Investigation on lewis acid mediated diels-alder reactions of 2-phosphono-2-alkenoates. Application to total synthesis of (±)-α- alasken-8-one via reductive alkylation of resulting adduct

Article abstract of DOI:10.1021/jo9017292

(Chemical Equation Presented) The Lewis acid mediated Diels-Alder reactions of three 2-phosphono-2-alkenoates including triethyl 2-phosphonoacrylate (1), triethyl 2-phosphonobut-2-enoate (2), and ethyl 2-(diethoxyphosphono)-3- methylbut-2-enoate (3) have been investigated. Of several Lewis acids tested, tin(IV) chloride was shown to be the most effective at enhancing the regio- and stereoselectivity of the reactions of 1 with the electron-rich dienes to result in the formation of the single regio- and/or stereoisomers in good yields. Bearing the β methyl group(s), 2 displayedmuch less reactivity than 1 while 3 was completely unreactive under the study's conditions. Throughout the investigation, we found that the cycloadditions of 2, especially of the Z-isomer, could be efficiently induced by using zinc chloride at elevated temperatures. Furthermore, a lithium naphthalenide (LN)-induced reductive alkylation process was applied to the resulting Diels-Alder adducts 4 to allow the phosphono group at the quaternary carbon centers to be replaced by various alkyl groups to afford the alkyl-substituted esters 12, therefore practically turning 1 and 2 into the useful synthetic equivalents of the corresponding 2-alkyl 2-alkenoates that usually display poor Diels-Alder reactivity. Application of this combined operation has facilitated the total synthesis of the sesquiterpene natural product α-alasken-8-one (8) in racemic form.

Full text of DOI:10.1021/jo9017292

pubs.acs.org/joc
Investigation on Lewis Acid Mediated Diels-Alder Reactions of
2-Phosphono-2-alkenoates. Application to Total Synthesis of
(()-r-Alasken-8-one via Reductive Alkylation of Resulting Adduct
Chuan-Cheng Liao and Jia-Liang Zhu*
Department of Chemistry, National Dong Hwa University, Hualien 974, Taiwan, R.O.C.
jlzhu@mail.ndhu.edu.tw
Received August 11, 2009
The Lewis acid mediated Diels-Alder reactions of three 2-phosphono-2-alkenoates including triethyl
2-phosphonoacrylate (1), triethyl 2-phosphonobut-2-enoate (2), and ethyl 2-(diethoxyphosphono)-
3-methylbut-2-enoate (3) have been investigated. Of several Lewis acids tested, tin(IV) chloride was
shown to be the most effective at enhancing the regio- and stereoselectivity of the reactions of 1 with the
electron-rich dienes to result in the formation of the single regio- and/or stereoisomers in good yields.
Bearing the β methyl group(s), 2 displayed much less reactivity than 1 while 3 was completely unreactive
under the study’s conditions. Throughout the investigation, we found that the cycloadditions of 2,
especially of the Z-isomer, could be efficiently induced by using zinc chloride at elevated temperatures.
Furthermore, a lithium naphthalenide (LN)-induced reductive alkylation process was applied to the
resulting Diels-Alder adducts 4 to allow the phosphono group at the quaternary carbon centers to be
replaced by various alkyl groups to afford the alkyl-substituted esters 12, therefore practically turning 1
and 2 into the useful synthetic equivalents of the corresponding 2-alkyl 2-alkenoates that usually display
poor Diels-Alder reactivity. Application of this combined operation has facilitated the total synthesis of
the sesquiterpene natural product R-alasken-8-one (8) in racemic form.
Introduction
as the acceptors for 1,4-addition processes.1,2 According to
literature reports, the phosphonate modifications, such as
the Horner-Wadsworth-Emmons olefination, were usua-
lly conducted after these addition reactions to ensure the
formation of a variety of unsaturated acyclic,1a,c,g carbo-
cyclic,1b,k-m and heterocyclic1h,i compounds. In addition,
the applications of 2-phosphono-2-alkenoates into ene3 and
1,3-cycloaddition reactions4 have also been occasionally
documented.
2-Phosphono-2-alkenoates are of considerable impor-
tance in synthetic chemistry where they are commonly used
(1) For selected examples, see: (a) Kleschick, W. A.; Heathcock, C. H.
J. Org. Chem. 1978, 43, 1256–1259. (b) Corbet, J. P.; Benezra, C. J. Org.
Chem. 1981, 46, 1141–1147. (c) Minami, T.; Nishimura, K.; Hirao, I. J. Org.
ꢀ
Chem. 1982, 47, 2360–2363. (d) Barton, D. H. R.; Gero, S. D.; Quiclet-Sire,
B.; Samadi, M. J. Chem. Soc., Chem. Commun. 1989, 1000–1001. (e) Junker,
H.-D.; Phung, N.; Fessner, W. D. Tetrahedron Lett. 1999, 40, 7063–7066.
(f) Yamazaki, S.; Yanase, Y.; Yamamoto, K. J. Chem. Soc., Perkin Trans. 1
2000, 1991–1996. (g) Shen, Y.; Jiang, G.-F.; Wang, G.; Zhang, Y. J. Fluorine
Chem. 2001, 109, 141–144. (h) Martyres, D. H.; Baldwin, J. E.; Adlington,
R. M.; Lee, V.; Probert, M. R.; Watkin, D. J. Tetrahedron 2001, 57, 4999–
In view of their activated carbon-carbon double bond,
one would expect that 2-phosphono-2-alkenoates may have
ꢀ
ꢀ
ꢀ
ꢀ
5007. (i) Bartolomea, J. M.; Alcazar, J.; Andres, I.; Bruyn, M. D.; Fernandez,
J.; Matesanz, E.; Emelen, K. V. Tetrahedron Lett. 2003, 44, 8545–8548.
(k) Janecki, T.; Blaszczyk, E.; Studzian, K.; Janecka, A.; Krajewska, U.;
(2) For a recent review, see: Janecki, T.; Kedzia, J.; Wasek, T. Synthesis
2009, 1227–1254.
(3) For an example, see: Snider, B B.; Phillips, G. B. J. Org. Chem. 1983,
48, 3685–3689.
ꢀ
Rozalski, M. J. Med. Chem. 2005, 48, 3516–3521. (l) Krawczyk, H; Albrecht,
L. Synthesis 2008, 3951–3956. (m) Albrecht, L.; Richter, B.; Kawczyk, H.;
Jorgensen, K. A. J. Org. Chem. 2008, 73, 8337–8343.
(4) For an example, see: Ye, Y.; Xu, G-Y; Zheng, Y.; Liu, L.-Z.
Heteroatom Chem. 2003, 14, 309–311.
DOI: 10.1021/jo9017292
r
Published on Web 09/17/2009
J. Org. Chem. 2009, 74, 7873–7884 7873
2009 American Chemical Society

Liao and Zhu
JOCArticle
also found wide application in Diels-Alder reactions as the
dienophile for assembling phosphonate-containing cycles.
However, in comparison with many other types of 2-sub-
stituted 2-alkenoates such as 2-halo,5a,b 2-carboxylate,5c-e
and 2-keto-2-alkenoates,5f,g much less attention has been
paid to 2-phosphono-2-alkenoates on their Diels-Alder
cycloadditions with only a few examples being available in
the literature.6-8 Among these results, Marchand-Brynaert
et al. reported several reactions of using trimethyl or triethyl
2-phosphonoacrylate as the dienophile to react with a few
achiral or homochiral N-protected 1-aminobutadienes in-
cluding N-buta-1,3-dienylsuccinimide,6a isopropyl N-dienyl-
L-pyroglutamate,6b N-butadienyl-(R)-4-phenyloxazolidin-2-
one, and N-butadienyl-(R)-4-phenyloxazolidine-2-thione.6c-e
They found that in refluxing acetonitrile these reactions took
place preferentially in an endo-to-phosphonate fashion to yield
the major isomers6 bearing the cis phosphono and amino
groups. The observed stereoselectivity was explained on the
basis of a special P-N stacking during the transition state.
Apart from these, there are only two individual cases described,
respectively, by McIntosh et al. and Siegel, which involve the
Diels-Alder reaction between methyl 2-diethoxyphosphonoa-
crylate and isoprene in refluxing toluene to afford a mixture of
two regioisomers (4:1) favoring the para-like one7 and the
reaction of triethyl 2-phosphonoacrylate with 6,6-diphenylful-
vene at room temperature for 5 days to provide two stereo-
isomers in a ratio of 4.5:1 (major = endo-to-carboxylate).8 In
both cases, the authors did not provide any spectroscopic
evidence to support the regio- or stereochemical assignments
for the major isomers. As can be seen, the examples reported so
far have been limited to the acrylate substrates, and in addition,
the thermal reaction conditions6,7 and/or the prolonged times
(>2 d)6a,8 were required presumably due to the inherent low
reactivity of the dienophiles. Moreover, while exhibiting certain
regio- and/or stereoselective bias, almost all of these reactions
produced two6a,c-e,7,8 or more6b regio- or stereoisomers, with
the minor ones constituting at least 15% of the products. In
regard to these limitations, development of more efficient and
general procedures for the Diels-Alder reactions of 2-phos-
phono-2-alkenoates is therefore necessary.
FIGURE 1. 2-Phosphono-2-alkenoates subjected to the study.
containing dienophiles, early reports by McClure and co-
workers revealed that the stereoselectivity (endo-to-acetyl) of
the Diels-Alder reactions between diethyl 3-oxo-1-butenyl
phosphonate ester [CH3COCHdCHPO(OEt)2] and the elec-
tron-rich dienes could be enhanced with the assistance of the
appropriate Lewis acids.10 Drawing on the experience from
these results, we then decided to evaluate the possibility of
applying the Lewis acid strategy to the 2-phosphono-2-
alkenoate system with the aim of increasing the efficiency
and selectivity of the reaction and thereafter exploring the
potential of utilizing the reaction to synthesize complex mole-
cules. To the best of our knowledge, the attempt of Lewis acids
on the Diels-Alder reactions of 2-phosphono-2-alkenoate has
never been reported before. In our investigation, we primarily
selected triethyl 2-phosphonoacrylate (1) (Figure 1) as the
substrate to directly compare our results with those previously
reported. In addition, we also chose ethyl 2-(diethoxy-
phosphono)but-2-enoate (2) and ethyl 2-(diethoxyphosphono)-
3-methylbut-2-enoate (3) as the dienophiles of interest in order
to survey the effect of β substitution on the cycloadditions.
It was found that the regio- and stereoselectivities of the
Diels-Alder reactions of 1 could be indeed enhanced by
Lewis acids as compared with the corresponding reactions
carried out without Lewis acids, and the extent of such
enhancement was highly dependent on the choice of Lewis
acid. Despite the fact that substrates 2 and 3 have been shown
to be much less reactive than 1, the selective Diels-Alder
cycloadditions of 2 still could be induced with the concomi-
tant use of the appropriate Lewis acid and the elevated
temperature. From 1 and 2, we were then able to prepare a
range of phosphonate-containing cycloadducts as the single
isomers. Furthermore, a lithium naphthalenide-mediated
reductive alkylation operation facilitated by the phosphono
group was applied to the resulting Diels-Alder adducts, thus
tactically allowing for the installation of various alkyl groups
to the quaternary carbon center of the unsaturated ring
systems. In this paper, we report the results from these
studies, as well as the application of the combined process
into the first total synthesis of (()-R-alasken-8-one, a natural
product belonging to the acorane-type sesquiterpene family.
