Intramolecular [4 + 3] cycloadditions - Stereochemical issues in the cycloaddition reactions of cyclopentenyl cations - A synthesis of (+)-dactylol

Article abstract of DOI:10.1139/V06-122

Five cyclopentanones were prepared for the purpose of examining the effects of stereogenic centers on the course of the intramolecular [4 + 3] cycloaddition reactions of cyclopentenyl cations. One substrate reacted with very high levels of diastereoselect

Full text of DOI:10.1139/V06-122

1456
Intramolecular [4 + 3] cycloadditions —
Stereochemical issues in the cycloaddition
reactions of cyclopentenyl cations — A synthesis
of (+)-dactylol1
Michael Harmata, Paitoon Rashatasakhon, and Charles L. Barnes
Abstract: Five cyclopentanones were prepared for the purpose of examining the effects of stereogenic centers on the
course of the intramolecular [4 + 3] cycloaddition reactions of cyclopentenyl cations. One substrate reacted with very
high levels of diastereoselectivity and was converted to (+)-dactylol. The cyclopentenone without stereogenic centers on
the tether or the five-membered ring gave two cycloadducts, the endo isomer being only slightly favored over the exo.
Other substrates reacted with generally good to poor stereoselectivity. An epimer of the substrate leading to (+)-
dactylol afforded all possible isomers of the cycloadduct with relatively poor stereoselectivity.
Key words: cycloaddition, total synthesis, dactylol.
Résumé : On a préparé cinq cyclopentanones dans le but d’examiner les effets des centres stéréogènes sur le cours des
réactions de cycloaddition [4 + 3] intramoléculaires des cations cyclopentényles. Un substrat réagit avec des degrés éle-
vés de diastéréosélectivité et conduit à la formation du (+)-dactylol. La cyclopenténone sans centres stéréogènes sur la
chaîne latérale ou sur le cycle à cinq chaînons conduit à la formation de deux cycloadduits dans lesquels l’isomère
endo est légèrement favorisé par rapport à l’isomère exo. D’autres substrats réagissent avec des stéréosélectivités qui
vont généralement de bonnes à mauvaises. Un épimère du substrat qui conduit au (+)-dactylol a permis d’isoler tous
les isomères possibles du cycloadduit avec une stéréosélectivité relativement faible.
Mots clés : cycloaddition, synthèse totale, dactylol.
[Traduit par la Rédaction] Harmata et al. 1469
Introduction
Results and discussion
The intramolecular [4 + 3] cycloaddition reaction of al-
lylic cations and dienes has been shown to be a powerful
route to polycyclic compounds (1). One variation on this
theme involves the use of cyclic cations in the cycloaddition
reaction. Appropriate modifications of the cycloadducts
from such reactions can then provide useful routes to natural
products (2). We and others realized the potential for this
process in the context of the synthesis of cyclooctanoids (3).
We recently reported a total synthesis of (+)-dactylol based
on this chemistry (2c). This report is a more detailed
description of that work, including studies to evaluate the ef-
fects of various stereocenters on the course of the cyclo-
addition reaction.
Diene synthesis
The basic approach for the preparation of substrates for
this study consisted of the alkylation of cyclopentanone
enolates with diene-containing electrophiles. The synthesis
of the dienes used is shown in Scheme 1. Treatment of 1a–
1c with TMSCH2MgCl–CeCl3 followed by iodide formation
afforded 3a–3c in excellent yields (4, 5).
Ester 1a was prepared by a literature procedure (6). Esters
1b and 1c were prepared as shown in Scheme 2. Protection
of 1,4-butanediol with allyl bromide followed by oxidation
gave the acid 5 in 69% yield from 4. Oxazolidinones were
formed from 5 in standard fashion and alkylated with high
stereoselectivity and in good yields to afford 6b and 6c. Re-
duction with LAH gave the alcohols 7b and 7c in excellent
yields. Swern oxidation, Wittig homologation, and deprotection
(7) afforded esters 1b and 1c in 81% and 77% yields, re-
spectively.
Received 1 September 2005. Accepted 4 December 2005.
Published on the NRC Research Press Web site at
http://canjchem.nrc.ca on 8 November 2006.
M. Harmata,2 P. Rashatasakhon, and C.L. Barnes.
Department of Chemistry, University of Missouri-Columbia,
Columbia, MO 65211, USA.
Preparation of cycloaddition substrates
Cycloaddition substrates were easily prepared by
alkylation. For example, the reaction of 8 with potassium
carbonate in the presence of 3a afforded the alkylation prod-
uct 9 in good yield. This was converted to the ketone 11 in
66% yield via reaction with potassium cyanide in hot DMSO
1This article is part of a Special Issue dedicated to Dr. Alfred
Bader.
2Corresponding author (e-mail: harmatam@missouri.edu).
Can. J. Chem. 84: 1456–1469 (2006)
doi:10.1139/V06-122
© 2006 NRC Canada

Harmata et al.
1457
Scheme 1.
Scheme 3.
O
TMSCH2MgCl
CeCl3
HO
COOMe
COOMe
O
HO
CH2TMS
R2 R3
R2 R3
K2CO3, acetone
COOMe
3a or 3b
R
2a: R2 = H, R3 = H, 82%
: R2 = H, R3 = H
1a
8
: R2 = H, R3 = Me, 78%
1b: R2 = H, R3 = Me
1c: R2 = Me, R3 = H
2b
2
: R = Me, R3 = H, 75%
2c
CH2TMS
: R=H, 86%
10: R=Me,88%
9
O
DCC-MeI
I
CH2TMS
R2 R3
KCN, DMSO
H2O, heat
11
: R=H, 66%
12: R=Me, 83%
R
: R2 = H, R3 = H, 94%
3a
: R2 = H, R3 = Me, 98%
3b
3c: R2 = Me, R3 = H, 94%
CH2TMS
Scheme 2.
Scheme 4.
1. NaH, CH2CHCH2Br
O
OH
HO
2. Jones
69%
O
MeOOC
4
1. NaH
2. n-BuLi
COOMe
R1
O
COOH
LAH
R2
Me
3. 3a or 3b or 3c
5
Me
13
O
CH2TMS
O
1. (COCl)2
R1
14: R1 = H, R2 = H, 67%
R2 R3
2. n-BuLi, oxazolidinone
15: R1 = Me, R2 = H, 70%
16: R1= H, R2 = Me, 79%
3. NaHMDS, MeI
O
6b: R1
=
=
, R2 = H,
O
N
O
79%
77%
R
3 = Me
17: R1 = H, R2 = H, 78%
18: R1 = Me, R2 = H, 94%
19: R1= H, R2 = Me, 74%
Me
Ph
KCN, DMSO
H2O, heat
R1
O
R2
Me
6c: R1
, R2 = Me,
N
O
R
3 = H
CH2TMS
Me
Ph
O
1. Swern
2. Ph3PCHCO2Me
3. Pd/C, TsOH, MeOH
Scheme 5.
OH
R2 R3
Me
Me
: R2 = H, R3 = Me, 92%
7b
7c
: R2 = Me, R3 = H, 88%
1. LDA, TfCl
C
O
O
2. TEA: TFE/Et2O
3. TsOH
HO
COOMe
H
R2 R3
Me
Me
74%
20
1b: R2 = H, R3 = Me, 81%
18
TMS
: R2 = Me, R3 = H, 77%
1c
Me
Me
+
(8). Ketone 12 was prepared in a similar fashion in 73%
overall yield (Scheme 3).
The ketoester 13 was readily prepared from (R)-pulegone
by a known procedure (9). Dianion formation followed by
alkylation and decarboalkoxylation afforded cycloaddition
substrates 17–19, as shown in Scheme 4.
CH2TMS
21 O _
could be carried out at this stage, we found that some
desilylation and double bond migration occurred during the
chromatography on silica gel.
Therefore, the crude product was subsequently treated
with tosic acid to give rise to alkene 20 as a 25:1 mixture of
isomers in 74% yield for the three steps. The diastereomeric
ratio was determined by GC and integration of the olefinic
The synthesis of (+)-dactylol
We begin with the synthesis of dactylol, since that was in-
deed the first cycloaddition in this series that we examined.
Treatment of 18 with Lithium diisopropylamide (LDA) and
reacting the resultant enolate with triflyl chloride gave an α-
chloroketone. This was not characterized but immediately
subjected to typical cycloaddition conditions: stirring at
–78 °C to room temperature in a 1:1 mixture of ether and
trifluoroethanol in the presence of 3 equiv. of triethylamine
(Scheme 5). Even though the purification of the cycloadduct
1
region of the H NMR of a crude product mixture. The mi-
nor isomer has not been characterized. The rationalization
for the favorable stereochemical outcome is depicted in
structure 21. We anticipated that the diene would approach
the dienophile in an endo fashion on the less-hindered face
of the dienophile. In addition, the methyl group on the tether
© 2006 NRC Canada

1458
Can. J. Chem. Vol. 84, 2006
Scheme 6.
Me
Me
Me
Me
CH2I2, Et2Zn
95%
C
O
MMPP
O C
O
C
O
O
+
C
O
DMF, 84%
H
H
H
Me
Me
Me
H
4:1
Me
20
24
23
22
Me
O
O
Me
Me
Me
Me
Me
1. Separate
2. H2/PtO2, 98%
OH
OR
1. Tebbe
2. HCl
60%
Protect (OH)
C
O
O
H
Me
Me
H
H
Me
Me
Me
Me
25
Me
Me
MMPP
26
27: R = Bn, 41%
28: R = TBS, 88%
Me
AcO
H
OR
Baeyer–Villiger
X
29: R = Bn
30
: R = TBS
Me
Me
Me
Scheme 7.
O
Me
O
Me
Me
HO
Me
MeO
Me
OH
OH
PhSeNa (51%)
OR
Tf2O
pyridine
90%
CH2N2
ether
C
O
O
KOH, MeOH, reflux
H
H
H
Me
Me
Me
Me
Me
Me
Me
3 steps
31
25
32
O
Me
O
O
MeO
Me
Me
Me
Me
MeO
Me
MeO
[1,5]
H
H
Me
Me
Me
Me
33
Me
Me
35
34
would occupy a pseudoequatorial orientation on the puck-
ered, incipient five-membered ring with the diene oriented
so as to minimize gauche interactions.
hydroxy group could be protected with either a benzyl or
TBS group. We anticipated that a Baeyer–Villiger oxidation
of either of these species would afford the corresponding ac-
etate 29 or 30.4 Unfortunately, no reaction occurred between
either 27 or 28 and MMPP, m-CPBA, or TFAA-H2O2 after a
24 h period at room temperature. Treatment of 26 with
MMPP afforded lactone 25 (10). We also attempted a reac-
tion between lactone 25 and sodium phenylselenide and ex-
pected to obtain a system suitable for further elaboration to
(+)-dactylol. However, the hydroxy acid 31 was obtained as
the sole product in 51% yield, via an apparent hydrolysis re-
action. Even though this result was not satisfactory, it
proved the existence and stability of the hydroxycarboxylic
acid 31, which became significant.
Thus, the next sequence to (+)-dactylol began with a hy-
drolysis of lactone 25 using KOH in refluxing aqueous
methanol and esterification of the corresponding hydroxy
acid with diazomethane (Scheme 7). The next challenging
step was the introduction of the double bond in dactylol by
dehydration of 32. Regioselectivity was a problem, as were
side reactions. For example, treatment of 32 with POCl3 in
pyridine, Tf2O in pyridine, or Martin’s sulfurane resulted in
The next stage of the synthesis is shown in Scheme 6.
Simmons–Smith cyclopropanation of 20 produced 22 in
95% yield. The Baeyer–Villiger reaction of 22 with MMPP
in DMF afforded a 4:1 mixture of two regioisomers after pu-
rification. Surprisingly, the major product was that resulting
from the migration of the less substituted carbon atom. At-
tempts to alter the regioselectivity using a variety of reaction
conditions were unsuccessful, as some reagents gave higher
regioselectivity but lower yields of the products.3 Studies we
have conducted suggest that the methyl substituent on the
five-membered ring has a major, but not exclusive, influence
on the regiochemistry of the reaction (10). The major isomer
23 was separated, and the cyclopropane ring was cleaved by
hydrogenolysis to afford 25 in 98% yield. The structure and
relative stereochemistry were established by X-ray crystal-
lography.
Our first attempt to convert 25 into dactylol began with a
methylenation reaction using Tebbe’s reagent (11). Hydroly-
sis of the resultant enol ether afforded the ketone 26, whose
3 Reagent, ratio 23:24, solvent, temperature, time, yield: (a) m-CPBA–NaHCO3, 6:1, CH2Cl2, RT, 5 d, 67%; (b) TFAA–H2O2, 5:1, CH2Cl2, 0
°C – RT, 3 d, 36%; (c) m-CPBA–TFA, 4:1, CH2Cl2, 0 °C–rt, 48 h, 53%; (d) peracetic acid – NaOAc, 9:1, AcOH, RT, 48 h, 31%;
(e) MMPP, 4:1, DMF, RT, 48 h, 84%.
4 Without protection of the alcohol group, the Baeyer–Villiger reaction proceeded by an unexpected course. See ref. 10.
© 2006 NRC Canada

