Total synthesis of (+)-cymbodiacetal: A re-evaluation of the biomimetic route

Article abstract of DOI:10.1021/jo101691n

A total synthesis of (+)-cymbodiacetal (1) has been completed from (R)-(+)-limonene oxide using a hetero-Diels-Alder cycloaddition as a key step. The key Diels-Alder cycloaddition proceeds with endo-selectivity (2:1, endo/exo) in quantitative yield, and t

Full text of DOI:10.1021/jo101691n

pubs.acs.org/joc
Total Synthesis of (þ)-Cymbodiacetal: A Re-evaluation of the
Biomimetic Route
Maliha Uroos, William Lewis, Alexander J. Blake, and Christopher J. Hayes*
School of Chemistry, University of Nottingham, University Park, Nottingham, U.K., NG7 2RD
chris.hayes@nottingham.ac.uk
Received August 29, 2010
A total synthesis of (þ)-cymbodiacetal (1) has been completed from (R)-(þ)-limonene oxide using a
hetero-Diels-Alder cycloaddition as a key step. The key Diels-Alder cycloaddition proceeds with
endo-selectivity (2:1, endo/exo) in quantitative yield, and the two diastereomeric spirochroman
products are isolable, stable products. Furthermore, the exo- and the endo-hetero-Diels-Alder
cycloaddition products (2 and 7) can be oxidized with m-CPBA to produce (þ)-cymbodiacetal (1) and
the C2-symmetric bis-hemiacetal structure 8, respectively. The isomeric hemiacetal 9 is produced in
both oxidation reactions. The structures of (þ)-cymbodiacetal (1), its C2-symmetric diastereoisomer
8, and the isomeric hemiacetal 9 were confirmed using X-ray crystallography.
Introduction
the monoterpene (R)-(þ)-limonene (4) was also isolated as a
major component of the essential oil from Cymbopogon
martinii,1 and as this material appears to be an obvious biosyn-
thetic precursor to 1 (Figure 1), it therefore follows that C2 and
C7 of 1 would also share (þ)-limonene’s R-configuration. This
stereochemical hypothesis was later shown to be correct
when in 2004 Kamat2 reported a biomimetic total synthe-
sis of 1 starting from (þ)-limonene oxide, thus confirming
the absolute stereochemistry of 1 to be as shown below
(Figure 1).
The structurally intriguing natural product (þ)-cymbo-
diacetal (1) was isolated in 1987 by Dev from the aerial parts
of flowering wild Cymbopogon martinii.1 Its structure was
elucidated using a combination of spectroscopic (1H, 13C
NMR, IR, MS) and X-ray crystallographic techniques, and
the fortuitous fact that 1 crystallized as a 1:1 solvate with
CDCl3 enabled the absolute stereochemistry to be deter-
mined from the X-ray data due to the presence of the heavy
atoms. However and rather peculiarly, the representation
derived from the X-ray analysis and the structure actually
drawn for 1 are presented as enantiomers of each other in
Figure 1 of the original isolation paper. Unfortunately, and
despite what is stated in the Experimental Section of the
isolation paper, the original X-ray data is not available from
the Cambridge Crystallographic database so it is not possible
to clarify this obvious discrepancy. Circumstantial evidence
for the absolute stereochemistry of 1 comes from the fact that
The spirochroman 2, which is a key intermediate in both
the proposed biosynthesis and Kamat’s total synthesis, is the
product of an exo-hetero-Diels-Alder dimerization of the
limonene-derived exocyclic enone 3.3 Kamat found enone 3
(2) D’Souza, A. M.; Paknikar, S. K.; Dev, V.; Beauchamp, P. S.; Kamat,
S. P. J. Nat. Prod. 2004, 67, 700.
(3) For other spirochroman-containing natural products, see: (a) Zhang,
Y.; Lu, Y.; Mao, L.; Proksch, P.; Lin, W. Org. Lett. 2005, 7, 3037. (b) Inouye,
Y.; Sugo, Y.; Kusumi, T.; Fusetani, N. Chem. Lett. 1994, 419. (c) Carreiras,
M. C.; Rodriguez, B.; Lopez-Garcia, R. E.; Rabanal, R. M. Phytochemistry
1987, 26, 3351. (d) Adesomoju, A. A.; Okogun, J. I. J. Nat. Prod. 1984, 47,
308. (e) Takemoto, T.; Nakajima, T. Yakugaku Zasshi 1955, 75, 1036.
(1) Bottini, A. T.; Dev, V.; Garfagnoli, D. J.; Hope, H.; Joshi, P.; Lohani,
H.; Mathela, C. S.; Nelson, T. E. Phytochemistry 1987, 26, 2301.