The profound effect of Lewis acids on increasing the
reactivity of various dienophiles toward electron-rich dienes,
as well as the regio- and stereoselectivity of Diels-Alder
reactions, has been well recognized.9 For phosphonate-
(5) For examples, see: (a) Lewis, J. W. J. Chem. Soc. C 1971, 1158–1161.
(b) Hartmut, P.; Gurdeep, S. S.; Stephan, K.; Gunadi, A.; Armin de, M.
Chem. Ber. 1994, 127, 1051–1064. (c) Effio, A.; Griller, D.; Ingold, K. U.;
Scaiano, J. C.; Sheng, S. J. J. Am. Chem. Soc. 1980, 102, 6063–6068.
(d) Ireland, R. E.; Courtney, L.; Fitzsimmons, B. J. J. Org. Chem. 1983,
48, 5186–5198. (e) Herrerea, R.; Jimenez-Vazquez, H. A.; Modelli, A.; Jones,
D.; Soederberg, B. C.; Tamariz, J. Eur. J. Org. Chem. 2001, 24, 4657–4669.
(f) Hoye, T. R.; Caruso, A. J.; Magee, A. S. J. Org. Chem. 1982, 47, 4152–
4156. (g) Inokuchi, T.; Okano, M.; Miyamoto, T. J. Org. Chem. 2001, 66,
8059–8063.
(6) (a) Defacqz, N.; Touillaux, R.; Tinant, B; Declercq, J-P; Peeters, D.;
Marchand-Brynaert, J. J. Chem. Soc., Perkin Trans. 2 1997, 1965–1968.
(b) Robiette, R.; Marchand-Brynaert, J. J. Chem. Soc., Perkin Trans. 2 2001,
2155–2158. (c) Robiette, R.; Cheboub-Benchaba, K.; Peeters, D.; Marchand-
Brynaert, J. J. Org. Chem. 2003, 68, 9809–9812. (d) Tinant, B.; Defacqz, N.;
Robiette, R.; Touillaux, R.; Marchand-Brynaert, J. Phosphorus, Sulfur,
Silicon 2004, 179, 389–402. (e) Monbaliu, J.-C.; Robiette, R.; Peeters, D.;
Marchand-Brynaert, J. Tetrahedron Lett. 2009, 50, 1314–1317.
(7) McIntosh, L. M.; Pillon, L. Z. Can. J. Chem. 1984, 62, 2089–2093.
(8) Siegel, H. Synthesis 1985, 798–801.
Results and Discussion
I. Investigation of the Diels-Alder Reactivity of 1-3.
Dienophiles 1-3 were all readily prepared on a multigram
scale from commercially available triethyl phosphonoace-
tate following the established procedures. Compound 1 was
€
synthesized via the Knovenagel condensation between tri-
ethyl phosphonoacetate and formaldehyde with piperidine
in refluxing methanol, followed by the dehydration of the
resulting crude alcohol in refluxing toluene with catalytic
(9) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Part B:
Reaction and Synthesis, 4th ed.; Kluwer Academic/Plenum Publishers:
New York, 2001; pp 336-339.
(10) (a) McClure, C. K.; Hansen, K. B. Tetrahedron Lett. 1996, 37, 2149–
2152. (b) McClure, C. K.; Herzog, K. J.; Bruch, M. D. Tetrahedron Lett.
1996, 37, 2153–2156.
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TABLE 1. Diels-Alder Reactions between 1 and 2,3-Dimethyl-1,3-
butadiene
TABLE 2. Diels-Alder Reactions between 1 and Isoprene
yieldb
time (h) (%)
ratio
(4b/4b0)d
entry
reaction conditions
ether/25 °C
ZnCl2 (8 equiv)/ether/25 °C
ZnCl2 (2 equiv)/ether/25 °C
ZnCl2 (2 equiv)/ether/25 °C
time (h)
yielda (%)
entry
reaction conditionsa
1b
2b
3b
4c
75
15
15
15
51
63
64
51
1
2
3
4
toluene/80 °C
24
20
20
15
71c
69c
64c
72
85:15
95:5
95:5
100:0
c
ZnCl2 (2 equiv)/ether/25 °C
BF3 OEt2 (1.2 equiv)/ether/0 °C
3
SnCl4 (1.2 equiv)/CH2Cl2/-30 °C
aIsolated yield. b10 equiv of the diene was used. c5 equiv of the diene
was used.
a10 equiv of isoprene was used in each case. bIsolated yield. Com-
bined yield of 4b and 4b0. dThe ratio was determined on the basis of
the integration of C-4 methyl signals on the 1H NMR spectrum (4b: δ
1.59 ppm ; 4b0: δ 1.66 ppm).
tosic acid under Dean-Stark conditions.1h Compounds 2
and 3 were similarly prepared in a three-step sequence, which
involved the potassium tert-butoxide-induced alkylation of
triethyl phosphonoacetate with iodoethane11 or 2-iodopro-
pane12 in DMSO, followed by the selenylation of resulting
triethyl 2-phosphonobutanoate or 2-phosphono-3-methyl-
butanoate with phenyl selenenyl chloride and sodium hy-
dride in THF, and finally the hydrogen peroxide-promoted
oxidative elimination of the selenylated intermediates in
CH2Cl2 to give the formation of 2 or 3.12 Compound 2 thus
obtained was a mixture of two isomers (E/Z = 49:51) which
were difficult to separate by chromatographic purification.
We thus directly used it as the mixture for the subsequent
investigation without the separation.
With the required dienophiles in hand, we then directed
our attention to investigate their Diels-Alder reactivity
starting with 1. We first examined the reactions between 1
and 2,3-dimethyl-1,3-butadiene performed with and without
ZnCl2 to clarify whether the reaction would be influenced by
the Lewis acid (Table 1). It was found that the cycloaddition
of 1 with an excess of the diene (10 equiv) could occur in
diethyl ether solution at ambient temperature to afford
adduct 4a in moderate yield (51%) (entry 1). However, the
reaction required extremely prolonged time (>3 d) to achieve
completion. According to the previous protocol of using zinc
chloride (ZnCl2) (8 equiv) to facilitate the Diels-Alder reaction
of ketovinylphosphonate in ether,10b we then applied the same
conditions to our reaction. As compared with the reaction in
entry 1, we observed that the cycloaddition process was indeed
favored by the presence of ZnCl2 as reflected by a much shorter
reaction time (15 h) and a higher yield of 4a (63%) (entry 2).
Through a brief screen, we further discovered that the amount
of ZnCl2 could be reduced to 2 equiv as the minimum to
maintain yield of the product (entry 3). It was also noticed that
the above reactions were all accompanied by the formation of
fair amounts of polymers resulting from the polymerization of
the diene. The attempt to solve the problem by reducing the
diene to 7 equiv or less resulted in more workable crude mixture
and less polymers, but at the expense of the yields of 4a (entry
4). Considering yield and ease of separating polar phospho-
nate-containing cycloadducts from less polar dienes and poly-
mers through chromatography, we thus uniformly employed
10 equiv of dienes for the following investigation.
Having proven the positive influence of the Lewis acid on
the cycloaddition, we subsequently explored a more impor-
tant issue, that is, the effect of Lewis acids on the regio- and
stereoselectivity of the Diels-Alder reactions. In addition to
ZnCl2, two Lewis acids traditionally used for the activation
of dienophiles, i.e., tin(IV) chloride (SnCl4) and trifluori-
de-diethyl etherate (BF3 OEt2), were screened by the reac-
3
tions of 1 with isoprene, trans-piperylene, and cyclopenta-
diene, respectively. As a comparison, the corresponding
thermal reaction conducted without Lewis acid was also
examined for each diene.
The reaction between isoprene and 1 performed in ether
was shown to be much slower than that of 2,3-dimethyl-1,3-
butadiene. When carried out in toluene at 80 °C, the reaction
could reach completion in 24 h to afford a pair of inseparable
regioisomers 4b and 4b0 in 71% yield. The NMR analysis
indicated that the ratio between them was 85:15 in favor of 4b
(Table 2, entry 1). On the other hand, the reaction conducted
with 2 equiv of ZnCl2 in ether at room temperature (entry 2)
provided the products in comparable yield (69%) as the
thermal reaction but displayed noticeably enhanced regios-
electivity in improving the 4b/4b0 ratio to 95:5. Also in an
ethereal solution, the replacement of ZnCl2 with BF3 OEt2
3
(1.2 equiv)13 merely gave similar results in terms of the yield
(64%) and isomeric ratio (4b/4b0 =95:5), except allowing for
a lower temperature (0 °C) for the reaction to be completed
(entry 3). After a few attempts, we found that with the use of
1.2 equiv13 of SnCl4 a completely regioselective reaction
could be achieved in CH2Cl2 under extremely mild condi-
tions (-30 °C) to give the formation of 4b as a single isomer
in good yield (72%) (entry 4). As a pure isomer, the predicted
para-like assignment of 4b could be easily confirmed by the
correlation between the C-3 olefinic proton (δ 5.29) and one
of the C-2 methylene protons (δ 2.69) on the 2D NOESY
spectrum (see the Supporting Information).
When 1 was allowed to react with trans-piperylene, both
regio- (ortho- or meta-orientation) and stereoselective (endo-
or exo-to-carboxylate) issues arose with the possibility of
yielding four regio- and/or stereoisomers. The conditions
attested for isoprene were also attempted on the reaction,
and the results are outlined in Table 3. When 1 and trans-
piperylene were heated at 80 °C in toluene, the reaction was
(11) Stritzke, K.; Schulz, S.; Nishida, R. Eur. J. Org. Chem. 2002, 3884–
3892.
(12) Ferguson, A. C.; Adlington, R. M.; Martyres, D. H.; Rutledge, P. J.;
Cowley, A. Tetrahedron 2003, 59, 8233–8243.
(13) It was found that at least 1.2 equiv of Lewis acid was required to
maintain the constant yield of the product(s).
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TABLE 3. Diels-Alder Reactions between 1 and trans-Piperylene
TABLE 4. Diels-Alder Reactions between 1 and Cyclopentadiene
yieldb
time (h) (%)
ratio
(4c/4c0)
yieldb (%)
entry
reaction conditionsa
reaction conditionsa
toluene/80 °C
time (h)
4d
4d0
1
2
3
4
toluene/80 °C
24
20
20
17
68c
63c
69c
74
87:13
94:6
85:15
100:0
c
entry
ZnCl2 (2 equiv)/ether/25 °C
1
2
24
15
64
71
9
trace
BF3 OEt2 (1.2 equiv)/ether/0 °C
3
SnCl4 (1.2 equiv)/CH2Cl2/-30 °C
SnCl4 (1.2 equiv)/CH2Cl2/--30 °C
a10 equiv of isoprene was used in each case. bIsolated yield.
a10 equiv of isoprene was used in each case. bIsolated yield. Com-
bined yield of 4c and 4c0.
