SmI2-mediated dialdehyde 'radical then aldol' cyclization cascades: a feasibility study

Article abstract of DOI:10.1016/j.tet.2009.09.035

Dialdehydes undergo 'radical then aldol' cyclization cascades upon treatment with SmI₂, generating four contiguous stereocenters with high diastereocontrol. The scope of the process has been explored and the cascade has been extended to also in

Full text of DOI:10.1016/j.tet.2009.09.035

Tetrahedron 65 (2009) 10816–10829
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
SmI2-mediated dialdehyde ‘radical then aldol’ cyclization
cascades: a feasibility study
*
Matthew D. Helm, Madeleine Da Silva, David Sucunza, Madeleine Helliwell, David J. Procter
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2009
Received in revised form 24 August 2009
Accepted 7 September 2009
Available online 12 September 2009
Dialdehydes undergo ‘radical then aldol’ cyclization cascades upon treatment with SmI2, generating four
contiguous stereocenters with high diastereocontrol. The scope of the process has been explored and the
cascade has been extended to also include lactone reduction.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Samarium
Radical
Cyclization
Cascade
1. Introduction
cyclization of dialdehyde 1 to give 2 as the key step in their
approach (Scheme 1).8
Since its introduction to the synthetic community by Kagan,
samarium(II) iodide (SmI2) has become one of the most important
reducing agents in organic synthesis.1 The versatile, single electron-
transfer reagent has been used to mediate many processes ranging
from functional group interconversions to complex carbon–carbon
bond-forming sequences.1 In particular, cyclization reactions medi-
ated by the reagent have met many synthetic challenges in natural
product synthesis.1f In this context, we have introduced several ster-
eoselective cyclizations using the lanthanide reagent in recent
years.2–6 Of the many reducing agents available to the synthetic
chemist, SmI2 is the one reagent able to orchestrate powerful se-
quential processes.1a The development of sequential reactions in
which a number of transformations convert simple starting materials
to complex products, using a single reagent, in a single synthetic
operation, isone of the mostimportantgoalsof the synthetic chemist.
Here we report in full our feasibility studies on the development
of a dialdehyde cyclization cascade mediated by SmI2 in which the
aldehyde groups undergo stereoselective reaction in a programmed
sequence to give complex products.7
O
O
O
HO
SmI2 (3 eq)
EtO2C
O
O
MeOH (4.4 eq)
O
O
O
O
OBn
CO2Et
OBn
2
THF, –5 °C
15 min
1
87%
Scheme 1. Takahashi and Nakata’s SmI2-mediated cyclization en route to mucocin.
Carbonyl-alkene cyclizations using SmI2 are believed to proceed
by reduction of the aldehyde to the ketyl radical anion followed by
addition to the alkene.1,9 The transformation of 1 to 2 is therefore
remarkable as only one aldehyde is reduced by the reagent. The
authors observed that the use of excess SmI2 or prolonged reaction
times led to reduction of the second aldehyde and the formation of
complex product mixtures. Intrigued by this result, we speculated
that a new class of sequential cyclization mediated by SmI2 might be
possible using dialdehyde substrates: one aldehyde acts as a radical
precursor while the other remains unreactive until late in the se-
quence when it behaves as an electrophile. We envisaged several
classes of dialdehyde cascade from which we selected to study the
feasibility of the sequence using substrates 3. We proposed that
aldehyde group 1 would react first through a facile 5-exo-trig radical
cyclization while aldehyde group 2 waits in line. After radical cy-
clization, aldehyde group 2, in samarium enolates 4,10 would un-
dergo aldol cyclization to form tricyclic systems 5 (Scheme 2).
2. Results and discussion
In 2002 Takahashi and Nakata described
a synthesis of
mucocin that involved the SmI2-mediated, aldehyde–alkene
* Corresponding author. Fax: þ44 161 275 4939.
E-mail address: david.j.procter@manchester.ac.uk (D.J. Procter).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.035

M.D. Helm et al. / Tetrahedron 65 (2009) 10816–10829
10817
We have also prepared dialdehyde substrate 3g (n¼2) to in-
vestigate the feasibility of forming a seven-membered lactone ring
in the second stage of the cascade (Scheme 4). Vinyl triflate 7b
underwent palladium-catalyzed carbonylation in the presence of
butan-1,4-diol to give ester 8g in 61%. Deprotection and oxidation
gave dialdehyde 3g in 54% yield (two steps).
O
2
aldehyde 1
O
O
n
O
O
O
1
O
R2
R1
O
R3
3
carbonyl–alkene
radical cyclization
aldehyde 2
O
O
OTf
butan–1,3–diol
OTBS
20 mol% Pd(OAc)2
OTBS
O
O
SmIII
O
HO
O
n
HO
OH
CO, Ph3P, Et3N
DMF, 40 °C, 14 h
61%
SmIII
Sm–enolate
O
O
n
R2
R1 R2
aldol reaction
8g (3:1 dr)
7b (3:1 dr)
R1
R3
5
4
1. HF, py, MeCN
2. DMP, CH2Cl2
54% (2 steps)
R3
Scheme 2. Proposed sequential dialdehyde cyclizations mediated by SmI2.
O
O
Although an example of a ketyl-olefin cyclization/intermolecular
aldol sequence has been reported by Enholm,11 to our knowledge, no
intramolecular variants have been reported presumably as both al-
dehydes in the starting material would be expected to react with
SmI2 to give complex product mixtures. If successful, we anticipated
that the sequential cyclizations of 3, in which four contiguous ster-
eocenters, including one quaternary stereocenter, are generated,
would occur with high diastereocontrol.
O
O
3g (3:1 dr)
Scheme 4. Synthesis of dialdehyde cyclization substrate 3g (n¼2).
Finally, we prepared formate 10 to investigate the possibility of
trapping the Sm-enolate intermediate with a formate ester in
a ‘radical then Dieckman’ cyclization cascade (Scheme 5). Palladium-
catalyzed carbonylation of 7b in the presence of ethane-1,2-diol gave
ester 8h. Mitsunobu reaction with formic acid was used to introduce
the formate group14 and deprotection of the silyl ether gave 9. Fi-
nally, a Swern oxidation15 gave formate-aldehyde 10 in excellent
yield (Scheme 5).
We began by preparing a range of dialdehyde substrates 3 (n¼1)
by a modification of our previously reported route to related sub-
strates.6 Addition of an organocopper to cyclohexanones 6a–c gave
vinyl triflates 7a–f after trapping of the intermediate enolates
with Comins’ reagent N-(5-chloro-2-pyridyl)bis(trifluoromethane-
sulfonimide).12 Organocopper addition to cyclohexenone 6b gave 7b
and 7d as a 3:1 mixture of diastereoisomers. Palladium-catalyzed
carbonylation in the presence of propan-1,3-diol gave esters 8a–f in
moderate to good yield. Deprotection and oxidation using the Dess–
Martin periodinane13 gave dialdehydes 3a–3f (Scheme 3).
O
O
HO
ethane–1,2–diol
20 mol% Pd(OAc)2
OTBS
7b
O
R1
R2
6a R1 = R2 = H
(3:1 dr)
OTBS
CO, Ph3P, Et3N
DMF, 40 °C, 14 h
60%
6b R1 = H, R2 = Me
6c R1 = R2 = Me
8h (3:1 dr)
1. R3MgBr, CuI
2. Comins' reagent
–45 °C to RT
1. PPh3, DEAD
HCO2H, Tol, RT
16 h, 81%
2. HF, py, MeCN
0 °C to RT, 3 h
76%
7a R1 = R2 = H, R3 = C(Me)=CH2, 81%
OTf
7b R1 = H, R2 = Me, R3 = C(Me)=CH2, 78%, dr 3:1
7c R1 = R2 = H, R3 = but–3-enyl, 74%
R1
OTBS
R2
7d R1 = H, R2 = Me, R3 = but–3-enyl, 83%, dr ~3:1
7e R1 = R2 = H, R3 = Me, 73%
R3
propan–1,3–diol
7f R1 = R2 = Me, R3 = C(Me)=CH2, 64%
a
O
O
O
O
O
COCl2, DMSO
NEt3, CH2Cl2
O
20–40 mol% Pd(OAc)2, CO
Ph3P, Et3N
OH
O
O
O
DMF, 40–50 °C
–78 °C to RT
3 h, 97%
8a R1 = R2 = H, R3 = C(Me)=CH2, 92%
O
R1
R2
O
8b R1 = H, R2 = Me, R3 = C(Me)=CH2, 79%, dr 3:1
8c R1 = R2 = H, R3 = but–3-enyl, 52%
OTBS
9 (3:1 dr)
10 (3:1 dr)
OH
8d R1 = H, R2 = Me, R3 = but–3-enyl, 43%, dr ~3:1
8e R1 = R2 = H, R3 = Me, 63%
Scheme 5. Synthesis of ‘dialdehyde’ cyclization substrate 10.
R3
8f R1 = R2 = Me, R3 = C(Me)=CH2, 83%
1. HF, py, MeCN
2. DMP, CH2Cl2
With dialdehydes 3a–3f in hand we investigated the proposed
cyclization sequence. Pleasingly, upon treatment with SmI2, dial-
dehydes 3a–3e underwent double cyclization to give tricyclic
products 5a–5e in good yield and with excellent control in the
construction of four stereocenters (Scheme 6).16 The cyclization of
3b and 3d, 3:1 mixture of diastereoisomers, led to 5b and 5d as
similar diastereoisomeric mixtures that were readily separated by
chromatography. The structure of 5a and 5b was confirmed by
X-ray crystallography (Scheme 6).7
3a R1 = R2 = H, R3 = C(Me)=CH2, 72%
3b R1 = H, R2 = Me, R3 = C(Me)=CH2, 76%, dr 3:1
3c R1 = R2 = H, R3 = but–3-enyl, 94%
3d R1 = H, R2 = Me, R3 = but–3-enyl, 87%, dr ~3:1
3e R1 = R2 = H, R3 = Me, 73%
O
R1
R2
O
O
O
R3
3f R1 = R2 = Me, R3 = C(Me)=CH2, 63%
Scheme 3. Synthesis of dialdehyde cyclization substrates 3a–3f (n¼1). a 7f was formed by
cuprate addition (82%), followed by triflate formation in a separate step (LDA; Comins’
reagent, 78%). Comins’ reagent: N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide).

10818
M.D. Helm et al. / Tetrahedron 65 (2009) 10816–10829
O
O
H
OH
OH
SmI2 (2.5 eq)
OH
3g (3:1 dr)
t–BuOH, THF
0 °C
11 15%
O
O
H
O
O
H
HO
O
OH
SmI2 (2 eq)
O
+
10 (3:1 dr)
t–BuOH, THF
0 °C
12 21%
13 22%
Scheme 8. Unsuccessful cyclizations of 3g and 10.
(Scheme 9). Substrate 3f is an exception and the aldol cyclization
proceeds through attack on the top face of a Sm(III)-enolate 17 in
a different conformation (also Scheme 9).
Sm
R3
Sm
O
O
O
R2
O
O
H
O
R2
R3
Sm
O
O
H
H
R2
R1
R1
H
O
Sm
Sm
R1
O
16
15
14
O
O
R3
Sm
chelation–controlled
aldol cyclization
anti–radical cyclization
5a–e
3a–e
H
O
Sm O
Sm
O
17
(from 3f)
O
Scheme 6. Sequential dialdehyde cyclizations mediated by SmI2.
Scheme 9. Origin of diastereoselectivity in the dialdehyde cyclization sequence.