DOI: 10.1021/jo101691n
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and a full set of spectroscopic data was obtained for
this compound.7 While the enone 3 appeared to account
for >90% of the crude material, the yield of pure 3 was
only 62% after chromatography. In order to account for
the missing mass balance, the remaining fractions from
the column were collected, and we were pleased to see that
the spirochroman 2 and its diastereoisomer 7 (ratio 1:2)
could also be isolated in a combined 20% yield. As the
stereochemistry of 2 and 7 could not be determined directly,
their stereochemistry was assigned at a later stage by con-
verting 2 into the natural product 1 (see below). As the
compounds 2 and 7 were obviously produced via the hetero-
Diels-Alder dimerization of the enone 3 during purification,
the separated pure sample of 3 was heated at 80 °C for 8 h in
order to convert all the enone 3 into 2 and 7. Pleasingly, the
hetero-Diels-Alder dimerization proved to be very efficient,
and the desired spirochromans 7 and 2 (2:1 ratio) were
isolated in quantitative yield.8
FIGURE 1. Biosynthetic hypothesis for the formation of (þ)-cym-
bodiacetal (1).
SCHEME 1. Synthesis of Spirochromans 2 and 7 via Hetero-
Diels-Alder Cycloaddition
Although Kamat had previously described the minor exo-
Diels-Alder product 2, it is somewhat surprising that major
endo-Diels-Alder product 7 hadn’t been observed in their
work.9 Compound 7 is clearly the major product of hetero-
Diels-Alder dimerization of 3 under their reported condi-
tions (rt, 7 days), and we checked this independently. In
addition, and contrary to the report of Kamat, we found the
exo-Diels-Alder product 2 to be a stable, easy to handle oil,
which could be purified easily using silica gel column chro-
matography. Indeed, Kamat states that 2 “was difficult to
obtain in pure form” and that it was oxidized in air, in the
presence of “diffused daylight”, to afford (þ)-cymbodiacetal
(1) after column chromatography. Once again, we indepen-
dently checked this claim by exposing a sample of pure 2
to air and sunlight over an extended period (15 days), but
no evidence of oxidation at all could be found under these
conditions, and 2 was recovered unchanged after this time.
For the sake of completeness, we also exposed the endo-
isomer 7 to the same air/sunlight conditions and once again
found that no oxidation reaction took place.
The stark difference in reactivity (stability) of 2 observed
by Kamat and by us is quite difficult to explain, but one
possibility could stem from the method used to prepare the
enone 3. In our work, a Swern oxidation was used to obtain
3, whereas Kamat used a PCC oxidation. In our hands, 3 was
relatively easy to handle, whereas Kamat found it difficult to
handle. It is possible, therefore, that chromium-based im-
purities (from PCC) were contaminating Kamat’s samples
of 3 and 2, and it was these impurities that were responsible
for the observed instability of 3 and for the oxidation of 2
to 1 upon standing in air/sunlight.10,11 We have subsequently
to be unstable and reported that it dimerized and oxidized
to give 1 directly upon exposure to air and silica gel column
chromatography. While this reported synthesis appears to be
beautifully simple, and supports the likely biosynthetic origin
of the natural product, several of its features caught our atten-
tion, as they appeared to contradict results obtained within our
own laboratory.4 We now report a full account of our studies
on the synthesis of (þ)-cymbodiacetal (1), which have resulted
in a total synthesis of the natural product 1, along with two
other isomeric structures, and we have been able to obtain our
own X-ray structure of 1 thus clarifying the original uncer-
tainty surrounding the absolute stereochemistry.
Results and Discussion
Our synthesis began by converting (R)-(þ)-limonene
oxide 5 into the corresponding allylic alcohol 6 in 96% yield
using Yamamoto’s conditions.5 The allylic alcohol 6 was
then cleanly oxidized to the enone 3 in good yield (80-90%
crude yield) under Swern conditions6 (Scheme 1). It was at
this point in our studies that we started to observe differences
between our results and those described by Kamat.2 First,
the enone 3 was found to be relatively stable in its crude form,
(8) For background information regarding this type of hetero-
Diels-Alder cycloaddition, see: (a) Desimoni, G.; Tacconi, G. Chem. Rev.
1975, 75, 651. (b) Colonge, J.; Descotes, G. R,β-Unsaturated Carbonyl
Compounds as Dienes. In Organic Chemistry; Hamer, J., Ed.; Academic
Press: New York, 1967; Vol. 8, pp 217-253.
(9) (a) Hetero-Diels-Alder cycloadditions of this type are reported to be
endo-selective: Hosoyama, H.; Shigemori, H.; In, Y.; Ishida, T.; Kobayashi,
J. Tetrahedron Lett. 1998, 39, 2159. (b) For a description of the Alder endo-
rule, see: Alder, K.; Stein, G. Angew. Chem. 1937, 50, 510.
(10) It has been reported that PCC can perform epoxidations (see ref 11).
It is therefore possible that 2 is being oxidized in situ to produce 14 (or closely
related species), which then reacts further under the acidic reaction condi-
tions to produce 1.
