are uncorrected. The IR spectra were
recorded in CHCl3 (or CDCl3) unless stated otherwise. The
NMR spectra were recorded for CDCl3 solutions at 25 °C on
250 or 300 MHz instruments. The coupling constants were
obtained by first-order analysis. The mass spectra were
measured using direct inlet and the lowest temperature
enabling evaporation or in a thermospray mode; chemical
ionization was used in certain cases (with NH4). GC analysis
was carried out using capillary columns (BP10 25 m × 2.65
µm). All reactions were carried out under nitrogen. The
identity of labeled compounds was established by comparison
of their spectral data with those published for the unlabeled
analogues or obtained for authentic, unlabeled samples. Yields
are given for isolated product showing one spot on a chro-
matographic plate and no impurities detectable in the NMR
spectrum.
Typ ica l P r oced u r e for th e En e-Typ e Cycliza tion (P r o-
ced u r e I). To a solution of dry catalyst A (5 mol %) in DME
(1 mL) was added a solution of citronellal 1a (154 mg, 1.0
mmol) in DME (1 mL). The resulting yellow solution was
stirred at room temperature for 24 h and then diluted with
ether and washed with saturated aqueous solution of NaHCO3
and brine. The combined organic layers were dried with MgSO4
and filtered through a pad of silica gel to remove inorganic
residues. The solvent was evaporated under reduced pressure,
and the residue was chromatographed on a column of silica
gel with a petroleum ether-ether mixture (9:1) to afford
neoisopulegol (3a ) (105 mg, 68%) as a colorless oil, whose
spectral data correspond to those described in the litera-
ture:15 IR ν 1650, 2900, 3560 cm-1; 1H NMR δ 0.91 (d, J ) 6.4
Hz, 3 H, CH3CH), 1.81 (s, 3 H, CH3CdCH2), 4.03 (br d, J )
2.3 Hz, 1 H, CH-OH), 4.81 (s, 1 H, CdCHH), 4.98 (s, 1 H,
CdCHH); 13C NMR δ 22.30 (q), 22.75 (q), 23.92 (t), 25.79 (d),
34.74 (t), 40.89 (t), 48.37 (d), 66.28 (d), 111.23 (t), 147.27 (s).
Continued elution furnished isopulegol (2a ) (17 mg, 11%),
whose 1H NMR spectrum was identical with that of an
authentic sample obtained from Fluka: 1H NMR δ 0.86 (d, J
) 6.6 Hz, 3 H, CH3CH), 1.71 (s, 3 H, CH3CdCH2), 3.46 (ddd,
J ) 10.4, 10.4, 4.3 Hz, 1 H, CH-OH), 4.86 (s, 1 H, CdCHH),
4.90 (s, 1 H, CdCHH). Further verification of the structures
of 2 and 3 was based on the PCC oxidation which, in each
case, gave isopulegone, whose treatment with methanolic KOH
afforded pulegone, identical with an authentic sample pur-
chased from Fluka.
colorless oil: IR ν(CdO) 1725, ν(CH) 2725 cm-1 1H NMR δ
;
0.97 (d, J ) 6.6 Hz, 3 H, CHCH3), 1.10-1.45 (m, 3 H), 1.60 (s,
3 H, CH3), 1.85-2.52 (m, 4 H), 5.09 (dt, J ) 7.1, 1.3 Hz, 1 H,
CHdC), 9.75 (t, J ) 2.4 Hz, 1 H, CHdO); 13C NMR δ 17.57
(q), 19.82 (q), 25.33 (t), 27.72 (d), 36.89 (t), 50.95 (t), 123.99
(d), 131.69 (s), 203.07 (d); MS g97% of d3.
(Z)-[8,8,8-2H3]-3,7-Dim eth yl-6-octen -1-a l (1c). Obtained
from 48 on Swern oxidation (in the same way as 1b) as a
1
colorless oil (92%): IR ν(CdO) 1725; H NMR δ 0.95 (d, J )
6.6 Hz, 3 H, CHCH3), 1.1-1.45 (m, 3 H), 1.67 (d, J ) 1.3 Hz,
3 H, CH3CdC), 1.83-2.48 (m, 4 H), 5.07 (dt, J ) 7.1 and 1.3
Hz, 1 H, CdCH), 9.74 (t, J ) 2.2 Hz, 1 H, CHdO); 13C NMR
δ 19.84 (q), 25.36 (t), 25.62 (q), 27.74 (d), 36.92 (t), 50.98 (t),
124.02 (d), 131.70 (s), 203.07 (d); MS g97% of d3.
[9,9,9-2H3]-(1S*,3S*,4S*,8S*)-p-Men th a n e-3,8-d iol (4b).
Obtained from citronellal-d3 (1b) as the minor product in the
same manner as its nonlabeled counterpart 4a using procedure
II (16%): 1H NMR δ 0.92 (d, J ) 6.6 Hz, 3 H, CHCH3), 1.21 (s,
3 H, CH3), 1.23-2.00 (m, 8 H), 3.71 (dt, J ) 10.4, 4.2 Hz, 1 H,
CHOH), 4.26 (br s, 2 H, 2 × OH); 13C NMR δ 21.94 (q), 26.99
(t), 29.85 (q), 31.31 (d), 34.49 (t), 44.50 (t), 53.24 (d), 72.83 (d),
74.86 (s).
[9,9,9-2H3]-(1S*,3R*,4S*,8S*)-p-Men th a n e-3,8-d iol (5b).
Obtained from citronellal-d3 (1b) as the major product in the
same manner as its nonlabeled counterpart 5a using procedure
II (72%): 1H NMR δ 0.89 (d, J ) 6.0 Hz, 3 H, CHCH3), 0.90-
1.20 (m, 3 H), 1.35 (s, 3 H, CH3), 1.59-1.94 (m, 5 H), 2.59-
3.30 (m, 2 H, 2 × OH), 4.39 (d, J ) 2.2 Hz, 1 H, CHOH); 13C
NMR δ 20.21 (t), 22.17 (q), 25.57 (d), 28.79 (q), 34.81 (t), 42.47
(t), 48.21 (d), 68.03 (d), 73.10 (s); MS m/z (%) 157 (M•+ - H2O;
8), 142 (6), 124 (3), 111 (7), 96 (61), 81 (100), 72 (8), 68 (22), 62
(56), 54 (25).
(56) 4a and 5a : (a) Nishimura, H.; Kaku, K.; Nakamura, T.;
Fukuzawa, Y.; Mizutani, J . Agric. Biol. Chem. 1982, 46, 319. (b)
Nishimura, H.; Noma, Y.; Mizutani, J . Agric. Biol. Chem. 1982, 46,
2601. (c) Asakawa, Matsuda, R.; Tori, M.; Hashimoto, T. Phytochem-
istry 1988, 27, 386. (d) Takahashi, H.; Noma, Y., Toyota, M.; Ashakawa,
Y. Phytochemistry 1994, 35, 1465. 4a : (e) Stein, D.; Sam, R.; Nouguier,
R.; Crich, D.; Bertrand, M. P. J . Org. Chem. 1997, 62, 275.
(57) The configurational assignment for 4a and 5a is based on the
coupling pattern of the CHOH in the 1H NMR. Thus, 5a , with an axial
OH, shows the proton in question as a broad doublet (J ) 2.5 Hz),
whereas the equatorial epimer 4a exhibits a dt with J ) 10.5 and 4.3
Hz.
Typ ica l P r oced u r e for th e P r in s-Typ e Cycliza tion
(P r oced u r e II). To the in situ generated catalyst B (5 mol
%) was added H2O (0.3 mL) followed by a solution of citronellal
1a (200 mg, 1.3 mmol) in DME (1 mL). The resulting mixture
was stirred at room temperature for 48 h and then diluted

2772 J . Org. Chem., Vol. 64, No. 8, 1999
Kocˇovsky´ et al.