Harmata et al.
1459
Scheme 8.
Scheme 9.
O
Me
Me
MeO
HO2C
OH
1. POCl3, HMPA,
pyridine
1. LDA, TfCl, –78 o
2. TEA; TFE/Et2O
3. TsOH, CH2Cl2
65%, 2.2:1
C
O
C
O
C
O
+
2. KOH
H
H
Me
Me
Me
Me
H
H
Me
Me
88%
32
36
38
11
39
CH2TMS
Me
HO
1. COCl2, DMF
2. mCPBA, pyridine/DMAP
3. LAH, Et2O
Scheme 10.
H
Me
Me
50%
Me
1. LDA, TfCl
37: (+)-Dactylol
C
O
C
O
O
+
2. TEA; TFE/Et2O
H
H
40
Me
Me
42
41
Me
the formation of a compound identified as 35. Presumably,
these reagents induced cation formation, which was fol-
lowed by a 1,5-transannular hydride shift to form 34, and
subsequent elimination to give tetra-substituted alkene 35,
whose structure was determined based on spectroscopic and
diastereoselectivity in favor of the endo product (3b). This
was indeed the case.
1
analytical data. The H NMR spectrum showed no signal for
The ketone 11 was treated with LDA and TfCl to furnish
the corresponding α-chloroketone, which was subjected to
the [4 + 3] cycloaddition and desilylation reactions
(Scheme 9). Two diastereomeric cycloadducts (38 and 39)
were obtained in 65% yield in a ratio of 2.2:1. The product
ratio was determined by gas chromatographic analysis and
olefinic protons. The most downfield peak appeared at
3.59 ppm as a singlet, which corresponded to the methyl es-
ter. There was also a singlet peak that integrated for three
protons at 1.65 ppm, suggesting the presence of a methyl
substituent on an olefin. The 13C NMR spectrum confirmed
the existence of ester and alkene (δ: 177.3, 136.9, 134.7).
By taking advantage of the dehydration procedure devel-
oped by Trost and Jungheim (12), we were able to overcome
this problem (Scheme 8). Phosphorus oxychloride (POCl3)
was added to a solution of 32 in HMPA with slow heating
from room temperature to 50 °C. After the white precipitate
that formed dissolved, pyridine was added and heating was
continued to 100 °C at which point the dehydration was
complete. Subsequent hydrolysis of the sterically hindered
methyl ester group using KOH in DMSO provided 36 as a
1
integration of the crude product H NMR spectrum. After
purification by flash chromatography on silica gel, the major
product was treated with excess NH2OH·HCl and KOH in
refluxing ethanol to form an oxime derivative. Recrystalliza-
tion of this oxime from hexane and EtOAc afforded crystals
of suitable quality for single crystal X-ray crystallographic
analysis. Thus, the major product was assigned as the endo
isomer 38. It should be noted that cycloadditions of this type
appear to take place under kinetic control.
We have examined simple diastereoselectivity computa-
tionally for the conversion of 40 to 41 and 42. We found that
while the lowest energy transition state corresponds to the
endo product 41, other transition state structures that lead to
the exo product are close in energy, and thus, for unsub-
stituted systems at least, simple diastereoselectivity should
not ever be expected to be substantial (Scheme 10) (16).
It is interesting to note that West and co-workers (3a)
have reported very high simple diastereoselectivity in the
formation of 44 via a domino Nazarov – [4 + 3] cyclo-
addition process as shown in Scheme 11. It is clear that
many new features of this aspect of the intramolecular [4 +
3] cycloaddition reaction of cyclopentenyl cations remain to
be uncovered.
1
single product (based on crude H NMR) in 84% yield. At
this point, we found that typical acid chloride formation pro-
cedures failed to give the acid chloride of the hindered acid
36.5 However, upon treatment with DMF and phosgene in
refluxing toluene, 36 was cleanly converted to the corre-
sponding acid chloride (13). In a benzene solution contain-
ing pyridine and DMAP, this acid chloride reacted with
mCPBA to form a mixed anhydride, which rearranged upon
stirring for 24 h at room temperature to a mixed carbonate
with retention of configuration (14). Reduction of the mixed
carbonate with LAH then afforded (+)-dactylol in 50% over-
all yield from 36. The spectral, analytical, and optical rota-
tion data were consistent with those reported in the literature
(15).
Relative stereoselection I — Cycloaddition of 12
The introduction of a stereogenic center in the tether join-
ing the diene and dienophile in these reactions introduces a
new complication. Our goal in pursuing the cycloaddition of
12 was essentially to discover the impact of the stereocenter
on the course of the reaction in an effort to elucidate which
of the stereocenters in 18 had a more profound impact on the
stereochemical outcome on that compound’s cycloaddition.
Simple diastereoselectivity
After the successful synthesis of (+)-dactylol, we decided
to examine the influence of all stereocenters on the course of
the reaction. First, however, we looked at simple diastereo-
selectivity. Past experience suggested that the intramolecular
[4 + 3] cycloaddition reaction of cyclopentenyl cations with
tethered butadienes would proceed with only a slight simple
5 For example, stirring the solution of 36 in hexane with 3 equiv. of oxalyl chloride or heating a hexane solution of 36 with excess thionyl
chloride resulted in no change.
© 2006 NRC Canada

1460
Can. J. Chem. Vol. 84, 2006
Scheme 11.
Scheme 14.
Me
Me
Me
Me
Me
FeCl3
CH2Cl2, –30 oC, 67%
C
O
1. LDA, TfCl, –78 o
C
Me
O
C
O
+
43
2. TEA; TFE/Et2O
3. TsOH, CH2Cl2
52%
O
44
H
Scheme 12.
49
7.8:2.1:1.7:1.0
49–50–51–52
17
CH2TMS
Me
1. LDA, TfCl, – C
78 o
C
O
O
C
O
+
2. TEA; TFE/Et2O
3. TsOH, CH2Cl2
66%, 5.5:1
Me
Me
H
H
Me
Me
Me
C
O
C
O
45
46
C
O
+
+
12
CH2TMS
H
H
H
52
51
50
Scheme 13.
CH2TMS
OH
Scheme 15.
Tf2O, CH2Cl2
2,6-lutidine,–78 o
82%
Me
C
Me
H3C
H3C
48
47
1. LDA, TfCl, –78 oC
2. TEA; TFE/Et2O
3. TsOH, CH2Cl2
71%
C
O
+
O
H
Me
Cycloaddition of 12 afforded four products, only two of
which, 45 and 46, could be cleanly isolated (Scheme 12).
Gas chromatographic analysis of the crude reaction mixture
indicated a product ratio of 47.2(45):8.1(46):1:2.3. The ma-
jor product of the reaction was 45, as expected on the basis
of the small but real endo preference observed in these sys-
tems and a report by Giguere and co-workers (17) on rela-
Me
53
19
1.3:4.4:2.0:1.0
53 54 55 56
CH2TMS
–
–
–
Me
Me
Me
C
O
C
O
C
O
+
+
tive diastereoselection in intramolecular [4
+
3]
H
H
H
Me
Me
cycloadditions. In that paper, Giguere and co-workers (17)
reported that treatment of 47 with triflic anhydride afforded
cycloadduct 48 as the major product of the reaction
(Scheme 13). Regardless of the mechanistic basis for the
outcome, one could assume that stereogenic centers adjacent
to dienes would produce similar stereochemical outcomes in
other intramolecular [4 + 3] cycloaddition reactions. This is
what is observed in the formation of 45 and 46. The struc-
ture of both compounds was established by X-ray analysis of
the corresponding oximes.6
Me
54
55
56
products were those derived from the transition states having
the diene approaching from the opposite side of the methyl
group on the stereogenic center. However, the level of facial
selectivity in this reaction was approximately 3:1, while the
endo–exo ratio was 3.4:1. The low level of facial selectivity
is surprising, but larger substituents at the stereogenic cen-
ters should produce a better result.
Relative stereoselection II — Cycloaddition of 17
The cycloaddition reaction of 17 was anticipated to be
reasonably selective. Endo–exo selectivity was not expected
to be high but facial selectivity was expected to be reason-
able, the diene approaching the less hindered face of the
dienophile (i.e., on the face opposite the methyl substituent).
There is a reasonable amount of precedent for this in the lit-
erature (18).
Surprisingly, the reaction produced all four possible iso-
meric products (49–52) in 52% yield overall from ketone 17
(Scheme 14). Gas chromatographic analysis of the crude
product mixture suggested that the products were formed in
a ratio of 7.8:2.1:1.7:1.0. They were separated by flash chro-
matography on silica gel and individually transformed into
their oxime derivatives. Consistent with other data, the major
Cycloaddition of 19 — The mismatched case
The last [4 + 3] cycloaddition in this study was the reac-
tion of ketone 19. Since the stereogenic center on the cyclo-
pentanone remained the same (R) while the one on diene
was switched from (R) to (S) compared with ketone 18, we
expected to see the diastereomer of 20 formed as the major
isomer. In fact, the reaction produced all four isomers of
cycloadduct (53–56) in 71% yield in
a
ratio of
1.3:4.4:2.0:1.0 (Scheme 15). Each product was purified,
characterized, and converted into an oxime derivative, and
the stereochemical assignment was made using X-ray crys-
tallography. The major isomer (54) derived from a transition
state having an endo approach of the diene with a tether con-
formation that minimized gauche interactions. However, at-
6 The oxime derived from 46 gave poor quality X-ray data. Finding a suitable crystal was problematic and the one found turned out to be
racemic, in spite of the fact that the bulk sample was clearly enantiomerically enriched based on optical rotation data. However, the data
were sufficient to establish the relative stereochemistry.
© 2006 NRC Canada