(4) For the only other previous work on the synthesis of (þ)-cymbodi-
acetal, see: Barrero, A. F.; Herrador, M. M.; Quilez del Moral, J. F.;
Arteaga, P.; Arteaga, J. F.; Dieguez, H. R.; Sanchez, E. M. J. Org. Chem.
2007, 72, 2988.
(5) Yasuda, A.; Yamamoto, H.; Nozaki, H. Bull. Chem. Soc. Jpn. 1979,
52, 1705.
(6) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(7) However, upon standing for prolonged periods, the enone 3 comple-
tely dimerizes to form the spirochromans 2 and 7.
(11) (a) Gamba, D.; Pisoni, D. S.; da Costa, J. S.; Petzhold, C. L.; Borges,
A. C. A.; Ceschi, M. A. J. Braz. Chem. Soc. 2008, 19, 1270. (b) Sundararaman,
P.; Herz, W. J. Org. Chem. 1977, 42, 813.
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FIGURE 2. X-ray crystal structure of 8.
SCHEME 2. Oxidation of endo-Hetero-Diels-Alder Product 7
FIGURE 3. X-ray crystal structure of 9.
SCHEME 3. Suggested Reaction Pathways for the Formation
of 8 and 9
repeated Kamat’s published synthetic procedures, but un-
fortunately, their synthesis of 1 could not be reproduced. We
therefore decided to perform our own oxidation studies on 2,
and its diastereoisomer 7, in order to develop an independent
and reliable synthesis of 1.
As mentioned above, the relative stereochemistries of 2
and 7 could only be determined retrospectively by convert-
ing one of them into the natural product 1, so our oxidation
studies began on the major diastereomer (which was subse-
quently shown to be the endo-isomer 7) that resulted from the
hetero-Diels-Alder dimerization of 3. Thus, treatment of 7
with m-CPBA resulted in rapid oxidation of the electron-rich
enol-ether to provide a mixture of unstable products that
were immediately treated with 2 M HCl.12 Workup and
subsequent purification by column chromatography led to
the isolation of two new oxidation products, neither of which
had spectroscopic data that matched that reported for (þ)-
cymbodiacetal (1) (Scheme 2).
The 13C NMR spectrum of the minor compound 8
(12% yield) showed only 10 resonances, and the proposed
C2-symmetric structure was confirmed via X-ray crystal-
lography (Figure 2).13 The high-resolution mass spectrum
of product 9 confirmed that it was an isomer of 8, and the 1H
and 13C NMR data showed that it did not have C2-symmetry.
X-ray crystallography was once again used to confirm the
overall structural assignment (Figure 3).13
It was very clear from the X-ray structure obtained for 8
that the major hetero-Diels-Alder dimerization product 7
must have formed via an endo-cycloaddition pathway and
that oxidation/cyclization of 7 does not lead to (þ)-cymbo-
diacetal (1). The formation of 8 and 9 from 7 can be explained
by invoking epoxidation of the enol ether to give the diaste-
reomeric epoxides 10 and 11 (Scheme 3). The epoxide 10
produced on the minor reaction pathway then opens in the
presence of water (and acid) to give the diol 12. Cyclization
of one of the two hydroxyls onto the ketone then forms
the observed bis-hemiacetal 8, which is a diastereoisomer of
(þ)-cymbodiacetal (1). Likewise, the major epoxide 11 opens
to give the diol 13, which after hemiacetalization produces
the observed major product 9 (Scheme 3).
Having unambiguously defined the stereochemistry of the
two hetero-Diels-Alder dimerization products 2 and 7,
we were now in a position to complete a total synthesis of
(þ)-cymbodiacetal (1) by conducting oxidation/cyclization
studies on the exo-cycloaddition product 2. Thus, 2 was
exposed to m-CPBA in CH2Cl2 (Scheme 4), and once TLC
analysis showed that all starting material had been consumed,
the reaction was quenched and NMR spectra were recorded
for the crude reaction mixture. As the crude mixture was
not soluble in CDCl3, the sample was dissolved in CD3OD,
and the NMR data were collected in that solvent. We were
pleased to see that a major new product had been formed,
but it was obviously not the epoxide 14 as it appeared to
possessC2-symmetry, similar tothe naturalproduct 1. Indeed,
(12) Catalysis of this transformation with either 2 M HCl (THF/H2O) or
pTSA (THF/H2O) leads to identical results, and the two methods can be used
interchangeably.
(13) The crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre. CCDC 790825 contains the supplementary
crystallographic data for 1, CCDC 790826 contains the supplementary crystal-
lographic data for 8, CCDC 790827 contains the supplementary crystallographic
data for 9, and CCDC 790828 contains the supplementary crystallographic
data for 16. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif.
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FIGURE 5. X-ray crystal structure of (þ)-cymbodiacetal (1).
FIGURE 4. X-ray crystal structure of C2-symmetric bisacetal 16.