(E)-8-(Dim eth ylp h en ylsilyl)oct-6-en -1-a l (9). Obtained
from 18 (in the same manner as 10 was prepared from 24) as
13C NMR δ 19.61 (t), 25.42 (t), 25.69 (t), 28.87 (t), 29.49 (t),
30.69 (t), 32.04 (t), 62.29 (t), 63.62 (t), 67.48 (t), 98.80 (d),
129.03 (d), 133.01 (d).
a colorless oil (153 mg, 59%): IR ν(CH) 2725, ν(CO) 1725 cm-1
1H NMR δ 0.26 (s, 6 H, Si(CH3)2), 1.23-1.43 (m, 2 H), 1.49-
1.73 (m, 2 H), 1.65 (d, J ) 7.6 Hz, 2 H, CHdCHCH2Si), 1.90-
2.05 (m, 2 H), 2.37 (dt, J ) 7.5 and 1.80 Hz, 2 H, CH2CHdO),
5.14-5.46 (m, 2 H, CHdCH), 7.28-7.56 (m, 5 H, aryl-H), 9.73
(t, J ) 1.7 Hz, 1 H, CHdO); 13C NMR δ -3.41 (2 × q), 21.42
(t), 21.60 (t), 29.28 (t), 32.33 (t), 43.70 (t), 126.05 (d), 127.66
(d), 128.83 (d), 128.87 (d), 133.58 (d), 138.85 (s), 202.69 (d).
(Z)-8-(Dim et h ylp h en ylsilyl)oct -6-en -1-a l (10). Chro-
mium trioxide (448 mg, 4.5 mmol) was added in three equal
portions to pyridine (0.73 mL, 9 mmol) in dry CH2Cl2 (7 mL).
After the solution was stirred at room temperature for 15 min,
a solution of 24 (262 mg, 1.0 mmol) in dry CH2Cl2 (2 mL) was
added. The reaction mixture was then stirred for 3 h and
quenched by pouring into wet ether. The ethereal layer was
successively washed with 10% NaOH (2 × 70 mL), a saturated
aqueous solution of CuSO4 (4 × 15 mL), water (10 mL), and
brine (2 × 15 mL) and dried with MgSO4. The solvent was
removed under reduced pressure, and the residue was chro-
matographed on silica gel using a petroleum ether-ether
mixture (4:1) as eluent to furnish 10 as a colorless oil (163
;
(E)-8-[(Tetr a h yd r o-2′H-p yr a n -2′-yl)oxy]-2-octen yl Ac-
eta te (16). Obtained from 15 on acetylation (in the same way
as 22 was prepared from 21) as a colorless oil (2.02 g, 93%):
IR ν(CdO) 1730 cm-1; 1H NMR δ 1.23-1.86 (m, 10 H), 1.97-
2.17 (m, 2 H, CH2CHdC), 2.06 (s, 3 H, COCH3), 3.31-3.94
(m, 4 H, 2 × CH2O), 4.50 (d, J ) 6.5 Hz, 2 H, CH2OAc), 4.57
(m, 1 H, OCHO), 5.47-5.66 (m, 1 H, CHdCH), 5.68-5.86 (m,
1 H, CHdCH); 13C NMR δ 19.60 (t), 20.90 (q), 25.40 (t), 25.67
(t), 28.61 (t), 29.46 (t), 30.68 (t), 32.06 (t), 62.24 (t), 65.15 (t),
67.39 (t), 98.77 (d), 123.78 (d), 136.29 (d), 170.71 (s).
(E)-7-[(Tet r a h yd r o-2′H -p yr a n -2-yl)oxy]-1-[(d im et h yl-
p h en ylsilyl)m eth yl]h ep t-1-en e (17). Obtained from 16 (in
the same way as 23 was prepared from 22) as a colorless oil
17 (0.90 g, 67%): 1H NMR δ 0.25 (s, 6 H, Si(CH3)2), 1.15-1.84
(m, 10 H), 1.65 (d, J ) 7.5 Hz, 2 H, CHdCHCH2Si), 1.96 (m,
2 H, CH2CHdC), 3.27-3.95 (m, 4 H, 2 × CH2O), 4.57 (m, 1 H,
OCHO), 5.14-5.46 (m, 2 H, CHdCH), 7.27-7.60 (m, 5 H, aryl-
H); 13C NMR δ -3.43 (2 × q), 19.64 (t), 21.55 (t), 25.49 (t),
25.66 (t), 29.60 (t), 29.72 (t), 30.75 (t), 32.64 (t), 62.23 (t), 67.59
(t), 98.77 (d), 125.38 (d), 127.63 (d), 128.82 (d), 129.60 (d),
133.58 (d), 138.96 (s).
mg, 63%): IR ν(CO) 1725 cm-1 1H NMR δ 0.28 (s, 6 H, Si-
;
(E)-7-[(Dim eth ylp h en ylsilyl)m eth yl]-1-h yd r oxyh ep t-6-
en e (18). Obtained from 17 on deprotection (in the same way
as 24 was prepared from 23) as a colorless oil (89%): IR ν(OH)
3615 cm-1; 1H NMR δ 0.25 (s, 6 H, Si(CH3)2), 1.20-1.61 (m, 7
H), 1.65 (d, J ) 7.2 Hz, 2 H, CHdCHCH2Si), 1.85-2.05 (m, 2
H, CH2CHdC), 3.61 (t, J ) 6.6 Hz, 2 H, CH2OH), 5.15-5.47
(m, 2 H, CHdCH), 7.29-7.56 (m, 5 H, aryl-H); 13C NMR δ
-3.43 (2 × q), 21.56 (t), 25.10 (t), 29.63 (t), 32.62 (2 × t), 62.97
(t), 125.53 (d), 127.64 (d), 128.84 (d), 129.48 (d), 133.59 (d),
138.97 (s).
Meth yl 8-[(Tetr ah ydr o-2′H-pyr an -2′-yl)oxy]-2-octyn oate
(19). To a mixture of zinc dust (1.30 g, 2 equiv) and tetra-
bromomethane (6.64 g, 2 equiv) in CH2Cl2 (28 mL) was added
triphenylphosphine (5.24 g, 2 equiv.) portionwise. After 24 h
at 23 °C, a solution of 6-(tetrahydro-2′-pyranyloxy)hexanal
(13)5b (2.0 g, 10 mmol, 1 equiv) in CH2Cl2 (10 mL) was slowly
added. The mixture was stirred for 90 min, poured into hexane
(540 mL), and filtered, and the solvent was evaporated under
reduced pressure. The residue was diluted with hexane (100
mL), and triphenylphosphine oxide was removed by filtration.
Upon removal of solvent, essentially pure 1,1-dibromoolefin
(3.28 g, 92%) was obtained as a colorless oil: 1H NMR δ 2.10
(q, J ) 7.1 Hz, 2 H, CH2CHdC), 3.27-3.93 (m, 4 H, 2 × CH2O),
4.56 (m, 1 H, OCHO), 6.37 (t, J ) 7.2 Hz, 1 H, CH2CHdCBr2);
13C NMR δ 19.67 (t), 25.48 (t), 25.71 (t), 27.62 (t), 29.44 (t),
30.75 (t), 32.91 (t), 62.32 (t), 67.31 (t), 88.64 (s), 98.85 (d),
(CH3)2), 1.06-1.65 (m, 4 H), 1.70 (d, J ) 8.5 Hz, 2 H, CHd
CHCH2Si), 1.92 (m, 2 H), 2.37 (dt, J ) 7.2, 1.8 Hz, 2 H,
CH2CHO), 5.14-5.53 (m, 2 H, CHdCH), 7.28-7.59 (m, 5 H,
aryl-H), 9.72 (t, J ) 1.7 Hz, 1 H, CHdO); 13C NMR δ -3.34 (2
× q), 17.61 (t), 21.72 (t), 26.67 (t), 29.06 (t), 43.73 (t), 125.20
(d), 127.44 (d), 127.66 (d), 128.91 (d), 133.54 (d), 138.76 (s),
202.70 (d).