Interestingly, the sequential cyclization of 3f containing a gem-
dimethyl group gave 5f containing the opposite configuration at
the quaternary stereocenter constructed during the aldol stage of
the cascade (Scheme 7). The structure of 5f was confirmed by X-ray
crystallographic analysis.7 We have previously observed a similar
switch in diastereoselectivity in the protonation of an analogous
Sm(III)-enolate.6 It is likely that this switch is evidence of a different
conformation for the intermediate Sm-enolate where the most
accessible face is now the top face.
It is interesting to speculate on the origin of the apparent se-
lectivity for one aldehyde over the other in our studies, and in the
reduction reported by Takahashi and Nakata.8 Provided the cascade
begins with the addition of a ketyl radical anion to the alkene,9 we
believe that there are two possible explanations for the apparent
difference in reactivity of the two aldehydes.
1) It is thought that the reduction of carbonyl groups with SmI2 is
reversible, with the ketyl radical anion being drained from the
equilibrium by cyclization.17 As only aldehyde group 1 in 3 is
able to undergo facile cyclization, that aldehyde is seen to react
in the presence of the other.
2) It is well appreciated that pre-coordination of Lewis acidic sa-
marium to the carbonyl and unsaturated ester components in
ketyl-olefin cyclizations is important for promoting reaction
and controlling the diastereoselectivity of such additions.18 Pre-
coordination of samarium to the aldehyde and ester carbonyl
groups may increase the reactivity of the proximal aldehyde
group 1 leading to its selective reduction over the remote al-
dehyde (Scheme 10).
Scheme 7. Sequential cyclization of dialdehyde 3f mediated by SmI2.
Unfortunately, attempts to form a larger lactone ring in the second
stage of the cyclization were unsuccessful: treatment of 3g with SmI2
gave a complex mixture from which 11 was isolated in 15% yield
(Scheme 8). Similarly, attempts to carry out a ‘radical then Dieckman’
cascade using substrate 10 were unsuccessful: alcohol 12 and formate
13 were the major products isolated in a combined yield of 43%
(Scheme 8). Presumably, substrates 3g and 10 fail to undergo the
second stage of the cascade as protonation of the Sm-enolate in-
termediate is faster than cyclization to form a seven-membered ring.
We believe that the highly diastereoselective cascade reactions
begin with an anti-selective ketyl-olefin cyclization through tran-
sition structure 14 to give samarium enolates 15.10 Chelation to
Sm(III) leads to selective enolate formation and subsequently to
diastereoselective aldol cyclization through six-membered transi-
tion structure 16 on the most open bottom face of enolates 15
3 (n = 1)
R3
R3
R2
R2
O
O
H
H
H
R1
R1
O
O
1
O
O
Sm
Sm
2
O
O
pre–coordination
activates and 'delivers'
aldehyde 1
5
Scheme 10. Pre-coordination as a possible origin of selectivity.

M.D. Helm et al. / Tetrahedron 65 (2009) 10816–10829
10819
Finally, we have studied the feasibility of extending the cascade
O
O
O
O
to include reduction of the lactone ring in the products (Scheme 11).
We have recently reported the first reductions of some simple ali-
phatic esters and lactones using SmI2 with water as a cosolvent.19,20
The reduction of lactones using SmI2–H2O is particularly selective in
that only six-membered lactones are reduced in the presence of
other lactones and esters.19 We have proposed that anomeric sta-
bilization of the radical anion formed by electron transfer from
Sm(II) to the lactone carbonyl is crucial for the success of the re-
ductions and therefore, the conformation of the radical-anion in-
termediates (and the lactone starting materials) is important.
SmI2
O
O
H
OH
OH
THF, t–BuOH
0 °C
3e
5e
then SmI2
THF, H2O
RT
HO HO
18e
H
76%, >95:5 dr
OH
OH
OH
HO
O
O
O
O
Scheme 13. One-pot, additive-controlled dialdehyde reaction cascade.
radical
HO
lactone
OH
OH
cyclization
reduction?
R2
R1
O
O
HO
3. Experimental
3.1. General methods and procedures
R1 R2
R1 R2
aldol
cyclization
R3
R3
R3
3
5
18
Scheme 11. Extending the dialdehyde cyclization cascade.
All reactions were carried out under an inert nitrogen atmosphere
unless otherwise stated. Glassware for inert atmosphere reactions
was oven-dried and cooled under a flow of nitrogen. Tetrahydrofuran
(THF) was distilled over sodium wire and benzophenone, CH2Cl2,
toluene and triethylamine were distilled over calcium hydride and
dimethyl formamide (DMF) was dried over activated molecular
sieves. All other solvents and reagents were purchased from com-
mercial sources and used as supplied. 1H NMR spectra were recorded
on a 300, 400 or 500 MHz spectrometer; 13C NMR spectra were
recorded on a 75, 100 or 125 MHz spectrometer. All chemical shift
values are reported in parts per million, with coupling constants in
hertz. The notation of signals is: dH chemical shift in ppm (number of
protons, multiplicity, J value(s), proton assignment). dC chemical shift
inppm (carbon assignment). If assignment is ambiguous, for example
in the case of overlapping aromatic signals, a range of shifts is
reported. Routine TLC analysis was carried out on aluminium sheets
coated with silica gel 60 F254, 0.2 mm thickness. Solvent systems
were petroleum ether 40–60/ethyl acetate. Plates were viewed with
a 254 nm ultraviolet lamp and dipped in aqueous potassium per-
manganate, p-anisaldehyde or DNP. Flash column chromatography
We began by studying the final, lactone reduction stage of the
extended sequence. Treatment of spirocyclic lactones 5c and 5e
with SmI2–H2O gave the expected tetraols 18c and 18e in good yield
(Scheme 12).
OH OH
SmI2 (8 eq)
H
5c
OH
OH
H2O, THF
0 °C to RT
81%
18c
OH OH
SmI2 (8 eq)
H
5e
OH
OH
H2O, THF
0 °C to RT
94%
18e
Scheme 12. Lactone reduction using SmI2–H2O.
Interestingly, attempted reduction of spirocyclic lactones 5b, 5d
and 5f returned only starting material. We believe the conforma-
tion of the lactone ring in 5b, 5d and 5f renders the lactone carbonyl
unreactive to SmI2–H2O. This hypothesis is supported in part by
X-ray crystallographic data (Schemes 6 and 7): the chair confor-
mation of the lactone rings in 5c and 5e facilitates reduction to give
axial radical anions stabilized by the anomeric effect,19 whereas the
distorted chair conformation of the lactone ring in 5b or the boat
conformation in 5f renders the lactone carbonyl unreceptive to
electron transfer.19
was carried out on 40–63 mm, 60A silica gel. Low-resolution mass and
high-resolution mass spectra were obtained using electron impact
ionisation (EI) and chemical ionisation (CI) techniques, or positive
and/or negative electrospray ionisation (ES). Melting points were
measured on a variable heater apparatus and are uncorrected. IR
spectra were recorded on a FTIR spectrometer as evaporated films
(from CH2Cl2) or neat, using sodium chloride windows.
3.2. General procedure 1. Formation of vinyl triflates 7a–f
We next investigated the extended cascade reaction. Although
attempts to carry out a one-pot sequence using SmI2–H2O were
unsuccessful,21 successive one-pot treatment of 3e with SmI2 in
THF/t-BuOH and SmI2–H2O gave 18e in 76% yield (Scheme 13).
In summary, we have shown the feasibility of SmI2-mediated,
dialdehyde, ‘radical then aldol’ cyclization cascades in which one
aldehyde is reduced while the other waits in line. In the cascade
reactions studied here, two rings and four contiguous stereo-
centers are generated with high diastereocontrol. We have also
identified some current limitations of the approach. We believe
the cascade reaction of dialdehydes constitutes a new class of
SmI2-mediated sequence.1a Finally, we have shown the feasibility
of extending the cascade sequence to include lactone reduction.
These studies provide a further illustration of the remarkable
selectivity possible in the reduction of lactones with SmI2–H2O
and raise the possibility of using conformational change to ‘switch
on’ reactivity in SmI2-mediated chemistry.
To a stirred suspension of copper(I) iodide in THF at ꢀ45 ꢁC was
added a solution of the Grignard reagent over 30 min. After stirring
for a further 30 min, a solution of the a,b-unsaturated ketone 6a–c
in THF was added dropwise. The reaction was stirred at ꢀ45 ꢁC until
the disappearance of the a,b-unsaturated ketone was observed by
TLC analysis of the reaction mixture, this generally occurred after
approximately 1 h. A solution of Comins’ reagent in THF was added
and the reaction was allowed to warm to room temperature and
stirred until completion as judged by TLC analysis. The reaction was
quenched by the addition of aqueous saturated NH4Cl and the
aqueous phase was extracted with Et2O (ꢂ3). The combined or-
ganic fractions were dried (Na2SO4) and concentrated in vacuo. The
crude vinyl triflate was purified by chromatography on silica gel.
3.2.1. 3-(3-(tert-Butyldimethylsilyloxy)propyl)-3-(prop-1-en-2-yl)-
cyclohex-1-enyl trifluoromethanesulfonate 7a. General procedure 1

10820
M.D. Helm et al. / Tetrahedron 65 (2009) 10816–10829
using isopropenyl magnesium bromide in THF (0.50 M, 16.0 mL,
8.00 mmol), copper(I) iodide (1.52 g, 8.00 mmol) in THF (8 mL), 3-(3-
(tert-butyldimethylsilyloxy)propyl)cyclohex-2-enone6 6a (1.07 g,
3.99 mmol) in THF (4 mL) and Comins’ reagent (3.46 g, 8.81 mmol)
in THF (9 mL) after 24 h gave 7a (1.44 g, 3.25 mmol, 81%) as a col-
1143 (m), 1004 (w), 835 (w). MS (EIþ) m/z (%): 471 (100, MþH); Calcd
for C21H: 470.2128. Found: 470.2131.
3.2.5. 3-(3-(tert-Butyldimethylsilyloxy)propyl)-3-methylcyclohex-1-
enyl trifluoromethanesulfonate 7e. General procedure
1 using
ourless oil. 1H NMR (CDCl3, 300 MHz)
d
0.05 (6H, s, Si(CH3)2), 0.90
MeMgBr in Et2O (3.00 M, 3.10 mL, 9.32 mmol), copper(I) iodide
(1.78 g, 9.32 mmol) inTHF (36 mL), 3-(3-(tert-butyldimethylsilyloxy)-
propyl)cyclohex-2-enone6 6a (1.00 g, 3.72 mmol) in THF (10 mL) and
Comins’ reagent (2.92 g, 7.43 mmol) in THF (6 mL) after 12 h gave 7e
(1.13 g, 2.71 mmol, 73%) as a pale yellow oil. 1H NMR (CDCl3,
(9H, s, C(CH3)3), 1.22–1.53 (4H, m, CH2), 1.55–1.80 (4H, m, CH2), 1.70
(3H, m, H2C]CCH3), 2.27 (2H, m, CH2COS), 3.58 (2H, m, CH2CH2O),
4.70 (1H, dd, J¼0.7, 1.6 Hz, C]CH2), 4.94 (1H, t, J¼1.5 Hz, C]CH2),
5.73 (1H, s, HC]COS). 13C NMR (CDCl3, 75 MHz)
d
ꢀ5.3 (Si(CH3)2),
18.3 (C(CH3)3), 18.7 (H2C]CCH3),19.0 (CH2CH2COS), 25.9 (SiC(CH3)3),
27.3 (CH2CH2O), 27.9 (CH2COS), 31.6 (CCH2(CH2)2COS), 35.1
(CCH2(CH2)2O), 45.3 (C), 63.2 (CH2O), 114.6 (H2C]C), 124.3
(HC]COS), 147.8 (HC]COS), 149.2 (C]CH2). CF3 not observed. nmax
(thin film/cmꢀ1): 2952 (s), 2891 (m), 2859 (s), 1686 (m), 1637 (m),
1418 (s), 1248 (s), 1209 (s). MS (ESþ) m/z (%): 443 (10, MþH), 460 (14,
MþNH4), 465 (100, MþNa). HRMS: calcd for C19 (MþH): 443.1894.