SCHEME 5. Synthesis of (þ)-Cymbodiacetal (1) by Oxidation
SCHEME 4. Preliminary Oxidation and Acetalization Studies
on Spirochroman 2
of 2
first treating with m-CPBA to obtain the crude epoxide 14.
This material was then reacted immediately with MeOH in
the presence of pTSA (10 mol %) to afford 17 in 43% yield
(Scheme 4).
Guided by these results, we were able to complete a total
synthesis of (þ)-cymbodiacetal (1) by first treating 2 with
m-CPBA to produce 14. A THF solution of the crude mate-
rial was then reacted with water in the presence of pTSA12
(10 mol %), and to our pleasure, (þ)-cymbodiacetal (1)
was produced as a major product (44%) from the two-step
sequence (Scheme 5).
Our synthetic sample of 1 showed identical spectro-
scopic data1 to that reported for the natural product, and
in addition we were able to obtain our own X-ray crystal
structure of the 1:1 solvate of 1 with CDCl3 (Figure 5),13
which unambiguously confirmed its absolute configuration.
In addition to the formation of 1, the acetal 9 was also
formed as a minor product (7%) in the reaction. We were
initially surprised at this finding, as we had previously seen 9
as the major product from the m-CPBA oxidation of the
endo-hetero-Diels-Alder product 7 (Scheme 2). The forma-
tion of 9 from the exo-hetero-Diels-Alder product 2 can be
accounted for by the following minor reaction pathway
shown in Scheme 6. Thus, oxidation of 2 with m-CPBA on
the upper face of the enol ether first produces the epoxide 18,
which upon opening with water produces the hemiacetal 19.
The hemiacetal 19 then rearranges, via the dihydroxy dione
20, to produce the new hemiacetal 21 and a second hemi-
acetal formation then finally affords 9. It is interesting to
note that the isomeric hemiacetal 22, which could form
directly from 19 or indirectly from 20, was not observed.
In conclusion, we have successfully completed a total
synthesis of (þ)-cymbodiacetal (1) from (R)-(þ)-limonene
oxide using a hetero-Diels-Alder cycloaddition as a key
step. We have shown that the Diels-Alder cycloaddition
proceeds with endo-selectivity (2:1, endo/exo) in quantitative
a closer inspection of the data revealed a striking similarity
between the new product 16 and (þ)-cymbodiacetal (1).
Subsequent purification of the crude reaction mixture by
column chromatography allowed the major product 16 to
be isolated in 41% yield as a crystalline solid. A single-crystal
X-ray structure was determined for 16 (Figure 4),13 and to our
surprise, it contained twoOCD3 groups, the presence of which
1
we had missed due to the fact that only H and 13C NMR
spectroscopy had been used to analyze the crude material.
Subsequent 2H NMR analysis of the purified material showed
a peak at 3.24 ppm for the CD3O moieties, and high-resolution
mass spectrometry also clearly showed their presence.
The formation of 16 is best explained by epoxidation
of 2 from the lower face (as drawn) to give the epoxide 14
as a transient intermediate. Upon workup and exposure to
CD3OD in the presence of acid (presumably residual chloro-
benzoic acid), the epoxide 14 then forms the oxocarbenium
ion 15, which is then trapped by CD3OD. Closure of the
second acetal under the same conditions then gives 16 as
the major product. In order to confirm this hypothesis, we
deliberately attempted to prepare the bis-acetal 17 from 2 by
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SCHEME 6. Suggested Pathway for the Formation of 9 from
Spirochroman 2
(CH), 44.1 (CH), 42.2 (CH2), 39.0 (CH2), 38.2 (CH), 33.8
(CH2), 32.7 (CH2), 32.6 (CH2), 30.0 (CH2), 21.0 (CH3),
20.8 (CH3); MS m/z (ESþ) 175.1089 (M þ Na C10H16NaO
requires 175.1093). These data are identical to those previously
reported.2