SCHEME 1
completed in 24 h to furnish a mixture of two inseparable
stereoisomers 4c and 4c0 in 68% yield (entry 1). The ratio
between them was identified as 87:13 on the basis of the
integrations of C-2 methine signals (4c: δ 2.89; 4c0: δ 3.06) on
the 1H NMR spectrum. Moreover, the splitting patterns of
C-2 methyl signals on the 13C NMR spectrum (4c: δ 18.0,
JP-C=5.5 Hz; 4c0: δ 18.4, JP-C=2.2 Hz) revealed that they
were both ortho-orientated diastereoisomers. On this basis,
we further observed that the 4c/4c0 ratio was increased by
ZnCl2 (4c/4c0 = 94:6) (entry 2) and unexpectedly decreased
(δ 4.03-4.18, 1.15) of the ester group, most likely because of
the exo orientation of the ethyl moiety. Therefore, 4d was
further converted into aldehyde 6 through the reduction with
DIBHAL-H and whose 2D NOESY spectrum (see Support-
ing Information) helped us to unambiguously confirm the
proposed structure of 4d as evidenced by the correlation
signal between the olefinic proton (δ 6.02) and the aldehyde
proton (δ 9.51) (Scheme 1).
After establishing the optimal reaction conditions for 1,
we continued to investigate the Diels-Alder reactivity of 2
and 3. Only differing from 1 by a methyl group at the
β position, 2 (E/Z = 49:51), however, displayed much less
by BF3 OEt2 (4c/0 = 85:15) (entry 3), which appeared to be
3
inconsistent with the regiochemical outcomes obtained with
isoprene. While the true reason is still not clear to us, we
suspect that the different diastereoselectivities observed in
two cases might be associated with the coordination states of
the dienophile with the Lewis acids,10a which, to some extent,
would direct the orientation of the dienophile to the diene
during the transition state. Much to our interest, it was found
that the use of SnCl4 here was shown to be effective again to
induce a completely stereocontrolled cycloaddition in af-
fording 4c exclusively in 74% yield (entry 4). The elucidation
of the relative configuration of 4c by spectroscopic methods
(NOE or NOESY) turned out to be difficult due to extensive
overlap of resonances and heteronuclear coupling to phos-
phorus. To address this problem, we managed to prepare its
crystalline tosylhydrazone derivative (5) and used the X-ray
crystallography analysis (see the Supporting Information) to
establish the stereochemistry of 4c. The trans steric relation-
ship between the C-2 methyl and the phosphono substituents
revealed that the reaction proceeded in an endo pathway
directed by the carboxylate group.
reactivity than
1
toward 2,3-dimethyl-1,3-butadiene
(Table 5). It was found that in the absence of Lewis acids,
no reaction could happen in toluene at 80 °C or even under
refluxing conditions (entry 1). Moreover, the reactions car-
ried out with BF3 OEt2 in ether at 0 °C or SnCl4 in CH2Cl2 at
3
-30 °C also did not provide any desired adduct(s), and the
effort to promote the cycloaddition by increasing the tem-
peratures (rt to refluxing) only resulted in the formation of
large amount of unidentified byproducts from the decom-
position of 2 (entries 2 and 3). These results indicated the low
reactivity of 2 and its incompatibility with the relatively
strong Lewis acids. The application of ZnCl2 to the reaction
performed in ether also met with no success at room tem-
perature, but could cause the desired cycloaddition to occur
under the reflux conditions. By using TLC to monitor the
progress of the reaction, we observed that the consumption
of 2 was rapid at the beginning but became unusually slow
after approximately 5 h. The reaction was allowed to proceed
for 24 h to give rise to the formation of two isomeric adducts
4e and 4e0 in 57% yield, coupled with 23% of recovered 2.
The NMR analysis indicated that the ratio between 4e and
4e0 was 88:12 and the E/Z ratio of recovered 2 was 98:2
(entry 4). Therefore, given the concept that the stereochem-
istry of the dienophile was preserved in a concerted process,
we were able to deduce the structures of 4e and 4e0 from the
ratio and the yield of the products and the E/Z ratios of the
starting and recovered 2 combined with the percentage of the
recovery. In this case, it was postulated that the prevailing
The aforementioned experiments indicated that SnCl4
used in dichloromethane was extremely effective for improv-
ing the regio- and stereoselectivity of the reactions of 1. To
further validate this, we investigated the reactions between 1
and cyclopentadiene under the thermal and SnCl4-mediated
conditions. As illustrated in Table 4, the thermal reaction
produced diastereoisomers 4d and 4d0 in 64% and 9% yield,
respectively (entry 1), while the reaction performed with
SnCl4 led to the almost exclusive formation of 4d in 71%
yield with only a trace amount of 4d0 (<2%) (entry 2), there-
fore once again demonstrating the remarkable efficiency of
the established reaction conditions. Based on the configura-
tion of 4c, we judged that 4d should also present as an endo
diastereoisomer. However, the NOESY spectrum of 4d
failed to provide any diagnostic cross peaks between the
olefinic protons (δ 6.19 and 5.96) and the ethyl protons
7876 J. Org. Chem. Vol. 74, No. 20, 2009

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JOCArticle
TABLE 5. Diels-Alder Reactions between 2 and 2,3-Dimethyl-1,
3-butadiene
FIGURE 2. Proposed transition state for the reaction of the
E-isomer of 2 with 2,3-dimethyl-1,3-butadiene.
reaction
conditionsa
yieldb
(%) (4e/4e0)c 2 (%) (E/Z)
ratio
recovered
entry
1
time (h)
24
toluene/80 °C to
reflux
TABLE 6. Diels-Alder Reactions between 2 and trans-Piperylene
2
3
BF3 OEt2 (1.2
3
24
24
equiv)/ether/0 °C
to reflux
SnCl4 (1.2 equiv)/
CH2Cl2/-30 °C
to reflux
4
5
ZnCl2 (2 equiv)/
ether/reflux
ZnCl2 (2 equiv)/
toluene/
24
24
57
61
88:12
71:29
23 (98:2)
9 (90:10)
reaction
entry conditionsa
time
(h)
yield
(%)b
ratio
recovered
(4f/4f’)d 2 (%) (E/Z)
1
2
ZnCl2 (2 equiv)/
ether/reflux
ZnCl2 (2 equiv)/
toluene/90 °C
24
24
41
100:0
70:30
33 (93:7)
19 (90:10)
c
90 °C
59c
a10 equiv of isoprene was used in each case. bIsolated and combined
yield of 4e and 4e0. cThe ratio was determined by the integration of C-3
methyl signals (4e: δ 1.62; 4e0: δ 1.60) on the 1H NMR spectrum.
a10 equiv of isoprene was used in each case. bIsolated yield. Com-
bined yield of 4f and 4f0. dThe ratio was determined by the integration of
the signals of C-4 olefinic protons (4f: δ 5.45; 4f0: δ 5.33) on the 1H NMR
spectrum.
formation of 4e from the Z-isomer should be attributed to
the preference for an endo-to-carboxylate transition state by
both isomers, during which an unfavorable steric interaction
between the terminal methyl group of the E-form and the
diene would hinder the approach of the two components to
each other (Figure 2), thus suppressing the formation of 4e0.
We wondered if the higher temperature was required to
circumvent the inherent low reactivity of the E-isomer and
then subsequently performed a reaction at 90 °C in toluene.
As shown in entry 5, such an attempt resulted in the increased
4e0/4e ratio (29:71) paralleling to the decreased E/Z ratio
(90:10) of the recovered 2 (9%) but did not significantly
improve the combined yield (61%) of the two isomers.
Hence, it was proposed that the reaction of the E-isomer
was promoted to some extent by employing the higher
temperature, which, however, could in turn accelerate the
decomposition of the starting material as reflected by the
formation of more unidentified byproducts and less recovery
of 2 as compared with the reaction in entry 4.
To confirm the endo pathway proposed for 2, we further
examined the reaction of 2 with trans-piperylene under the
ZnCl2-assisted reaction conditions (Table 6). It was interest-
ing to find that the reaction conducted in refluxing ether only
resulted in a single diastereoisomer 4f in 41% yield, plus 33%
of recovered 2 (E/Z = 93:7) (entry 1). As with 4c, the direct
elucidation of the structure of 4f through the spectroscopic
methods was shown to be difficult. Therefore, we again
restored to the X-ray crystallographic analysis of its tosylhy-
drazone derivative (7) (see the Supporting Information).14
The structure of 7 confirmed that 4f was derived from the
Z-isomer and generated through an endo-to-carboxylate
transition state as we proposed for 4e and 4e0. Moreover,
the reaction carried out in toluene at 90 °C produced a
mixture of two inseparable isomers 4f and 4f0 (4f/4f0 =
70:30) in 59% yield, together with 19% of recovered 2 (E/Z=
90:10) (entry 2). For 4f0, we were only able to prove its ortho
regiochemical assignment by the fine coupling constant of C-2
methyl signals on the 13C NMR spectrum (δ 18.1, JP-C=2.39
Hz) but still did not allow assignment of its stereochemistry due
to the low content in the mixture and the difficulty of separating
it from the major isomer. On the basis of the isomeric ratios of
recovered 2 in both cases, we assume that 4f0 should be
produced from the E-isomer following the same endo transition
state as for 4f. However, the possibility of forming 4f0 in an exo
pathway still cannot be completely ruled out.
With the recognition of the relatively poor dienophilicity
of 2, we were not surprised to find that compound 3,
possessing an additional β methyl group, was even much
less reactive than 2. It completely did not react with 2,3-
dimethyl-1,3-butadiene under all of the aforementioned
conditions (Tables 1-6). Besides, the severe decomposition
of 3 was observed throughout these cases. Furthermore, the
reactions performed with two other reagent systems inclu-
ding TiCl4/CH2Cl2 and AlCl3/ether, or even under extreme
conditions (toluene/130 °C, sealed tube), also failed to
provide any desired product but rather complex mixtures.
As we discussed above, the unfavorable steric hindrance
exerted by the germinal methyl groups should be responsible
for the nonreactive nature of 3.
The investigation on the Diels-Alder reactivity of phos-
phonate substrates 1-3 was thus completed. In the investi-
gation, 1 was shown to be most reactive toward the dienes.
An intriguing feature was that it could undergo the highly
regio- (para or ortho) and stereoselective (endo-to-carboxy-
late) cycloadditions with the assistance of SnCl4, to afford
the single isomeric adducts in good yields. We have also
proved that the introduction of the methyl group(s) to the
β position of 1 caused the dienophilicity to be dramatically
decreased. Nevertheless, in accordance with the inherent
preference for an endo-to-carboxylate transition mode, the
β methyl group of 2 enabled the reactivity of the admixed Z,
E-isomers to be efficiently differentiated, thus providing an
€
(14) Warmers, U.; Konig, W. A. Phytochemistry 1999, 52, 695–704.