Found: 443.1897.
500 MHz) d 0.05 (6H, s, Si(CH3)2), 0.90 (9H, s, C(CH3)3), 1.04 (3H, s,
CCH3), 1.31–1.43 (3H, m, CH2(CH2)2O, 1H from CH2(CH2)2COS), 1.43–
1.59 (3H, m, CH2CH2O, 1H from CH2(CH2)2COS), 1.73–1.87 (2H, m,
CH2CH2COS), 2.22–2.33 (2H, m, CH2COS), 3.59 (2H, t, J¼6.3 Hz, CH2O),
5.51 (1H, s, CH]COS). 13C NMR (CDCl3, 125 MHz)
d
ꢀ5.3 (Si(CH3)2),
18.3 (C(CH3)3), 19.5 (CH2CH2COS), 25.9 (C(CH3)3), 26.7 (CCH3), 27.4
(CH2CH2O), 27.6 (CH2COS), 33.4 (CH2CH2CH2COS), 35.6 (C), 38.2
(CH2(CH2)2O), 63.5 (CH2O),127.1 (CH]COS),148.5 (CH]COS), CF3 not
observed. nmax (thin film/cmꢀ1): 2915 (w), 2857 (w), 1418 (m), 1361
(m), 1247 (m), 1208 (m), 1143 (m), 1099 (w). MS (ESþ) m/z (%): 325
(34), 417 (54, MþH), 434 (100, MþNH4), 439 (31, MþNa). HRMS:
Calcd for C17H35O4NF3SSi (MþNH4): 434.2003. Found: 434.2004.
3.2.2. rac-(3R,6R)-3-(3-(tert-Butyldimethylsilyloxy)propyl)-6-
methyl-3-(prop-1-en-2-yl)cyclohex-1-enyl trifluoromethanesulfonate
7b. For the preparation of 7b, see Ref. 6.
3.2.3. 3-(But-3-enyl)-3-(3-(tert-butyldimethylsilyloxy)propyl)-
cyclohex-1-enyl trifluoromethanesulfonate 7c. General procedure 1
using butenyl magnesium bromide in THF (0.52 M, 20.0 mL,
10.4 mmol), copper(I) iodide (2.06 g, 10.6 mmol) in THF (36 mL), 3-
(3-(tert-butyldimethylsilyloxy)propyl)cyclohex-2-enone6 6a (1.12 g,
4.16 mmol) in THF (10 mL) and Comins’ reagent (3.26 g, 8.32 mmol)
in THF (6 mL) after 12 h gave 7c (1.40 g, 3.07 mol, 74%) as a pale
3.2.6. 3-(3-(tert-Butyldimethylsilyloxy)propyl)-6,6-dimethyl-3-(prop-
1-en-2-yl)cyclohex-1-enyl trifluoromethanesulfonate 7f. To a stirred
suspension of copper(I) iodide (926 mg, 4.86 mmol) in THF (5.00 mL)
at ꢀ45 ꢁC was added a solution of isopropenyl magnesium bromide
(0.50 M, 9.73 mL, 4.86 mmol) in THF over 30 min. After stirring for
a further 30 min, a solution of 3-(3-(tert-butyldimethylsilyloxy)-
propyl)-6,6-dimethylcyclohex-2-enone6 6c (721 mg, 2.43 mmol) in
THF (2.50 mL) was added dropwise. The reaction was stirred at
ꢀ45 ꢁC for 1 h before the reaction was quenched by the addition of
aqueous saturated NH4Cl (10 mL) and upon warming to ambient
temperature the aqueous phase was extracted with Et2O (20 mLꢂ3).
The combined organic fractions were dried (Na2SO4) and concentrated
in vacuo. The crude product was subsequently purified by chroma-
tography on silica gel to give 5-(3-(tert-butyldimethylsilyloxy)-
yellow oil. 1H NMR (CDCl3, 500 MHz)
d 0.06 (6H, s, Si(CH3)2); 0.90
(9H, s, C(CH3)3), 1.38–1.53 (8H, m, CH2), 1.83–1.77 (2H, m,
CH2CH2COS), 2.02 (2H, q, J¼8.3 Hz, CH2CH]CH2), 2.28 (2H, t,
J¼6.3 Hz, CH2COS), 3.59 (2H, t, J¼6.3 Hz, CH2O), 4.95 (1H, dd, J¼10.1,
1.8 Hz, cis CH2]CH), 5.02 (1H, dd, J¼17.2,1.8 Hz, trans CH2]CH), 5.54
(1H, s, HC]COS), 5.79 (1H, ddt, J¼17.1, 10.1, 6.7 Hz, CH]CH2). 13C
NMR (CDCl3, 125 MHz)
d
ꢀ5.4 (Si(CH3)2), 18.3 (C(CH3)3), 19.3
(CH2CH2COS), 25.9 (C(CH3)3), 27.1 (CH2), 27.5 (CH2COS), 28.1
(CH2CH]CH2), 31.1 (CH2), 35.3 (CH2), 38.2 (CH2), 38.5 (C), 63.3
(CH2O), 114.5 (H2C]CH), 126.1 (CH]COS), 138.6 (CH]CH2), 148.9
(C]COS). CF3 not observed. nmax (thin film/cmꢀ1): 2938 m (s), 1419
(s),1142 (m),1004 (w), 836 (w). MS (ESþ) m/z (%): 474 (100, MþNH4);
Calcd for C20H (MþH): 457.2050. Found: 457.2045.
propyl)-2,2-dimethyl-5-(prop-1-en-2-yl)cyclohexanone
(678 mg,
0.03
2.00 mmol, 82%) as a colourless oil. 1H NMR (CDCl3, 400 MHz)
d
(6H, s, Si(CH3)2), 0.88 (9H, s, C(CH3)3),1.05 (3H, s, C(CH3)2), 1.11 (3H, s,
C(CH3)2), 1.18–1.39 (4H, m, CH2), 1.50–1.60 (2H, m, CH2), 1.64 (3H, s,
H2C]CCH3),1.68–1.87 (2H, m, CH2), 2.29 (1H, d, J¼14.6 Hz, C(O)CH2),
2.61 (1H, dd, J¼14.6, 2.3 Hz, C(O)CH2), 3.44–3.62 (2H, m, CH2O), 4.69
(1H, s, C]CH2), 4.91 (1H, s, C]CH2).13C NMR (CDCl3,100 MHz)
d
ꢀ5.3
3.2.4. rac-(3S,6R)-3-(But-3-enyl)-3-(3-(tert-butyldimethylsilyloxy)-
propyl)-6-methylcyclohex-1-enyl trifluoromethanesulfonate 7d. Gen-
eral procedure 1 using butenyl magnesium bromide in THF (0.50 M,
17.7 mL, 8.85 mmol), copper(I) iodide (1.76 g, 9.20 mmol) in THF
(25 mL), 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-methylcyclohex-
2-enone6 6b (1.00 g, 3.54 mmol) in THF (10 mL) and Comins’ reagent
(2.78 g, 7.08 mmol) in THF (6 mL) after 12 h gave 7d (1.39 g,
2.95 mmol, 83%; dr 3:1) as a pale yellow oil. 1H NMR (CDCl3, 500 MHz)
(Si(CH3)2), 18.4 (C(CH3)3), 18.9 (H2C]CCH3), 25.4 (C(CH3)2), 25.8
(C(CH3)2), 26.0 (C(CH3)3), 27.0 (CH2), 30.7 (CH2), 34.8 (CH2), 35.8
(CH2), 44.2 (C), 47.0 (C(O)CH2), 47.4 (C(O)C(CH3)2), 63.3 (CH2O), 114.2
(C]CH2), 147.4 (C]CH2), 216.1 (C]O). nmax (thin film/cmꢀ1): 2936
(s), 2859 (m), 1706 (s, C]O), 1637 (w), 1462 (m), 1385 (w), 1255 (m),
1201 (w), 1101 (s). MS (ESþ) m/z (%): 247 (50, (M-SiMe2t-Bu)þNa),
339 (5, MþH), 361 (100, MþNa). HRMS: calcd for C20H38O2NaSi
(MþNa): 361.2533. Found: 361.2525. To a stirred solution of diiso-
propylamine (0.32 mL, 2.26 mmol) in THF (2.00 mL) at ꢀ78 ꢁC was
added a solution of n-butyllithium in hexanes (2.15 M, 1.05 mL,
2.26 mmol). After stirring for 20 min, a solution of 5-(3-(tert-butyl-
dimethylsilyloxy)propyl)-2,2-dimethyl-5-(prop-1-en-2-yl)cyclohex-
anone (638 mg, 1.88 mmol) in THF (2.00 mL) was added dropwise.