(R)-2-Methylene-5-(prop-1-en-2-yl)cyclohexanone (3) (and
Spirochromans 2 and 7). A solution of DMSO (1.86 mL, 26.2
mmol) in CH2Cl2 (6 mL) was added dropwise to a stirred and
cooled solution of oxalyl chloride (1.11 mL, 13.1 mmol) in
CH2Cl2 (5 mL) at -78 °C. After 1.5 h, a solution of allylic
alcohol 6 (1.00 g, 6.56 mmol) in CH2Cl2 (33 mL) was added
at -78 °C. After a further 1.5 h, triethylamine (8.20 mL,
59.04 mmol) was added, and the reaction mixture was stirred
for 2 h. The reaction mixture was warmed to 0 °C and stirred
for 20 min. The reaction was quenched with saturated NaH-
CO3 (30 mL), diluted with CH2Cl2 (20 mL), extracted with
CH2Cl2 (20 mL ꢀ 3), washed with water (50 mL ꢀ 2), dried over
MgSO4, filtered, and concentrated in vacuo to give the crude
product. Purification by column chromatography (pentane/
Et2O; 20/1) afforded the spirochroman 2 (65 mg, 7%) as
a colorless oil: [R]26 þ59.0 (c 1.6 CHCl3); IR νmax/cm-1
D
(CHCl3) 3550, 3086, 2925, 2840, 1715, 1644, 1452, 1375,
1305, 1151, 1130, 1070, 982; NMR δH (400 MHz, CDCl3,
298 K) 4.76 (2H, br s), 4.73 (1H, app t, J = 1.5 Hz), 4.71 (1H,
app t, J = 0.8 Hz), 2.87 (1H, dd, J = 12.3, 11.2 Hz), 2.33 (1H,
app tt, J = 12.4, 3.6 Hz), 2.24-2.17 (3H, m), 2.15-2.10 (4H,
m), 1.98-1.85 (3H, m), 1.78-1.70 (8H, m), 1.66-1.59 (1H, m),
1.56-1.44 (2H, m), 1.39-1.24 (1H, m); NMR δC (100 MHz,
CDCl3, 298 K) 212.5 (C), 149.3 (C), 147.5 (C), 144.0 (C), 110.0
(CH2), 108.8 (CH2), 105.6 (C), 79.4 (C), 48.6 (CH), 43.5 (CH2),
41.8 (CH), 39.0 (CH2), 33.1 (CH2), 28.6 (CH2), 27.8 (CH2), 27.4
(CH2), 25.5 (CH2), 22.6 (CH2), 20.9 (CH3), 20.4 (CH3); MS
m/z (ESþ) 301.2150 (M þ H C20H29O2 requires 301.2162).
Anal. Calcd for C20H28O2: C, 79.96; H, 9.39. Found: C, 79.94;
H, 9.42. These data are in agreement with those previously
reported for 2.2 Further elution with (pentane/Et2O; 15/1)
afforded the pure enone 3 (610 mg, 62%) as a colorless oil:
yield to provide two stable, isolable isomeric spirochroman
products (7 and 2), which do not spontaneously oxidize in air
and sunlight to form 1. These findings are clearly contrary to
results previously reported in the literature.2 Furthermore,
we have shown that the exo- and the endo-hetero-Diels-
Alder cycloaddition products (2 and 7) can be oxidized
with m-CPBA to produce (þ)-cymbodiacetal (1) and the
C2-symmetric bis-hemiacetal 8, respectively. The isomeric
hemiacetal 9 is also produced in both oxidation reactions,
and all structural and stereochemical assignments have been
confirmed via X-ray crystallography.
[R]27 þ71.3 (c 1.17 CHCl3); IR νmax/cm-1 (CHCl3) 2926,
D
2839, 1718, 1699, 1644, 1455, 1375, 1151, 1130, 896; NMR
δH (400 MHz, CDCl3, 298 K) 5.86 (1H, br s), 5.16 (1H, app
dd, J = 3.4, 2.1 Hz), 4.80 (1H, app t, J = 1.3 Hz), 4.72 (1H, br
s), 2.69 (1H, app tt, J = 8.1, 1.1 Hz), 2.65-2.58 (1H, m),
2.55-2.43 (2H, m), 2.32 (1H, dd, J = 16.6, 5.3 Hz), 2.10-1.92
(1H, m), 1.75 (3H, s), 1.71-1.59 (1H, m); NMR δC (100 MHz,
CDCl3, 298 K) 201.5 (C), 147.3 (C), 144.5 (C), 120.6 (CH2),
110.4 (CH2), 45.7 (CH2), 42.7 (CH), 31.2 (CH2), 29.1 (CH2),
20.8 (CH3); MS m/z (ESþ) 301.2157 (2M þ H C20H29O2
requires 301.2162). Further elution with (pentane/Et2O; 10/1)
afforded the spirochroman 7 (132 mg, 13%) as a colorless oil:
Experimental Section
(R)-2-Methylene-5-(prop-1-en-2-yl)cyclohexanol 6. Freshly
distilled tetramethylpiperidine (2.44 mL, 14.5 mmol) was diluted
with benzene (20 mL), the resulting solution was cooled to
0 °C, n-butyllithium (6.28 mL, 14.5 mmol, 2.30 M solution in
hexanes) was then added, and the colorless solution turned
yellow. After 30 min of stirring, diethylaluminum chloride
(16.6 mL, 16.6 mmol, 1.00 M solution in hexanes) was added,
the yellow color disappeared, and a turbid solution formed.