J. Org. Chem. Vol. 74, No. 20, 2009 7877

Liao and Zhu
JOCArticle
SCHEME 2. Retrosynthetic Strategy for the Synthesis of R-Alasken-8-one (8)
opportunity for us to selectively promote the cycloadditions
of the Z-form while completely or partially suppressing the
reactions of the E-form by choosing the appropriate Lewis
acid and reaction conditions. In general, the protocol offered
an efficient access into a range of phosphonate-containing
cycles in a high degree of regio- and stereocontrol, which, as
described below, practically facilitated the chemical manip-
ulation of the resulting adduct into the sesquiterpene natural
product R-alasken-8-one via a key reductive alkylation
operation.
generation of 4b in good yield, we envisioned that the
phosphono group of 4b could be replaced by 2-oxopropyl
functionality via a newly attempted reductive alkylation
reaction to result in keto ester 9, which, after chemical
modifications, could be further converted into keto aldehyde
10 as the precursor for the annulation. After the spiro
skeleton was constructed, we planned to first introduce a
protected 2-hydroxy-2-propyl group to the C-7 position of
intermediate 11 as a latent substituent for the installation of
iospropylidene moiety. This bulky group was thought to be
added from the side of the Δ3 double bond of the cyclohexene
ring to avoid a skew butane-type interaction with C5-C6
methylene unites16a and also designed to direct the approach
of the methyl transfer reagent during the later 1,4-addition
step to ensure the correct stereochemical relationship bet-
ween C-10 and C-1. Finally, sequential deprotection and
dehydration would complete the total synthesis of 8.
II. Reductive Alkylation of the Diels-Alder Adduct and the
First Total Synthesis of (()-r-Alasken-8-one. Having deli-
neated the scope and efficiency of the Lewis acid-mediated
Diels-Alder reaction of the 2-phosphono-2-alkenonates, we
turned to its application to the first total synthesis of
R-alasken-8-one (8), an acorane-type sesquiterpene natural
€
product isolated by Konig’s group from the essential oil of
the liverwort Calypogeia fissa collected in the Harz moun-
tains in Germany.14 The structure and absolute stereochem-
istry of the naturally occurring (-)-R-alasken-8-one were
established on the basis of the spectroscopic methods and the
chemical correlation with (-)-R-alaskene, a known natural
product isolated from the same source. To date, more than
50 members belonging to this sesquiterpene family have been
isolated from natural sources,15 which are characterized by a
functionalized spiro[4,5]decane core containing two methyl
groups at the C-4 and C-10 positions (acorane numbering)
and an isopropyl or iospropylidene or isopropenyl moiety at
the C-7 position. Toward the synthesis of these natural
products, the stereocontrolled construction of the spirocyclic
carbon skeleton presents the greatest obstacle, and therefore,
a successful synthesis is essentially dependent on the efficient
creation of a quaternary carbon center which is suitably
substituted for the direct annulation into a spiro system.16
Our retrosynthetic strategy for the total synthesis of 8 is
illustrated in Scheme 2. Benefiting from the regiocontrolled
The reductive alkylation was intended to be induced by
treating the Diels-Alder adducts with an electron-donating
reagent to reductively cleave the phosphono group, followed
by trapping the in situ generated enolates with an alkylating
agent to allow for the installation of an alkyl group to the
quaternary carbon centers. Liu et al. previously reported the
application of a lithium naphthalenide (LN)-induced reduc-
tive alkylation process to the R-phosphono ketones for
introducing an alkyl group to the angular position of the
bicyclic ring systems.17 In this context, we recently have also
developed an efficient procedure to convert the R-cyano
esters into the corresponding R, β-unsaturated esters using
a LN-mediated reductive selenylation as a key operation.18
In light of these experiences, we envisaged that the reductive
alkylation operation should be applicable to R-phosphono
esters. To confirm this, we first evaluated the reductive
benzylation of 4a by using LN19 and di-tert-butylbiphenyl
(LiDBB),20 respectively, as the reducing reagent (Scheme 3).
It was observed that upon the treatment with LN in a THF
solution, 4a could be readily reduced (∼30 min) under mild
reaction conditions (-30 °C) to afford the enolate inter-
mediate. The subsequent addition of benzyl bromide
(6 equiv) to the reaction mixture resulted in the alkylated
product 12a in 70% yield. On the other hand, a relatively low
(15) (a) Sorm, F; Herout, V. Collect. Czech. Chem. Commun. 1948, 13,
177–206. (b) Vrkoc, J.; Jonas, J.; Herout, V.; Sorm, F. Collect. Czech. Chem.
Commun. 1963, 28, 1084–1086. (c) McClure, R. J.; Schorno, K. S.; Bertrand,
J A.; Zalkow, L. H. J. Chem. Soc., Chem. Commun. 1968, 1135–1136.
(d) Minato, H.; Fujita, R.; Takeda, K. Chem. Pharm. Bull. 1971, 19, 638–
640. (e) Kaiser, R.; Naegeli, P. Tetrahedron Lett. 1972, 13, 2009–2012.
(f) Kaiser, R.; Naegeli, P. Tetrahedron Lett. 1972, 13, 2013–2016.
(g) Nawamaki, K.; Kuroyanagi, M. Phytochemistry 1996, 43, 1175–1182.
(16) For examples, see: (a) McCrae, D. A.; Dolby, L. J. Org. Chem. 1977,
42, 1607–1610. (b) Martin, S. F.; Chou, T. S. J. Org. Chem. 1978, 43, 1027–
1031. (c) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.; White, C. T.
In The Total Synthesis of Natural Products; Apsimon, J., Ed.; Wiley: New York,
1983; Vol. 5, pp 284-305. (b) Chen, Y.-J.; Lin, W. Y. Tetrahedron 1993, 49,
10263–10270. (c) Srikrishna, A.; Kumar, P. P. Tetrahedron 2000, 56, 8189–8195.
(17) Chien, C. F.; Wu, J-D; Ly, T. W.; Shia, K. S.; Liu, H. J. Chem.
Commun. 2002, 248–249.
(18) Ko, Y. C.; Zhu, J. L. Synthesis 2007, 23, 3659–3665.
(19) For preparing a stock solution of LN, see: Liu, H. J.; Yip, J.; Shia,
K. S. Tetrahedron Lett. 1997, 38, 2253–2256.
(20) For preparing a stock solution of LiDBB, see: Freeman, P. K.;
Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924–1930.
7878 J. Org. Chem. Vol. 74, No. 20, 2009

Liao and Zhu
JOCArticle
TABLE 7. LN-Mediated Reductive Alkylation Reactions of 4b-f
aIsolated. bAfter the addition of R3X, the reaction was allowed to proceed at -30 °C for 30 min. c5 equiv of HMPA was introduced to the reaction
mixture at -30 °C after the addition of R3X. dAfter the addition of R3X at -30 °C, the reaction was allowed to proceed at rt for 12 h. eThe product was
obtained as a mixture of two diastereomers in a ratio of 51:49, and the stereochemistry remains to be determined. fThe product was obtained as a mixture
of two diastereomers in a ratio of 60:40, and the stereochemistry remains to be determined.
SCHEME 3. LN-Mediated Reductive Benzylation of 4a
configurations of 12c and 12e, which were established by the
X-ray diffraction analysis of the tosylhydrazone or 3,5-dini-
trobenzoate derivatives (see the Supporting Information),
revealed that the introduction of the alkyl groups was sterically
directed by the C-2 or C-6 methyl group of 4c or 4e/4e0. It is
also noteworthy that for some reactions, the addition of
hexamethylphosphoramide (HMPA) (entry 2) and/or the
prolonged reaction time (12 h) as well as the higher tempera-
ture (rt) (entries 2, 5, and 6) were required after the LN
treatment to circumvent the relative low reactivity of the
alkylating reagent (entry 2) or the starting substrate (entries
5 and 6). We were thus able to efficiently introduce a variety of
alkyl groups to the quaternary carbon centers of the unsatu-
rated ring systems. The reductive alkylation operation, com-
bined with the Diels-Alder reactions, has therefore practically
turned 1 and 2 into the useful synthetic equivalents of the
corresponding 2-alkyl 2-alkenoates that usually exhibit poor
Diels-Alder reactivity.
yield (63%) of 12a was obtained with the employment of
LiDBB, suggesting that LN was more effective than LiDBB
for the reaction.
The LN-induced reductive alkylation process was proven
to be general when applied into the remaining Diels-Alder
adducts 4b-f (Table 7). By treating with LN and various
alkylating reagents including allyl bromide, 4-bromo-1-bu-
tene, benzyl bromide, methyl iodide, and propargyl bromide,
these R-phosphono esters were all converted into the corre-
sponding R-alkyl-substituted esters 12b-g in synthetically
useful yields (50-74%). Compounds 12c-e were produced
as single diastereomers (entries 2-4), whereas 12f and 12g
were formed as mixtures of two isomers in a ratio of
51:49 and 60:40, respectively (entries 5 and 6). The relative
The synthesis of the titled target 8 commenced with the
oxidation of 12b under the Wacker oxidative conditions to
afford keto ester 9 in 65% yield (Scheme 4). To elaborate 9
into the key precursor 10, we first reduced 9 into the
corresponding diol by using lithium aluminum hydride in
J. Org. Chem. Vol. 74, No. 20, 2009 7879

Liao and Zhu
JOCArticle
SCHEME 4
THF. Not as we expected, the subsequent oxidation of the
resulting crude diol with PCC or PDC in CH2Cl2 provided 10
only in 29% and 26% yield, respectively, together with
large amounts of the six-membered hemiacetal byproducts
resulting form the cyclization of the mono-oxidized inter-
mediates. The employment of other oxidative conditions
including Dess-Martin periodinane/CH2Cl2, RuO4/CH2Cl2,
or (Ph3P)3RuCl2/CH2Cl2 also did not provide any reasonable
yields of 10 (<25%). After considerable experimentation,
it was discovered that a much more efficient oxidation could
be affected under the Swern oxidative conditions [DMSO/
(CO)2Cl2/Et3N/CH2Cl2] to yield 10 in 75% yield over two
steps. With 10 in hand, we then submitted it to the intramole-
cular condensation reaction for assembling the spiro skeleton,
and this could be readily achieved by treating 10 with metha-
nolic KOH solution in THF to result in the clean generation of
the key intermediate 11 in 89% yield. Herein, the formation of
11 also represents the formal synthesis of two other sesquiter-
pene natural products, acorone and isoacorone, whose total
syntheses through the intermediary of 11 were reported, res-
pectively, by McCrae and Martin.16a,b As we designed, a
protected hydroxyl propyl group would be next introduced to
the C-7 position of 11. To this end, 11 was sequentially treated
with TiCl4, Et3N, and acetone to give the alcohol,21 which,
without purification, was further allowed to react with triethyl-
silyl trifluormethanesulfonate in the presence of 2,6-lutidine to
provide silyl ether 13 in 76% yield as a 74:26 mixture of two
diastereomers. The subsequent 1,4-addition reaction of 13 with
lithium dimethylcuprate proceeded smoothly in affording
compound 14 in 72% yield. Three of the seven possible
diastereoisomers were detected for 14 in a ratio of 54:28:18.