After 1 h, a solution of Comins’ reagent (1.48 g, 3.77 mmol) in THF
(4 mL) was added and the reaction was stirred for 2 h at ꢀ78 ꢁC be-
fore being allowed to warm to 0 ꢁC and stirred for 1 h. The reaction
was quenched with water (10 mL) and the aqueous phase was
extracted with Et2O (10 mLꢂ3). The combined organic fractions were
washed with ice cold aqueous NaOH (0.1 M, 5 mLꢂ2) before being
dried (Na2SO4) and concentrated in vacuo. Purification by chroma-
tography on silica gel gave 7f (691 mg,1.47 mmol, 78%) as a colourless
d
0.05 (s, Si(CH3)2, minor diastereoisomer), 0.06 (6H, s, Si(CH3)2), 0.90
(9H, s, C(CH3)3), 1.14 (3H, d, J¼7.0 Hz, CHCH3), 1.32–1.47 (9H, m, CH2),
1.85–1.94 (1H, m, 1H from CH2CHCH3), 1.94–2.01 (2H, m,
CH2CH]CH2), 2.44(1H, sextet, J¼6.5 Hz, CHCH3), 3.59 (2H, t, J¼5.8 Hz,
CH2O), 4.95 (dd, J¼10.1, 1.8 Hz, cis CH2]CH, minor diastereoisomer),
4.96 (1H, dd, J¼10.1, 1.8 Hz, cis CH2]CH), 5.02 (dd, J¼17.1, 1.8 Hz, trans
CH2]CH, minor diastereoisomer), 5.03 (1H, dd, J¼17.1, 1.8 Hz, trans
CH2]CH), 5.49 (1H, s, HC]COS), 5.80 (1H, ddt, J¼17.2, 10.4, 6.70 Hz,
CH]CH2). 13C NMR (CDCl3,125 MHz,)
d
ꢀ5.3 (Si(CH3)2), 17.8 (CHCH3),
18.3 (C(CH3)3), 25.9 (C(CH3)3), 27.1 (CH2CH2O), 28.0 (CH2CHCH3), 28.3
(CH2CH]CH2), 29.2 (CH2CH2CHCH3), 32.3 (CHCH3), 35.3
(CH2(CH2)2O), 38.3 (CH2CH2CHCH3), 38.8 (C), 63.4 (CH2O), 114.5
(H2C]CH), 118.5 (q, J¼319.7 Hz, CF3), 125.8 (HC]COS), 138.6
(CH]CH2),152.8 (HC]COS). nmax (thin film/cmꢀ1): 2935 (m),1416 (s),
oil. 1H NMR (CDCl3, 400 MHz)
d 0.05 (6H, s, Si(CH3)2), 0.90 (9H, s,

M.D. Helm et al. / Tetrahedron 65 (2009) 10816–10829
10821
C(CH3)3), 1.12 (3H, s, C(CH3)2), 1.14 (3H, s, C(CH3)2), 1.31–1.55 (6H, m,
CH2), 1.57–1.69 (2H, m, CH2), 1.71 (3H, s, H2C]CCH3), 3.52–3.65 (2H,
m, CH2O), 4.75 (1H, s, C]CH2), 4.93 (1H, s, C]CH2), 5.60 (1H, s,
29.1 (CHCH3), 30.2 (CH2), 32.0 (CH2CH2OH), 34.5 (CH2), 44.6 (C), 59.2
(CH2OH), 61.0 (C(O)OCH2), 63.4 (CH2OSi), 113.0 (H2C]C), 134.8
(C(O)C]CH), 144.7 (C(O)C]CH), 149.0 (H2C]C), 168.2 (C]O). 1H
HC]COS). 13C NMR (CDCl3,100 MHz)
d
ꢀ5.3 (Si(CH3)2), 18.3 (C(CH)3),
NMR (CDCl3, 500 MHz, minor diastereoisomer) d 0.05 (6H, s,
18.7 (H2C]CCCH3), 25.6(C(CH3)2), 25.9(C(CH3)3), 26.4(C(CH3)2), 27.3
(CH2), 28.7 (CH2), 35.0 (CH2), 35.2 (CH2), 35.3 (C(CH3)2), 46.3 (C), 63.2
(CH2O), 114.6 (C]CH2), 122.1 (HC]COS), 147.7 (C]CH2), 155.6
(HC]COS). CF3 not observed. nmax (thin film/cmꢀ1): 2932 (s), 2891
(m), 2863 (s), 1670 (w), 1634 (w), 1463 (w), 1414 (s), 1366 (w), 1248
(m). MS (ESþ) m/z (%): 471 (10, MþH), 493 (100, MþNa). HRMS: calcd
for C21H37O4F3NaSSi (MþNa): 493.2026. Found: 493.2035.
Si(CH3)2),0.90(9H,s,C(CH3)3),1.07(3H, d,J¼6.9 Hz,CHCH3),1.33–1.81
(8H, m, CH2), 1.72 (3H, s, H2C]CCH3), 1.92 (2H, quintet, J¼6.1 Hz,
OCH2CH2CH2O), 2.06 (1H, br s, OH), 2.54–2.72 (1H, m, CHCH3), 3.50–
3.65 (2H, m, CH), 3.71 (2H, br s, CH), 4.33 (2H, t, J¼6.0 Hz, CH2OC(O)),
4.53(1H, s, C]CH2), 4.89(1H, s, C]CH2), 6.86(1H, s, C(O)C]CHC).13
C
NMR (CDCl3,125 MHz, minor diastereoisomer)
d
ꢀ5.3 (Si(CH3)2),18.3
(C(CH3)3), 18.8 (CHCH3), 19.8 (H2C]CCH3), 26.0 (SiC(CH3)3), 26.5
(CH2), 27.5 (CH2), 28.1 (CHCH3), 30.2 (CH2), 32.0 (CH2CH2OH), 35.0
(CH2), 44.9 (C), 59.2 (CH2OH), 61.0 (C(O)OCH2), 63.4 (CH2OSi), 114.3
(H2C]C),134.7 (C(O)C]CH),145.0 (C(O)C]CH),147.9 (H2C]C),167.9
(C]O). nmax (thin film/cmꢀ1): 3468 (br), 2931 (m), 2858 (w),1705 (m,
C]O), 1458 (w), 1377 (w), 1249 (s), 1097 (m). MS (ESþ) m/z (%): 433
(100, MþNa). HRMS: calcd for C23H46O4NSi (MþNH4): 428.3191.
Found: 428.3193.
3.3. General procedure 2. Carbonylative coupling of vinyl
triflates 7a–f with a diol to give 8a–8h
Carbon monoxide gas was bubbled through a suspension of the
vinyl triflate (1 equiv), palladium acetate (0.2 or 0.4 equiv), tri-
phenylphosphine (0.4 or 0.8 equiv), diol (40 equiv) and triethyl-
amine (2 equiv) in DMF for 30 min. The reaction was then heated at
40 or 50 ꢁC under an atmosphere of carbon monoxide until the
disappearance of the vinyl triflate was observed by TLC analysis.
Upon cooling, the reaction was quenched with water and extracted
with Et2O (ꢂ3). The combined organic extracts were dried (Na2SO4)
and concentrated in vacuo. The crude products were purified by
chromatography on silica gel.
3.3.3. 3-Hydroxypropyl 3-(but-3-enyl)-3-(3-(tert-butyldimethyl-
silyloxy)propyl)cyclohex-1-enecarboxylate 8c. General procedure
2 using 3-(but-3-enyl)-3-(3-(tert-butyldimethylsilyloxy)propyl)-
cyclohex-1-enyl trifluoromethanesulfonate 7c (230 mg, 0.504 mmol),
palladium acetate (23.0 mg, 0.101 mmol), triphenylphosphine
(53.0 mg, 0.201 mmol), propan-1,3-diol (1.46 mL, 20.1 mmol) and
triethylamine (0.140 mL, 1.01 mmol) in DMF (1.7 mL) at 40 ꢁC
gave, after 12 h, 8c (107 mg, 0.261 mmol, 52%) as a yellow oil. 1H
3.3.1. 3-Hydroxypropyl 3-(3-(tert-butyldimethylsilyloxy)propyl)-3-
(prop-1-en-2-yl)cyclohex-1-enecarboxylate 8a. General procedure 2
using 3-(3-(tert-butyldimethylsilyloxy)propyl)-3-(prop-1-en-2-yl)-
cyclohex-1-enyl trifluoromethanesulfonate 7a (868 mg, 1.96 mmol),
palladium acetate (88.0 mg, 0.392 mmol), triphenylphosphine
(206 mg, 0.784 mmol), propan-1,3-diol (5.67 mL, 78.4 mmol) and
triethylamine (0.547 mL, 3.92 mmol) in DMF (10 mL) at 40 ꢁC gave,
after 24 h, 8a (717 mg, 1.81 mmol, 92%) as a yellow oil. 1H NMR
NMR (CDCl3, 500 MHz)
d 0.04 (6H, s, Si(CH3)2), 0.89 (9H, s,
C(CH3)3), 1.36–1.51 (8H, m, CH2), 1.62–1.67 (2H, m, CH2CH2CC(O)),
1.91 (2H, quintet, J¼6.0 Hz, OCH2CH2CH2O), 1.97–2.04 (2H, m,
CH2CH]CH2), 2.20 (2H, t, J¼6.0 Hz, CH2CC]O), 3.57 (2H, t,
J¼6.0 Hz, CH2OSi), 3.70 (2H, t, J¼6.0 Hz, CH2OH), 4.30 (2H, t,
J¼6.0 Hz, CH2OC(O)), 4.93 (1H, d, J¼10.1 Hz CH]CH2 cis), 5.00
(1H, d, J¼17.1 Hz, CH]CH2 trans), 5.78 (1H, ddt, J¼17.7, 10.1,
6.5 Hz, CH]CH2), 6.74 (1H, s, C(O)C]CHC). 13C NMR (125 MHz,
(CDCl3, 300 MHz) d 0.05 (6H, s, Si(CH3)2), 0.89 (9H, s, C(CH3)3), 1.15–
1.80 (8H, m, CH2), 1.72 (3H, m, H2C]CCH3), 1.92 (2H, quintet,
J¼6.0 Hz, OCH2CH2CH2O), 2.06–2.35 (2H, m, CH2C]CH), 3.58 (2H, m,
CH), 3.71 (2H, t, J¼5.8 Hz, CH2OH), 4.32 (2H, t, J¼5.8 Hz, CH2OC(O)),
4.58 (1H, dd, J¼0.8, 1.7 Hz, C]CH2), 4.90 (1H, t, J¼1.5 Hz, C]CH2),
CDCl3)
d
ꢀ5.64 (Si(CH3)2), 18.4 (C(CH3)3), 18.9 (CH2CH2CC(O)),
24.3 (CH2CC(O)), 26.0 (C(CH3)3), 27.2 (CH2), 28.2 (CH2CH]CH2),
31.4 (CH2), 31.9 (CH2CH2OH), 35.1 (CH2), 37.7 (C), 38.4 (CH2), 59.2
(CH2OH), 61.2 (CH2OC(O)), 63.6 (CH2OSi), 114.3 (CH2]CH), 129.3
(HC]CC(O)), 139.0 (CH]CH2), 147.4 (HC]CC(O)), 168.1 (C]O).
nmax (thin film/cmꢀ1): 3427 (s), 2932 (s), 2857 (s), 1712 (s, C]O),
1641 (w), 1460 (w), 1389 (w), 1268 (s), 1098 (s), 1055 (m), 972 (w),
911 (w), 836 (s), 776 (m). MS (ESþ) m/z (%): 433 (100, MþNa).
HRMS: Calcd for C23H (MþNa): 433.2745. Found: 433.2741.
6.95 (1H, s, C(O)C]CHC).13C NMR (CDCl3,100 MHz)
d
ꢀ5.3 (Si(CH3)2),
18.4 (C(CH3)3), 18.6 (CH2), 18.8 (H2C]CCH3), 24.8 (CH2), 26.0
(C(CH3)3), 27.4 (CH2), 31.8 (CH2), 31.9 (CH2), 34.9 (CH2), 44.6 (C), 59.3
(CH2OH), 61.2 (CH2OC(O)), 63.4 (CH2OSi), 114.1 (H2C]C), 129.7
(HC]CC(O)), 145.3 (HC]CC(O)), 148.4 (H2C]C), 167.9 (C]O). nmax
(thin film/cmꢀ1): 3411 (br), 2950 (s), 2892 (m), 2858 (s), 1713 (s,
C]O), 1643 (w), 1470 (w), 1389 (w), 1257 (s), 1098 (s). MS (ESþ) m/z
(%): 397 (10, MþH), 414 (15, MþNH4), 419 (100, MþNa). HRMS: calcd
for C22H41O4Si (MþH): 397.2769. Found: 397.2764.
3.3.4. rac-(3S,6R)-3-Hydroxypropyl 3-(but-3-enyl)-3-(3-(tert-butyl-
dimethylsilyloxy)propyl)-6-methylcyclohex-1-enecarboxylate
8d. General procedure 2 using rac-(3S,6R)-3-(but-3-enyl)-3-(3-(tert-
butyldimethylsilyloxy)propyl)-6-methylcyclohex-1-enyl trifluoro-
methanesulfonate 7d (1.59 g, 3.38 mmol, dr 3:1), palladium acetate
(152 mg, 0.676 mmol), triphenylphosphine (354 mg, 1.35 mmol),
propan-1,3-diol (9.70 mL, 135 mmol) and triethylamine (0.942 mL,
6.76 mmol) in DMF (11.2 mL) at 40 ꢁC, after 12 h, gave 8d (618 mg,
1.46 mmol, 43%, dr 3:1) as a yellow oil. 1H NMR (CDCl3, 500 MHz)
3.3.2. rac-(3R,6R)-3-Hydroxypropyl 3-(3-(tert-butyldimethylsilyloxy)-
propyl)-6-methyl-3-(prop-1-en-2-yl)cyclohex-1-enecarboxylate
8b.