(1S*,2R*)-2-Vin ylcycloh exa n ol (11):58 IR ν(OH) 3600,
3680 cm-1; 1H NMR δ 1.06-1.94 (m, 8 H), 1.94-2.10 (m, 1 H,
CHCHdCH2), 3.23 (dt, J ) 4.0, 10.0 Hz, 1 H, CH2CHOH),
5.04-5.21 (m, 2 H, CHdCH2), 5.66 (ddd, J ) 8.0, 10.2, and
17.3 Hz, 1 H, CHdCH2); 13C NMR δ 24.75 (t), 25.12 (t), 31.08
(t), 33.81 (t), 51.20 (d), 72.76 (d), 116.66 (t), 140.79 (d).
(1R*,2R*)-2-Vin ylcycloh exa n ol (12):58a IR ν(OH) 3590,
3660 cm-1; 1H NMR δ 1.05-1.78 (m, 8 H), 2.09-2.30 (m, 1 H,
CHCHdCH2), 3.79-3.89 (m, 1 H, CH2CHOH), 5.04-5.19 (m,
2 H, CHdCH2), 5.92 (ddd, J ) 6.6, 10.7, and 17.3 Hz, 1 H,
CH)CH2); 13C NMR δ 20.83 (t), 24.20 (t), 25.51 (t), 32.10 (t),
45.23 (d), 69.29 (d), 115.96 (t), 140.80 (d).
E t h yl (E)-8-[(Tet r a h yd r o-2′H -p yr a n -2′-yl)oxy]-2-oct -
en oa te (14). Aldehyde 13 (2.2 g, 11.0 mmol) was added
dropwise over a period of 15 min to a refluxing solution of
(carbethoxymethylene)triphenylphosphorane (3.83 g, 11.0 mmol)
in benzene (10 mL). TLC analysis with a hexane-AcOEt
mixture (4:1) indicated that the reaction was complete after 3
h. The solvent was evaporated, and the residue was dissolved
in hexane and filtered through silica gel to remove triphen-
ylphosphine oxide. Evaporation of the solvent furnished the
unsaturated ester 14 (96:4) (2.64 g, 89%) as a colorless oil,
whose spectral data correspond to those described in the
138.64 (d); HRMS m/z 354.9731 (calcd for
C12H19O2Br2,
354.9731; M•+ - H). To a solution of the latter dibromoolefin
(847 mg, 2.38 mmol), obtained from the above reaction, in THF
(30 mL), was added dropwise n-BuLi (3.14 mL, 5.02 mmol,
1.6 M solution in hexane) at -78 °C under nitrogen. After 20
min, methyl chloroformate (0.92 mL, 11.9 mmol) was added
dropwise. The mixture was stirred at -78 °C for 10 min,
allowed to warm to room temperature for 45 min, and then
poured into ether and brine. The organic layer was washed
with an aqueous solution of NaHCO3 and with brine and dried
over MgSO4, and the solvent was evaporated. The crude
product was purified by flash chromatography on silica gel
using a hexane-AcOEt mixture (30:1) as eluent to furnish 19
(0.49 g, 81%) as an oil, whose spectral data correspond to those
described in the literature:31 IR ν 2235, 1710 cm-1; 1H NMR δ
1.05-1.90 (m, 12 H), 2.31 (t, J ) 6.9 Hz, 2 H, CH2CtC), 3.25-
3.95 (m, 4 H, 2 × CH2O), 3.71 (s, 3 H, OCH3), 4.53 (m, 1 H,
OCHO); 13C NMR δ 18.54 (t), 19.59 (t), 25.42 (t), 25.49 (t), 27.30
(t), 29.08 (t), 30.68 (t), 52.41 (q), 62.26 (t), 67.12 (t), 72.89 (s),
89.55 (s), 98.81 (d), 154.14 (s).
1
literature:24 IR ν(CdO) 1710, ν(CdC) 1657 cm-1; H NMR δ
1.28 (t, J ) 7.1 Hz, 3 H, CH3), 1.35-1.55 (m, 12 H), 2.13-2.59
(m, 2 H, CH2CHdC), 3.31-3.94 (m, 4 H, 2 × CH2O), 4.18 (q,
J ) 7.1 Hz, 2 H, OCH2CH3), 4.57 (m, 1 H, OCHO), 5.81 (d, J
) 15.7 Hz, 1 H, CHdCHCO2Me), 6.19 (dt, J ) 15.7, 6.9 Hz, 1
H, CHdCHCO2Me); 13C NMR δ 14.20 (q), 19.64 (t), 25.43 (t),
25.74 (t), 27.79 (t), 29.43 (t), 30.70 (t), 30.03 (t), 60.04 (t), 62.31
(t), 67.31 (t), 98.83 (d), 121.33 (d), 149.07 (d), 166.65 (s).
(E)-8-[(Tetr ah ydr o-2′H-pyr an -2′-yl)oxy]-2-octen -1-ol (15).
Obtained from 14 on diisobutylaluminum hydride reduction
(in the same way as 21 was prepared from 20) as a colorless
oil (103 mg, 90%), whose spectral data correspond to those
described in the literature:24a,b,25 IR ν(OH) 3605, 3440 cm-1
;
1H NMR δ 1.27-1.94 (m, 13 H), 1.97-2.16 (m, 2 H, CH2CHd
C), 3.30-3.95 (m, 4 H, 2 × CH2O), 4.07 (d, J ) 4.4 Hz, 2 H,
CH2OH), 4.57 (m, 1 H, OCHO), 5.47-5.78 (m, 2 H, CHdCH);
Met h yl (Z)-8-[(t et r a h yd r o-2′H -p yr a n -2′-yl)oxy]-2-oct -
en oa te (20). A mixture of acetylene 19 (0.52 g, 2.04 mmol),
quinoline (0.75 mL, 6.33 mmol), and Lindlar catalyst (0.37 g)
in hexane (57 mL) was stirred under 1 atm of H2 (g) for 4.5 h.
After removal of the solids by filtration through Celite, the
(58) (a) Crandall, J . K.; Arrington, J . P.; Hen, J . J . Am. Chem. Soc.
1967, 89, 6208 and 6212. (b) Hoenig, H.; Seufer, W. P. Synthesis 1990,
1137. (c) Cope, A. C.; Grisar, J . M.; Peterson, P. E. J . Am. Chem. Soc.
1960, 82, 4299 and references cited therein.

Catalysts for Carbonyl Ene and Prins Reactions
J . Org. Chem., Vol. 64, No. 8, 1999 2773
solution was washed with 1 M HCl, water, an aqueous solution
of NaHCO3, and brine and dried over MgSO4. Upon removal
of the solvent, pure 20 (517 mg, 99%) was obtained as a
gel (10 g) by eluting with a hexanes-ether mixture (4:1) to
afford 24 (249 mg, 95%) as a colorless oil: IR ν(OH) 3620 cm-1
;
1H NMR δ 0.27 (s, 6 H, Si(CH3)2), 1.16-1.64 (m, 7 H), 1.70 (d,
J ) 7.9 Hz, 2 H, CHdCHCH2Si), 1.93 (m, 2 H, CH2CHdC),
3.61 (t, J ) 6.4 Hz, 2 H, CH2OH), 5.16-5.48 (m, 2 H, CHd
CH), 7.28-7.61 (m, 5 H, aryl-H); 13C NMR δ -3.32 (2 × q),
17.52 (t), 25.44 (t), 26.98 (t), 29.41 (t), 32.65 (t), 62.93 (t), 124.75
(d), 127.66 (d), 128.09 (d), 128.90 (d), 133.55 (d), 138.88 (s).