At the end, treatment of 14 with p-toluenesulfonic acid
C-1 positions of two major isomers of 14 should be identical
with that of the natural product.
In conclusion, we have demonstrated that the highly
selective Diels-Alder cycloadditions of 1 and 2 can be
achieved under the appropriate Lewis acid-mediated reac-
tion conditions. Moreover, the synthetic utility of the
Diels-Alder reactions has been significantly expanded with
the application of the resulting adducts into the LN-induced
reductive alkylation process, thereby leading to the genera-
tion of a series of cyclic alkyl substituted esters with some of
them being difficult to access by other synthetic methods. As
we described herein, the concise total synthesis of (()-R-
alasken-8-one further underscore the value of this combined
operation in natural product synthesis. Applications of
Lewis acid-mediated reaction conditions into chiral 2-phos-
phono-2-alkenote molecules as well as the above reductive
alkylation strategy into the synthesis of structurally related
bicyclic spiro natural products such as phytoalexane- and
vertispirane-type sesquiterpenes are currently underway in
our laboratory.
Experimental Section
Ethyl 1-(Diethoxyphosphoryl)-3,4-dimethylcyclohex-3-ene-
carboxylate (4a). To a flame-dried 15 mL round-bottom flask
were added anhydrous ZnCl2 (0.41 g, 3.02 mmol) and ether
(5 mL). The mixture was stirred under a nitrogen atmosphere for
20 min until ZnCl2 was completely dissolved and then was added
with a solution of 1 (0.36 g, 1.51 mmol) in ether (2 mL). The
mixture was stirred at 25 °C for 30 min before 2,3-dimethyl-1,3-
butadiene (1.75 mL, 15.1 mmol) was added. After being stirred
at 25 °C for15 h, the reaction mixture was diluted with EtOAc
(120 mL) and successively washed with water (2 ꢀ 20 mL) and
brine (1ꢀ20 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification by flash chromatography
(silica gel, hexane-EtOAc, 5:1, 3:1, 1:1) afforded 4a as a viscous
oil: yield 0.31 g (64%); IR (neat) 1732, 1635, 1250, 1184, 1049,
1024 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.21-4.09 (m, 6H),
2.60 (br d, J=16.6 Hz), 2.46-2.34 (m, 2H), 2.11-2.02 (m, 1H),
1.90-1.81 (m, 2H), 1.62 (br s, 3H), 1.55 (br s, 3H), 1.31 (t, J =
7.0 Hz, 6H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.6 (d, JC-P=3.1 Hz), 124.6, 123.3 (d, JC-P=13.4
Hz), 62.8 (d, JC-P = 12.3 Hz), 62.7 (d, JC-P = 11.7 Hz), 61.2,
(p-TsOH H2O) in toluene at 90 °C for 1 h furnished
3
R-alasken-8-one (8) and its 10-epimer 15 in 54% and 26%
yield, respectively. The spectral data (IR, 1H NMR, 13C NMR,
mass spectra) of 8 were found to agree well with those reported
for the natural product.14 In addition, the ratio between 8 and
15 indicated that the relative stereochemistry of the C-10 and
(21) Nicolaou, K. C.; Zhang, H.; Ortiz, A.; Dagneau, P. Angew. Chem.,
Int. Ed. 2008, 47, 8605–8610.
7880 J. Org. Chem. Vol. 74, No. 20, 2009

Liao and Zhu
JOCArticle
48.5 (d, JC-P=132.5 Hz), 33.8 (d, JC-P=3.6 Hz), 28.3 (d, JC-P
=
phosphoryl)-3,4,6-trimethylcyclohex-3-enecarboxylate (4e0): Ty-
pical Procedure for the ZnCl2-Mediated Diels-Alder Reactions
of 2 in Ether. To anhydrous ZnCl2 (0.33 g, 2.44 mmol) was added
1.5 mL of dry ether. The mixture was stirred under a nitrogen
atmosphere for 20 min until ZnCl2 was completely dissolved,
and then a solution of 2 (E/Z=49:51) (0.31 g, 1.24 mmol) in dry
ether (3.0 mL) was added. Stirring was continued at 25 °C for
30 min before 2,3-dimethyl-1,3-butadiene (1.41 mL, 12.2 mmol)
was added. The reaction mixture was then heated at reflux for
24 h, cooled to 25 °C, and diluted with EtOAc (130 mL). The
solution was washed with water (2 ꢀ 15 mL) and brine (1 ꢀ
20 mL), dried over Na2SO4, filtered, and concentrated. Purifica-
tion by flash chromatography (silica gel, hexane-EtOAc, 3:1,
2:1, 1:2) afforded 0.071 g of recovered 2 (23%, E/Z=98:2) and
0.26 g of a mixture of 4e and 4e0 (57%) in a ratio of 88:12. For the
mixture: IR (neat) 1734, 1639, 1236, 1052, 1025 cm-1; 1H NMR
(400 MHz, CDCl3). For 4e: δ 4.17-4.07 (m, 6H), 2.70 (br sextet,
J=7.1 Hz, 1H), 2.52-2.46 (dm, J=5.3 Hz, 2H), 2.13 (br d, J=
17.8 Hz, 1H), 1.83-1.74 (m, 1H), 1.64 (s, 3H), 1.53 (s, 3H), 1.32
(t, J=7.0 Hz, 3H), 1.29 (t, J=6.9 Hz, 3H), 1.23 (t, J=7.1 Hz,
3H), 1.10 (d, J = 7.0 Hz, 3H). For 4e0: δ4.25-4.15 (m, 6H),
2.65-2.54 (m, 1H), 2.41 (br sextet, J =6.7 Hz, 1H), 2.31 (br d,
J=16.1 Hz, 1H), 2.21-2.15 (m, 1H), 1.95-1.86 (m, 1H), 1.61 (s,
3H), 1.56 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H), 1.28 (t, J = 7.0 Hz,
3H), 1.25 (t, J=6.9 Hz, 3H), 1.11 (d, J=6.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3). For 4e: δ 171.3 (d, JC-P=3.2 Hz), 122.5 (d,
13.0 Hz), 25.7 (d, JC-P = 4.3 Hz), 19.1, 18.8, 16.4(d, JC-P = 5.8
Hz), 14.1; HRMS-FAB m/z [M þ H]þ calcd for C15H28O5P
319.1674, found 319.1669. Anal. Calcd for C15H27O5P: C, 56.59;
H, 8.55. Found: C, 56.72; H, 8.64.
1-(Diethoxyphosphoryl)-4-methylcyclohex-3-enecarboxylate (4b):
Typical Procedure for the SnCl4-Mediated Diels-Alder Reactions
of 1. To a solution of 1 (0.11 g, 0.48 mmol) in DCM (2 mL) at
-30 °C was added 0.57 mL of SnCl4 (1 M in DCM, 0.57 mmol)
under a N2 atmosphere. The mixture was stirred at -30 °C for
30 min before isoprene (0.48 mL, 4.75 mmol) was added. The
reaction mixture was stirred at -30 °C for 15 h and diluted with
EtOAc (80 mL) and water (20 mL). The aqueous layer was
separated and extracted with EtOAc (2 ꢀ 15 mL). The combined
organic extracts were washed with water (2 ꢀ 15 mL) and brine
(15 mL), dried over Na2SO4, filtered, and concentrated. Purifica-
tion by flash chromatography (silica gel, hexane-EtOAc, 5:1, 3:1,
1:1) afforded 4b as a viscous oil: yield 0.10 g (72%); IR (neat) 3047,
1726, 1680, 1644, 1252, 1184, 1022, 881 cm-1; 1H NMR(400 MHz,
CDCl3) δ 5.29 (br s, 1H), 4.16-4.01 (m, 6H), 2.69 (br d, J =
17.1 Hz, 1H), 2.44-2.33 (m, 2H), 2.08-1.96 (m, 1H), 1.90-1.77
(m, 2H), 1.54 (br s, 3H), 1.25 (t, J=7.1 Hz, 6H), 1.18 (t, J=7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 170.5 (d, JC-P = 3.5 Hz),
133.2, 118.2 (d, JC-P=13.8 Hz), 62.8 (d, JC-P=7.0 Hz), 61.2, 47.4
(d, JC-P = 133.1 Hz), 28.1 (d, JC-P = 3.5 Hz), 26.7 (d, JC-P
=
12.7 Hz), 25.3 (d, JC-P = 3.9 Hz), 23.3, 16.4 (d, JC-P = 5.8 Hz),
14.0; HRMS-FAB m/z [M þ H]þ calcd for C14H26O5P 305.1518,
found 305.1513. Anal. Calcd for C14H25O5P: C, 55.25; H, 8.28.
Found: C, 55.39; H, 8.31.
J
C-P = 13.7 Hz), 121.7 (d, JC-P = 1.7 Hz), 62.6 (d, JC-P
=
6.9 Hz), 62.5 (d, JC-P=7.6 Hz), 61.1, 53.1 (d, JC-P=131.4 Hz),
36.9 (d, JC-P=13.0 Hz), 30.5 (d, JC-P=3.8 Hz), 29.8 (d, JC-P=
1.3 Hz), 19.1, 18.8, 16.9, 16.4 (d, J JC-P=5.9 Hz), 14.0. For 4e0:
170.8 (d, JC-P=2.2 Hz), 124.1, 122.2 (d, JC-P=7.7 Hz), 62.5 (d,
(1S*,2S*)-Ethyl 1-(Diethoxyphosphoryl)-2-methylcyclohex-3-
enecarboxylate (4c). The typical procedure for the preparation
of 4b was followed by using 1 (1.76 g, 7.46 mmol) and trans-
piperylene (7.82 mL, 74.60 mmol) as the starting substrates.
Flash chromatography (silica gel, hexane-EtOAc, 5:1, 3:1, 1:1)
afforded 1.69 g (74%) of 4c as a yellowish oil: IR (neat) 3024,
J
C-P = 7.6 Hz), 62.2 (d, JC-P = 7.4 Hz), 61.0, 52.1 (d, JC-P =
132.6 Hz), 37.8 (d, JC-P=7.7 Hz), 34.5 (d, JC-P=3.6 Hz), 32.3
(d, JC-P =3.6 Hz), 18.8, 18.7, 17.6 (d, JC-P =8.7 Hz), 16.3 (d,
J
C16H30O5P 333.1831, found 333.1826.