General procedure 2 using rac-(3R,6R)-3-(3-(tert-butyldimethylsilyl-
oxy)propyl)-6-methyl-3-(prop-1-en-2-yl)cyclohex-1-enyl trifluoro-
methanesulfonate 7b6 (301 mg, 0.659 mmol, dr 3:1), palladium
acetate (30.0 mg, 0.132 mmol), triphenylphosphine (69.0 mg,
0.264 mmol), propan-1,3-diol (1.43 mL, 19.8 mmol) and triethyl-
amine (0.184 mL, 1.32 mmol) in DMF (3 mL) at 40 ꢁC, after 16 h, gave
8b (214 mg, 0.521 mmol, 79%, dr 3:1) as a yellow oil. 1H NMR (CDCl3,
d
0.04 (6H, s, Si(CH3)2), 0.88 (9H, s, C(CH3)3), 1.02 (3H, d, J¼6.8 Hz,
CH3), 1.04 (d, J¼6.8 Hz, CH3 (minor diastereoisomer)), 1.24–1.62 (9H,
m, CH2), 1.72–1.81 (1H, m, 1H from CH2CHCH3), 1.88–1.97 (2H, m,
CH2CH2OH), 1.98–2.08 (2H, m, CH2CH]CH2), 2.60–2.61 (1H, m,
CHCH3), 3.53–3.60 (2H, m, CH2OSi), 3.70 (2H, t, J¼6.0 Hz, CH2OH),
4.26–4.35 (2H, m, CH2OC(O)), 4.92 (dd, J¼10.1, 1.8 Hz CH]CH2 cis,
minor diastereoisomer), 4.93 (1H, dd, J¼10.1, 1.8 Hz CH]CH2 cis),
4.99 (dd, J¼16.9, 1.8 Hz, CH]CH2 trans, minor diastereoisomer), 5.01
(1H, dd, J¼16.9, 1.8 Hz, CH]CH2 trans), 5.80 (1H, ddt J¼16.9, 10.3,
6.6 Hz, CH]CH2), 6.66 (1H, s, C(O)C]CHC). 13C NMR (125 MHz,
500 MHz, major diastereoisomer) d 0.04 (6H, s, Si(CH3)2), 0.89 (9H, s,
C(CH3)3), 1.04 (3H, d, J¼6.6 Hz, CHCH3), 1.33–1.81 (8H, m, CH2), 1.73
(3H, s, H2C]CCH3), 1.92 (2H, quintet, J¼6.1 Hz, OCH2CH2CH2O), 2.06
(1H, br s, OH), 2.54–2.72 (1H, m, CHCH3), 3.50–3.65 (2H, m, CH), 3.71
(2H, br s, CH), 4.33 (2H, t, J¼6.0 Hz, CH2OC(O)), 4.65 (1H, s, C]CH2),
4.87 (1H, s, C]CH2), 6.89 (1H, s, C(O)C]CHC). 13C NMR (CDCl3,
125 MHz, major diastereoisomer)
19.0 (H2C]CCH3), 20.1 (CHCH3), 26.0 (C(CH3)3), 27.3 (CH2), 27.4 (CH2),
d
ꢀ5.3 (Si(CH3)2), 18.3 (C(CH3)3),
CDCl3)
d
ꢀ5.6 (Si(CH3)2), 18.0 (C(CH3)3), 19.7 (CHCH3), 25.6 (C(CH3)3),
26.2 (CH2), 26.7 (CH2), 26.9 (CH2), 27.6 (CHCH3), 28.0 (CH2), 31.6

10822
M.D. Helm et al. / Tetrahedron 65 (2009) 10816–10829
(CH2CH2OH), 34.7 (CH2), 37.6 (C), 38.0 (CH2), 58.8 (CH2OH), 60.7
(C(O)OCH2), 63.3 (CH2OSi),114.0 (H2C]CH),134.0 (C(O)C]CH),138.6
(H2C]CH), 146.7 (C(O)C]CH), 167.6 (C]O). nmax (thin film/cmꢀ1):
3434 (s), 2928 (s), 2857 (s), 1712 (s, C]O), 1640 (w), 1472 (w), 1388
(w), 1361 (w), 1255 (s), 1060 (m), 1005 (w), 939 (w), 910 (w), 836 (s),
813 (w), 775 (m). MS (ESþ) m/z (%): 425 (100, MþH). HRMS: Calcd for
C24H (MþH): 425.3082. Found: 425.3078.
14 h, gave 8g (285 mg, 0.671 mmol, 61%, dr 3:1) as a yellow oil. 1H
NMR (CDCl3, 500 MHz, major diastereoisomer) 0.03 (6H, s, Si(CH3)),
0.87 (9H, s, C(CH3)3), 1.03 (3H, d, J¼6.9 Hz, CHCH3), 1.32–1.82 (12H,
m, CH2), 1.71 (3H, s, H2C]CCH3), 2.51–2.70 (1H, m, CHCH3), 3.48–
3.63 (2H, m, CH2OSi), 3.68 (2H, t, J¼6.3 Hz, CH2OH), 4.10–4.24 (2H, m,
CH2OC(O)), 4.65 (1H, s, C]CH2), 4.85 (1H, s, C]CH2), 6.86 (1H, s,
C(O)C]CHC). 13C NMR (CDCl3, 125 MHz, major diastereoisomer)
d
d
ꢀ5.3 (Si(CH3)2), 18.4 (C(CH3)3), 19.0 (H2C]CCH3), 20.1 (CHCH3),
3.3.5. 3-Hydroxypropyl
methylcyclohex-1-enecarboxylate 8e. General procedure
3-(3-(tert-butyldimethylsilyloxy)propyl)-3-
using
25.2 (CH2), 26.0 (C(CH3)3), 27.3 (CH2), 27.4 (CH2), 29.1 (CH2), 29.3
(CH2), 30.2 (CH2), 34.5 (CHCH3), 44.5 (C), 62.4 (CH2OH), 63.5
(C(O)OCH2), 64.1 (CH2OSi), 113.0 (H2C]C), 135.0 (C(O)C]CH), 144.3
(C(O)C]CH), 149.0 (H2C]C),167.8 (C]O). 1H NMR (CDCl3, 500 MHz,
2
3-(3-(tert-butyldimethylsilyloxy)propyl)-3-methylcyclohex-1-enyl tri-
fluoromethanesulfonate 7e (1.00 g, 2.40 mmol), palladium acetate
(108 mg, 0.481 mmol), triphenylphosphine (252 mg, 0.961 mmol),
propan-1,3-diol (6.94 mL, 96.0 mmol) and triethylamine (0.669 mL,
4.80 mmol) in DMF (8 mL) at 40 ꢁC after 12 h gave 8e (564 mg,
minor diastereoisomer)
d 0.04 (6H, s, Si(CH3)), 0.88 (9H, s, C(CH3)3),
1.06 (3H, d, J¼6.9 Hz, CHCH3), 1.32–1.82 (12H, m, CH2), 1.70 (3H, s,
H2C]CCH3), 2.51–2.70 (1H, m, CHCH3), 3.48–3.63 (2H, m, CH2OSi),
3.68 (2H, t, J¼6.3 Hz, CH2OH), 4.10–4.24 (2H, m, CH2OC(O)), 4.52 (1H,
s, C]CH2), 4.87 (1H, s, C]CH2), 6.83 (1H, s, C(O)C]CHC). 13C NMR
1.52 mmol, 63%) as a brown oil. 1H NMR (CDCl3, 500 MHz)
d 0.03
(6H, s, Si(CH3)2), 0.88 (9H, s, C(CH3)3), 0.99 (3H, s, CCH3), 1.41–1.29
(3H, m, CH2(CH2)2OSi, 1H from CH2CH2OSi), 1.42–1.54 (3H, m,
CH2(CH2)2CC(O), 1H from CH2CH2OSi), 1.56–1.70 (2H, m,
CH2CH2C(O)), 1.89 (2H, quintet, J¼6.3 Hz, OCH2CH2CH2O), 2.12 (1H,
dt, J¼19.7, 7.8 Hz, 1H from CH2CC(O)), 2.24 (1H, dt, J¼17.6, 5.6 Hz, 1H
from CH2CC(O)), 3.56 (2H, t, J¼6.3 Hz, CH2OSi), 3.68 (2H, t, J¼6.1 Hz,
CH2OH), 4.27 (2H, t, J¼6.1 Hz, CH2OC(O)), 6.69 (1H, s, C(O)C]CHC).
(CDCl3, 125 MHz, minor diastereoisomer)
d
ꢀ5.3 (Si(CH3)), 18.4
(C(CH3)3),18.8 (H2C]CCH3), 19.9 (CHCH3), 25.1 (CH2), 26.0 (C(CH3)3),
26.5 (CH2), 27.4 (CH2), 27.5 (CH2), 28.1 (CH2), 29.3 (CH2), 35.0
(CHCH3), 44.8 (C), 62.0 (CH2OH), 63.3 (C(O)OCH2), 64.1 (CH2OSi),
114.3 (C]CH2), 134.9 (C(O)C]CH), 144.5 (C(O)C]CH), 147.9
(C]CH2), 167.5 (C]O). nmax (thin film/cmꢀ1): 3468 (br), 2931 (m),
2858 (w), 1705 (m, C]O), 1458 (w), 1377 (w), 1249 (s), 1097 (m). MS
(ESþ) m/z (%): 433 (100, MþNa). HRMS: calcd for C23H46O4NSi
(MþNH4): 428.3191. Found: 428.3193.
13C NMR (125 MHz, CDCl3)
d
ꢀ5.64 (Si(CH3)2), 18.0 (C(CH3)3), 18.6
(CH2CH2CC(O)), 24.0 (CH2CC]O), 25.6 (C(CH3)3), 26.1 (CH3), 27.1
(CH2CH2CH2CC(O)), 31.5 (CH2CH2OH), 33.2 (CH2CH2OSi), 34.7 (C),
37.6 (CH2(CH2)2OSi), 58.8 (CH2OH), 60.8 (CH2OC(O)), 63.3 (CH2OSi),
128.1 (HC]CC(O)), 148.0 (HC]CC(O)), 167.8 (C]O). nmax (thin film/
cmꢀ1): 3453 (s), 2933 (s), 2894 (s),1713 (s, C]O),1644 (m),1471 (m),
1463 (m), 1389 (m), 1360 (w), 1274 (s), 1154 (w), 1099 (s), 1056 (m),
1005 (w), 938 (w), 836 (s), 775 (s). MS (EIþ) m/z (%): 393 (100,
MþNa). HRMS: Calcd for C20H (MþH): 371.2612. Found: 371.2613.