5-Meth yl-5-h exen -1-a l (25). To a stirred solution of ethyl
4-isopropenylbutyrate59 (0.48 g, 3 mmol) in dichloromethane
(30 mL) at -78 °C was added diisobutylaluminum hydride (6
mmol, 1 M solution in CH2Cl2) over a period of 20 min under
nitrogen atmosphere. After 10 min, the reaction mixture was
quenched with saturated aqueous solution of ammonium
chloride and allowed to warm to room temperature over 0.5
h. The product was extracted with ether and dried with
MgSO4. After filtration, the solvent was removed under
reduced pressure and the residual oil was flash chromato-
graphed on silica gel (10 g) eluting with hexanes-ether
mixture (16:1) to furnish 25 (218 mg, 65%) as a colorless oil:35
1H NMR δ 1.64 (s, 3 H, CH3), 1.70 (m, 2 H) 1.98 (t, J ) 7.4 Hz,
2 H), 2.36 (dt, J ) 7.3 and 1.7 Hz, 2 H), 4.62 (s, 1 H, CdCHH),
4.68 (s, 1 H, CdCHH), 9.71 (t, J ) 1.6 Hz, 1 H, CHO); 13C
NMR δ 19.83 (t), 22.10 (q), 36.93 (t), 43.21 (t), 110.82 (t), 144.59
(s), 202.41 (d).
1
colorless oil: IR ν 1718, 1645 cm-1; H NMR δ 1.10-1.95 (m,
12 H), 2.63 (m, 2 H, CH2CHdC), 3.25-3.92 (m, 4 H, 2 × CH2O),
3.66 (s, 3 H, OCH3), 4.53 (m, 1 H, OCHO), 5.73 (d, J ) 11.6
Hz, 1 H, CHdCHCO2Me), 6.19 (dt, J ) 11.3, 7.6 Hz, 1 H, CHd
CHCO2Me); 13C NMR δ 19.60 (t), 25.46 (t), 25.90 (t), 28.79 (t),
28.87 (t), 29.48 (t), 30.71 (t), 50.86 (q), 62.22 (t), 67.37 (t), 98.75
(d), 119.23 (d), 150.62 (d), 166.74 (s).
(Z)-8-[(Tetr ah ydr o-2′H-pyr an -2′-yl)oxy]-2-octen -1-ol (21).
To a solution of 20 (128 mg, 0.5 mmol) in toluene (10 mL) at
-20 °C was added diisobutylaluminum hydride (1.0 mL, 1.0
M solution in toluene). After 25 min, water (2.5 mL) was added
dropwise and the resulting solution was allowed to warm to
room temperature over 2 h. The product was extracted with
ether, the combined organic layers were dried over MgSO4,
and the solvent was evaporated to furnish the required product
21 (96 mg, 84%): IR ν(OH) 3618, 3680 cm-1; 1H NMR δ 1.21-
1.93 (m, 13 H), 1.93-2.14 (m, 2 H, CH2CHdC), 3.28-3.91 (m,
4 H, 2 × CH2O), 4.15 (s, 2 H, CH2OH), 4.54 (m, 1 H, OCHO),
5.39-5.67 (m, 2 H, CHdCH); 13C NMR δ 19.60 (t), 25.40 (t),
25.66 (t), 27.14 (t), 29.21 (t), 29.41 (t), 30.67 (t), 58.39 (t), 62.29
(t), 67.47 (t), 98.82 (d), 128.61 (d), 132.63 (d).
(Z)-8-[(Tetr a h yd r o-2′H-p yr a n -2′-yl)oxy]-2-octen yl Ac-
eta te (22). To a solution of alcohol 21 (1.83 g, 8.06 mmol) in
dry THF (17 mL) at room temperature was added pyridine
(0.97 mL, 12 mmol). Acetic anhydride (1.13 mL, 12 mmol) was
then added, and the resulting reaction mixture was stirred
overnight. Evaporation of the solvent afforded a crude residue
which was diluted with ether (150 mL) and washed with
saturated aqueous solution of CuSO4 (2 × 15 mL), water (10
mL), a saturated aqueous solution of NaHCO3 (2 × 15 mL),
and brine (10 mL). The ethereal layer was dried with MgSO4,
filtered, and evaporated. The residue was chromatographed
on a column of silica gel (50 g) with a petroleum ether-ether
mixture (9:1) to furnish 22 (1.98 g, 91%): IR ν(CdO) 1730
cm-1; 1H NMR δ 1.89-1.26 (m, 12 H), 2.08 (m, 2 H, CH2CHd
CH), 2.06 (s, 3 H, CO2CH3), 3.27-3.94 (m, 4 H, 2 × CH2O),
4.57 (m, 1 H, OCHO), 4.61 (d, J ) 6.6 Hz, 2 H, dCHCH2OH),
5.44-5.92 (m, 2 H, CHdCH); 13C NMR δ 19.62 (t), 20.92 (q),
25.44 (t), 25.79 (t), 27.41 (t), 29.20 (t), 29.52 (t), 30.71 (t), 60.30
(t), 62.26 (t), 67.42 (t), 98.79 (d), 123.35 (d), 135.18 (d), 170.90
(s).
(Z)-7-[(Tet r a h yd r o-2′H -p yr a n -2′-yl)oxy]-1-[(d im et h yl-
p h en ylsilyl)m eth yl]h ep t-1-en e (23). Phenyldimethylchloro-
silane (1.29 mL, 7.8 mmol) was added to a suspension of finely
cut lithium wire (275 mg) in dry THF (15 mL). After being
stirred for 90 min at room temperature, the solution turned
dark red. Continued vigorous stirring for 3 h then produced a
brownish solution which was transferred with the aid of a
cannula to a suspension of CuCN (0.49 g, 5.5 mmol) in dry
THF (7 mL) at 0 °C. After 90 min, the reaction mixture was
cooled to -60 °C and a solution of acetate 22 (1.05 g, 3.9 mmol)
in dry THF (7 mL) was added. The resulting mixture was
stirred at -60 °C for 12 h, poured into a 1:1 mixture of
saturated aqueous NH4Cl/saturated aqueous Na2CO3 (250
mL), and extracted with ether. The combined ethereal layers
were dried, filtered, and evaporated. The residue was chro-
matographed on silica gel using a hexanes-ether mixture (30:1
to 4:1) to furnish 23 (1.01 g, 75%) as a colorless oil: 1H NMR
δ 0.27 (s, 6 H, Si(CH3)2), 1.0-1.68 (m, 10 H), 1.72 (d, J ) 7.9
Hz, 2 H, CHdCHCH2Si), 1.90-1.99 (m, 2 H), 3.25-3.96 (m, 4
H, 2 × CH2O), 4.57 (m, 1 H, OCHO), 5.17-5.47 (m, 2 H, CHd
CH), 7.28-7.57 (m, 5 H, aryl-H); 13C NMR δ -3.31 (2 × q),
17.50 (t), 19.65 (t), 25.49 (t), 26.00 (t), 27.01 (t), 29.50 (t), 29.65
(t), 30.75 (t), 62.25 (t), 67.58 (t), 98.79 (d), 124.62 (d), 127.66
(d), 128.25 (d), 128.89 (d), 133.53 (d), 138.92 (s).