C-P = 3.7 Hz), 14.1. HRMS-FAB: m/z [M þ H]þ calcd for
1
1736, 1654, 1248, 1051, 1024, 682 cm-1; H NMR (400 MHz,
CDCl3) δ 5.62 (dm, J = 10.8 Hz, 1H), 5.55 (dm, J = 10.8 Hz,
1H), 4.23-4.07 (m, 6H), 2.92 (br s, 1H), 2.37-2.18 (m, 2H),
2.14-1.98 (m, 2H), 1.31 (t, J=7.2 Hz, 6H), 1.27 (t, J=7.2 Hz,
3H), 1.21 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
170.2 (d, JC-P = 2.6 Hz), 130.9 (d, JC-P = 8.8 Hz), 125.0, 62.6
(1S*,2S*,6S*)-1-(Diethoxyphosphoryl)-2,6-dimethylcyclohex-
3-enecarboxylic Acid Ethyl Ester (4f). The procedure for the
preparation of 4e/4e0 (88:12) was followed by using 2 (E/Z =
49:51) (0.68 g, 2.70 mmol) and trans-piperylene (2.83 mL, 27.02
mmol) as the starting substrates. Flash chromatography (silica gel,
hexane-EtOAc, 5:1, 3:1, 2:1, 1:2) afforded 0.22 g of recovered 2
(33%, E/Z=93:7) plus 0.35 g (41%) of 4f as a viscous oil: IR (neat)
(d, JC-P=7.1 Hz), 62.3 (d, JC-P=7.3 Hz), 60.9, 51.4 (d, JC-P
135.4 Hz), 33.1 (d, JC-P=2.0 Hz), 25.5 (d, JC-P=4.2 Hz), 22.5
(d, JC-P = 7.9 Hz), 18.0 (d, JC-P = 5.4 Hz), 16.4 (d, JC-P
=
1734, 1660, 1242, 1051, 126, 696 cm-1 1H NMR (400 MHz,
;
=
5.2 Hz), 16.3 (d, JC-P = 5.2 Hz), 14.0; HRMS-FAB m/z [M þ
H]þ calcd for C14H26O5P 305.1518, found 305.1516. Anal.
Calcd for C14H25O5P: C, 55.25; H, 8.28, found: C, 55.37; H,
8.28.
CDCl3) δ 5.55 (dm, J=12.3 Hz, 1H), 5.51 (dm, J=12.3 Hz, 1H),
4.25-4.06 (m, 6H), 2.89 (m, 1H), 2.74-2.61 (m, 1H), 2.11 (br d,
J=17.0 Hz, 1H), 1.87 (br d, J=17.0 Hz, 1H), 1.31 (t, J=7.1 Hz,
3H), 1.30 (t, J=7.1 Hz, 3H), 1.27 (t, J=7.0 Hz, 3H), 1.25 (d, J=
7.2 Hz, 3H), 1.17 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ170.4 (d, JC-P=2.9 Hz), 130.7 (d, JC-P=9.6 Hz), 123.5,
62.3 (d, JC-P = 7.3 Hz), 62.0 (d, JC-P = 7.2 Hz), 60.8, 55.9 (d,
(1S*,2R*,4S*)-2-(Diethoxyphosphoryl)bicyclo[2.2.1]hept-5-ene-
2-carboxylic Acid Ethyl Ester (4d). The typical procedure for the
preparation of 4b was followed by using 1 (0.33 g, 1.41 mmol) and
cyclopentadiene (0.93 g, 14.13 mmol) (pregenerated by the ther-
molysis of dicyclopentadiene before the use) as the starting sub-
strates. Flash chromatography (silica gel, hexane-EtOAc, 5:1, 3:1,
2:1 1:1) afforded 0.31 g of 4d (71%) as a colorless oil and a trace
amount of 4d0 (∼2 mg, <2%). For 4d: IR (neat) 3064, 1730, 1637,
1240, 1049, 1022 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.19 (dd,
J=5.4, 3.0 Hz, 1H), 5.96 (dd, J=5.4 Hz, 2.6 Hz), 4.19-4.03 (m,
6H), 3.44 (dm, J=6.8 Hz, 1H), 2.92 (br s, 1H), 2.34 (ddd, J=20.1,
12.1, 3.0 Hz,1H), 2.01-1.86 (m, 2H), 1.34-1.29 (m, 1H), 1.32 (t,
J=7.0 Hz, 4H), 1.26 (t, J=7.0 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 171.1, 139.3, 135.0 (d, JC-P=13.0
Hz), 62.8 (d, JC-P=7.1 Hz), 62.7 (d, JC-P=6.6 Hz), 61.1, 55.1 (d,,
JC-P=134.4 Hz), 31.1, 31.0 (d, JC-P=8.3 Hz), 17.6, 17.5 (d, JC-P
=
5.3 Hz), 16.5 (d, JC-P = 4.1 Hz), 16.4 (d, JC-P = 4.1 Hz), 14.0;
HRMS-FAB m/z [M þ H]þ calcd for C15H28O5P 319.1674, found
319.1668. Anal. Calcd for C15H27O5P: C, 56.59; H, 8.55. Found: C,
56.46; H, 8.54.
Ethyl 1-Benzyl-3,4-dimethylcyclohex-3-enecarboxylate (12a):
Typical Procedure for the LN-Promoted Reductive Alkylation of
4. A 0.342 M solution of LN (4 mL, 1.37 mmol)20 precooled to
-35 °C was quickly added by syringe to a solution of 4a (015 g,
0.46 mmol) in anhydrous THF (4 mL) at -35 °C under a
nitrogen atmosphere. The resulting dark-green mixture was
stirred at -35 °C for 30 min, benzyl bromide (0.34 mL, 2.77
mmol) was added, and stirrin was continued at -35 °C for
30 min. The mixture was then quenched with water (10 mL) and
extracted with EtOAc (2 ꢀ 40 mL). The combined organic
extracts were washed with water (10 mL) and brine, dried over
Na2SO4, filtered, and concentrated. Flash chromatography
J
J
C-P=130.4 Hz), 48.9, 47.6, 42.5 (d, JC-P=2.4 Hz), 33.0, 16.4 (d,
C-P = 6.7 Hz), 16.3 (d, JC-P = 7.4 Hz), 14.1; HRMS-FAB m/z
[M þ H]þ calcd for C14H24O5P 303.1361, found 303.1358.
(1R*,6S*)-Ethyl 1-(Diethoxyphosphoryl)-3,4,6-trimethylcy-
clohex-3-enecarboxylate (4e) and (1R*,6R*)-Ethyl 1-(Diethoxy-
J. Org. Chem. Vol. 74, No. 20, 2009 7881

Liao and Zhu
JOCArticle
(silica gel, hexane-EtOAc, 20:1, 5:1) afforded 12a (0.087 g,
70%) as a viscous oil: IR (neat) 3062, 3030, 1722, 1604, 1495,
1447, 1180, 1093, 742, 701 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.27-7.18 (m, 3H), 7.07 (br d, J=7.3 Hz, 2H), 4.06 (q, J=7.1
Hz, 2H), 2.89 (d, J=13.2 Hz, 1H), 2.81 (d, J=13.2 Hz, 1H), 2.30
(br d, J=16.7 Hz, 1H), 2.07-1.98 (m, 3H), 1.94 (br d, J=16.7
Hz, 1H), 1.61 (s, 3H), 1.60-1.55 (m, 1H), 1.58 (s, 3H), 1.16 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.2, 137.6,
130.0, 128.0, 126.4, 124.3, 123.8, 60.1, 47.1, 44.6, 38.6, 30.5, 29.3,
19.2, 18.7, 14.1; HRMS-FAB m/z [M þ H]þ calcd for C18H25O2
273.1855, found 273.1859.
12e as a colorless oil: yield 0.23 g (75%); IR (neat) 1730, 1210,
1090 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.12 (q, J=7.1 Hz,
2H), 2.43 (br d, J=17.0 Hz, 1H), 2.21 (bd d, J=17.0 Hz, 1H),
1.98-1.89 (m, 1H), 1.75 (br d, J=17.7 Hz, 1H), 1.68 (br d, J=
17.7 Hz, 1H), 1.61 (br s, 3H), 1.58 (br s, 3H), 1.23 (t, J=7.1 Hz,
3H), 1.14 (s, 3H), 0.84 (d, J=6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 177.7, 122.6, 122.3, 60.0, 44.5, 37.1, 36.4, 34.5, 23.8,
19.1, 18.8, 16.9, 14.3; HRMS-EI m/z [M]þ calcd for C13H22O2
210.1620, found 210.1612.
(2S*,6S*)-Ethyl 1-Allyl-2,6-dimethylcyclohex-3-enecarboxy-
late (12f). By using 4f (0.32 g, 1.01 mmol) and allyl bromide
(0.53 mL, 6.06 mmol) as the starting substrates, the preparation
of 12f was almost same as for preparing 12a except for allowing
the reaction to proceed at 25 °C for 12 h after the addition of allyl
bromide. Flash chromatography (silica gel, hexane-EtOAc,
200:1, 150:1, 100:1) afforded 12f as a mixture of two diastereo-
mers (51:49): yield 0.17 g (74%); IR (neat) (for the mixture)
3076, 3019, 1726, 1654, 1637, 1203 cm-1; 1H NMR (400 MHz,
C6D6) major δ 6.15-6.05 (m, 1H), 5.10-4.99 (m, 4H),
4.02-3.86 (m, 2H), 2.99-2.90 (m, 1H), 2.52-1.97 (m, 3H),
1.68-1.56 (m, 2H), 1.07 (d, J=7.3 Hz, 3H), 0.99 (d, J=7.3 Hz,
3H), 0.93 (t, J = 7.0 Hz, 3H); minor δ 6.27-6.14 (m, 1H),
5.56-5.37 (m, 4H), 4.02-3.86 (m, 2H), 2.99-2.90 (m, 1H),
2.52-1.97 (m, 3H), 1.68-1.56 (m, 2H), 1.05 (d, J=6.7 Hz, 3H),
0.99 (d, J = 7.3 Hz, 3H), 0.94 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, C6D6) major δ 175.0, 136.1, 131.5, 123.3, 117.0, 59.7,
50.5, 37.0, 32.6, 32.0, 29.8, 16.9, 16.5, 14.1; minor δ 174.7, 137.3,
130.5, 124.8, 116.4, 59.5, 51.0, 37.5, 36.7, 31.8, 28.7, 18.2, 17.6,
14.0; HRMS-EI (for the mixture) m/z [M]þ calcd for C14H22O2
222.1620, found 222.1612.