Harmata et al.
1461
tack occurred on what appears to be the more sterically
hindered face of the oxyallylic cation intermediate.
Surprisingly, the overall facial selectivity in this case,
(53 + 55):(54 + 56), was 1:1.6 in favor of the products de-
rived from the approach of the diene to the more hindered
face of the cyclopentanone. The endo–exo ratio, (53 +
54):(55 + 56) was 1.9:1 in favor of endo products. The rela-
tive stereoselectivity (53 + 56):(54 + 55) was 1:2.8 in favor
of the products having a cis relationship between the angular
hydrogen and the methyl group on the newly formed five-
membered ring.
magnesium sulfate, filtered, and the solvents were removed
by rotavap. The crude product was purified by flash chroma-
tography (hexane–EtOAc, 4:1).
6-Trimethylsilylmethyl-hepta-4,6-dien-1-ol (2a)
Yield: 82%, colorless oil. IR (neat, cm–1): 3353 (ms),
1
2947 (s), 1252 (s), 859 (s). H NMR (250 MHz, CDCl3) δ:
6.09 (d, J = 15.6 Hz, 1H), 5.58 (dt, J = 7.0, 15.6 Hz, 1H),
4.78 (d, J = 1.5 Hz, 1H), 4.66 (s, 1H), 3.68–3.61 (m, 2H),
2.18 (q, J = 7.3 Hz, 1H), 1.77 (br t, J = 4.5 Hz, 1H), 1.72–
1.61 (m, 2H), 1.69 (s, 2H), 0.00 (s, 9H). 13C NMR
(62.9 MHz, CDCl3) δ: 143.7, 133.6, 129.7, 112.0, 62.3, 32.3,
29.0, 22.1, –1.2. HR-MS (EI) calcd. for C11H20OSi (M+):
198.1440; found: 198.1438.
Conclusion
The intramolecular [4 + 3] cycloaddition of cyclopentenyl
cations to dienes is a useful route to cyclooctanoids. High
levels of stereocontrol in this reaction are possible, but it is
clear that effects that might appear to be cooperative need
not be and that further studies of these cycloadditions will be
necessary to achieve results that are more generally suitable
for applications in synthesis. This conclusion is true for acy-
clic dienes tethered to cyclopentenyl cations. High levels of
simple diastereoselection are possible with tethered furans
(3). Whether this inherent selectivity can be used to produce
high levels of relative stereocontrol remains to be seen. We
plan to perform further work to solve the problems that exist
and continue to apply the methodology to the synthesis of
cyclooctanoids. Further results will be reported in due
course.7
(3R)-Methyl-6-trimethylsilylmethyl-hepta-4,6-dien-1-ol
(2b)
Yield: 78%, colorless oil. [α]20D –24.42 (c 1.0, CHCl3). IR
(neat, cm–1): 3334 (m), 2957 (s), 2929 (m), 2898 (m), 1596
(w), 1422 (w), 1250 (m), 1157 (m), 1054 (m), 967 (m), 853
1
(s). H NMR (300 MHz, CDCl3) δ: 6.07 (d, J = 15.7 Hz,
1H), 5.45 (dd, J = 8.3, 11.3 Hz, 1H), 4.80 (d, J = 1.9, 1H),
4.68 (s, 1H), 3.66 (br s, 1H), 2.37 (sept, J = 7.1 Hz, 1H),
1.70 (s, 2H), 1.66–1.35 (m, 2H), 1.35 (br s, 1H), 1.05 (d, J =
6.7 Hz, 3H), 0.00 (s, 9H). 13C NMR (75 MHz, CDCl3) δ:
143.7, 135.7, 132.0, 112.3, 61.2, 39.8, 34.0, 22.1, 21.0, –1.2.
Anal. calcd. for C12H24O3Si: C 67.86, H 11.39; found: C
67.92, H 11.47.
(3S)-Methyl-6-trimethylsilylmethyl-hepta-4,6-dien-1-ol (2c)
Yield: 75%, colorless oil. [α]20D +26.67 (c 1.0, CHCl3). IR
(neat, cm–1): 3378 (s), 2957 (s), 2877 (s), 1459 (m), 1420
(m), 1380 (m), 1254 (s), 1055 (s), 853 (s). 1H NMR
(300 MHz, CDCl3) δ: 6.07 (d, J = 15.7 Hz, 1H), 5.45 (dd,
J = 8.3, 11.3 Hz, 1H), 4.80 (d, J = 1.9, 1H), 4.68 (s, 1H),
3.66 (br s, 1H), 2.37 (sept, J = 7.1 Hz, 1H), 1.70 (s, 2H),
1.66–1.35 (m, 2H), 1.35 (br s, 1H), 1.05 (d, J = 6.7 Hz, 3H),
0.00 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 143.7, 135.7,
132.0, 112.3, 61.2, 39.8, 34.0, 22.1, 21.0, –1.2. HR-MS (EI)
calcd. for C12H24OSi (M+): 212.1596; found: 212.1610.
Experimental
General procedure for Peterson olefination: synthesis of
2a–2c
A 500 mL round-bottomed flask was charged with pow-
dered cerium(III) chloride heptahydrate (CeCl3-7H2O,
13.02 g, 34.96 mmol). The flask was immersed in an oil
bath and evacuated to a full vacuum (about 0.1 mmHg
(1 mmHg = 133.322 4)). The solid was magnetically stirred
as the flask was heated at 150 °C for 2 h. After the flask was
cooled to room temperature, it was vented to the atmosphere
and quickly purged with a steam of argon for 30 s. The flask
was capped with a rubber septum and 60 mL of THF was
added. The white suspension was stirred at room tempera-
ture for 1 h, cooled to –78 °C in a dry ice – 2-propanol bath,
and a 1 mol/L solution of trimethylsilylmethylmagnesium
chloride (35 mL, 35 mmol) was added over a period of
15 min. After the cold mixture was stirred for an additional
15 min, 9.99 mmol of 1a, 1b, or 1c was added dropwise and
the mixture was allowed to warm slowly to room tempera-
ture over a period of 3 h. The reaction was quenched with
ice-cold 1 mol/L HCl (60 mL) and stirred for 5 min. The
layers were separated, and the aqueous phase was extracted
with ether. The combined organic layers were washed with
saturated sodium bicarbonate solution (100 mL), dried over
General procedure for conversion of alcohols to iodides:
synthesis of 3a–3c
To a solution of 2a, 2b, or 2c (4.70 mmol) in THF
(47 mL) was added 9.42 mmol of DCC-MeI salt. The mix-
ture was stirred in an oil bath at 35 °C for 6 h. The solvent
was removed under reduced pressure, and the crude product
was purified by flash chromatography (100% hexane). Due
to the instability of the products, the characterizations were
performed by NMR and IR only.
(7-Iodo-2-methylene-hept-3-enyl)-trimethylsilane (3a)
Yield: 94%, colorless oil. IR (neat, cm–1): 3078 (w), 2945
(s), 2896 (s), 1597 (m), 1423 (m), 1241 (m), 1155 (s), 967
1
(m), 846 (s). H NMR (250 MHz, CDCl3) δ: 6.12 (d, J =
15.7 Hz, 1H), 5.51 (dt, J = 7.0, 15.6 Hz, 1H), 4.81 (d, J =
7 Supplementary data for this article are available on the journal Web site (http://canjchem.nrc.ca) or may be purchased from the Depository
of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 5104. For more
information on obtaining material refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml. CCDC 282839–282845 and 282856 contain the
crystallographic data for this manuscript. These data can be obtained, free of charge, via http://www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax +44 1223 336033; or de-
posit@ccdc.cam.ac.uk).
© 2006 NRC Canada

1462
Can. J. Chem. Vol. 84, 2006
2.0 Hz, 1H), 4.69 (s, 1H), 3.19 (t, J = 6.9 Hz, 2H), 2.21 (q,
J = 7.0 Hz, 2H), 1.92 (quint, J = 7.0 Hz, 2H), 1.69 (d, J =
0.7 Hz, 2H), –0.48 (s, 9H). 13C NMR (62.9 MHz, CDCl3) δ:
143.6, 134.6, 128.0, 112.5, 33.3, 33.1, 22.1, 6.3, –1.2.
and the mixture was stirred at room temperature for 3 h.
Volatile compounds were removed under reduced pressure,
and the crude product was used in the next step without fur-
ther purification. A solution of (4R)-methyl-(5S)-phenyl-
oxazolidin-2-one or (4S)-methyl-(5R)-phenyl-oxazolidin-2-
one (16.89 g, 95.31 mmol) in dried THF (320 mL) was
cooled to –78 °C and 2.2 mol/L n-BuLi (43.3 mL,
95.31 mmol) was added dropwise. After the addition of
n-BuLi, 4-(2-propenyloxy)butanoyl chloride (18.6 g,
114.38 mmol) was added in one portion. The reaction flask
was moved into an ice-water bath and stirred for 30 min.
The reaction was quenched with 1 mol/L K2CO3 (200 mL)
and extracted with EtOAc. The combined organic phases
were dried over MgSO4, filtered, and concentrated. The
crude product was purified by flash chromatography
(hexane–EtOAc, 4:1) on silica gel.
(7-Iodo-(5R)-methyl-2-methylene-hept-3-enyl)-trimethyl-
silane (3b)
Yield: 98%, colorless oil. [α]20D –43.94 (c 1.0, CHCl3). IR
(neat, cm–1): 3078 (w), 2955 (s), 2927 (m), 2897 (m), 1597
1
(m), 1422 (m), 1249 (s), 1158 (m), 969 (m), 851 (s). H
NMR (300 MHz, CDCl3) δ: 6.12 (d, J = 15.7 Hz, 1H), 5.35
(dd, J = 8.4, 15.6 Hz, 1H), 4.84 (d, J = 1.9 Hz, 1H), 4.71 (s,
1H), 3.23–3.09 (m, 2H), 2.35 (sept, J = 6.8 Hz, 1H), 1.90–
1.80 (m, 2H), 1.70 (s, 2H), 1.05 (d, J = 6.7 Hz, 3H), 0.01 (s,
9H). 13C NMR (75 MHz, CDCl3) δ: 143.5, 134.0, 132.9,
112.7, 40.6, 38.0, 22.1, 20.3, 4.9, –1.2.
(7-Iodo-(5R)-methyl-2-methylene-hept-3-enyl)-trimethyl
silane (3c)
(4R)-Methyl-(5S)-phenyl-3-(4-propenyloxy)butanoyl-
oxazolidin-2-one
Yield: 94%, colorless oil. [α]20D +39.71 (c 1.0, CHCl3). IR
Yield: 94%, colorless oil. [α]20D +41.72 (c 1.0, CHCl3). IR
(neat, cm–1): 3072 (w), 2932 (m), 2860 (m), 1783 (s), 1702
(s), 1455 (m), 1349 (s), 1198 (s), 1120 (m). 1H NMR
(300 MHz, CDCl3) δ: 7.45–7.29 (m, 5H), 5.98–5.85 (m,
1H), 5.66 (d, J = 7.30 Hz, 1H), 5.28 (dq, J = 17.2, 1.5 Hz,
1H), 5.17 (dq, J = 10.4, 1.5 Hz, 1H), 4.76 (quint, J = 6.8 Hz,
1H), 3.97 (dm, J = 5.5 Hz, 2H), 3.52 (t, J = 6.3 Hz, 2H),
3.14–2.97 (m, 2H), 1.99 (sept, J = 7.1 Hz, 2H), 0.89 (d, J =
6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ: 172.7, 153.0,
134.8, 133.3, 128.7, 128.6, 125.6, 116.8, 78.9, 71.7, 69.1,
54.7, 32.5, 24.4, 14.5. Anal. calcd. for C17H21NO4: C 67.31,
H 6.98; found: C 67.55, H 6.81.
(neat, cm–1): 3079 (w), 2952 (s), 2927 (m), 2887 (m), 1594
(m), 1421 (m), 1252 (s), 1160 (m), 970 (m), 853 (s). H
1
NMR (300 MHz, CDCl3) δ: 6.12 (d, J = 15.7 Hz, 1H), 5.35
(dd, J = 8.4, 15.6 Hz, 1H), 4.84 (d, J = 1.9 Hz, 1H), 4.71 (s,
1H), 3.23–3.09 (m, 2H), 2.35 (sept, J = 6.8 Hz, 1H), 1.90–
1.80 (m, 2H), 1.70 (s, 2H), 1.05 (d, J = 6.7 Hz, 3H), 0.01 (s,
9H). 13C NMR (75 MHz, CDCl3) δ: 143.6, 134.0, 132.9,
112.7, 40.6, 38.0, 22.1, 20.3, 4.9, –1.2.
4-(2-Propenyloxy)-butanoic acid (5)
To a solution of 1,4-butanediol (54.0 g, 600 mmol) in dry
DMF (400 mL) was added 60% NaH (5.76 g, 240 mmol)
portionwise while the solution was stirred in an ice-water
bath. After the addition of NaH, the reaction flask was re-
moved from the bath. The mixture was stirred at room tem-
perature for 30 min and cooled in the ice-water bath again.
Allyl bromide (17.3 mL, 200 mmol) was added dropwise,
and the mixture stirred for 1 h. The reaction was quenched
with water (500 mL) and extracted with EtOAc. The organic
phase was concentrated on a rotatory evaporator, and the res-
idue dissolved in acetone (400 mL). The solution was cooled
in the ice bath and Jones reagent (prepared from 133.6 g of
CrO3, 115 mL of H2SO4, and 350 mL of H2O) was added
dropwise with stirring until a red color persisted (approxi-
mately 70 mL of Jones reagent was used). Volatile solvents
were removed under reduced pressure. The residue was di-
luted with water and extracted with EtOAc. The combined
organic phases were washed with saturated NaHCO3 solu-
tion (300 mL × 2), and the organic layer was discarded. The
aqueous phase was acidified by addition of 6 mol/L HCl un-
til pH ≤ 4, and extracted with ether (100 mL × 3). The com-
bined organic phase was dried over MgSO4 and filtered. The
solvent was removed under reduced pressure, and the prod-
uct was obtained as a colorless liquid (19.9 g, 69%). NMR
and IR data were consistent with those published in litera-
ture (19).
(4S)-Methyl-(5R)-phenyl-3-(4-propenyloxy)butanoyl-
oxazolidin-2-one
Yield: 95%, colorless oil. [α]20D –40.00 (c 1.0, CHCl3). IR
(neat, cm–1): 3074 (w), 2935 (m), 2861 (m), 1784 (s), 1708
1
(s), 1350 (s), 1198 (s), 1120 (m). H NMR (300 MHz,
CDCl3) δ: 7.45–7.29 (m, 5H), 5.98–5.85 (m, 1H), 5.66 (d,
J = 7.30 Hz, 1H), 5.28 (dq, J = 17.2, 1.5 Hz, 1H), 5.17 (dq,
J = 10.4, 1.5 Hz, 1H), 4.76 (quint, J = 6.8 Hz, 1H), 3.97
(dm, J = 5.5 Hz, 2H), 3.52 (t, J = 6.3 Hz, 2H), 3.14–2.97 (m,
2H), 1.99 (sept, J = 7.1 Hz, 2H), 0.89 (d, J = 6.6 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ: 172.7, 153.0, 134.9, 133.3,
128.7, 128.6, 125.6, 116.7, 78.9, 71.7, 69.1, 54.7, 32.5, 24.4,
14.5. Anal. calcd. for C17H21NO4: C 67.31, H 6.98; found: C
67.42, H 6.79.
(4R)-Methyl-(5S)-phenyl-3-(4-propenyloxy-2(R)-methyl-
butanoyl)-oxazolidine-2-one (6b) and (4S)-methyl-(5R)-
phenyl-3-(4-propenyloxy-(2S)-methyl-butanoyl)-
oxazolidine-2-one (6c)
To a flame-dried, 1 L, round-bottomed flask was placed
27.1 g (89.33 mmol) of (4R)-methyl-(5S)-phenyl-3-(4-pro-
penyloxy)butanoyl-oxazolidin-2-one or (4S)-methyl-(5R)-
phenyl-3-(4-propenyloxy)butanoyl-oxazolidin-2-one and freshly
distilled THF (350 mL). The solution was cooled to –78 °C,
and 2.0 mol/L NaHMDS in THF (53.6 mL, 107.2 mmol)
was added dropwise over 20 min. The mixture was stirred at
–78 °C for 30 min and MeI (38.0 mL, 268.0 mmol) was
added. After stirring at –78 °C for an additional 4 h, the re-
action was quenched with half-saturated NH4Cl solution
(300 mL). The organic phase was separated, and the aqueous
(4R)-Methyl-(5S)-phenyl-3-(4-propenyloxy)butanoyl-
oxazolidin-2-one and (4S)-methyl-(5R)-phenyl-3-(4-
propenyloxy)butanoyl-oxazolidin-2-one
Oxalyl chloride (30 mL, 343.34 mmol) was added to a so-
lution of acid 5 (16.5 g, 114.45 mmol) in hexane (220 mL)
© 2006 NRC Canada