3-Meth ylen ecycloh exa n -1-ol (26):35 1H NMR δ 3.75 (m,
1 H, CHOH), 4.70 (s, 1 H, CdCHH), 4.74 (s, 1 H, CdCHH);
identical with an authentic sample prepared by a literature
procedure.35
3-Meth ylcycloh ex-3-en -1-ol (27):60 1H NMR δ 1.58 (s, 3
H, CH3), 3.86 (br s, 1 H, CHOH), 5.29 (m, 1 H, CHdC);
identical with an authentic sample prepared by a literature
procedure.60
3-(2′-Meth ylen ecycloh exyl)p r op a n a l (28). Obtained on
diisobutylaluminum hydride reduction of ethyl 3-(2′-methyl-
enecyclohexyl)propionate61 (in the same way as 25 was pre-
pared from ethyl 4-isopropenylbutyrate) as a colorless oil (120
mg, 26%):36 1H NMR δ 1.15-1.72 (m, 7 H), 1.77-2.06 (m, 3
H), 2.07-2.19 (m, 1 H), 2.44-2.47 (m, 2 H), 4.57 (s, 1 H, Cd
CHH), 4.69 (s, 1 H, CdCHH), 9.75 (t, J ) 1.5 Hz, 1 H, CHO);
13C NMR δ 26.90 (t), 28.59 (t), 31.58 (t), 33.69 (t), 34.22 (t),
42.16 (t), 42.57 (d), 106.55 (t), 151.60 (s), 202.75 (d).
(2R *,5S *)-1,2,3,4,4a ,5,6,7-oct a h yd r on a p h t h a le n -2-ol
(29)36,62 a n d 1,2,3,4,5,6,7,8-octa h yd r on a p h th a len -2-ol
(30).36,63 Meth od A. Cyclization of 28 was carried according
to procedure I: To a DME solution of PhCH2(Et)3N+[Mo-
(CO)4ClBr2]- (A) as catalyst (5 mol %) was added a solution of
28 (152 mg, 1.0 mmol) in DME (1 mL). The mixture was stirred
at room temperature for 30 min and worked up. Chromatog-
raphy on silica gel using a hexanes-ether mixture (6:1 to 4:1)
afforded 2936,62 (126 mg, 83%): IR (neat) ν(OH) 3350, 1440,
1040, 945 cm-1 1H NMR δ 1.16-2.07 (m, 12 H), 2.17-2.29
;
(m, 2 H), 4.07 (m, 1 H, CHOH), 5.52 (m, 1 H, CdCH); 13C NMR
δ 21.14 (t), 25.59 (t), 28.71 (t), 30.58 (t), 32.33 (t), 36.93 (d),
42.55 (t), 67.15 (d), 124.02 (d), 136.11 (s). Continued elution
gave the more polar isomer 3036,63 (26 mg, 17%): 1H NMR δ
1.10-2.58 (m, 15 H), 3.85-4.0 (m, 1 H); 13C NMR δ 22.89 (t),
23.02 (t), 28.43 (t), 29.80 (t), 39.42 (t), 30.23 (t), 31.26 (t), 67.46
(d), 125.19 (s), 127.50 (s).
(59) (a) Comer, W. T.; Temple, D. L. J . Org. Chem. 1973, 38, 2121.
(b) Beckwith, A. L. J .; Moad, G. Aust. J . Chem. 1977, 30, 2733. (c)
Hendrickson, J . B.; Boudreaux, G. J .; Palumbo, P. S. J . Am. Chem.
Soc. 1986, 108, 2358.
(60) (a) Friedrich, E. C.; Lucca, G. D. J . Org. Chem. 1983, 48, 4563.
(b) Kirby, G. W.; McGuigan, H.; McLean, D. J . Chem. Soc., Perkin
Trans. 1 1985, 1961. (c) Andersson, P. G. J . Org. Chem. 1996, 61, 4154.
(61) (a) Gream, G. E.; Serelis, A. K. Aust. J . Chem. 1974, 27, 629.
(b) Hibino, J . I.; Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron Lett.
1985, 26, 5579.
(62) van den Heuevel, W. J . A.; Wallis, E. S. J . Org. Chem. 1962,
27, 1233. For the cis-isomer, see: J ulia, S.; J ulia, M.; Brasseur, L. Bull.
Soc. Chim. Fr. 1962, 374.
(63) (a) House, H. O.; Blankley, C. J . J . Org. Chem. 1968, 33, 53.
(b) D’Incan, E.; Loupy, A.; Maia, A.; Seyden-Penne, J .; Vitout, P.
Tetrahedron 1982, 38, 2923. (d) Marshall, J . A.; Conrow, R. E. J . Am.
Chem. Soc. 1983, 105, 17.
(Z)-7-[(Dim eth ylp h en ylsilyl)m eth yl]-1-h yd r oxyh ep t-6-
en e (24). A solution of 23 (346 mg, 1.0 mmol) in MeOH (15
mL) was stirred in the presence of p-toluenesulfonic acid (30
mg) at room temperature. After 7 h, the mixture was poured
into a saturated aqueous solution of NaHCO3, extracted with
ether, and dried over MgSO4. The solvent was evaporated
under reduced pressure, and the residue was purified on silica

2774 J . Org. Chem., Vol. 64, No. 8, 1999
Kocˇovsky´ et al.
Meth od B. Cyclization of 28 was carried according to
procedure II: Silver(I) trifluorosulfonate (50 mg, 3 equiv)
was added to a stirred suspension of C6H5CH2(C2H5)3N+-
[Mo(CO)5Br]-‚nH2O (30 mg; 1 equiv) in DME (2 mL) at 0 °C
under nitrogen. The reaction mixture was allowed to warm to
room temperature and stirred for 15 min. To the catalyst thus
generated (5 mol %) was added a solution of 28 (198 mg, 1.3
mmol) in DME (1 mL). The resulting mixture was stirred at
room temperature for 30 min and then diluted with ether and
worked up. The crude product was chromatographed on silica
gel using a hexanes-ether mixture (5:1) to furnish 29 (79 mg,
40%) and 30 (95 mg, 48%).
24.9 (t), 29.4 (d), 36.6 (t), 36.7 (t), 68.5 (t), 72.8 (t), 126.5 (d),
127.4 (d), 127.5 (d), 128.3 (d), 134.4 (s), 138.5 (s); MS g98% of
d2.
(E)-[8,8-2H 2]-1-(Ben zyloxy)-3,7-d im et h yl-6-oct en -8-yl
Ch lor id e (40). To a solution of N-chlorosuccinimide (294 mg;
2.2 mmol) in dry CH2Cl2 (10 mL) was added dropwise dimethyl
sulfide (0.176 mL; 2.4 mmol) at 0 °C under nitrogen. The
reaction mixture was cooled to -20 °C, and a solution of the
alcohol 39 (528 mg; 2 mmol) in CH2Cl2 (1 mL) was added
gradually over a period of 10 min. The resulting solution was
allowed to warm to 0 °C, stirred for 5 h at that temperature,
and poured into an ice-cold brine (10 mL). The organic layer
was separated, and the aqueous phase was extracted with
Et2O (2 × 5 mL). The combined organic layers were washed
with two 5 mL portions of cold brine and dried over MgSO4.
Upon removal of the solvent, pure allylic chloride 40 (520 mg,
92%)41,43 was obtained as a yellow oil: 1H NMR δ 0.89 (d, J )
6.6 Hz, 3 H, CH3), 1.10-1.71 (m, 5 H), 1.72 (s, 3 H, CH3), 1.91-
2.15 (m, 2 H, CH2CHdC), 3.44-3.58 (m, 2 H, CH2OCH2Ph),
4.49 (s, 2 H, OCH2Ph), 5.50 (m, J ) 7.2, 1.3 Hz, 1 H, CdCH),
7.33 (s, 5 H, arom); 13C NMR δ 13.99 (q), 19.44 (q), 25.47 (t),
29.53 (d), 36.37 (t), 36.60 (t), 68.52 (t), 72.90 (t), 127.47 (d),
127.59 (d), 128.31 (d), 131.16 (d), 131.32 (s), 138.59 (s).