(2S*,6S*)-Ethyl 2,6-Dimethyl-1-(prop-2-ynyl)cyclohex-3-ene-
carboxylate (12g). By using 4f (0.20 g, 0.64 mmol) and propargyl
bromide (0.41 mL, 3.84 mmol) as the starting substrates, the
preparation of 12g was almost same as for preparing 12a except
for allowing the reaction to proceed at 25 °C for 12 h after the
addition of propargyl bromide. Flash chromatography (silica
gel, hexane-EtOAc, 200:1, 150:1, 80:1) afforded 12g as a
mixture of two diastereomers (60:40): yield 0.070 g (50%); IR
(neat) (for the mixture) 3305, 3021, 2119, 1728, 1658, 1456, 1267,
640 cm-1; 1H NMR (400 MHz, CDCl3) major δ 5.51 (dm, J =
10.1 Hz, 1H), 5.39 (dm, J = 10.1 Hz, 1H), 4.21-4.13 (m, 2H),
2.87-2.78 (m, 1H), 2.48-2.29 (m, 3H), 2.25-2.10 (m, 1H), 1.94
(t, J=2.6, 1H), 1.73 (dm, J=16.5 Hz, 1H), 1.26 (t, J=7.1 Hz,
3H), 1.05 (d, J=7.3 Hz, 3H), 0.91 (d, J=7.0 Hz, 3H); minor δ
5.53 (m, 2H), 4.21-4.12 (m, 2H), 2.51-2.15 (m, 5H), 1.96 (t, J=
2.5 Hz, 1H), 1.73 (m, 1H), 1.27 (t, J=7.1 Hz, 3H), 1.09 (d, J=
6.8 Hz, 3H), 0.94 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) major δ 174.7, 130.9, 123.1, 82.1, 70.1, 60.4, 50.4, 33.2,
31.5, 29.8, 22.6, 16.7, 16.4, 14.3; minor δ 174.2, 130.1, 124.5,
82.9, 70.2, 60.2, 50.8, 38.1, 31.7, 28.6, 22.1, 18.1, 17.5, 14.2;
HRMS-FAB (for the mixture) m/z [M þ H]þ calcd for C14H21O2
221.1542, found 221.1540.
Ethyl 1-Allyl-4-methylcyclohex-3-enecarboxylate (12b). The
typical procedure for the preparation of 12a was followed by
using 4b (0.14 g, 0.47 mmol) and allyl bromide (0.25 mL, 2.85
mmol). Flash chromatography (silica gel, hexane-EtOAc,
100:1, 80:1, 40:1) afforded 12b as a colorless oil: yield 0.072 g
1
(72%); IR (neat) 3078, 1732, 1461, 1207, 1034, 916 cm-1; H
NMR (400 MHz, CDCl3) δ 5.72 (dm, J=18.0 Hz, 1H), 5.32 (br
s, 1H), 5.06-5.03 (m, 1H), 5.02-4.99 (m, 1H), 4.12 (q, J =
7.2 Hz, 1H), 4.11 (q, J = 7.2 Hz, 1H), 2.45 (br d, J = 17.0 Hz,
1H), 2.32 (dd, J=13.7, 7.7 Hz, 1H), 2.25 (dd, J=13.7, 7.7 Hz,
1H), 2.01-1.87 (m, 4H), 1.67-1.58 (m, 1H), 1.62 (br d, J =
1.0 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 176.3, 133.9, 133.2, 119.0, 117.7, 60.2, 44.7, 42.3, 32.8,
29.7, 27.4, 23.3, 14.3; HRMS-EI m/z [M]þ calcd for C13H20O2
208.1463, found 208.1459. Anal. Calcd for C13H20O2: C, 74.96;
H, 9.68. Found: C, 75.07; H, 9.71.
(1R*,2S*)-Ethyl 1-(But-3-enyl)-2-methylcyclohex-3-enecar-
boxylate (12c). By using 4c (0.81 g, 2.66 mmol) and 4-bromo-
1-butene (1.65 mL, 15.96 mmol) as the starting substrates, the
preparation of 12c was almost same as for preparing 12a except
for adding 2.34 mL of HMPA (13.31 mmol) to the reaction
mixture right after the addition of 4-bromo-1-butene at -35 °C
and allowing the reaction to proceed at 25 °C for 12 h after the
addition of HMPA. Flash chromatography (silica gel, hexa-
ne-EtOAc, 160:1, 120:1) afforded 12c as a yellowish oil: yield
0.36 g (60%); IR (neat) 3076, 3020, 1732, 1641, 1257, 1192 cm-1
;
1H NMR (400 MHz, CDCl3) δ 5.77 (dm, J=17.1 Hz, 1H), 5.59
(d, J = 12.0 Hz, 1H), 5.55 (d, J = 12.0 Hz, 1H), 4.98 (dm, J =
17.1 Hz, 1H), 4.92 (br d, J = 10.2 Hz, 1H), 4.15 (dq, J = 20.0,
7.1 Hz, 2H), 2.19-2.12 (m, 1H), 2.07-1.99 (m, 2H), 1.96-1.87
(m, 1H), 1.83-1.67 (m, 5H), 1.27 (t, J=7.1 Hz, 3H), 0.89 (d, J=
6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.7, 138.5, 130.9,
124.7, 114.4, 60.0, 47.7, 38.2, 33.8, 29.4, 22.0, 20.4, 18.0, 14.3;
HRMS-EI m/z [M]þ calcd for C14H22O2 222.1620, found
222.1614.
(1S*,2R*,4S*)-Ethyl 2-Benzylbicyclo[2.2.1]hept-5-ene-2-car-
boxylate (12d). The typical procedure for the preparation of
12a was followed using 4d (0.13 g, 0.43 mmol) and benzyl
bromide (0.32 mL, 2.58 mmol). Flash chromatography (silica
gel, hexane-EtOAc, 100:1, 80:1, 40:1) afforded 12d as a viscous
oil: yield 0.052 g (50%); IR (neat) 3062, 3033, 1732, 1604, 1496,
1454, 1182, 1115, 741, 702 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.28-7.19 (m, 3H), 7.10 (br d, J=7.5 Hz, 2H), 6.18 (dd, J=5.6,
3.0 Hz, 1H), 5.98 (dd, J=5.6, 2.9 Hz, 1H), 4.07-3.91 (m, 2H),
3.23 (d, J=13.5 Hz, 1H), 2.96 (br s, 1H), 2.94 (d, J=13.5 Hz,
1H), 2.87 (br s, 1H), 1.83 (dd, J=12.2, 2.6 Hz, 1H), 1.70 (d, J=
7.2 Hz, 1H), 1.69 (dd, J=12.2, 3.6 Hz, 1H), 1.52 (dm, J=6.7 Hz,
1H), 1.14 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
175.9, 138.7, 138.4, 134.9, 129.5, 128.2 126.5, 60.1, 56.0, 50.3,
47.1, 46.0, 42.8, 36.0, 14.2; HRMS-FAB m/z [M þ H]þ calcd for
C17H21O2 257.1542, found 257.1540. Anal. Calcd for C17H20O2:
C, 79.65; H, 7.86. Found: C, 79.84; H, 7.91.
Ethyl 4-Methyl-1-(2-oxopropyl)cyclohex-3-enecarboxylate
(9). To a solution of 12b (0.55 g, 2.65 mmol) in 38 mL of a
7:7:24 H2O/THF/DMF mixture was added 0.12 g of PdCl2 (0.65
mmol) and 0.38 g of CuCl (3.67 mmol). The mixture was flashed
with oxygen gas for 15 min and then stirred under an oxygen
atmosphere at 25 °C for 12 h. The reaction mixture was poured
into water (20 mL) and extracted with EtOAc (2ꢀ60 mL). The
combined organic extracts were successively washed with satu-
rated NH4Cl aqueous solution (20 mL), saturated NaHCO3
aqueous solution (20 mL), water (20 mL), and brine (15 mL).
After concentration, the crude mixture was subjected to the
chromatography purification (silica gel, hexane-EtOAc, 20:1,
15:1, 8:1) to afford 0.39 g of 9 (65%): IR (neat) 3008, 1722, 1720,
(1S*,6R*)-Ethyl 1,3,4,6-Tetramethylcyclohex-3-enecarboxy-
late (12e). The typical procedure for the preparation of 12a
was followed using a mixture of 4e and 4e0 (88:12) (0.46 g, 1.37
mmol) and iodomethane (0.51 mL, 8.22 mmol). Flash chroma-
tography (silica gel, hexane-EtOAc, 100:1, 80:1, 40:1) afforded
1
1583, 1209, 1162, 1097 cm-1; H NMR (400 MHz, CDCl3) δ
5.30 (br s, 1H), 4.12 (q, J = 7.2 Hz, 2H), 2.82 (d, J = 17.7 Hz,
1H), 2.73 (d, J=17.7 Hz, 2H), 2.51 (br d, J=17.3 Hz, 1H), 2.11
7882 J. Org. Chem. Vol. 74, No. 20, 2009

Liao and Zhu
JOCArticle
(s, 3H), 2.03-1.93 (m, 2H), 1.91-1.79 (m, 3H), 1.64 (br s, 3H),
1.21 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 206.9,
176.8, 132.5, 118.7, 60.5, 48.1, 41.9, 32.9, 30.6, 29.7, 27.0, 23.3,
14.1; HRMS-EI m/z [M]þ calcd for C13H20O3 224.1412, found
224.1408. Anal. Calcd for C13H20O3: C, 69.61; H, 8.99. Found:
C, 69.74; H, 8.87.
4-Methyl-1-(2-oxopropyl)cyclohex-3-enecarbaldehyde (10).
To a suspension of LAH (0.61 g, 15.2 mmol) in anhydrous THF
(13 mL) at 0 °C was slowly added a solution of 9 (0.49 g, 2.18
mmol) in 13 mL of dry THF under a nitrogen atmosphere. After
being stirred at 0 °C for 2 h and 25 °C for 12 h, the reaction mixture
was cooled to 0 °C, slowly quenched with 5 mL of aqueous NaOH
solution (10%), and extracted with EtOAc (2 ꢀ 50 mL). The
combined organic extracts were washed with water and brine,
dried over MgSO4, filtered, and concentrated to furnish 0.36 g of
crude diol, which was directly used for the next step.
the purification by flash chromatography (silica gel, hexa-
ne-EtOAc, 150:1, 100:1) to afford 0.32 g of 13 (76%) as a 74:26
mixture of two isomers: IR (neat) (for the mixture) 3012, 2956,
1
2912, 1707, 1596, 1587, 1032, 742 cm-1; H NMR (400 MHz,
C6D6) major δ 7.28 (d, J=5.9 Hz, 1H), 5.90 (d, J=5.9 Hz, 1H),
5.32 (br s, 1H), 3.32 (br d, J= 16.9 Hz, 1H), 2.27-2.12 (m, 2H),
1.88-1.71 (m, 3H), 1.69 (s, 3H), 1.57 (br s, 3H), 1.34 (s, 3H),
1.28-1.21 (m, 1H), 0.95 (t, J= 7.9 Hz, 9H), 0.57 (q, J=7.9 Hz,
6H); minor: δ 7.26 (d, J= 5.9 Hz, 1H), 5.88 (d, J= 5.9 Hz, 1H),
5.29 (br s, 1H), 2.84 (br d, J= 17.3 Hz, 1H), 2.57-2.48 (m, 2H),
1.88-1.71 (m, 3H), 1.67 (s, 3H), 1.58 (br s, 3H), 1.43 (s, 3H),
1.28-1.21 (m, 1H), 0.95 (t, J= 7.9 Hz, 9H), 0.57 (q, J=7.9 Hz,
6H); 13C NMR (100 MHz, C6D6) major δ 206.6, 167.9, 131.4,
119.9, 76.0, 67.9, 48.2, 35.3, 33.2, 33.1, 28.3, 26.9, 23.1, 7.2, 7.0;
minor δ 206.0 167.4, 132.1, 119.8, 76.2, 67.1, 48.6, 36.3, 33.7, 31.2,
28.3, 27.1, 23.2, 7.2, 7.0; HRMS-EI (for the mixture) m/z [M]þ
calcd for C20H34O2Si 334.2328, found 334.2324.