Harmata et al.
1463
phase was extracted with EtOAc (200 mL × 3). The com-
bined organic phases were dried over MgSO4, filtered, and
concentrated. The crude product was purified by flash chro-
matography (hexane–EtOAc, 10:1) on silica gel.
(m, 4H), 2.87 (br t, J = 5.7 Hz, 1H), 1.83–1.50 (m, 3H), 0.93
(d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ: 134.4,
117.1, 71.8, 68.6, 68.0, 34.1, 34.0, 17.1. Anal. calcd. for
C8H16O2: C 66.63, H 11.18; found: C 66.73, H 11.28.
6b
Synthesis of 6-allyloxy-(4R)-methyl-hex-2-enoic acid
methyl ester and 6-allyloxy-(4S)-methyl-hex-2-enoic acid
methyl ester
Yield: 84%, colorless oil. [α]20 +9.59 (c 1.0, CHCl3). IR
(neat, cm–1): 2980 (m), 2937 (m)D, 2872 (m), 1782 (s), 1700
(s), 1457 (m), 1347 (s), 1242 (s), 1197 (s). 1H NMR
(300 MHz, CDCl3) δ: 7.42–7.29 (m, 5H), 5.99–5.84 (m,
1H), 5.63 (d, J = 7.1 Hz, 1H), 5.28 (dq, J = 1.7, 17.2 Hz,
1H), 5.17 (dq, J = 1.7, 8.9 Hz, 1H), 4.74 (quint, J = 6.9 Hz,
1H), 3.95–3.89 (m, 3H), 3.53–3.48 (m, 2H), 2.18–2.03 (m,
1H), 1.79–1.67 (m, 1H), 1.23 (d, J = 6.9 Hz, 3H), 0.88 (d,
J = 6.6, 3H). 13C NMR (75 MHz, CDCl3) δ: 176.5, 152.6,
134.8, 133.4, 128.5, 125.5, 116.3, 78.6, 71.5, 68.1, 54.7,
35.1, 33.4, 17.5, 14.4. Anal. calcd. for C18H23NO4: C 68.12,
H 7.30; found: C 68.28, H 7.16.
DMSO (9.4 mL, 132.41 mmol) was added to a cooled so-
lution (–78 °C) of oxalyl chloride (5.8 mL, 66.20 mmol) in
methylene chloride (460 mL). After 5 min, a solution of 7b
or 7c (6.80 g, 47.29 mmol) in 10 mL of methylene chloride
was added. The mixture was stirred for 30 min at –78 °C,
and triethylamine (29.0 mL, 208.08 mmol) was added. After
stirring for an additional 1 h at –30 °C, the reaction was
quenched and washed with water (200 mL × 2). The organic
phase was dried over magnesium sulfate, filtered, and con-
centrated. The crude product was dissolved in 1,2-dichloro-
ethane (50 mL), Ph2PCHCOOMe (16.56 g, 47.26 mmol)
was added, and it was refluxed for 6 h. Volatile solvents
were removed under reduced pressure, and the crude product
was purified by flash chromatography (hexane–EtOAc, 4:1)
on silica gel.
6c
Yield: 81%, colorless oil. [α]20 –9.44 (c 1.0, CHCl3). IR
(neat, cm–1): 2980 (m), 2932 (m)D, 2871 (m), 1784 (s), 1698
(s), 1459 (m), 1342 (s), 1244 (m), 1196 (s). 1H NMR
(250 MHz, CDCl3) δ: 7.45–7.27 (m, 5H), 5.99–5.84 (m,
1H), 5.63 (d, J = 7.1 Hz, 1H), 5.28 (dq, J = 1.7, 17.2 Hz,
1H), 5.17 (dq, J = 1.7, 10.4 Hz, 1H), 4.74 (quint, J = 6.7 Hz,
1H), 3.95–3.87 (m, 3H), 3.53–3.46 (m, 2H), 2.18–2.04 (m,
1H), 1.79–1.67 (m, 1H), 1.23 (d, J = 6.9 Hz, 3H), 0.88 (d,
J = 6.6, 3H). 13C NMR (62.9 MHz, CDCl3) δ: 176.7, 152.7,
134.9, 133.5, 128.6, 125.6, 116.5, 78.7, 71.6, 68.2, 54.8,
35.2, 33.5, 17.6, 14.5. Anal. calcd. for C18H23NO4: C 68.12,
H 7.30; found: C 67.81, H 7.51.
6-Allyloxy-(4R)-methyl-hex-2-enoic acid methyl ester
Yield: 88%, colorless oil. [α]20D –43.85 (c 1.0, CHCl3). IR
(neat, cm–1): 2956 (s), 2867 (s), 1726 (s), 1658 (m), 1436
1
(m), 1273 (s), 1180 (m), 1103 (m). H NMR (300 MHz,
CDCl3) δ: 6.87 (dd, J = 8.0, 15.7 Hz, 1H), 5.95–5.82 (m,
1H), 5.80 (dd, J = 1.0, 15.8 Hz, 1H), 5.26 (dq, J = 1.6,
17.2 Hz, 1H), 5.16 (dq, J = 1.6, 9.9 Hz, 1H), 3.93 (m, 2H),
3.73 (s, 3H), 3.45–3.39 (m, 2H), 2.52 (sept, J = 7.0 Hz, 1H),
1.65 (q, J = 6.7 Hz, 2H), 1.07 (d, J = 6.7 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ: 167.1, 154.0, 134.7, 119.5, 116.7, 71.7,
67.7, 51.3, 35.7, 33.3, 19.3. Anal. calcd. for C11H18O3: C
66.64, H 9.15; found: C 66.47, H 8.98.
4-Allyloxy-(2R)-methyl-butan-1-ol (7b) and 4-allyloxy-
(2S)-methyl-butan-1-ol (7c)
To a cooled solution (0 °C) 6b or 6c (25.27 g,
79.61 mmol) in diethyl ether (320 mL) was added 6.05 g
(159.23 mmol) of LiAlH4 portionwise over 40 min and
stirred for 2 h. The reaction was quenched by a slow addi-
tion of water and 1 N NaOH (20 mL). The mixture was fil-
tered, and the white precipitate was washed with ether
(300 mL × 2). The combined ether solution was concen-
trated, and crude product was purified by vacuum distillation
(bp = 60–65 °C, 0.1 mmHg).
6-Allyloxy-(4S)-methyl-hex-2-enoic acid methyl ester
Yield: 85%, colorless oil. [α]20D +45.35 (c 1.0, CHCl3). IR
(neat, cm–1): 2957 (m), 2873 (m), 1730 (s), 1660 (m), 1435
1
(m), 1274 (m), 1183 (m), 1104 (m). H NMR (300 MHz,
CDCl3) δ: 6.87 (dd, J = 8.0, 15.7 Hz, 1H), 5.95–5.82 (m,
1H), 5.80 (dd, J = 1.0, 15.8 Hz, 1H), 5.26 (dq, J = 1.6,
17.2 Hz, 1H), 5.16 (dq, J = 1.6, 9.9 Hz, 1H), 3.93 (m, 2H),
3.73 (s, 3H), 3.45–3.39 (m, 2H), 2.52 (sept, J = 7.0 Hz, 1H),
1.65 (q, J = 6.7 Hz, 2H), 1.07 (d, J = 6.7 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ: 167.1, 154.0, 134.7, 119.5, 116.7, 71.7,
67.7, 51.3, 35.7, 33.3, 19.3. Anal. calcd. for C11H18O3: C
66.64, H 9.15; found: C 66.81, H 9.36.
7b
Yield: 92%, colorless oil. [α]20D +14.16 (c 1.0, CHCl3). IR
(neat, cm–1): 3397 (s), 3081 (w), 2930 (s), 2870 (s), 1458
1
(m), 1097 (s), 1044 (m). H NMR (300 MHz, CDCl3) δ:
5.99–5.83 (m, 1H), 5.27 (dq, J = 1.6, 17.3 Hz, 1H), 5.18 (dq,
J = 1.2, 10.4 Hz, 1H), 3.98 (d, J = 5.6 Hz, 2H), 3.60–3.40
(m, 4H), 2.87 (br t, J = 5.7 Hz, 1H), 1.83–1.50 (m, 3H), 0.93
(d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ: 134.4,
117.1, 71.8, 68.6, 68.0, 34.1, 34.0, 17.1. Anal. calcd. for
C8H16O2: C 66.63, H 11.18; found: C 66.73, H 11.31.
6-Hydroxy-(4R)-methyl-hex-2-enoic acid methyl ester
(1b) and 6-hydroxy-(4R)-methyl-hex-2-enoic acid methyl
ester (1c)
To a solution of 6-allyloxy-(4R)-methyl-hex-2-enoic acid
methyl ester or 6-allyloxy-(4S)-methyl-hex-2-enoic acid
methyl ester (8.25 g, 41.60 mmol) in anhydrous methanol
(150 mL) was added 10% Pd–C (4.16 g) and p-
toluenesulfonic acid (2.08 g). The mixture was stirred and
heated under a reflux condition for 24 h, then filtered, and
concentrated. The crude product was purified by flash chro-
matography (hexane–EtOAc, 2:1).
7c
Yield: 88%, colorless oil. [α]20D –12.53 (c 1.0, CHCl3). IR
(neat, cm–1): 3413 (s), 2957 (s), 2926 (s), 2870 (s), 1459
1
(m), 1099 (s), 1047 (s). H NMR (250 MHz, CDCl3) δ:
5.99–5.83 (m, 1H), 5.27 (dq, J = 1.6, 17.3 Hz, 1H), 5.18 (dq,
J = 1.2, 10.4 Hz, 1H), 3.98 (d, J = 5.6 Hz, 2H), 3.60–3.40
© 2006 NRC Canada