After a further 40 min of stirring at 0 °C, the epoxide 5 (1.10 g,
7.23 mmol) was added as a solution in benzene (7 mL). The
reaction mixture was stirred for 45 min at 0 °C and then for
2 h at rt. The reaction was quenched with the slow addition
of saturated NaHCO3 (20 mL) at 0 °C, extracted with CHCl3
(20 mL ꢀ 3), washed with brine (30 mL), dried over MgSO4, fil-
tered, and concentrated in vacuo to give the crude product. Puri-
fication by column chromatography (pentane/Et2O; 4/1) afforded
the product 6 as a 1:1 mixture of diastereoisomers (1.05 g, 96%) as
a colorless oil: [R]25D þ54.0 (c 0.95 CHCl3); IR νmax/cm-1 (CHCl3)
2954, 2929, 2857, 1668, 1457; NMR δH (400 MHz, CDCl3, 298 K)
4.95 (1H, s), 4.85 (1H, s), 4.79 (1H, s), 4.77 (1H, s), 4.71 (4H, s),
4.37 (1H, s), 4.15-4.06 (1H, m), 2.60-2.41 (3H, m), 2.26-2.13
(3H, m), 2.11-1.95 (2H, m), 1.89-1.78 (2H, m), 1.73 (6H, s),
1.53-1.43 (1H, m), 1.33-1.18 (3H, m); NMR δC (100 MHz,
CDCl3, 298 K) 151.3 (C), 149.9 (C), 149.5 (C), 148.7 (C) 109.9
(CH2), 109.2 (CH2), 108.9 (CH2), 103.9 (CH2), 72.5 (CH), 72.2
[R]26 þ96.5 (c 1.65 CHCl3); IR νmax/cm-1 (CHCl3) 3532,
D
3086, 2919, 2839, 1721, 1700, 1644, 1455, 1375, 1305, 1152,
1130, 986; NMR δH (400 MHz, CDCl3, 298 K) 4.80 (1H, s),
4.75 (1H, s), 4.72 (2H, s), 2.58-2.40 (3H, m), 2.34-2.21 (2H,
m), 2.18-1.93 (5H, m), 1.90-1.82 (2H, m), 1.80-1.70 (10H, m),
1.49-1.23 (2H, m); NMR δC (100 MHz, CDCl3, 298 K) 208.4
(C), 149.3 (C), 146.8 (C), 144.7 (C), 110.5 (CH2), 108.8 (CH2),
102.3 (C), 81.1 (C), 46.1 (CH), 43.2 (CH2), 41.5 (CH), 35.3 (CH2),
34.2 (CH2), 28.6 (CH2), 28.1 (CH2), 27.7 (CH2), 26.7 (CH2), 22.4
(CH2), 21.0 (CH3), 20.9 (CH3); MS m/z (ESþ) 301.2155 (M þ H
C20H29O2 requires 301.2162). Anal. Calcd for C20H28O2 requires
C, 79.96; H, 9.39. Found: C, 79.65; H, 9.40.
(10R,40R,7R)-40,7-Di(prop-1-en-2-yl)-3,4,5,6,7,8-hexahydrospiro-
[chromene-2,10-cyclohexan]-20-one (2) and (10S,40R,7R)-40,7-Di-
(prop-1-en-2-yl)-3,4,5,6,7,8-hexahydrospiro[chromene-2,10-cyclo-
hexan]-20-one (7). The enone 3 (234 mg, 1.56 mmol) was heated in
a sealed tube at 80 °C for 8 h in an oil bath in the absence of solvent.
The 1H NMR spectrum of the crude reaction mixture confirmed
complete consumption of starting material 3, and the residue was
J. Org. Chem. Vol. 75, No. 24, 2010 8469

Uroos et al.
JOCArticle
purified by column chromatography (pentane/Et2O; 20/1) to
afford 2 (77 mg, 33%) and 7 (154 mg, 66%) as colorless oils,
whose data were identical to that previously obtained in this work.
Synthesis of 8 and 9. Spirochroman 7 (55 mg, 0.18 mmol)
was dissolved in CH2Cl2 (1.5 mL) and cooled to 0 °C, and then
m-CPBA (40 mg of 70 wt %, 0.16 mmol) was added in one
portion and stirred at 0 °C for 45 min. The reaction was quenched
with saturated NaHCO3 (10 mL), diluted with CH2Cl2 (10 mL),
extracted with CH2Cl2 (10 mL ꢀ 3), dried over MgSO4, filtered,
and concentrated in vacuo to give the crude product as a colorless
oil. The crude product was dissolved in THF (1.00 mL), and 2 M
HCl (1.00 mL) was then added. The resulting solution was stirred
for a further 1 h at rt. The reaction was quenched with saturated
NaHCO3 (10 mL), diluted with CH2Cl2 (10 mL), extracted with
CH2Cl2 (10 mL ꢀ 3), dried over MgSO4, filtered, and concen-
trated in vacuo to give the crude product. Purification by column
chromatography (pentane/Et2O; 10/1-4/1-2/1) afforded the
product 8 (7 mg, 12%) and 9 (26 mg, 43%) both as white crys-
talline solids.