To a solution of oxalyl chloride (0.75 mL, 8.58 mmol) in dry
DCM (25 mL) at -78 °C under a N2 atmosphere was added
anhydrous DMSO (0.72 mL, 10.14 mmol). The resulting mix-
ture was stirred at -78 °C for 10 min before the above diol in 2
mL of DCM was added. After being stirred for 1 h, the mixture
was added with Et3N (3.26 mL, 23.40 mmol), stirred for an
additional 1 h at -78 °C, and then quenched with water (5 mL).
The organic layer was separated, washed with water and brine,
and concentrated under reduced pressure. The residue was
purified using flash silica gel chromatography (hexane-
EtOAc, 30:1, 20:1, 10:1) to give 0.29 g of 10 (75% over two
steps): IR (neat) 3010, 2729, 1720, 1716, 1363 cm-1; 1H NMR
(400 MHz, C6D6) δ 9.69 (s, 1H), 5.18 (br s, 1H), 2.38 (br d, J=
17.7 Hz, 1H), 2.27 (d, J=17.9 Hz, 1H), 2.12 (d, J=17.9 Hz, 1H),
1.78-1.65 (m, 2H), 1.64-1.55 (m, 2H), 1.51 (s, 3H), 1.46 (d, J=
1.0 Hz, 3H), 1.37-1.31 (m, 1H); 13C NMR (100 MHz, C6D6) δ
205.0, 204.9, 133.3, 118.8, 49.5, 45.0, 30.6, 29.4, 28.3, 26.5, 23.1.
8-Methylspiro[4.5]deca-3,7-dien-2-one (11). To a solution of
10 (0.26 g, 1.46 mmol) in THF (25 mL) was added an aqueous
solution of KOH (1M, 2.5 mL, 2.46 mmol). The mixture was
stirred at 25 °C for 7 h, diluted with EtOAc (120 mL), and
washed with water (20 mL) and brine (20 mL). After concentra-
tion, the residue was subjected to the purification by flash
chromatography (silica gel, hexane-EtOAc, 30:1, 20:1, 10:1)
to afford 0.22 g of 11 (89%): IR (neat) 3012, 2964, 2913, 1716,
1675, 1587, 794 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.55 (d,
J=5.6 Hz, 1H), 6.07 (d, J=5.6 Hz, 1H), 5.38 (br s, 1H), 2.23 (d,
J = 18.7 Hz, 1H), 2.15 (d, J = 18.7 Hz, 1H), 2.14 (br d, J =
17.0 Hz, 1H), 2.05 (br s, 2H), 1.91 (d, J=17.0 Hz, 1H), 1.69 (br s,
3H), 1.68-1.61 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 209.8,
172.2, 134.0, 132.0, 118.9, 47.5, 43.7, 36.5, 32.7, 28.0, 23.4; HRMS-
EI m/z [M]þ calcd for C11H14O 162.1045, found 162.1053.
(5R*)-8-Methyl-1-[2-(triethylsilyloxy)prop-2-yl]spiro[4.5]deca-
3,7-dien-2-one (13). To a solution of 11 (0.21 g, 1.27 mmol) in
dry CH2Cl2 (26 mL) at -78 °C was added TiCl4 (1 M in CH2Cl2,
3.04 mL, 3.04 mmol) followed by Et3N (1.04 mL, 7.48 mmol).
After being stirred at -78 °C for 15 min and then -45 °C for
30 min, the mixture was cooled to -85 °C and mixed with 0.53 mL
of reagent acetone (7.22 mmol). The reaction mixture was stirred at
-85 °C for an additional 2.5 h before being mixed with 30 mL of
saturated NaHCO3 aqueous solution and Celite (3 g). The result-
ing suspension was filtered, and the filtrate was diluted with
CH2Cl2 (120 mL), washed with water and brine, dried over
MgSO4, and concentrated to afford the crude alcohol. The result-
ing crude alcohol was subsequently dissolved by 26 mL of dry
CH2Cl2, cooled to -78 °C, and mixed with 2,6-lutidine (1.79 mL,
15.21 mmol) followed by triethylsilyl trifluormethanesulfonate
(1.45 mL, 6.34 mmol). The reaction mixture was stirred at
-78 °C for 2 h and -40 °C for 12 h, quenched with 10 mL of
saturated NaHCO3 aqueous solution, and extracted with CH2Cl2
(2 ꢀ 50 mL). The combined organic extracts were washed with
water and brine. After concentration, the residue was subjected to
(5R*)-4,8-Dimethyl-1-[2-(triethylsilyloxy)prop-2-yl]spiro[4.5]dec-
7-en-2-one (14). To a suspension of purified CuI (636.5 mg, 3.28
mmol) in anhydrous ether (6.1 mL) at -14 °C was slowly added
MeLi (1.6 M in ether, 3.51 mL, 5.61 mmol) within 6 min. The
resulting pale yellow solution was stirred at -14 °C for an
additional 20 min and then was slowly added with a solution of
13 (0.31 g, 0.94 mmol) in 6 mL of dry ether. After being stirred
at -14 °C for 1 h, the reaction mixture was diluted with EtOAc
(40 mL), washed with water and brine, dried over Na2SO4, and
filtered. After concentration, the residue was subjected to purifica-
tion by flash chromatography (silica gel, hexane-EtOAc, 200:1,
150:1) to afford 0.24 g of 14 (72%) as a 54:28:18 mixture of three
isomers: IR (neat) (for the mixture) 1736, 1643, 1034, 1014, 744,
725 cm-1;1H NMR (400 MHz, CDCl3) (for the mixture) δ5.38 (br
s, 0.46H), 5.33 (br s, 0.54H), 2.84 (br d, J=17.7 Hz, 0.46H), 2.72
(br d, J = 16.9 Hz, 0.54H), 2.61-2.52 (m, 0.46H), 2.48 (dd, J =
18.1, 9.0 Hz, 0.54H), 2.44-2.32 (m, 0.46H), 2.26 (ddd, J = 18.1,
7.1, 0.5 Hz, 0.54H), 2.22-1.66 (m, 7H), 1.65 (br s, 1.38H), 1.62 (br
s, 1.62H), 1.49 (d, J=12.9 Hz, 2H), 1.40 (s, 1.12H), 1.34 (s, 2.16H),
1.32 (s, 0.72H), 1.00 (d, J= 6.6 Hz, 1.43H), 0.95-0.89 (m, 10H),
0.84 (d, J=7.2 Hz, 0.57 Hz), 0.62-0.54 (m, 6H); 13C NMR (100
MHz, CDCl3) (for the mixture) δ 219.9, 219.0, 217.7, 132.9, 132.5,
132.4, 121.2, 120.4, 120.1, 76.1, 75.8, 70.8, 64.9, 64.1, 47.3, 45.9,
45.7, 45.4, 44.8, 44.5, 39.8, 37.9, 34.0, 33.6, 32.8, 32.7, 30.5, 30.4,
29.8, 29.5, 29.0, 28.4, 28.2, 28.0, 27.7, 27.3, 25.6, 23.4, 23.3, 17.8,
17.1, 15.3, 7.1, 7.0, 6.8, 6.7; MS (EI, 70 eV) m/z=321.4 [M - Et]þ.
(4R*,5S*)-4,8-Dimethyl-1-(prop-2-ylidene)spiro[4.5]dec-7-en-
2-one [(()-r-Alasken-8-one, 8] and (4S*,5S*)-4,8-Dimethyl-
1-(prop-2-ylidene)spiro[4.5]dec-7-en-2-one (R-10-epi-Alasken-8-
one, 15). To a solution of 14 (36.5 mg, 0.10 mmol) in toluene
(3.5 mL) was added p-toluenesulfonic acid monohydrate (40.2 mg,
0.21 mmol). The mixture was stirred at 90 °C for 1 h, cooled to
25 °C, diluted with EtOAc (40 mL), and successively washed with
5% NaHCO3 aqueous solution (2 ꢀ 5 mL), water (10 mL), and
brine (10 mL). Purification of the residue first by flash chroma-
tography (silica gel, hexane-EtOAc, 150:1, 100:1, 60:1) and then
by preparative TLC (silica gel, petroleum ether-THF, 120:1)
afforded 12.3 mg of 8 (54%) and 5.9 mg of 15 (26%). 8: IR
1
(neat) 3156, 3014, 1633, 1630, 1442 cm-1; H NMR (400 MHz,
CDCl3) δ 5.34 (br s, 1H), 2.53 (dd, J=17.5, 7.6 Hz, 1H), 2.23 (s,
3H), 2.18-2.02 (m, 5H), 1.93 (s, 3H), 1.91 (dd, J = 17.5, 2.8 Hz,
1H), 1.88-1.78 (m, 1H), 1.77-1.70 (dm, J=14.6 Hz,1H), 1.69 (s,
3H), 0.94 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
208.7, 149.5, 138.3, 134.7, 119.9, 46.3, 45.7, 34.3, 33.5, 28.0, 27.8,
23.9, 23.5, 23.4, 16.8; HRMS-EI m/z [M]þ calcd for C15H22O
218.1671, found 218.1676.
Compound 15: 1H NMR (400 MHz, CDCl3) δ 5.41 (br s, 1H),
2.54 (dd, J=17.3, 7.7 Hz, 1H), 2.46 (dm, J=18.1 Hz, 1H), 2.21
(s, 3H), 2.16-1.96 (m, 6H), 1.93-1.91 (m, 1H), 1.92 (s, 3H), 1.67
(br s, 3H), 0.90 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 208.4, 149.6, 138.1, 134.0, 120.6, 46.0, 45.7, 35.8, 32.6,
J. Org. Chem. Vol. 74, No. 20, 2009 7883

Liao and Zhu
JOCArticle
30.7, 28.0, 23.8, 23.7, 23.5, 18.1; HRMS-EI m/z [M]þ calcd for
C15H22O 218.1671, found 218.1683.
Supporting Information Available: Synthesis and characteri-
zation of the mixtures of 4b/4b0 to 4d/4d0, 4f/4f0, and compounds
5-7; 2D NOESY spectra of 4b and 6, synthesis and ORTEP
drawings of the tosylhydrazone and 3,5-dinitrobenzoate deri-
vatives of 12c and 12e (16 and 17), CIF files of 5, 7, 16, and 17,
Acknowledgment. We are grateful to the National Science
Council of Republic of China (Taiwan) and National Dong
Hwa University for financial support and the Department of
Chemistry of National Chung Hsing University for the help
with the HRMS and X-ray crystallography analyses.
and copies of H and 13C NMR spectra of compounds 2-17.
1
This material is available free of charge via the Internet at http://
pubs.acs.org.
7884 J. Org. Chem. Vol. 74, No. 20, 2009