1464
Can. J. Chem. Vol. 84, 2006
1b
General procedure for the alkylation of ketoester 13:
synthesis of 14–16
[α]20 –40.73 (c 1.0, CHCl3). IR (neat, cm–1): 3437 (m),
D
To a flame-dried, 50 mL, round-bottomed flask equipped
with a magnetic bar was placed 0.65 g (17 mmol) of 60%
NaH in mineral oil and 27 mL of freshly distilled THF. The
mixture was stirred in an ice bath, and a solution of 13
(15 mmol) in 3 mL of THF was added slowly. The mixture
was stirred for 5 min, and 2.5 mol/L solution of n-BuLi
(15 mmol) was added. After stirring for an additional 5 min,
a solution of alkyl iodide 3a, 3b, or 3c (10 mmol) in 3 mL
of THF was added into the orange-yellow solution. The mix-
ture was stirred and allowed to warm to room temperature
overnight. The reaction was quenched with water (25 mL)
and extracted with ether (30 mL × 3). The combined organic
phases were dried over magnesium sulfate, filtered, and con-
centrated with a rotatory evaporator. The crude product was
purified by column chromatography (silica gel, pentane–
ether, 20:1) to give a mixture of diastereomers.
2958 (s), 2879 (m), 1725 (s), 1657 (s), 1437 (m), 1275 (s),
1210 (s), 1175 (s). H NMR (300 MHz, CDCl3) δ: 6.88 (dd,
1
J = 8.0, 15.7 Hz, 1H), 5.83 (dd, J = 1.0, 15.7 Hz, 1H), 3.73
(s, 3H), 3.68–3.61 (m, 2H), 2.53 (m, 1H), 2.24 (s, 1H),
1.064 (q, J = 6.78 Hz, 2H), 1.08 (d, J = 6.8 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ: 167.2, 154.1, 119.5, 60.2, 51.4,
38.5, 33.0, 19.3. Anal. calcd. for C8H14O3: C 60.74, H 8.92;
found: C 60.91, H 8.77.
1c
[α]20 +44.08 (c 1.0, CHCl3). IR (neat, cm–1): 3429 (s),
D
2956 (s), 2879 (s), 1726 (s), 1658 (s), 1439 (s), 1276 (s),
1
1210 (s), 1175 (s). H NMR (250 MHz, CDCl3) δ: 6.88 (dd,
J = 8.0, 15.7 Hz, 1H), 5.83 (dd, J = 1.0, 15.7 Hz, 1H), 3.73
(s, 3H), 3.68–3.61 (m, 2H), 2.53 (m, 1H), 2.24 (s, 1H),
1.064 (q, J = 6.78 Hz, 2H), 1.08 (d, J = 6.8 Hz, 3H). 13C
NMR (62.9 MHz, CDCl3) δ: 167.2, 154.1, 119.6, 60.4, 51.4,
38.6, 33.1, 19.3. Anal. calcd. for C8H14O3: C 60.74, H 8.92;
found: C 60.60, H 8.96.
14
Yield: 67%, yellow oil. [α]20 +49.70 (c 1.0, CHCl3). IR
D
(neat, cm–1): 3083 (w), 2957 (s), 2967 (s), 1753 (s), 1730
(s), 1436 (m), 1250 (m), 857 (s). 1H NMR (250 MHz,
CDCl3) δ: 6.05 (d, J = 15.6 Hz, 1H), 5.55 (dt, J = 7.0,
15.6 Hz, 1H), 4.78 (d, J = 2.2 Hz, 1H), 4.66 (s, 1H), 3.75
and 3.74 (s, 3H), 2.86 and 2.74 (d, J = 10.0 and 11.44 Hz,
1H), 2.70–2.40 (m, 1H), 2.39–2.21 (m, 1H), 2.14–2.07 (m,
2H), 2.03–1.74 (m, 1H), 1.72–1.59 (m, 1H), 1.68 (s, 2H),
1.50–1.34 (m, 4H), 1.18 and 1.16 (d, J = 6.34 and 6.45 Hz,
3H), 0.00 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 213.6,
212.5, 169.63, 169.59, 143.8, 133.6, 129.8, 111.9, 111.2,
62.9, 62.8, 52.3, 50.5, 47.9, 36.2, 35.0, 34.1, 33.6, 32.6,
32.5, 30.4, 29.3, 27.8, 27.4, 27.3, 22.1, 19.7, 19.1, 15.8,
–1.2. Anal. calcd. for C19H32O3Si: C 67.81, H 9.58; found:
C 67.66, H 9.52.
General procedure for the alkylation of ketoester 8:
synthesis of 9 and 10
To a solution of 8 (5 mmol) in acetone (25 mL) was added
alkyl iodide 3a or 3b (2.5 mmol) and K2CO3 (7.5 mmol).
The mixture was heated under a reflux condition under N2
for 12 h. After the mixture was cooled to room temperature,
water (30 mL) was added and the mixture was extracted
with Et2O (30 mL × 3). Combined organic phases were
washed with brine, dried over MgSO4, filtered, and concen-
trated under reduced pressure. The crude product was puri-
fied by column chromatography (silica gel, pentane–ether,
20:1).
9
15
Yield: 86%, colorless oil. IR (neat, cm–1): 3079 (w), 2956
(s), 2896 (s), 1751 (s), 1730 (s), 1436 (m), 1251 (m), 1159
Yield: 70%, yellow oil. [α]20 +37.22 (c 1.0, CHCl3). IR
D
(neat, cm–1): 2955 (s), 2874 (m), 1756 (s), 1731 (s), 1250
(m), 853 (s). H NMR (300 MHz, CDCl3) δ: 6.02 (d, J =
1
1
(m), 855 (s). H NMR (300 MHz, CDCl3) δ: 6.06 (d, J =
15.6 Hz, 1H), 5.54 (dt, J = 7.0, 15.6 Hz, 1H), 4.78 (d, J =
2.0 Hz, 1H), 4.66 (s, 1H), 3.71 (s, 3H), 2.57–1.86 (m, 8H),
1.68 (s, 2H), 1.64–1.32 (m, 4H), 0.00 (s, 9H). 13C NMR
(75 MHz, CDCl3) δ: 214.7, 171.5, 143.7, 133.7, 128.6,
112.0, 60.4, 52.5, 37.9, 33.6, 32.9, 32.8, 24.7, 22.1, 19.6,
–1.2. Anal. calcd. for C18H30O3Si: C 67.03, H 9.38; found:
C 66.88, H 9.12.
15.7 Hz, 1H), 5.47–5.35 (m, 1H), 4.78 (d, J = 1.7 Hz, 1H),
4.66 (s, 1H), 3.75 and 3.74 (s, 3H), 2.95 and 2.85 (d, J =
10.3 and 9.5 Hz, 1H), 2.75–2.42 (m, 1H), 2.35–2.13 (m,
2H), 1.99–1.59 (m, 2H), 1.68 (s, 2H), 1.39–1.23 (m, 3H),
1.18–1.06 (m, 4H), 1.00 (d, J = 6.7 Hz, 3H), 0.00 (s, 9H).
13C NMR (75 MHz, CDCl3) δ: 213.6, 212.6, 169.6, 169.6,
143.8, 143.8, 135.9, 135.8, 131.9, 131.8, 112.1, 112.0, 63.0,
62.8, 52.3, 50.5, 48.2, 37.2, 37.1, 36.2, 35.1, 35.1, 34.6,
34.1, 33.6, 28.8, 27.5, 22.1, 22.1, 20.9, 20.5, 19.2, –1.2.
Anal. calcd. for C20H34O3Si: C 68.52, H 9.78; found: C
68.70, H 9.85.
10
Yield: 88%, colorless oil. IR (neat, cm–1): 3080 (w), 2957
(s), 2928 (s), 1754 (s), 1729 (s), 1600 (m), 1460 (m), 1250
1
(s), 1157 (m), 856 (s). H NMR (300 MHz, CDCl3) δ: 6.05
16
and 6.01 (d, J = 15.7 and 15.7 Hz, 1H), 5.44–5.32 (m, 1H),
4.79 (d, J = 2.0 Hz, 1H), 4.66 (d, J = 2.0 Hz, 1H), 3.70 and
3.69 (s, 3H), 2.63–1.77 (m, 8H), 1.68 (s, 2H), 1.67–1.12 (m,
3H), 1.00 and 0.99 (d, J = 6.7 and 6.7 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ: 214.71, 214.65, 171.6, 171.4, 143.74,
143.69, 135.5, 132.1, 132.0, 112.13, 112.08, 60.4, 60.3,
52.4, 38.0, 37.8, 37.5, 37.4, 32.9, 32.7, 32.0, 31.9, 31.8,
22.1, 22.0, 20.8, 20.7, 19.5, –1.2. HR-MS (EI) calcd. for
C19H31O3Si (M+): 336.2121; found: 336.2121.
Yield: 79%, yellow oil. [α]20 +45.50 (c 1.0, CHCl3). IR
D
(neat, cm–1): 3084 (w), 2956 (s), 2867 (s), 1759 (s), 1729
(s), 1444 (m), 1250 (s), 1158 (m), 849 (s). 1H NMR
(300 MHz, CDCl3) δ: 5.97 (d, J = 15.7 Hz, 1H), 5.42–5.30
(m, 1H), 4.74 (d, J = 2.0 Hz, 1H), 4.61 (br s, 2H), 3.70 and
3.69 (s, 3H), 2.81 and 2.69 (d, J = 9.6 and 11.6 Hz, 1H),
2.65–2.10 (m, 4H), 1.97–1.53 (m, 2H), 1.64 (s, 2H), 1.40–
1.19 (m, 3H), 1.12 and 1.11 (d, J = 6.3 and 6.4 Hz, 3H),
© 2006 NRC Canada