(E)-[8,8,8-2H3]-1-(Ben zyloxy)-3,7-dim eth yl-6-octen e (41).
To a solution of the allylic chloride 40 (340 mg; 1.2 mmol) in
ether (6.2 mL) was added lithium aluminum deuteride (51 mg;
g96% 2H-enrichment). After 6 h at reflux a single spot on the
TLC plate was observed. Dry Na2SO4 was added, followed by
slow addition of water to decompose the excess of the reagent.
After removal of the solids by filtration, the ethereal solution
was washed with brine and dried with MgSO4, and the solvent
was evaporated to yield the benzyl ether 41 (290 mg; 97%)44
as a colorless oil: 1H NMR δ 0.81 (d, J ) 6.3 Hz, 3 H, CH3),
0.95-1.72 (m, 5 H), 1.52 (s, 3 H, CH3), 1.91 (m, 2 H, CH2CHd
C), 3.42 (m, J ) 6.8, 1.9 Hz, 2 H, CH2OCH2Ph), 4.42 (s, 2 H,
PhCH2O), 5.02 (br t, J ) 7.1 Hz, 1 H, CdCH), 7.25 (s, 5 H,
arom); 13C NMR δ 17.55 (q), 19.53 (q), 25.43 (t), 29.53 (d), 36.70
(t), 37.18 (t), 68.70 (t), 72.88 (t), 124.79 (d), 127.43 (d), 127.58
(d), 128.31 (d), 131.01 (s), 138.67 (s); MS g98% of d2.
6-(Ben zyloxy)-4-m eth ylh exa n a l (37). A steady stream of
ozone in oxygen generated with
a Wallace and Tiernan
ozonizer was bubbled through a solution of 1-(benzyloxy)-3,7-
dimethyloct-6-ene (12.3 g, 50 mmol) and pyridine (4.3 mL, 50
mmol) in dry CH2Cl2 (120 mL) for 4.5 h at -78 °C. Dimethyl
sulfide (8.6 mL) was added, and the solution was allowed to
warm to room temperature. After 5 h, the volatile materials
were removed under reduced pressure and the residue was
diluted with water and extracted with hexane. The combined
organic layers were washed with 5% HCl and brine, dried with
MgSO4, and evaporated. The crude product (11 g) was purified
by flash chromatography on a column of silica gel using
petroleum ether-ether mixture (9:1) as eluent to furnish 37
(6.65 g, 61%), whose spectral data correspond to those de-
scribed in the literature:38 IR (neat) ν(CH) 2725, ν(CdO) 1725
cm-1; 1H NMR δ 0.93 (d, J ) 6.0 Hz, 3 H, CHCH3), 1.37-1.88
(m, 5 H), 2.34-2.56 (m, 2 H, CH2CHO), 3.54 (t, J ) 6.4 Hz, 2
H, CH2CH2O), 4.52 (s, 2 H, OCH2C6H5), 7.36 (s, 5 H, aryl-H),
9.78 (t, J ) 1.7 Hz, 1 H, CHO); 13C NMR δ 19.22 (q), 28.78 (t),
29.44 (d), 36.37 (t), 41.52 (t), 68.18 (t), 72.89 (t), 127.46 (d),
127.54 (d), 128.28 (d), 138.45 (s), 202.65 (d).
Eth yl (E)-2,6-Dim eth yl-8-(ben zyloxy)-2-octen oa te (38).
Aldehyde 37 (1.16 g, 5.26 mmol) was added dropwise over a
period of 15 min to a refluxing solution containing ethyl
2-(triphenylphosphoranylidene)propionate (2.4 g, 6.64 mmol)
in dichloromethane (5 mL). After 4 h, the reaction was found
to be complete by TLC analysis with hexanes-ethyl acetate
mixture (5:1) as the developing solvent. The solvent was
evaporated, and the residue was dissolved in petroleum ether
and filtered through silica gel (10 g) to remove starting
phosphorane and triphenylphosphine oxide. Removal of the
solvent under reduced pressure gave unsaturated ester 38 as
a 98:2 E/Z mixture (1.48 g, 93%):40 IR ν(CdO) 1700, ν(CdC)
(E)-[8,8,8-2H3]-3,7-Dim eth yl-6-octen -1-ol (42). A solution
of the benzyl ether 41 (880 mg; 3.53 mmol) in THF (20 mL)
was added slowly to a solution of lithium (2.58 g; 112 mmol;
30% dispersion in oil; containing 1% sodium) in ammonia (70
mL) at -78 °C. After 15 min, the excess of lithium was
decomposed by adding 3-hexyne until the blue color was
completely dissipated and the resulting yellow solution was
then quenched with methanol until colorless. At rt, water was
added and the volatiles were carefully removed by rotary
evaporation under reduced pressure. The resulting cloudy
solution was extracted with ether (4 × 60 mL), and the
combined ethereal layers were washed with water and brine
and dried with MgSO4. After filtration, the solvent was
removed under reduced pressure and the residue was chro-
matographed on silica gel (45 g) with a petroleum ether-ether
mixture (9:1) followed by pure ether to furnish 42 as a colorless
1
1645, and ν(C-O) 1270 cm-1; H NMR δ 0.69 (d, J ) 6.3 Hz,
3 H, CHCH3), 1.15-1.58 (m, 5 H), 1.07 (t, J ) 7.1 Hz, 3 H,
CO2CH2CH3), 1.61 (s, 3 H, CH3), 1.95 (m, 2 H, CH2CHdC),
3.28 (t, J ) 6.5 Hz, 2 H, CH2OBn), 3.96 (q, J ) 7.2 Hz, 2 H,
OCH2CH3), 4.28 (s, 2 H, OCH2C6H5), 6.52 (t, J ) 7.6 Hz, 1 H,
vinyl-H), 7.11 (s, 5 H, aryl-H); 13C NMR δ 12.27 (q), 14.26 (q),
19.37 (q), 26.16 (t), 29.67 (d), 35.72 (t), 36.53 (t), 60.34 (t), 68.42
(t), 72.92 (t), 127.47 (d), 127.58 (d), 128.40 (d), 138.54 (s), 141.05
(s), 142.29 (d), 168.24 (s).
(E)-[8,8-2H2]-1-(Ben zyloxy)-3,7-dim eth yl-6-octen -8-ol (39).
To a suspension of lithium aluminum deuteride (90 mg; 2.14
mmol; g96% 2H-enrichment) in Et2O (30 mL) at 0 °C was
added dropwise over a period of 15 min a solution of ethyl (E)-
2,6-dimethyl-8-(benzyloxy)octenoate64 (38) (650 mg; 2.14 mmol)
in Et2O (5 mL), and the mixture was stirred at room temper-
ature for 10 min. Solid, anhydrous Na2SO4 was added and the
excess of the reagent was decomposed by a slow addition of
water. The solid was filtered off, the filtrate was washed with
brine and dried with MgSO4, and the solvent was evaporated.
The residue was purified by flash chromatography on silica
gel (14 g) using a hexane-AcOEt mixture (9:1) as eluent to
1
oil (0.51 g; 91%):44 IR ν(OH) 3620 and 3680 cm-1; H NMR δ
0.78 (d, J ) 6.6 Hz, 3 H, CH3CH), 0.94-1.66 (m, 6 H), 1.48 (s,
3 H, CHdCCD3CH3), 1.76-1.98 (m, 2 H, CH2CHdC), 3.40-
3.67 (m, 2 H, CH2OH), 4.97 (br t, J ) 7.1 Hz, 1 H, CHdC); 13
C
NMR δ 17.54 (q), 19.46 (q), 25.39 (t), 29.11 (d), 37.16 (t), 39.84
(t), 61.11 (t), 124.66 (d), 131.15 (s).