3.3.8. rac-(3R,6R)-2-hydroxyethyl 3-(3-(tert-butyldimethylsilyloxy)-
propyl)-6-methyl-3-(prop-1-en-2-yl)cyclohex-1-enecarboxylate
8h. General procedure
2
using rac-(3R,6R)-3-(3-(tert-butyldi-
methylsilyloxy)propyl)-6-methyl-3-(prop-1-en-2-yl)cyclohex-1-enyl
trifluoromethanesulfonate 7b6 (1.08 g, 2.37 mmol, dr 3:1), palladium
acetate (106 mg, 0.473 mmol), triphenylphosphine (249 mg,
0.946 mmol), ethane-1,2-diol (3.97 mL, 71.0 mmol) and triethylamine
(0.659 mL, 4.73 mmol) in DMF (12 mL) at 40 ꢁC, after 14 h, gave 8h
(564 mg, 1.42 mmol, 60%, dr 3:1) as a yellow oil. 1H NMR (CDCl3,
3.3.6. 3-Hydroxypropyl
3-(3-(tert-butyldimethylsilyloxy)propyl)-
6,6-dimethyl-3-(prop-1-en-2-yl)cyclohex-1-enecarboxylate
8f. General procedure 2 using 3-(3-(tert-butyldimethylsilyloxy)-
propyl)-6,6-dimethyl-3-(prop-1-en-2-yl)cyclohex-1-enyl trifluo-
romethanesulfonate 7f (691 mg, 1.47 mmol), palladium acetate
(132 mg, 0.587 mmol), triphenylphosphine (308 mg, 1.18 mmol),
propan-1,3-diol (4.20 mL, 58.7 mmol) and triethylamine
(0.409 mL, 2.94 mmol) in DMF (7.5 mL) at 50 ꢁC, after 5 days, gave
8f (517 mg, 1.22 mmol, 83%) as a yellow oil. 1H NMR (CDCl3,
300 MHz)
d 0.04 (6H, s, Si(CH3)2), 0.05 (s, Si(CH3)2, minor di-
astereoisomer), 0.88 (9H, s, C(CH3)3), 0.89 (s, C(CH3)3, minor di-
astereoisomer),1.05 (3H, d,J¼6.8 Hz, CHCH3),1.08 (d, J¼7.9 Hz,CHCH3,
minor diastereoisomer), 1.31–181 (8H, m, CH2), 1.73 (3H, s, H]CCH3),
2.18 (1H, br s, OH), 2.55–2.72 (1H, m, CHCH3), 3.48–3.65 (2H, m,
CH2OSi), 3.81–3.93 (2H, m, CH2OH), 4.26–4.34 (2H, m, CH2OC(O)),
4.54 (s, C]CH2, minor diastereoisomer), 4.65 (1H, s, C]CH2), 4.87
(1H, s, C]CH2), 4.89 (s, C]CH2, minor diastereoisomer), 6.89 (s,
C(O)C]CHC, diastereoisomer minor), 6.92 (1H, s, C(O)C]CHC). 13C
400 MHz)
d 0.04 (6H, s, Si(CH3)2), 0.89 (9H, s, C(CH3)3), 1.15 (3H, s,
C(CH3)2), 1.22 (3H, s, C(CH3)2), 1.29–1.68 (8H, m, CH2), 1.71 (3H, s,
H2C]CCH3), 1.91 (2H, quintet, J¼6.1 Hz, OCH2CH2CH2O), 2.17 (1H,
br s, OH), 3.50–3.64 (2H, m, CH), 3.70 (2H, t, J¼6.1 Hz, CH), 4.30
(2H, m, CH2OC(O)), 4.59 (1H, s, C]CH2), 4.88 (1H, s, C]CH2), 6.74
NMR (CDCl3, 75 MHz)
d
ꢀ5.3 (Si(CH3)2), 18.4 (C(CH3)3), 18.8
(H2C]CCH3, minor diastereoisomer), 19.0 (H2C]CCH3), 19.9
(CHCH3, minor diastereoisomer), 20.1 (CHCH3), 26.0 (C(CH3)3), 26.5
(CH2, minor diastereoisomer), 27.3 (CH2), 27.5 (CH2), 28.2 (CHCH3,
minor diastereoisomer), 29.1 (CHCH3), 30.2 (CH2), 34.5 (CH2), 35.1
(CH2, minor diastereoisomer), 44.7 (C), 45.0 (C, minor di-
astereoisomer), 61.6 (CH2OH), 63.4 (C(O)OCH2), 66.2 (CH2OSi),
113.1 (H2C]C), 114.4 (H2C]C, minor diastereoisomer), 134.7
(C(O)C]CH), 145.1 (C(O)C]CH), 145.3 (C(O)C]CH, minor di-
astereoisomer), 147.9 (H2C]C, minor diastereoisomer), 149.0
(H2C]C), 168.2 (C]O). nmax (thin film/cmꢀ1): 3435 (br), 3083 (w),
2858 (s), 2729 (w), 1714 (s, C]O), 1636 (m), 1462 (m), 1385 (m),
1334 (w),1253 (s),1099 (s). MS (ESþ) m/z (%): 397 (5, MþH), 414 (10,
MþNH4), 419 (100, MþNa). HRMS: calcd for C22H44O4NSi
(MþNH4): 414.3034. Found: 414.3033.
(1H, s, C(O)C]CHC). 13C NMR (CDCl3, 100 MHz)
d
ꢀ5.3 (Si(CH3)2),
18.4 (C(CH3)3), 18.8 (H2C]CCH3), 26.0 (C(CH3)3), 27.3 (C(CH3)2),
27.5 (CH2), 28.2 (C(CH3)2), 28.3 (CH2), 32.0 (CH2), 33.4 (C(CH3)2),
34.8 (CH2), 36.5 (CH2), 45.0 (C), 59.2 (CH2OH), 60.7 (C(O)OCH2),
63.4 (CH2OSi), 113.9 (H2C]C), 137.8 (C(O)C]CH), 144.5
(C(O)C]CH), 148.3 (H2C]C), 168.0 (C]O). nmax (thin film/cmꢀ1):
3440 (br), 2948 (s), 2839 (s), 2735 (w), 1714 (s, C]O), 1633 (m),
1461 (m), 1388 (m), 1361 (m), 1327 (w), 1253 (s), 1100 (s). MS (ESþ)
m/z (%): 425 (20, MþH), 447 (100, MþNa). HRMS: calcd for
C24H45O4Si (MþH): 425.3082. Found: 425.3082.
3.3.7. rac-(3R,6R)-4-Hydroxybutyl 3-(3-(tert-butyldimethylsilyloxy)-
propyl)-6-methyl-3-(prop-1-en-2-yl)cyclohex-1-enecarboxylate
8g. General procedure
2
using rac-(3R,6R)-3-(3-(tert-butyl-
dimethylsilyloxy)propyl)-6-methyl-3-(prop-1-en-2-yl)cyclohex-1-
enyl trifluoromethanesulfonate 7b6 (502 mg, 1.10 mmol, dr 3:1),
palladium acetate (49.0 mg, 0.220 mmol), triphenylphosphine
(115 mg, 0.440 mmol), 1,4-butanediol (2.92 mL, 33.0 mmol) and
triethylamine (0.306 mL, 2.20 mmol) in DMF (6 mL) at 40 ꢁC, after
3.4. General procedure 3. Formation of diols by HF-mediated
TBDMS ether cleavage
To a solution of silyl ethers 8a–g (1 equiv) in a 2:1 mixture of
acetonitrile and pyridine at 0 ꢁC was added dropwise aqueous

M.D. Helm et al. / Tetrahedron 65 (2009) 10816–10829
10823
60% HF (10–25 equiv). The reaction was then stirred at room
temperature until the starting alcohol had been consumed (TLC
analysis). The reaction was quenched by dropwise addition of
aqueous saturated NaHCO3. Once effervescence had subsided, the
mixture was extracted with Et2O (ꢂ3). The combined organic
extracts were washed with aqueous saturated CuSO4 (ꢂ2), brine
(ꢂ2) and then dried (Na2SO4). Concentration in vacuo gave the
diols, which in some cases needed to be purified by chroma-
tography on silica gel.
(100, MþNa). HRMS: calcd for C17H32ON (MþNH4): 314.2326.
Found: 314.2326.
3.4.3. 3-Hydroxypropyl 3-(but-3-enyl)-3-(3-hydroxypropyl)cyclohex-
1-enecarboxylate. General procedure 3 using 3-hydroxypropyl 3-
(but-3-enyl)-3-(3-(tert-butyldimethylsilyloxy)propyl)cyclohex-1-
enecarboxylate 8c (200 mg, 0.487 mmol), aqueous 60% HF
(0.160 mL, 4.90 mmol), pyridine (2.5 mL) and MeCN (5.00 mL),
after 12 h, gave 3-hydroxypropyl 3-(but-3-enyl)-3-(3-hydroxy-
propyl)-cyclohex-1-enecarboxylate (141 mg, 0.476 mmol, 98%) as
3.4.1. 3-Hydroxypropyl 3-(3-hydroxypropyl)-3-(prop-1-en-2-yl)-
cyclohex-1-enecarboxylate. General procedure 3 using 3-hydroxy-
propyl 3-(3-(tert-butyldimethylsilyloxy)propyl)-3-(prop-1-en-2-yl)
cyclohex-1-enecarboxylate 8a (400 mg, 1.01 mmol), aqueous 60%
HF (0.340 mL, 10.1 mmol), pyridine (2 mL) and MeCN (4 mL),
after 4 h, gave 3-hydroxypropyl 3-(3-hydroxypropyl)-3-(prop-1-
en-2-yl)cyclohex-1-enecarboxylate (278 mg, 0.985 mmol, 98%)
a yellow oil. 1H NMR (CDCl3, 500 MHz)
d 1.39–1.56 (8H, m, CH2),
1.66 (2H, quintet, J¼6.1 Hz, CH2CH2CC(O)), 1.91 (2H, quintet,
J¼6.1 Hz, OCH2CH2CH2O), 2.01 (2H, q, J¼5.3 Hz, CH2CH]CH2), 2.21
(2H, t, J¼6.0 Hz, CH2CC(O)), 3.62 (2H, t, J¼6.1 Hz, C(CH2)2), 3.71
(2H, t, J¼6.1 Hz, O(CH2)2CH2O), 4.30 (2H, t, J¼6.0 Hz, CH2OC(O)),
4.94 (1H, dd, J¼10.1, 1.8 Hz CH]CH2 cis), 5.01 (1H, dd, J¼17.1,
1.8 Hz, CH]CH2 trans), 5.79 (1H, ddt, J¼17.1, 10,1, 6.6 Hz,
CH]CH2), 6.74 (1H, s, C(O)C]CH). 13C NMR (125 MHz, CDCl3)
as a colourless oil. 1H NMR (CDCl3, 300 MHz)
d 1.25–1.81 (8H, m,
CH2), 1.71 (3H, m, H2C]CCH3), 1.91 (2H, quintet, J¼6.1 Hz,
OCH2CH2CH2O), 2.05–2.20 (1H, m, 1H from CH2C]CH), 2.24–
2.33 (1H, m, 1H from CH2C]CH), 2.41 (1H, br s, OH), 3.61 (2H, t,
J¼4.9 Hz, C(CH2)2CH2O), 3.70 (2H, t, J¼6.0 Hz, O(CH2)2CH2O),
4.30 (2H, t, J¼6.1 Hz, CH2OC(O)), 4.57 (1H, dd, J¼0.8, 1.7 Hz,
C]CH2), 4.90 (1H, t, J¼1.4 Hz, C]CH2), 6.94 (1H, s, C(O)C]CHC).
d
19.1 (CH2CH2CC(O)), 24.6 (CH2CC(O)), 27.4 (CH2), 28.5
(CH2CH]CH2), 31.6 (CH2), 32.1 (C(O)OCH2CH2), 35.5 (CH2), 38.0
(C), 38.7 (CH2), 59.5 (O(CH2)2CH2O), 61.6 (C(O)OCH2), 63.6
(C(CH2)2CH2O), 114.7 (CH2]CH), 129.8 (HC]CC(O)), 139.1
(CH]CH2), 147.4 (HC]CC(O)), 168.3 (C]O). nmax (thin film/cmꢀ1):
3362 (br), 2936 (s), 2862 (m), 1709 (s, C]O), 1640 (m), 1454 (w),
1394 (w), 1271 (s), 1265 (s), 1084 (m), 1056 (s), 910 (m), 751 (w).