Harmata et al.
1465
1
1.05–1.00 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H), –0.04 (s, 9H).
13C NMR (75 MHz, CDCl3) δ: 213.3, 212.3, 169.5, 169.4,
143.6, 143.5, 135.7, 135.6, 131.8, 131.7, 111.93, 111.87,
62.8, 62.7, 52.1, 50.5, 47.8, 37.1, 36.8, 36.1, 35.0, 34.7,
34.6, 34.0, 33.4, 28.4, 27.6, 21.98, 21.96, 20.7, 20.5, 19.6,
19.0, –1.3. HR-MS (EI) calcd. for C20H34O3Si (M+):
350.2277; found: 350.2241.
(m), 1458 (m), 1249 (s), 1158 (m), 968 (m), 854 (s). H
NMR (300 MHz, CDCl3) δ: 6.02 (d, J = 15.6 Hz, 1H), 5.50–
5.35 (m, 1H), 4.79 (d, J = 2.0 Hz, 1H), 4.66 (s, 1H), 2.50–
2.05 (m, 4H), 1.95–1.60 (m, 2H), 1.69 (s, 2H), 1.40–1.18
(m, 5H), 1.13 and 1.09 (d, J = 6.4 and 6.5 Hz, 3H), 1.01 and
1.00 (d, J = 6.7 and 6.7 Hz, 3H), 0.00 (s, 9H). 13C NMR
(75 MHz, CDCl3) δ: 221.7, 220.7, 143.9, 143.8, 136.2,
136.0, 131.8, 131.6, 112.0, 111.9, 50.9, 47.3, 46.9, 46.4,
38.5, 37.4, 37.1, 36.9, 35.2, 34.8, 29.7, 28.6, 28.3, 27.4,
22.2, 22.1, 20.9, 20.8, 20.5, 20.3, –1.2. Anal. calcd. for
C18H32OSi: C 73.90, H 11.03; found: C 73.85, H 10.95.
General procedure for decarbomethoxylation: synthesis
of 11–12 and 17–19
To a solution of β-keto ester (3.0 mmol) in DMSO
(6.0 mL) was added potassium cyanide (6.0 mmol) and wa-
ter (6.0 mmol). The mixture was heated under reflux for 30
min, allowed to cool to room temperature, diluted with water
(20 mL), and extracted with ether (20 mL × 3). The com-
bined organic phases were dried over magnesium sulfate, fil-
tered, and concentrated. The crude product was purified by
flash chromatography (silica gel, pentane–ether, 20:1).
19
Yield: 74%, colorless oil. [α]20D +66.45 (c 1.0, CHCl3). IR
(neat, cm–1): 3081 (w), 2956 (s), 2923 (s), 2865 (m), 1744
(s), 1250 (s), 1158 (m), 850 (s). 1H NMR (250 MHz, CDCl3)
δ: 6.02 (d, J = 15.7 Hz, 1H), 5.47–5.36 (m, 1H), 4.78 (d, J =
2.1 Hz, 1H), 4.65 (d, J = 1.4 Hz, 1H), 2.50–2.06 (m, 5H),
1.91–1.62 (m, 3H), 1.69 (s, 2H), 1.43–1.21 (m, 2H), 1.13
and 1.08 (d, J = 6.4 and 6.6 Hz, 3H), 1.17–1.06 (m, 1H),
1.02 and 1.00 (d, J = 6.7 and 6.7 Hz, 3H), 0.00 (s, 9H). 13C
NMR (62.9 MHz, CDCl3): 221.6, 220.6, 143.8, 136.1,
136.0, 131.8, 131.7, 111.9, 51.0, 47.0, 46.8, 46.4, 38.6, 37.4,
37.1, 37.0, 35.1, 34.8, 29.7, 28.4, 28.3, 27.8, 22.1, 20.84,
20.76, 20.6, 20.3, –1.2. HR-MS (EI) calcd. for C18H32OSi
(M+): 292.2222; found: 292.2241.
11
Yield: 66%, colorless oil. IR (neat, cm–1): 3079 (w), 2956
(s), 1740 (s), 1250 (s), 1157 (m), 856 (s). 1H NMR
(300 MHz, CDCl3) δ: 6.06 (d, J = 15.6 Hz, 1H), 5.57 (dt,
J = 7.06, 15.6 Hz, 1H), 4.78 (d, J = 2.01, 1H), 4.66 (s, 1H),
2.36–1.93 (m, 7H), 1.88–1.72 (m, 2H), 1.69 (s, 2H), 1.62–
1.21 (m, 4H), 0.39 (s, 9H). 13C NMR (62.9 MHz, CDCl3) δ:
221.3, 143.8, 133.5, 130.1, 111.8, 49.1, 38.1, 32.8, 29.6,
29.4, 27.5, 22.2, 20.7, –1.2. Anal. calcd. for C16H28OSi: C
72.66, H 10.67; found: C 72.50, H 10.49.
␣-Chlorination of cyclopentanone, intramolecular [4 +
3] cycloaddition, and desilylation of allylsilane:
synthesis of 20
12
To a cooled solution (–78 °C) of ketone 18 (2.0 mmol) in
THF (15 mL) was slowly added a solution of LDA (prepared
by adding a 2.5 mol/L solution of n-BuLi (2.5 mmol) into a
solution of diisopropylamine (3.0 mmol) in THF (5 mL) at
0 °C). The mixture was stirred at –78 °C for 30 min and
trifluoromethanesulfonyl chloride (2.5 mmol) was added
dropwise. After stirring for 5 min, the reaction was quenched
with water (20 mL) and extracted with ether (15 mL × 3).
The combined organic phases were washed with water
(20 mL), dried over magnesium sulfate, filtered, and concen-
trated. Volatile solvents were removed under high vacuum.
The resulting colorless oil was dissolved in freshly distilled
ether (10 mL), cooled to –78 °C, and diluted with trifluoro-
ethanol (10 mL). The mixture was stirred for a few minutes
and triethylamine (6.0 mmol) was added dropwise. The reac-
tion was allowed to warm to room temperature overnight,
quenched with water (20 mL), and extracted with ether
(15 mL × 3). The combined organic phases were dried over
magnesium sulfate, filtered, and concentrated. The crude
product was dried under high vacuum. The resulting yellow
oil was dissolved in methylene chloride (20 mL), and
TsOH·H2O (0.2 mmol) was added. The mixture was stirred
at room temperature for 6 h and washed with water (20 mL).
The organic phase was separated and dried over magnesium
sulfate, filtered, and concentrated. The crude product was
purified by flash chromatography on silica gel using hex-
ane–EtOAc (30:1) as the eluent. Ketone 20 was obtained as
a colorless oil in 74% yield. [α]20 +44.60 (c 1.0, CHCl3).
IR (neat, cm–1): 3073 (w), 2952 (s)D, 2867 (s), 1735 (s), 1643
Yield: 83%, colorless oil. [α]20D –10.13 (c 1.0, CHCl3). IR
(neat, cm–1): 3080 (w), 2956 (s), 2870 (s), 1738 (s), 1249
(s), 1160 (m), 857 (s). H NMR (250 MHz, CDCl3) δ: 6.02
1
(d, J = 15.7 Hz, 1H), 5.48–5.36 (m, 1H), 4.79 (d, J = 2.2 Hz,
1H), 4.66 (br s, 1H), 2.35–1.93 (m, 6H), 1.87–1.65 (m, 2H),
1.69 (s, 2H), 1.60–1.15 (m, 4H), 1.02 and 1.01 (d, J = 6.7
and 6.7 Hz, 3H), 0.00 (s, 9H). 13C NMR (62.9 MHz, CDCl3)
δ: 221.3, 143.9, 143.8, 136.1, 136.0, 131.8, 131.6, 111.94,
111.89, 49.3, 49.1, 38.14, 38.11, 37.4, 37.1, 35.2, 34.8,
29.63, 29.59, 27.8, 27.5, 22.14, 22.12, 20.9, 20.7. 20.5, –1.2.
HR-MS (EI) calcd. for C17H30OSi (M+): 278.2066; found:
278.2079.
17
Yield: 78%, colorless oil. [α]20D +71.31 (c 1.0, CHCl3). IR
(neat, cm–1): 3081 (w), 2954 (s), 2862 (s), 1743 (s), 1459
(w), 1250 (s), 1158 (m), 857 (s). 1H NMR (250 MHz,
CDCl3) δ: 6.06 (d, J = 15.3 Hz, 1H), 5.63–5.54 (m, 1H),
4.78 (d, J = 2.2 Hz, 1H), 4.66 (s, 1H), 2.52–2.03 (m, 6H),
1.97–1.62 (m, 2H), 1.69 (s, 2H), 1.51–1.20 (m, 3H), 1.18–
1.05 (m, 1H), 1.14 and 1.09 (d, J = 6.4 and 6.7 Hz, 3H),
0.00 (s, 9H). 13C NMR (62.9 MHz, CDCl3) δ: 221.6, 220.7,
143.8, 133.5, 133.4, 130.1, 130.1, 111.8, 50.8, 47.0, 46.8,
46.4, 35.6, 36.9, 32.8, 32.7, 30.2, 29.7, 29.4, 28.3, 27.5,
22.2, 20.8, 20.3, –1.2. Anal. calcd. for C17H30OSi: C 73.31,
H 10.86; found: C 73.41, H 10.68.
18
Yield: 94%, colorless oil. [α]20D +41.65 (c 1.0, CHCl3). IR
(w), 1455 (m), 1154 (w). H NMR (300 MHz, CDCl3) δ:
4.83 (d, J = 13.5 Hz, 2H), 2.46–1.68 (m, 8H), 1.58–0.92 (m,
1
(neat, cm–1): 3079 (w), 2955 (s), 2870 (s), 1740 (s), 1593
© 2006 NRC Canada