0 °C for 45 min. The reaction was quenched with saturated
NaHCO3 (10 mL), diluted with CH2Cl2 (10 mL), extracted with
CH2Cl2 (10 mL ꢀ 3), dried over MgSO4, filtered, and concen-
trated in vacuo to give the crude product as a white solid. The
crude product was dissolved in MeOH (1 mL), and pTSA (3 mg,
0.1 mmol) was added. The resulting solution was stirred for 12 h
at rt. The reaction was quenched with saturated NaHCO3
(10 mL), extracted with CH2Cl2 (10 mL ꢀ 3), dried over MgSO4,
filtered, and concentrated in vacuo to give the crude product.
Purification by column chromatography (pentane/Et2O; 20/1)
afforded the product 17 (25 mg, 43%) as very thick oil: [R]21
D
þ48.5 (c 0.3 CHCl3); IR νmax/cm-1 (CHCl3) 3695, 2938,
1643, 1602, 1452, 1375, 1158, 1124, 1096, 1062, 1035, 1014,
894; NMR δH (400 MHz, CDCl3, 298 K) 4.70 (2H, s), 3.25 (3H,
s), 2.07-2.01 (1H, m), 1.92 (1H, app t, J = 11.5 Hz), 1.85-1.76
(1H, m), 1.73 (3H, s), 1.71-1.40 (6H, m); NMR δC (100 MHz,
CDCl3, 298 K) 149.6 (C), 108.6 (CH2), 100.4 (C), 71.9 (C), 47.4
(CH3), 40.6 (CH), 34.0 (CH2), 32.9 (CH2), 27.0 (CH2), 26.3
(CH2), 21.2 (CH3); MS m/z (ESþ) 385.2333 (M þ Na C22H34-
NaO4 requires 385.2349).
Data for 8: mp 215-218 °C; [R]25D þ39.1 (c 0.40 CHCl3); IR
ν
max/cm-1 (CHCl3) 3574, 2944, 2359, 1644, 1456, 1165, 989, 908;
(þ)-Cymbodiacetal 1 and Hemiacetal 9. Spirochroman (2) (68
mg, 0.23 mmol) was dissolved in CH2Cl2 (1.30 mL) and cooled
to 0 °C, and then m-CPBA (54 mg of 70 wt %, 0.23 mmol) was
added in one portion and the resulting solution was stirred at
0 °C for 45 min. The reaction was quenched with saturated
NaHCO3 (10 mL), diluted with CH2Cl2 (10 mL), extracted with
CH2Cl2 (10 mL ꢀ 3), dried over MgSO4, filtered, and concen-
trated in vacuo to give the crude product as a white solid. pTSA
(4 mg, 0.02 mmol) was then added to the stirred solution of the
above crude product in (1.00 mL) THF/H2O (1:1). The result-
ing solution was stirred for 1 h. The reaction was quenched
with saturated NaHCO3 (10 mL), diluted with CH2Cl2 (10 mL),
extracted with CH2Cl2 (10 mL ꢀ 3), dried over MgSO4, fil-
tered, and concentrated in vacuo to give the crude product.
Purification by column chromatography (pentane/Et2O; 10/
1-4/1-2/1) afforded the products 1 (33 mg, 44%) and 9 (5 mg,
7%) as white crystalline solids.
NMR δH (500 MHz, CDCl3, 298 K) 4.73 (1H, s), 4.69 (1H, s),
2.34 (1H, app tt, J = 12.6, 3.7 Hz), 2.17-2.10 (1H, m), 2.01-1.93
(2H, m), 1.82-1.76 (1H, m), 1.72 (3H, s), 1.65-1.55 (3H, m),
1.24-1.19 (1H, m); NMR δC (125 MHz, CDCl3, 298 K) 148.2
(C), 109.2 (CH2), 99.6 (C), 74.9 (C), 40.8 (CH), 40.3 (CH2), 32.0
(CH2), 27.7 (CH2), 26.3 (CH2), 21.3 (CH3); MS m/z (ESþ)
357.2037 (M þ Na C20H30NaO4 requires 357.2036).
Data for 9: mp 108-110 °C; [R]23D -30.8 (c 0.30 CHCl3); IR
ν
max/cm-1 (CHCl3) 3577, 3494, 2943, 2858, 1707, 1644, 1454,
1376, 1129, 1102, 983, 901; NMR δH (400 MHz; CDCl3)
4.78 (1H, s), 4.75 (1H, s), 4.72 (1H, s), 4.71 (1H, s), 2.57-2.49
(1H, m), 2.35-2.21 (3H, m), 2.03 (1H, dd, J = 13.8, 5.0 Hz),
1.98-1.91 (1H, m), 1.88-1.80 (4H, m), 1.78-1.68 (7H, m),
1.63-1.48 (7H, m); NMR δC (100 MHz, CDCl3, 298 K) 149.2
(C), 148.4 (C), 109.4 (CH2), 109.1 (CH2), 107.4 (C), 103.5 (C),
81.3 (C), 69.6 (C), 42.1 (CH), 41.0 (CH2), 36.3 (CH), 35.9 (CH2),
34.3 (CH2), 32.3 (CH2), 28.3 (CH2), 28.20 (CH2), 25.8 (CH2),
22.8 (CH2), 21.7 (CH3), 20.7 (CH3); MS m/z (ESþ) 357.2035 (M
þ Na C20H30NaO4 requires 357.2036).