13C NMR (CDCl3, 75 MHz)
d 18.6 (CH2), 18.9 (H2C]CCH3), 24.8
(CH2), 27.4 (CH2), 31.8 (CH2), 31.9 (CH2), 34.8 (CH2), 44.6 (C), 59.4
(O(CH2)2CH2O), 61.4 (C(O)OCH2), 63.2 (C(CH2)2CH2O), 114.2
(C]CH2), 129.9 (HC]CC(O)), 145.0 (C]CH2), 148.3 (HC]CC(O)),
168.0 (C]O). nmax (thin film/cmꢀ1): 3353 (br), 2937 (s), 2864
(m), 1710 (s, C]O), 1637 (w), 1452 (w), 1377 (w), 1254 (s), 1109
(w), 1054 (m). MS (ESþ) m/z (%): 283 (8, MþH), 305 (100, MþNa).
HRMS: calcd for C16H26O4Na (MþNa): 305.1723. Found:
305.1730.
MS (EIþ) m/z (%): 319 (100, MþNa). HRMS: Calcd for C17
(MþNa): 319.1880. Found: 319.1881.
H
3.4.4. rac-(3S,6R)-3-Hydroxypropyl 3-(but-3-enyl)-3-(3-hydroxy-
propyl)-6-methylcyclohex-1-enecarboxylate. General procedure 3
using rac-(3S,6R)-3-hydroxypropyl 3-(but-3-enyl)-3-(3-(tert-butyl-
dimethylsilyloxy)propyl)-6-methylcyclohex-1-enecarboxylate 8d
(111 mg, 0.261 mmol, dr 3:1), aqueous 60% HF (90.0 mL,
2.60 mmol), pyridine (1.3 mL) and MeCN (2.6 mL), after 12 h, gave
rac-(3S,6R)-3-hydroxypropyl 3-(but-3-enyl)-3-(3-hydroxypropyl)-
6-methylcyclohex-1-enecarboxylate (78.0 mg, 0.251 mmol, 96%,
3.4.2. rac-(3R,6R)-3-Hydroxypropyl 3-(3-hydroxypropyl)-6-methyl-
3-(prop-1-en-2-yl)cyclohex-1-enecarboxylate. General procedure 3
using rac-(3R,6R)-3-hydroxypropyl 3-(3-(tert-butyldimethylsilyl-
oxy)propyl)-6-methyl-3-(prop-1-en-2-yl)cyclohex-1-enecarboxy-
late 8b (1.20 g, 2.92 mmol, dr 3:1), aqueous 60% HF (2.44 mL,
73.3 mmol), pyridine (10 mL) and MeCN (20 mL), after 24 h, gave
dr 3:1) as a yellow oil. 1H NMR (CDCl3, 500 MHz)
d 1.06 (d,
J¼6.9 Hz, CH3, minor diastereoisomer), 1.07 (3H, d, J¼7.3 Hz, CH3),
1.30–1.60 (8H, m, CH2), 1.71–1.77 (2H, m, CH2CHCH3), 1.88 (2H,
quintet, J¼6.0 Hz, CH2CH2OC(O)), 2.00 (2H, q, J¼5.7 Hz,
CH2CH]CH2), 2.60–2.64 (1H, m, CHCH3), 3.57 (2H, t, J¼6.6 Hz,
C(CH2)2CH2O), 3.67 (2H, t, J¼6.0 Hz, O(CH2)2CH2O), 4.26–4.31 (2H,
m, CH2OC(O)), 4.89 (dd, J¼10.1, 1.6 Hz, CH]CH2 cis, minor di-
astereoisomer), 4.91 (1H, dd, J¼10.1, 1.6 Hz, CH]CH2 cis), 4.96 (dd,
J¼17.4, 1.6 Hz, CH]CH2 trans minor diastereoisomer), 4.98 (1H,
dd, J¼17.1, 1.6 Hz, CH]CH2 trans), 5.76 (1H, ddt, J¼17.1, 10,1,
6.3 Hz, CH]CH2), 6.67 (1H, s, C(O)C]CHC). 13C NMR (CDCl3,
rac-(3R,6R)-3-hydroxypropyl
3-(3-hydroxypropyl)-6-methyl-3-
(prop-1-en-2-yl)cyclohex-1-enecarboxylate (835 mg, 2.82 mmol,
96%, dr 3:1) as a yellow oil. 1H NMR (CDCl3, 300 MHz, major di-
astereoisomer)
d
1.03 (3H, d, J¼6.8 Hz, CHCH3), 1.18–1.86 (8H, m,
CH2), 1.72 (3H, s, H2C]CCH3), 1.91 (2H, quintet, J¼6.0 Hz,
OCH2CH2CH2O), 2.50–2.71 (1H, m, CHCH3), 3.59 (2H, t, J¼5.2 Hz,
C(CH2)2CH2O), 3.70 (2H, t, J¼6.0 Hz, O(CH2)2CH2O), 4.31 (2H, t,
J¼6.0 Hz, CH2OC(O)), 4.65 (1H, s, C]CH2), 4.86 (1H, s, C]CH2),
6.88 (1H, s, C(O)C]CH). 13C NMR (CDCl3, 75 MHz, major di-
125 MHz)
d 20.0 (CHCH3), 26.5 (CH2CHCH3), 26.8 (CH2), 27.0
(CH2), 27.9 (CHCH3), 28.3 (CH2CH]CH2), 31.8 (OCH2CH2CH2O),
35.5 (CH2), 38.0 (C), 38.4 (CH2), 59.0 (O(CH2)2CH2O), 61.2
(C(O)OCH2), 63.2 (C(CH2)2CH2O), 114.4 (CH2]CH), 134.5
(HC]CC(O)), 138.8 (CH]CH2), 146.8 (HC]CC(O)), 167.9 (C]O).
nmax (thin film/cmꢀ1): 3356 (br), 3075 (w), 2934 (s), 2869 (m),
1709 (s, C]O), 1639 (m), 1452 (m), 1394 (w), 1363 (w), 1335 (w),
1257 (s), 1119 (w), 1059 (s), 910 (m), 769 (w). MS (ESþ) m/z (%):
333 (100, MþNa). HRMS: Calcd for C18H (MþNa): 333.2036.
Found: 333.2038.
astereoisomer)
d 19.1 (H2C]CCH3), 20.1 (CHCH3), 27.3 (CH2), 27.4
(CH2), 29.1 (CHCH3), 30.3 (CH2), 31.9 (CH2), 34.5 (OCH2CH2CH2O),
44.6 (C), 59.3 (O(CH2)2CH2O), 61.3 (C(O)OCH2), 63.2 (C(CH2)2CH2O),
113.2 (H2C]C), 135.0 (C(O)C]CH), 144.5 (C(O)C]CH), 148.8
(H2C]C), 168.1 (C]O). 1H NMR (CDCl3, 300 MHz, minor di-
astereomer)
d
1.04 (3H, d, J¼6.6 Hz, CHCH3), 1.18–1.86 (8H, m, CH2),
1.71 (3H, s, H2C]CCH3), 1.91 (2H, quintet, J¼6.0 Hz, OCH2CH2
-
CH2O), 2.50–2.71 (1H, m, CHCH3), 3.59 (2H, t, J¼5.2 Hz,
C(CH2)2CH2O), 3.70 (2H, t, J¼6.0 Hz, O(CH2)2CH2O), 4.31 (2H, t,
J¼6.0 Hz, CH2OC(O)), 4.52 (1H, s, C]CH2), 4.88 (1H, s, C]CH2),
6.84 (1H, s, C(O)C]CH). 13C NMR (CDCl3, 75 MHz, minor di-
3.4.5. 3-Hydroxypropyl 3-(3-hydroxypropyl)-3-methylcyclohex-1-
enecarboxylate. General procedure 3 using 3-hydroxypropyl 3-(3-
(tert-butyldimethylsilyloxy)propyl)-3-methylcyclohex-1-enecarboxy-
late 8e (560 mg, 1.51 mmol), aqueous 60% HF (0.510 mL, 15.2 mmol),
pyridine (7.5 mL) and MeCN (15 mL), after 12 h, gave 3-hydroxy-
astereoisomer)
d 18.8 (H2C]CCH3), 19.8 (CHCH3), 26.0 (CH2), 26.4
(CH2), 27.5 (CH2), 28.1 (CHCH3), 29.7 (CH2), 34.9 (OCH2CH2CH2O),
44.9 (C), 59.3 (O(CH2)2CH2O), 61.2 (C(O)OCH2), 63.2 (C(CH2)2CH2O),
114.5 (H2C]C), 134.9 (C(O)C]CH), 144.7 (C(O)C]CH), 147.8
(H2C]C), 167.8 (C]O). nmax (thin film/cmꢀ1): 3351 (br), 2939 (s),
1701 (s, C]O), 1450 (w), 1247 (m), 1057 (m). MS (ESþ) m/z (%): 319
propyl
(380 mg, 1.48 mmol, 98%) as a colourless oil. 1H NMR (CDCl3,
500 MHz)
1.04 (3H, s, CH3), 1.92 (2H, quintet, J¼5.8 Hz,
3-(3-hydroxypropyl)-3-methylcyclohex-1-enecarboxylate
d

10824
M.D. Helm et al. / Tetrahedron 65 (2009) 10816–10829
CH2CH2OC(O)), 1.35–1.75 (8H, m, CH2), 2.25 (1H, td, J¼5.6, 1.5 Hz, 1H
from CH2CC(O)), 2.29 (1H, td, J¼5.5, 1.8 Hz, 1H from CH2CC(O)), 3.64
(2H, t, J¼6.3 Hz, C(CH2)2CH2OH), 3.71 (2H, t, J¼6.0 Hz,
O(CH2)2CH2OH), 4.31 (2H, t, J¼6.0 Hz, CH2OC(O)), 6.71 (1H, s,
1636 (m), 1452 (m), 1377 (w), 1254 (s). MS (ESþ) m/z (%): 311 (90,
MþH), 333 (100, MþNa). HRMS: calcd for C18H30O4Na (MþNa):
333.2036. Found: 333.2052.
C(O)C]CHC). 13C NMR (125 MHz, CDCl3)
d 19.0 (CH2), 24.3
(CH2CC(O)), 26.5 (CH3), 27.3 (CH2), 31.8 (OCH2CH2CH2O), 33.6 (CH2),
35.1 (C), 38.0 (CH2), 59.1 (O(CH2)2CH2O), 61.3 (C(O)OCH2), 63.2
(C(CH2)2CH2O), 128.7 (HC]CC(O)), 148.2 (HC]CC(O)), 168.2 (C]O).
nmax (thin film/cmꢀ1): 3370 (br), 2929 (s), 2863 (m), 1709 (s, C]O),
1683 (s), 1273 (s), 1243 (s), 1084 (m), 1049 (s), 918 (w). MS (ESþ) m/z
(%): 279 (100, MþNa). HRMS: calcd for C14H24O4Na (MþNa):
279.1572. Found: 279.1570.
3.5. General procedure 4. Oxidation of diols to dialdehydes
3a–g using the Dess–Martin periodinane (DMP)
DMP (3 equiv) was added to a solution of the diol (1 equiv)
in CH2Cl2 and the reaction was stirred until complete (TLC
analysis). The reaction was quenched with aqueous saturated
NaHCO3 and extracted with Et2O (ꢂ3). The combined organic
extracts were dried (Na2SO4) and concentrated in vacuo before
purification by rapid chromatography through a short plug of
silica gel.