1466
Can. J. Chem. Vol. 84, 2006
6H), 1.04 (d, J = 6.4 Hz, 3H), 1.00 (d, J = 6.1 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ: 220.8, 146.5, 115.0, 61.1, 58.6,
52.7, 46.9, 43.2, 39.9, 39.4, 35.1, 31.7, 28.0, 21.0, 18.3.
Anal. calcd. for C15H22O: C 82.52, H 10.16; found: C 82.25,
H 10.20.
0.55–0.28 (m, 4H). 13C NMR (62.9 MHz, CDCl3) δ: 178.0,
90.6, 56.8, 46.8, 43.5, 42.6, 41.7, 41.1, 35.6, 32.1, 25.4,
23.0, 18.6, 17.5, 15.1, 14.3. Anal. calcd. for C16H24O2: C
77.38, H 9.74; found: C 77.50, H 9.71.
Hydrogenolysis of a cyclopropane: synthesis of 25
Simmons–Smith cyclopropanation: synthesis of 22
To a 20 mL hydrogenation vessel was placed 0.90 mmol
of cyclopropane 23, 9.0 mL of glacial acetic acid, PtO2 (4
equiv.), and NaOAc (4 equiv.). The vessel was connected to
a hydrogenation apparatus, and the system was flushed with
H2 gas for a few minutes. The hydrogen pressure was ad-
justed to 100 psi (1 psi = 6.894 757 kPa), and the mixture
was stirred under hydrogen for 12 h. The vessel was vented,
and the catalyst was filtered off. The filtrate was partitioned
between ether (20 mL) and water (20 mL). The organic
phase was separated, and the aqueous phase was extracted
with ether (20 mL × 2). The combined organic phases were
dried over magnesium sulfate, filtered, and concentrated.
The crude product was purified by flash chromatography
(hexane–EtOAc, 10:1). Lactone 25 was synthesized in 98%
To a cooled solution (0 °C) of 20 (2.29 mmol) in methy-
lene chloride (5 mL) was added methylene iodide (5.4 mL,
5.8 mmol) and 1.0 mol/L solution of diethylzinc in hexane
(23 mL, 23 mmol). The mixture was stirred vigorously for
12 h while it was allowed to warm to room temperature. The
reaction was quenched with water (20 mL), 1 N HCl (5 mL)
was added, and it was extracted with ether (20 mL × 3). The
combined organic phases were dried over magnesium sul-
fate, filtered, and concentrated using a rotatory evaporator.
The crude product was purified by flash chromatography
(3:1, hexane–CH2Cl2). Ketone 22 was obtained in 95% yield
as a colorless oil. [α]20 +12.63 (c 1.0, CHCl3). IR
D
(neat, cm–1): 2956 (s), 2869 (s), 1728 (s), 1457 (m), 1390
1
yield as a white crystalline solid. mp 91 to 92 °C. [α]20
(m), 1164 (m), 1114 (m). H NMR (250 MHz, CDCl3) δ:
D
+15.23 (c 1.0, CHCl3). IR (KBr, cm–1): 2955 (s), 2872 (s),
2.63–2.51 (m, 1H), 2.28–2.11 (m, 3H), 1.99–1.94 (m, 4H),
1.84–1.77 (m, 1H), 1.56–1.43 (m, 1H), 1.36–1.13 (m, 5H),
1.03 (d, J = 6.88 Hz, 3H), 0.99–0.95 (m, 1H), 0.91 (d, J =
5.33 Hz, 3H), 0.83–0.75 (m, 1H), 0.51–0.39 (m, 2H), 0.31–
0.15 (m, 2H). 13C NMR (62.9 MHz, CDCl3) δ: 220.1, 61.6,
55.0, 41.2, 42.8, 39.1, 35.1, 31.6, 27.3, 21.1, 18.4, 17.0,
14.7, 12.3. Anal. calcd. for C16H24O: C 80.70, H 10.41;
found: C 82.60, H 10.30.
1
1720 (s), 1455 (m), 1113 (m). H NMR (300 MHz, CDCl3)
δ: 4.36 (q, J = 3.5 Hz, 1H), 2.73–2.60 (m, 1H), 2.43–2.34
(m, 1H), 2.07 (dd, J = 8.3, 13.8 Hz, 1H), 1.93–1.82 (m, 2H),
1.75–1.16 (m, 8H), 1.12 (s, 3H), 1.09 (d, J = 6.9 Hz, 3H),
0.98–0.96 (m, 6H). 13C NMR (75 MHz, CDCl3) δ: 177.3,
85.3, 54.0, 51.3, 46.3, 43.0, 42.6, 42.0, 36.5, 36.4, 32.9,
32.5, 29.5, 27.3, 23.2, 18.3. Anal. calcd. for C16H26O2: C
76.75, H 10.47; found: C 76.80, H 10.56.
Baeyer–Villiger oxidation: synthesis of 23 and 24
To a solution of ketone 22 (2.15 mmol) in DMF (4 mL)
was added MMPP (10.63 g, 21.50 mmol), and the resulted
suspension was stirred at room temperature for 24 h. The
mixture was diluted with water (20 mL) and extracted with
ether (20 mL × 3). The combined ether solutions were dried
over magnesium sulfate, filtered, and concentrated. The crude
product was purified by flash chromatography (hexane–
EtOAc, 10:1).
Hydrolysis of lactone 25 and esterification of carboxylic
acid 31: synthesis of 32
To a 10 mL round-bottomed flask equipped with a reflux
condenser was placed 25 (0.05 g, 0.20 mmol), MeOH
(2.0 mL), water (1.0 mL), and KOH (0.5 g). The mixture
was heated and stirred under a reflux condition for 12 h. The
mixture was allowed to cool to room temperature, was di-
luted with 2 N HCl (5 mL), and extracted with ether (10 mL
× 3). The organic phase was dried over magnesium sulfate,
filtered, and concentrated. The crude product was dissolved
in 5 mL of ether; a solution of diazomethane in ether was
added until a yellow color persisted. The mixture was stirred
for 5 min, and the solvent was removed under reduced pres-
sure. The crude product was purified by flash chromatogra-
phy (hexane–EtOAc, 4:1). Ester 32 was obtained as a
colorless oil (0.053 g, 95%). [α]20 –27.08 (c 1.0, CHCl3).
IR (neat, cm–1): 3424 (m), 2960 (s)D, 2872 (s), 1720 (s), 1466
23
Yield: 68%, white solid (recrystallized from hexane–
EtOAc), mp 52–54 °C. [α]20 +26.46 (c 1.0, CHCl3). IR
D
(KBr, cm–1): 2956 (d), 2869 (d), 1728 (d), 1457 (m), 1390
1
(m), 1164 (m), 1114 (s). H NMR (300 MHz, CDCl3) δ:
4.36–4.31 (m, 1H), 2.70–2.46 (m, 3H), 2.03 (dd, J = 7.4,
13.5 Hz, 1H), 1.94–1.83 (m, 1H), 1.78–1.65 (m, 2H), 1.61–
1.33 (m, 3H), 1.25–1.03 (m, 2H), 1.10 (d, J = 6.9 Hz, 3 H),
0.92 (br s, 1H), 0.88 (d, J = 6.0 Hz, 3H), 0.53–0.42 (m, 2H),
0.38–0.27 (m, 2H). 13C NMR (75 MHz, CDCl3) δ: 177.3,
85.4, 57.7, 51.1, 44.5, 42.0, 41.4, 38.0, 36.0, 33.0, 26.6,
22.2, 18.0, 16.7, 14.9, 14.7. Anal. calcd. for C16H24O2: C
77.38, H 9.74; found: C 77.23, H 9.89.
1
(m), 1175 (m). H NMR (300 MHz, CDCl3) δ: 3.80–3.74
(m, 1H), 3.67 (s, 3H), 2.26 (dd, J = 9.3, 15.0 Hz, 1H), 2.04–
1.83 (m, 4H), 1.73–1.35 (m, 6H), 1.26–1.15 (m, 3H), 1.03
(d, J = 7.0 Hz, 3H), 0.96–0.93 (m, 9H). 13C NMR (75 MHz,
CDCl3) δ: 178.6, 72.4, 55.4, 51.4, 49.7, 46.9, 41.4, 39.4,
37.7, 36.8, 35.9, 32.0, 31.9, 31.2, 24.1, 20.2, 19.3. Anal.
calcd. for C17H30O3: C 72.30, H 10.71; found: C 72.42, H
10.61.
24
Yield: 16%, white solid (recrystallized from hexane–
EtOAc), mp 65–67 °C. [α]20 –103.65 (c 1.0, CHCl3). IR
(KBr, cm–1): 2956 (s), 2917 D(s), 2871 (s), 1722 (s), 1452
1
Dehydration of alcohol 32 using Tf2O–pyridine:
synthesis of 35
To a solution of 32 (0.01 g, 0.04 mmol) in pyridine
(w), 1374 (w), 1266 (w), 1098 (s). H NMR (250 MHz,
CDCl3) δ: 2.66–2.38 (m, 3H), 2.21–1.79 (m, 5H), 1.67–1.53
(m, 2H), 1.39–1.21 (m, 2H), 1.13–0.96 (m, 1H), 1.02 (d, J =
6.8 Hz, 3H), 0.89 (d, J = 6.4 Hz, 3H), 0.79–0.73 (m, 1H),
(1.0 mL) was added Tf2O (0.013 mL, 0.08 mmol), and it
© 2006 NRC Canada

Harmata et al.
1467
was stirred for 12 h at room temperature. The mixture was
diluted with water (5 mL) and extracted with ether (5 mL ×
3). Combined organic phases were washed with 0.5 N HCl
(5 mL) and brine, dried over magnesium sulfate, filtered,
and concentrated. After a chromatographic purification (sil-
ica gel, hexane–EtOAc, 10:1), 35 was obtained in 90% yield
24 h, filtered, and concentrated. The volatile compounds
were removed under high vacuum, and the residue was dis-
solved in ether (2 mL). The solution was cooled in an ice-
water bath and 0.013 g (0.33 mmol) of LiAlH4 was added.
The suspension was stirred at 0 °C for 2 h and slowly
quenched with water, filtered, and the white precipitate
washed thoroughly with ether (5 mL × 3). The combined or-
ganic phases were concentrated, and the crude product was
purified by flash chromatography (hexane–EtOAc, 10:1).
(+)-Dactylol (37) was obtained as a white solid (0.012 g,
50%). mp 49 to 50 °C (lit. value (15e), mp 50.3–51.5 °C).
[α]20 +21.38 (c 1.0, CHCl3) (lit. value (15e)) [α]20 +22.5).
as a colorless oil. [α]20 +94.86 (c 1.0, CHCl3). IR
D
(neat, cm–1): 2949 (s), 2918 (s), 1730 (s), 1467 (m), 1220
1
(m), 1158 (s). H NMR (250 MHz, CDCl3) δ: 3.59 (s, 3H),
2.50–2.30 (m, 1H), 2.25–1.59 (m, 8H), 1.65 (s, 3H), 1.44–
1.35 (m, 2H), 1.20–1.10 (m, 2H), 0.97 (s, 3H), 0.87 (d, J =
6.5 Hz, 3H), 0.86 (s, 3H). 13C NMR (62.9 MHz, CDCl3) δ:
177.3, 136.9, 134.7, 61.7, 51.5, 38.1, 36.4, 35.7, 35.1, 34.43,
34.35, 29.6, 27.6, 26.2, 25.7, 22.1, 16.3. Anal. calcd. for
C17H28O2: C 77.22, H 10.67; found: C 77.34, H 10.44.
D
D
IR (neat, cm–1): 3500 (w), 2955 (s), 2872 (s), 1465 (m). H
NMR (300 MHz, CDCl3) δ: 5.49 (t, J = 8.4 Hz, 1H), 2.21
(d, J = 13.4 Hz, 1H), 2.07 (d, J = 13.4 Hz, 1H), 1.95–1.85
(m, 2H), 1.82 (s, 3H), 1.80–1.71 (m, 1H), 1.70–1.60 (m,
1H), 1.57–1.49 (m, 2H), 1.46 (dd, J = 15.0, 7.9 Hz, 1H),
1.33 (br s, 1H), 1.09–0.95 (m, 2H), 0.91 (d, J = 6.6 Hz, 3H),
0.90 (s, 3H), 0.85 (s, 3H), 0.71 (d, J = 114.6 Hz, 1H). 13C
NMR (75 MHz, CDCl3) δ: 135.9, 124.6, 82.8, 52.9, 43.1,
40.4, 39.4, 39.3, 36.5, 35.2, 29.5, 29.3, 28.9, 27.9, 19.2.
Anal. calcd. for C15H26O: C 81.02, H 11.78; found: C 81.27,
H 12.00.
1
Dehydration of alcohol 32 using POCl3–HMPA–
pyridine and hydrolysis of ester: synthesis of 36
A 10 mL round-bottomed flask was charged with 0.053 g
(0.19 mmol) of 32, 2.0 mL of HMPA, and 0.2 mL of POCl3.
The resulting white suspension was stirred for 1 h at room
temperature and for another 1 h in an oil bath at 50 °C.
Pyridine (0.2 mL) was added, and the mixture was stirred at
50 °C for 1 h, at 75 °C for 45 min, and at 100 °C for 30 min.
The mixture was allowed to cool to room temperature and
was quenched by the dropwise addition of water (2 mL).
The mixture was extracted with ether (5 mL × 3). The com-
bined organic phases were washed with water (5 mL), dried
over magnesium sulfate, filtered, and concentrated. The vol-
atile compounds were removed under high vacuum, and the
residue was dissolved in DMSO (2 mL). A few drops of wa-
ter and 0.1 g of KOH were added, and the mixture was
heated under reflux for 1 h. The reaction was allowed to
cool to room temperature, 2 N HCl (5 mL) was added, and
the mixture was extracted with ether (10 mL × 3). The or-
ganic phase was dried over magnesium sulfate, filtered, and
concentrated. The crude product was purified by flash chro-
matography (hexane–EtOAc, 10:1). Acid 36 was obtained as
[4 + 3] Cycloaddition of 11: synthesis of 38 and 39
Ketone 11 was subjected to an α-chlorination, [4 + 3]
cycloaddition, and desilylation conditions using the proce-
dure described in the synthesis of ketone 20. Cycloadduct 38
and 39 were obtained and separated by hexane–EtOAC
(20:1).
38
Yield: 47%, colorless oil. IR (neat, cm–1): 3069 (m), 2950
1
(s), 2872 (s), 1730 (s), 1454 (m). H NMR (250 MHz,
CDCl3) δ: 4.84 (s, 1H), 4.80–4.73 (m, 1H), 2.45–2.30 (m,
3H), 2.26–2.09 (m, 2H), 2.00–1.80 (m 3H), 1.79–1.40 (m,
6H), 1.39–1.29 (m, 1H), 1.21–1.09 (m, 1H). 13C NMR
(62.9 MHz, CDCl3) δ: 221.3, 146.0, 115.4, 58.2, 51.7, 43.7,
41.5, 40.0, 36.7, 36.3, 33.8, 26.3, 19.8. Anal. calcd. for
C13H18O: C 82.06, H 9.53; found: C 81.92, H 9.65.
a white solid (0.04 g, 88%). mp 133–135 °C. [α]20 +17.78
D
(c 1.0, CHCl3). IR (KBr, cm–1): 3435–2372 (s), 2952 (s),
1697 (s), 1466 (m), 1249 (m), 1205 (s). 1H NMR (300 MHz,
CDCl3) δ: 12.00 (br, 1H), 5.50 (t, J = 8.4 Hz, 1H), 2.55 (d,
J = 13.4 Hz, 1H), 2.31 (d, J = 13.5 Hz, 1H), 2.15–1.81 (m,
5H), 1.77 (s, 3H), 1.72–1.60 (m, 2H), 1.25–1.10 (m, 2H),
1.02 (d, J = 15.0 Hz, 1H), 0.95 (d, J = 6.5 Hz, 3H), 0.89 (s,
3H), 0.88 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 183.5,
135.4, 125.9, 58.2, 52.0, 40.7, 39.1, 38.9, 38.2, 34.7, 29.7,
28.1, 26.4, 20.1. Anal. calcd. for C16H26O2: C 76.75, H
10.47; found: C 76.94, H 10.40.
39
Yield: 18%, colorless oil. IR (neat, cm–1): 3071 (w), 2957
1
(s), 2870 (m), 1737 (s), 1451 (m). H NMR (250 MHz,
CDCl3) δ: 4.80–4.65 (m, 2H), 2.70 (dd, J = 7.1, 15.0 Hz,
1H), 2.26–2.54 (m, 1H), 2.38 (dd, J = 3.2, 13.6 Hz, 1H),
2.30–2.07 (m, 5H), 1.91–1.27 (m, 8H). 13C NMR
(62.9 MHz, CDCl3) δ: 221.4, 145.8, 114.6, 58.5, 51.6, 44.8,
38.9, 36.1, 33.2, 30.0, 27.8, 26.2, 21.6. Anal. calcd. for
C13H18O: C 82.06, H 9.53; found: C 81.95, H 9.33.
Carboxy inversion: synthesis of (+)-dactylol (37)
[4 + 3] Cycloaddition of 12: synthesis of 45 and 46
Ketone 12 was subjected to an α-chlorination, [4 + 3]
cycloaddition, and desilylation conditions using the proce-
dure described in the synthesis of ketone 20. Cycloadducts
45 and 46 were obtained and separated by pentane–Et2O
(20:1).
A dried, 10 mL, round-bottomed flask was charged with
0.03 g (0.11 mmol) of acid 36, 2.0 mL of 20% solution of
COCl2 in toluene, and four drops of DMF. The mixture was
stirred at room temperature for 1 h, and then heated under
reflux for 30 min. The mixture was allowed to cool to room
temperature and was diluted with pentane (5 mL), filtered,
and concentrated. The resulting colorless oil was dissolved
in benzene (2.0 mL). m-CPBA (0.019 g, 0.11 mmol),
pyridine (0.1 mL, 0.12 mmol), and DMAP (0.005 g) were
added. The mixture was stirred at room temperature for
45
Yield: 57%, colorless oil. [α]20D +41.46 (c 1.0, CHCl3). IR
(neat, cm–1): 3070 (w), 2950 (s), 2863 (m), 1733 (s), 1456
1
(m). H NMR (250 MHz, CDCl3) δ: 4.87 (br s, 1H), 4.80 (t,
© 2006 NRC Canada