Data for 1: mp 205-208 °C (lit.1 mp 206-207 °C); [R]24
D
þ26.5 (c 0.20 CHCl3) (lit.1 [R]24D þ26 ( 5 (c 0.12, CHCl3); IR
ν
max/cm-1 (CHCl3) 3699, 3600, 2928, 2855, 2360, 1602, 1454,
Synthesis of 16. Spirochroman 2 (60 mg, 0.20 mmol) was
dissolved in CH2Cl2 (1.50 mL) and cooled to 0 °C, and then
m-CPBA (44 mg of 70 wt %, 0.18 mmol) was added in one
portion. The resulting solution was stirred at 0 °C for 45 min.
The reaction was quenched with saturated NaHCO3 (10 mL),
diluted withCH2Cl2 (10mL), extractedwithCH2Cl2 (10mL ꢀ 3),
dried over MgSO4, filtered, and concentrated in vacuo to give the
crude product as a white solid. The crude productwasdissolvedin
CD3OD (1 mL) and the resulting solution was stirred for 12 h at
rt. The solvent was removed in vacuo to give the crude product.
Purification by column chromatography (pentane/Et2O; 20/1)
afforded the product 16 (30 mg, 41%) as white crystalline solid:
1378, 1112, 1069, 1004, 895; NMR δH (400 MHz, CDCl3, 298 K)
4.72 (1H, app t, J = 1.4 Hz), 4.71 (1H, d, J = 0.81 Hz), 2.17-
2.10 (2H, m), 2.00-1.92 (1H, m), 1.85-1.75 (2H, m), 1.74-1.67
(4H, m), 1.64-1.50 (3H, m); NMR δC (100 MHz, CDCl3, 298 K)
149.0 (C), 109.0 (CH2), 98.1 (C), 71.8 (C), 41.5 (CH2), 41.1 (CH),
33.0 (CH2), 26.7 (CH2), 26.0 (CH2), 21.2 (CH3); NMR δC (100
MHz, CD3OD, 298 K) 150.7 (C), 109.1 (CH2), 98.9 (C), 72.8 (C),
42.4 (CH), 41.9 (CH2), 34.1 (CH2), 27.5 (CH2), 27.3 (CH2), 21.1
(CH3); MS m/z (ESþ) 357.2034 (M þ Na C20H30NaO4 requires
357.2036). These data are in agreement with those previously
reported in the isolation paper of cymbodiacetal (1) except for
the peak originally reported at 75.5 ppm in the 13C NMR
(CDCl3).1 We record this peak at 71.8 ppm and attribute the
discrepancy to a typographical error in the original work. The
13C NMR data that we obtained for 1 in CD3OD matched that
reported for the previously reported synthetic sample.2 The data
obtained for the bis-acetal 9 were identical to those recorded
previously in this work.
mp 192-195 °C; [R]24 þ58.5 (c 1.30 CHCl3); IR νmax/cm-1
D
(CHCl3) 3532, 3086, 2991, 2939, 2860, 2216, 2129, 2070, 1710,
1643, 1454, 1361, 1300, 1168, 1115, 1091, 1069, 987; NMR δH
(400 MHz, CDCl3, 298 K) 4.70 (2H, s), 2.06-2.00 (1H, m),
1.97-1.87 (1H, m), 1.85-1.76 (1H, m), 1.73 (3H, s), 1.71-1.67
(1H, m), 1.66-1.58 (1H, m), 1.56-1.48 (3H, m), 1.43 (1H, dd,
J = 13.5, 12.8 Hz); δD (61.4 MHz; CDCl3) 3.24 (OCD3);NMRδC
(100 MHz, CDCl3, 298 K) 149.5 (C), 108.5 (CH2), 100.4 (C), 71.9
(C), 40.6 (CH), 34.0 (CH2), 32.8 (CH2), 27.0 (CH2), 26.4 (CH2),
21.2 (CH3); MS m/z (ESþ) 391.2734 (M þ Na C22H28D6NaO4
requires 391.2726).
Acknowledgment. We thank the HEC (Pakistan) for pro-
viding a Scholarship (to M.U.) and also AstraZeneca and
Pfizer for providing additional financial support of this work.
(þ)-Cymbodiacetal Dimethyl Acetal (17). Spirochroman (2)
(50 mg, 0.16 mmol) was dissolved in CH2Cl2 (1.00 mL) and
cooled to 0 °C, m-CPBA (39 mg of 70 wt %, 0.16 mmol) was
added in one portion, and the resulting solution was stirred at
Supporting Information Available: 1H and 13C NMR spec-
tra of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
8470 J. Org. Chem. Vol. 75, No. 24, 2010