(Z)-1-(Ben zyloxy)-3,7-d im eth yl-6-octen -8-ol (43). To a
stirred solution of ethyltriphenylphosphonium bromide (1.86
g, 5 mmol) in THF (7 mL) was added butyllithium (1.6 M, 3.1
mL) at 0 °C. After 1 h at that temperature the mixture was
cooled to -78 °C, 6-(benzyloxy)-4-methylhexanal (37)65 (1.1 g,
5 mmol) was added dropwise, and the mixture was stirred for
5 min at -78 °C. Additional butyllithium (1.6 M, 3.1 mL) was
then added, resulting in the formation of the deep red ylide.
The mixture was allowed to reach 0 °C, and then paraform-
aldehyde (0.30 g) was added. Stirring was continued at 0 °C
for 1 h and then for 10 h at room temperature followed by
afford 39 (499 mg, 89%):41 IR ν(OH) 3610 cm-1 1H NMR δ
;
0.73 (d, J ) 6.3 Hz, 3 H, CH3), 0.90-1.68 (m, 6 H), 1.48 (s, 3
H, CH3), 1.87 (m, 2 H, CH2CHdC), 3.34 (t, J ) 6.7 Hz, 2 H,
CH2CH2OCH2), 4.33 (s, 2 H, OCH2C6H5), 5.21 (t, J ) 7.2 Hz,
1 H, CdCH), 7.16 (s, 5 H, arom); 13C NMR δ 13.5 (q), 19.4 (q),
(64) Shishido, K.; Irie, O.; Shibuya, M. Tetrahedron Lett. 1992, 33,
4589.
(65) Ruzicka, L.; Schinz, H. Helv. Chim. Acta 1934, 17, 1602.

Catalysts for Carbonyl Ene and Prins Reactions
J . Org. Chem., Vol. 64, No. 8, 1999 2775
addition of ice-water and extraction with ether. The ethereal
extract was worked up, and the residue was purified on silica
gel (15 g), using a petroleum ether-ether mixture (7:1 to 3:1)
as eluent to afford the (Z)-alcohol 43 (93:7) (590 mg, 45%) as
a colorless oil: IR ν(OH) 3450, 3615 cm-1; 1H NMR δ 0.87 (d,
J ) 6.6 Hz, 3 H, CH3), 1.02-1.74 (m, 6 H), 1.78 (s, 3 H, CH3),
1.90-2.25 (m, 2 H, CH2CHdC), 3.41-3.59 (m, 2 H, CH2CH2-
OCH2), 4.10 (m, 2 H, CH2OH), 4.49 (s, 2 H, OCH2C6H5), 5.25
(t, J ) 7.6 Hz, 1 H, CdCH), 7.33 (s, 5 H, aryl-H); 13C NMR δ
19.58 (q), 21.26 (q), 24.89 (t), 28.97 (d), 36.30 (t), 37.17 (t), 61.42
(t), 68.32 (t), 72.91 (t), 127.50 (d), 127.66 (d), 128.32 (d), 128.48
(d), 134.30 (s), 138.46 (s).
H, CdCH), 7.33 (s, 5 H, aryl-H); 13C NMR δ 19.54 (q), 25.45
(t), 25.65 (q), 29.55 (d), 36.70 (t), 37.20 (t), 68.71 (t), 72.90 (t),
124.83 (d), 127.45 (d), 127.60 (d), 128.33 (d), 131.05 (s), 138.68
(s).
(Z)-[8,8,8-2H3]-3,7-Dim eth yl-6-octen -1-ol (48). Obtained
by deprotection of 47 (in the same manner as 42 was prepared
from 41) as a colorless oil (84%):44 IR ν(OH) 3620, 3680 cm-1
;
1H NMR δ 0.89 (d, J ) 6.6 Hz, 3 H, CH3CH), 1.10-1.61 (m, 6
H), 1.66 (d, J ) 1.3 Hz, 3 H, CHdCCD3CH3), 1.83-2.10 (m, 2
H, CH2CHdC), 3.56-3.77 (m, 2 H, CH2OH), 5.08 (br t, J )
6.9 Hz, 1 H, CdCH); 13C NMR δ 19.46 (q), 25.40 (t), 25.61 (q),
29.11 (d), 37.17 (t), 39.84 (t), 61.12 (t), 124.69 (d), 131.16 (s).
Meth yl (Z)-8-(Ben zyloxy)-2,6-dim eth yl-2-octen oate (44).
A mixture of the allylic alcohol 43 (500 mg) and active
manganese dioxide66 (5.75 g) in hexane (80 mL) was stirred
at 0 °C for 30 min. Filtration and evaporation of solvent under
reduced pressure furnished (Z)-1-(benzyloxy)-3,7-dimethyl-6-
octen-8-al (487 mg, 98%): IR ν 1095, 1380, 1455, 1670, 2865,
(1S*,3R*,4S*)-p-Men th a n e-3,8-d iol Ca r bon a te (49a ). To
a solution of the cis-diol 5a (500 mg; 2.92 mmol) and pyridine
(460 mg) in toluene (10 mL) was added a 20% solution of
phosgene in toluene (8.25 mL; 1.93 M; 1.1 equiv) at 0 °C. After
15 min, the reaction mixture was quenched with 1 M HCl,
the product was extracted into Et2O (3 × 50 mL), and the
combined organic layers were washed with water, 5% aqueous
NaHCO3, and brine and dried over MgSO4. The solvent was
removed under reduced pressure, and the solid residue was
crystallized from hexane to afford the carbonate 49a (537 mg;
1
2925, 2955 cm-1; H NMR δ 0.92 (d, J ) 6.3 Hz, 3 H, CH3),
1.76 (s, 3 H, CH3), 2.46-2.66 (m, 2 H, CH2CHdC), 3.40-3.59
(m, 2 H, CH2CH2OCH2), 4.50 (s, 2 H, OCH2C6H5), 6.49 (t, J )
8.0 Hz, 1 H, CdCH), 7.33 (s, 5 H, aryl-H); 13C NMR δ 16.39
(q), 19.28 (q), 24.18 (t), 29.45 (d), 36.51 (t), 36.95 (t), 68.22 (t),
72.93 (t), 127.50 (d), 127.58 (d), 128.32 (d), 135.81 (s), 138.46
(s), 149.77 (d), 191.06 (d). The aldehyde thus obtained was
stirred with a mixture of sodium cyanide (0.82 g), acetic acid
(0.30 g), and manganese dioxide (5.75 g) in dry methanol (45
mL) for 12 h at 20-25 °C. After removal of methanol, the
residue was partitioned between ether and water. Evaporation
of the ethereal extract afforded the desired crude product.
Further purification was carried out by flash chromatography
on silica gel (20 g) using a hexanes-ether mixture (9:1) as
eluent to yield 44 as a colorless oil (265 mg, 48%): IR ν(CO)
2.72 mmol; 93%): mp 94-95 °C; IR ν(CdO) 1730 cm-1 1H
;
NMR δ 0.92 (d, J ) 6.5 Hz, 3 H, CH3CH), 1.05-1.25 (m, 5 H),
1.38 (s, 3 H, eq-CH3), 1.51 (s, 3 H, ax-CH3), 1.55-1.66 (m, 2
H), 2.13 (dd, J ) 14.5, 3.0 Hz, 1 H, 2-H), 4.85 (d, J ) 2.6 Hz,
1 H, CHO); 13C NMR δ 21.19 (t), 21.52 (q), 25.19 (d), 25.69 (q),
27.96 (q), 32.86 (t), 38.45 (t), 39.07 (d), 74.44 (d), 83.11 (s),
149.63 (s); HRMS (EI) m/z 199.133 41 (calcd for C11H19O3,
199.133 42; MH+). In the NOE difference experiments, irradia-
tion at 4.85 ppm (CH-O) gave 2% enhancement of the signal
at 1.51 ppm (CH3-axial), while irradiation at 1.51 ppm resulted
in 11% enhancement of the signal at 4.85 ppm (CH-O); no
enhancement of the latter signal was observed upon irradia-
tion at 1.38 ppm (CH3-equatorial).