1468
Can. J. Chem. Vol. 84, 2006
J = 1.9 Hz, 1H), 2.49–2.36 (m, 3H), 2.30–2.13 (m, 2H),
1.99–1.62 (m, 5H), 1.55–1.22 (m, 4H), 1.16–1.05 (m, 1H),
1.00 (d, J = 6.2 Hz, 3H). 13C NMR (62.9 MHz, CDCl3) δ:
221.3, 145.8, 115.3, 59.1, 59.0, 43.7, 43.1, 40.3, 39.5, 37.4,
35.1, 31.9, 19.7, 18.2. HR-MS (EI) calcd. for C14H20O (M+):
204.1514; found: 204.1499.
52
Yield: 4%, colorless oil. IR (neat, cm–1): 3072 (w), 2948
(s), 2872 (s), 1738 (s), 1635 (w), 1455 (m). 1H NMR
(300 MHz, CDCl3) δ: 4.79–4.74 (m, 2H), 2.52–1.52 (m,
13H), 1.44–1.19 (m, 2H), 1.13 (d, J = 6.8 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ: 220.4, 145.6, 115.3, 59.6, 52.3,
50.8, 37.5, 35.7, 34.3, 30.7, 29.9, 29.6, 21.8, 15.6. HR-MS
(EI) calcd. for C14H20O (M+): 204.1514; found: 204.1524.
46
Yield: 9%, colorless oil. [α]20D –108.75 (c 1.0, CHCl3). IR
(neat, cm–1): 3070 (w), 2951 (s), 2866 (m), 1733 (s), 1449
(m). 1H NMR (250 MHz, CDCl3) δ: 4.80–4.73 (m, 2H), 2.72
(dd, J = 5.9, 12.5 Hz, 1H), 2.62–2.50 (m, 1H), 2.38 (dd, J =
2.9, 11.5 Hz, 1H), 2.27–1.61 (m, 8H), 1.40–1.22 (m, 2H),
1.09–0.95 (m, 2H), 1.00 (d, J = 5.4 Hz, 3H). 13C NMR
(62.9 MHz, CDCl3) δ: 221.4, 145.7, 114.7, 59.3, 58.3, 44.8,
39.1, 37.1, 34.4, 31.3, 31.2, 29.2, 26.2, 18.6. HR-MS (EI)
calcd. for C14H20O (M+): 204.1514; found: 204.1517.
[4 + 3] Cycloaddition of 19: synthesis of 53–56
Ketone 19 was subjected to an α-chlorination, [4 + 3]
cycloaddition, and desilylation conditions using the proce-
dure described in the synthesis of ketone 20. Cycloadducts
53–56 were obtained and separated by pentane–Et2O (30:1
to 10:1).
53
Yield: 11%, colorless oil. [α]20D +67.40 (c 1.0, CHCl3). IR
[4 + 3] Cycloaddition of 17: synthesis of 49–52
(neat, cm–1): 2950 (s), 2927 (s), 2867 (m), 1732 (s), 1455
(m), 1379 (m). H NMR (250 MHz, CDCl3) δ: 4.85 (br s,
Ketone 17 was subjected to an α-chlorination, [4 + 3]
cycloaddition, and desilylation conditions using the proce-
dure described in the synthesis of ketone 20. Cycloadducts
49–52 were obtained and separated by pentane–Et2O (20:1
to 10:1). Ketone 49 and 50 were not completely isolable.
The mixture was obtained as slightly yellow oil (41%). Fur-
ther chromatographic purification on silica gel (pentane–
Et2O, 30:1) afforded a sufficient amount of each isomer
along with a mixture of the two isomers.
1
1H), 4.80–4.78 (m, 1H), 2.45–2.36 (m, 1H), 2.30–1.90 (m,
7H), 1.80–1.57 (m, 3H), 1.50–1.40 (m, 1H), 1.38–1.23 (m,
2H), 1.04 (d, J = 6.3 Hz, 3H), 0.83 (d, J = 7.2Hz, 3H). 13C
NMR (62.9 MHz, CDCl3) δ: 221.1, 147.6, 115.2, 60.8, 53.4,
52.9, 46.6, 39.5, 39.3, 37.5, 34.1, 31.7, 28.1, 21.0, 15.1.
Anal. calcd. for C15H22O: C 82.52, H 10.16; found: C 82.67,
H 10.33.
54
49
Yield: 41%, colorless oil. [α]20D +34.55 (c 1.0, CHCl3). IR
[α]20 +62.08 (c 1.0, CHCl3). IR (neat, cm–1): 3072 (w),
D
(neat, cm–1): 2950 (s), 2933 (s), 2868 (m), 1731 (s), 1452
(m), 1165 (w). H NMR (250 MHz, CDCl3) δ: 4.92–4.88
(m, 1H), 4.85 (br s, 1H), 2.64–2.53 (m, 2H), 2.35–2.12 (m,
5H), 1.94–1.81 (m, 2H), 1.60–1.18 (m, 5H), 1.12 (d, J =
6.2 Hz, 3H), 0.93 (d, J = 6.3 Hz, 3H). 13C NMR (62.9 MHz,
CDCl3) δ: 223.6, 146.1, 114.2, 61.2, 58.7, 51.5, 48.0, 40.8,
28.3, 34.9, 34.8, 34.5, 30.7, 17.3, 15.1. Anal. calcd. for
C15H22O: C 82.52, H 10.16; found: C 82.36, H 9.97.
1
2949 (s), 2866 (s), 1731 (s), 1642 (m), 1452 (m). H NMR
1
(250 MHz, CDCl3) δ: 4.83 (s, 1H), 4.77 (t, J = 2.0 Hz, 1H),
2.46–2.33 (m, 2H), 2.31–2.15 (m, 2H), 2.13–2.00 (m, 2H),
1.99–1.84 (m, 2H), 1.81–1.61 (m, 3H), 1.59–1.24 (m, 3H),
1.22–1.08 (m, 1H), 1.04 (d, J = 66 Hz, 3H). 13C NMR
(62.9 MHz, CDCl3) δ: 220.8, 146.6, 115.1, 60.2, 52.7, 51.3,
46.1, 41.8, 39.2, 36.4, 33.6, 28.0, 26.3, 21.0. HR-MS (EI)
calcd. for C14H20O (M+): 204.1514; found: 204.1510.
55
50
Yield 12%, colorless oil. [α]20 +75.05 (c 1.0, CHCl3). IR
[α]20 +13.64 (c 1.0, CHCl3). IR (neat, cm–1): 3069 (w),
(neat, cm–1): 2950 (s), 2932 (s)D, 2863 (m), 1732 (s), 1456
(m), 1375 (m). H NMR (250 MHz, CDCl3) δ: 4.77 (br s,
1H), 4.75–4.72 (m, 1H), 2.71 (dd, J = 7.6, 14.9 Hz, 1H),
2.50–1.60 (m, 10H), 1.43–1.07 (m, 3H), 1.02 (d, J = 6.9 Hz,
3H), 1.00 (d, J = 6.5 Hz, 3H). 13C NMR (62.9 MHz, CDCl3)
δ: 220.8, 145.7, 114.8, 60.5, 58.1, 54.1, 38.7, 38.4, 37.2,
34.8, 34.6, 32.0, 31.3, 23.8, 18.6. Anal. calcd. for C15H22O:
C 82.52, H 10.16; found: C 82.39, H 10.19.
D
1
2934 (s), 2869 (m), 1733 (s), 1643 (m), 1456 (m). H NMR
1
(250 MHz, CDCl3) δ: 4.91–4.88 (m, 1H), 4.85 (br s, 1H),
2.64 (dd, J = 4.7, 12.6 Hz, 1H), 2.54 (d, J = 13.6 Hz, 1H),
2.38–2.12 (m, 5H), 1.99–1.41 (m, 7H), 1.28–1.17 (m, 1H),
1.12 (d, J = 6.0 Hz, 3H). 13C NMR (62.9 MHz, CDCl3) δ:
223.5, 146.3, 114.2, 57.9, 55.0, 51.6, 47.3, 40.1, 36.9, 34.3,
34.2, 30.7, 25.8, 15.1. HR-MS (EI) calcd. for C14H20O (M+):
204.1514; found: 204.1520.
56
51
Yield: 7%, colorless oil. [α]20 +32.17 (c 1.0, CHCl3). IR
Yield 7%, colorless oil. [α]20 +25.40 (c 1.0, CHCl3). IR
D
D
(neat, cm–1): 3072 (w), 2953 (s), 2871 (s), 1737 (s), 1637
(w), 1457 (m). H NMR (250 MHz, CDCl3) δ: 4.78–4.71
(neat, cm–1): 2956 (s), 2868 (s), 1737 (s), 1460 (m), 1169
(m), 1121 (w). H NMR (250 MHz, CDCl3) δ: 4.82–4.76
1
1
(m, 2H), 2.75–2.63 (m, 1H), 2.48–2.34 (m, 2H), 2.29–2.04
(m, 5H), 1.89–1.26 (m, 6H), 1.13 (dd, J = 6.7, 20.7 Hz, 1H),
1.04 (d, J = 7.0 Hz, 3H). 13C NMR (62.9 MHz, CDCl3) δ:
221.0, 145.8, 114.8, 59.8, 54.2, 51.5, 38.3, 37.5, 36.5, 34.7,
33.9, 30.1, 23.9, 21.6. HR-MS (EI) calcd. for C14H20O (M+):
204.1514; found: 204.1503.
(m, 2H), 2.53–1.61 (m, 12H), 1.50–1.18 (m, 2H), 1.11 (d,
J = 6.7 Hz, 3H), 0.89 (d, J = 7.2 Hz, 3H). 13C NMR
(62.9 MHz, CDCl3) δ: 220.5, 146.0, 115.7, 59.4, 54.3, 51.3,
36.9, 35.2, 35.0, 34.4, 33.4, 31.9, 29.4, 18.4, 15.4. Anal.
calcd. for C15H22O: C 82.52, H 10.16; found: C 82.51, H
9.99.
© 2006 NRC Canada

Harmata et al.
1469
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Acknowledgment
This paper is dedicated to Dr. Alfred R. Bader on the oc-
casion of his 80th birthday and as a tribute to his many con-
tributions to organic chemistry, art, scholarship, and
humanity. This work was supported by the National Science
Foundation, to whom we are grateful.
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© 2006 NRC Canada