1
1710 cm-1; H NMR δ 0.90 (d, J ) 6.3 Hz, 3 H, CH3), 1.03-
1.77 (m, 5 H), 1.89 (d, J ) 1.3 Hz, 3 H, CH3CdCH), 2.35-2.58
(m, 2 H, CH2CHdC), 3.51 (m, J ) 6.9, 1.9 Hz, 2 H, CH2CH2-
OCH2), 3.72 (s, 3 H, OCH3), 4.50 (s, 2 H, OCH2C6H5), 5.92 (t,
J ) 7.4 Hz, 1 H, CdCH), 7.33 (s, 5 H, aryl-H); 13C NMR δ
19.37 (q), 20.66 (q), 27.06 (t), 29.61 (d), 36.58 (t), 36.61 (t), 51.16
(q), 68.55 (t), 72.86 (t), 126.60 (s), 127.43 (d), 127.56 (d), 128.30
(d), 138.61 (s), 143.67 (d), 168.45 (s).
[9,9,9-2H3]-(1S*,3R*,4S*,8S*)-p-Men th a n e-3,8-d iol Ca r -
bon a te (49b). Prepared from the diol 5b (in the same manner
as its nonlabeled counterpart 49a ) in 91% yield: IR (CH2Cl2)
ν 1730 cm-1 1H NMR δ 0.92 (d, J ) 6.6 Hz, 3 H, CH3CH),
;
1.05-1.25 (m, 5 H), 1.51 (s, 3 H, CH3), 1.55-1.66 (m, 2 H),
2.12 (dd, J ) 14.5, 3.0 Hz, 1 H, 2-H), 4.85 (d, J ) 2.5 Hz, 1 H,
CHO); 13C NMR δ 21.23 (t), 21.56 (q), 25.22 (d), 27.91 (q), 32.91
(t), 38.49 (t), 39.12 (d), 74.45 (d), 83.0 (s), 149.67 (s).
(Z)-[8,8-2H2]-1-(Ben zyloxy)-3,7-dim eth yl-6-octen -8-ol (45).
Obtained from 44 on LiAlD4 reduction (in the same way as 39
was prepared from 38) as a colorless oil (86%): IR ν(OH) 3615
cm-1; 1H NMR δ 0.74 (d, J ) 6.3 Hz, 3 H, CH3), 1.00-1.67 (m,
6 H), 1.71 (s, 3 H, CH3), 1.81-2.17 (m, 2 H, CH2CHdC), 3.31-
3.52 (m, 2 H, CH2CH2OCH2), 4.33 (s, 2 H, OCH2C6H5), 5.19 (t,
J ) 7.4 Hz, 1 H, CdCH), 7.18 (s, 5 H, aryl-H); 13C NMR δ
19.57 (q), 21.22 (q), 24.89 (t), 28.96 (d), 36.29 (t), 37.16 (t), 68.31
(t), 72.91 (t), 127.5 (d), 127.66 (d), 128.32 (d), 128.53 (d), 134.22
(s), 138.45 (s). Spectral characteristics were analogous to those
for an authentic sample of 43.
(Z)-[8,8-2H 2]-1-(Ben zyloxy)-3,7-d im et h yl-6-oct en -8-yl
Ch lor id e (46). Obtained from 45 (in the same way as 40 was
prepared from 39) as a colorless oil (89%):67 1H NMR δ 0.90
(d, J ) 6.6 Hz, 3 H, CH3), 1.10-1.76 (m, 5 H), 1.80 (s, 3 H,
CH3), 1.95-2.21 (m, 2 H, CH2CHdC), 3.42-3.58 (m, 2 H, CH2-
OCH2Ph), 4.50 (s, 2 H, OCH2Ph), 5.36 (m, J ) 7.4, 1.4 Hz, 1
H, CdCH), 7.33 (s, 5 H, aryl-H); 13C NMR δ 19.44 (q), 21.47
(q), 25.33 (t), 29.47 (d), 36.59 (t), 36.86 (t), 68.50 (t), 72.91 (t),
127.46 (d), 127.59 (d), 128.32 (d), 130.96 (s), 131.47 (d), 138.60
(s).
(1S*,3S*,4S*)-p-Men th a n e-3,8-d iol Ca r bon a te (51a ). Ob-
tained from the corresponding diol 4a (in the same way as 49a
was prepared from 5a ) in 86% yield: IR ν(CdO) 1730 cm-1
;
1H NMR δ 0.94 (d, J ) 6.6 Hz, 3 H, CH3CH), 1.08-1.29 (m, 5
H) 1.30 (s, 3 H, ax-CH3), 1.37 (s, 3 H, eq-CH3), 1.65-1.87 (m,
2 H), 2.02-2.19 (m, 1 H), 4.13 (dt, J ) 11.0, 4.4 Hz, 1 H, CHO);
13C NMR δ 21.60 (q), 22.50 (q), 24.81 (t), 27.69 (q), 30.64 (d),
33.45 (t), 39.75 (t), 46.07 (d), 76.81 (d), 84.48 (s), 149.03 (s).
[9,9,9-2H3]-(1S*,3S*,4S*,8S*)-p-Men th a n e-3,8-d iol Ca r -
bon a te (51b). Obtained from the corresponding diol 4b (in
the same way as 49a was prepared from 5a ) in 90% yield: IR
1
ν(CdO) 1730 cm-1; H NMR δ 0.94 (d, J ) 6.6 Hz, 3 H, CH3-
CH), 1.07-1.30 (m, 5 H), 1.37 (s, 3 H, eq-CH3), 1.65-1.87 (m,
2 H), 2.02-2.19 (m, 1 H), 4.13 (dt, J ) 11.0, 4.4 Hz, 1 H, CHO);
13C NMR δ 21.70 (q), 24.94 (t), 27.71 (q), 30.79 (d), 33.58 (t),
39.85 (t), 46.18 (d), 76.90 (d), 84.41 (s), 149.14 (s).
(Z)-[8,8,8-2H3]-1-(Ben zyloxy)-3,7-d im eth yl-6-octen e (47).
Obtained from 46 on LiAlD4 reduction (in the same way as 41
was prepared from 40) as a colorless oil (93%):44 1H NMR δ
0.89 (d, J ) 6.3 Hz, 3 H, CH3), 1.04-1.76 (m, 5 H), 1.68 (s, 3
H, CH3), 1.83-2.15 (m, 2 H, CH2CHdC), 3.43-3.58 (m, 2 H,
CH2OCH2Ph), 4.50 (s, 2 H, OCH2Ph), 5.10 (br t, J ) 6.6 Hz, 1
Ack n ow led gm en t. We are grateful to EPSRC for
Grant GR/K07140 and EPSRC and Pfizer Central
Research for a CASE award to G.A. We also thank Drs.
G. Griffith and A. Gogoll for measuring some of the
NMR spectra.
Su p p or tin g In for m a tion Ava ila ble: IR, MS, and HRMS
spectral characteristics and elemental analyses for the new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(66) Attenburrow, A.; Cameron, A. F. B.; Chapman, J . H.; Evans,
R. M.; Hems, B. A.; J ansen, A. B. A.; Walker, T. J . Chem. Soc. 1952,
1094.
(67) For the unlabeled product, see: Inoue, S.; Kaneko, T.; Taka-
hashi, Y.; Miyamoto, O.; Sato, K. J . Chem. Soc., Chem. Commun. 1987,
1036.
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