3.4.6. 3-Hydroxypropyl 3-(3-hydroxypropyl)-6,6-dimethyl-3-(prop-
1-en-2-yl)cyclohex-1-enecarboxylate. General procedure 3 using 3-
hydroxypropyl 3-(3-(tert-butyldimethylsilyloxy)propyl)-6,6-di-
methyl-3-(prop-1-en-2-yl)cyclohex-1-enecarboxylate 8f (517 mg,
1.22 mmol), aqueous 60% HF (0.400 mL, 12.2 mmol), pyridine
(5 mL) and MeCN (10 mL), after 12 h, gave 3-hydroxypropyl 3-(3-
hydroxypropyl)-6,6-dimethyl-3-(prop-1-en-2-yl)cyclohex-1-ene-
carboxylate (360 mg, 1.16 mmol, 95%) as a colourless oil. 1H NMR
3.5.1. 3-Oxopropyl 3-(3-oxopropyl)-3-(prop-1-en-2-yl)cyclohex-1-
enecarboxylate 3a. General procedure 4 using 3-hydroxypropyl 3-
(3-hydroxypropyl)-3-(prop-1-en-2-yl)cyclohex-1-enecarboxylate
(441 mg, 1.56 mmol), DMP (1.99 g, 4.69 mmol) and CH2Cl2
(15 mL), after 5 h, gave 3a (316 mg, 1.14 mmol, 73%) as a colour-
(CDCl3, 400 MHz)
d
1.17 (3H, s, CCH3), 1.23 (3H, s, CCH3), 1.31–1.70
less oil. 1H NMR (CDCl3, 400 MHz)
d 1.23–1.35 (1H, m, CH), 1.43–
(8H, m, CH2), 1.72 (3H, s, H2C]CCH3), 1.92 (2H, quintet, J¼6.1 Hz,
OCH2CH2CH2O), 2.10 (1H, br s, OH), 3.59–3.67 (2H, m, C(CH2)),
3.72 (2H, t, J¼5.9 Hz, O(CH2)), 4.31 (2H, t, J¼6.1 Hz, CH2OC(O)),
4.61 (1H, s, C]CH2), 4.90 (1H, s, C]CH2), 6.75 (1H, s, C(O)C]CHC).
1.55 (1H, m, CH2), 1.58–1.88 (3H, m, CH2), 1.68 (3H, m,
H2C]CCH3), 1.80–1.90 (1H, m, CH2), 2.05–2.17 (1H, CH2C]CH),
2.18–2.39 (2H, m, CCH2CH2CHO and CH2C]CH), 2.41–2.52 (1H,
m, CCH2CH2CHO), 2.80 (2H, td, J¼6.1 Hz, J¼1.6 Hz, OCH2CH2CHO),
4.46 (2H, t, J¼6.2 Hz, CH2CH2OC(O)), 4.59 (1H, s, C]CH2), 4.92
(1H, t, J¼1.3 Hz, C]CH2), 6.80 (1H, s, C(O)C]CHC), 9.75 (1H, t,
J¼1.4 Hz, C(CH2)2CHO), 9.79 (1H, t, J¼1.6 Hz, O(CH2)2CHO). 13C
13C NMR (CDCl3, 75 MHz)
d 18.9 (H2C]CCH3), 27.3 (C(CH3)2), 27.5
(CH2), 28.2 (C(CH3)2), 28.3 (CH2), 31.9 (CH2), 33.4 (C(CH3)2), 34.8
(CH2), 36.7 (CH2), 45.0 (C), 59.4 (O(CH2)2CH2O), 61.0 (C(O)OCH2),
63.3 (C(CH2)2CH2O), 114.0 (H2C]C), 138.1 (C(O)C]CH), 144.3
(C(O)C]CH), 148.1 (H2C]C), 167.9 (C]O). nmax (thin film/cmꢀ1):
3302 (br), 2948 (m), 2864 (m), 1715 (s, C]O), 1620 (w), 1540 (w),
1455 (w), 1251 (m). MS (ESþ) m/z (%): 328 (60, MþNH4), 333 (100,
MþNa). HRMS: calcd for C18H30O4Na (MþNa): 333.2036. Found:
333.2047.
NMR (CDCl3, 75 MHz)
d 18.4 (CH2), 18.8 (H2C]CCH3), 24.7 (CH2),
30.0 (CH2), 31.6 (CH2), 39.1 (CCH2CH2CHO), 42.8 (OCH2CH2CHO),
44.1 (C), 58.1 (C(O)OCH2), 114.9 (H2C]C), 130.4 (CH]CC(O)),
143.9 (H2C]C), 147.4 (CH]CC(O)), 167.0 (C(O)OCH2), 199.5 (CHO),
201.8 (CHO). nmax (thin film/cmꢀ1): 2934 (s), 2869 (m), 1721 (br s,
C]O), 1642 (w), 1455 (w), 1382 (w), 1274 (s). MS (ESþ) m/z (%):
301 (100, MþNa). HRMS: calcd for C16H22O4Na: 301.1410. Found:
301.1401.
3.4.7. rac-(3R,6R)-4-Hydroxybutyl 3-(3-hydroxypropyl)-6-methyl-3-
(prop-1-en-2-yl)cyclohex-1-enecarboxylate. General procedure
3
using rac-(3R,6R)-4-hydroxybutyl 3-(3-(tert-butyldimethylsilyl-
oxy)propyl)-6-methyl-3-(prop-1-en-2-yl)cyclohex-1-enecarboxy-
late 8g (280 mg, 0.659 mmol, dr 3:1), aqueous 60% HF (0.659 mL,
19.8 mmol), pyridine (5 mL) and MeCN (10 mL), after 12 h, gave rac-
(3R,6R)-4-hydroxybutyl 3-(3-hydroxypropyl)-6-methyl-3-(prop-1-
en-2-yl)cyclohex-1-enecarboxylate (166 mg, 0.534 mmol, 81%, dr
3:1) as a colourless oil. 1H NMR (CDCl3, 300 MHz, major di-
3.5.2. rac-(3R,6R)-3-Oxopropyl 6-methyl-3-(3-oxopropyl)-3-(prop-1-
en-2-yl)cyclohex-1-enecarboxylate 3b. Generalprocedure4 using rac-
(3R,6R)-3-hydroxypropyl 3-(3-hydroxypropyl)-6-methyl-3-(prop-1-
en-2-yl)cyclohex-1-enecarboxylate (200 mg, 0.675 mmol, dr 3:1),
DMP (859 mg, 2.02 mmol) and CH2Cl2 (6.8 mL), after 4 h, gave 3b
(155 mg, 0.530 mmol, 79%, dr 3:1) as a colourless oil. 1H NMR
(CDCl3, 300 MHz, major diastereoisomer)
d
0.99 (3H, d, J¼7.0 Hz,
astereoisomer)
d
1.05 (3H, d, J¼6.8 Hz, CHCH), 1.20–1.90 (12H, m,
CHCH3), 1.17–1.49 (2H, m, CH2), 1.57–1.93 (4H, s, CH2), 1.67 (3H, s,
H2C]CCH3), 2.19–2.64 (3H, m, CHCH3, CH2), 2.79 (2H, td, J¼6.1,
1.4 Hz, OCH2CH2CHO), 4.35–4.54 (2H, m, CH2OC(O)), 4.64 (1H, s,
C]CH2), 4.88 (1H, s, C]CH2), 6.73 (1H, s, C(O)C]CHC), 9.73 (1H, br
s, C(CH2)2CHO), 9.79 (1H, t, J¼1.5 Hz, O(CH2)2CHO). 13C NMR
CH2), 1.73 (3H, s, H2C]CCH3), 2.53–2.74 (1H, m, CHCH3), 3.49–
3.67 (2H, m, C(CH2)2CH2O), 3.70 (2H, t, J¼6.3 Hz, O(CH2)3CH2O),
4.08–4.30 (2H, m, CH2OC(O)), 4.67 (1H, s, C]CH2), 4.88 (1H, s,
C]CH2), 6.89 (1H, s, C(O)C]CHC). 13C NMR (CDCl3, 75 MHz,
major diastereoisomer)
d
19.1 (H2C]CCH3), 20.1 (CHCH3), 25.2
(CDCl3, 75 MHz, major diastereoisomer) d 19.0 (H2C]CCH3), 20.0
(CH2), 27.4 (CH2), 27.5 (CH2), 29.1 (CHCH3), 29.4 (CH2), 30.3 (CH2),
34.5 (CH2), 44.6 (C), 62.5 (O(CH2)3CH2O), 63.3 (C(O)OCH2), 64.1
(C(CH2)2CH2O), 113.2 (H2C]C), 135.3 (C(O)C]CH), 144.0
(C(O)C]CH), 148.9 (H2C]C), 167.7 (C]O). 1H NMR (CDCl3,
(CHCH3), 27.1 (CH2), 29.0 (CHCH3), 29.7 (CH2), 30.0 (CH2), 39.1
(CCH2CH2CHO), 42.8 (OCH2CH2CHO), 44.1 (C), 58.0 (C(O)OCH2),
113.9 (H2C]C), 135.5 (CH]CC(O)), 143.4 (CH]CC(O)), 147.9
(H2C]C), 167.2 (C(O)OCH2), 199.4 (CHO), 201.8 (CHO). 1H NMR
300 MHz, minor diastereoisomer)
d
1.07 (3H, d, J¼6.2 Hz, CHCH),
(CDCl3, 300 MHz, minor diastereoisomer)
d
1.02 (3H, d, J¼7.9 Hz,
1.20–1.90 (12H, m, CH2), 1.72 (3H, s, H2C]CCH3), 2.53–2.74 (1H,
m, CHCH3), 3.49–3.67 (2H, m, C(CH2)2CH2O), 3.70 (2H, t, J¼6.3 Hz,
O(CH2)3CH2O), 4.08–4.30 (2H, m, CH2OC(O)), 4.55 (1H, s, C]CH2),
4.90 (1H, s, C]CH2), 6.84 (1H, s, C(O)C]CHC). 13C NMR (CDCl3,
CHCH3), 1.17–1.49 (2H, m, CH2), 1.57–1.93 (4H, s, CH2), 1.67 (3H, s,
H2C]CCH3), 2.19–2.64 (3H, m, CHCH3, CH2), 2.79 (2H, td, J¼6.1,
1.4 Hz, OCH2CH2CHO), 4.35–4.54 (2H, m, CH2OC(O)), 4.53 (1H, s,
C]CH2), 4.90 (1H, s, C]CH2), 6.70 (1H, s, C(O)C]CHC), 9.75 (1H, br
s, C(CH2)2CHO), 9.79 (1H, t, J¼1.5 Hz, O(CH2)2CHO). 13C NMR
75 MHz, minor diastereoisomer)
d 18.9 (H2C]CCH3), 19.8
(CHCH3), 26.0 (CH2), 26.4 (CH2), 27.5 (CH2), 27.5 (CH2), 28.1
(CHCH3), 29.4 (CH2), 34.9 (CH2), 44.9 (C), 62.5 (O(CH2)3CH2O),
63.3 (C(O)OCH2), 64.2 (C(CH2)2CH2O), 114.4 (H2C]C), 135.2
(C(O)C]CH), 144.3 (C(O)C]CH), 147.8 (H2C]C), 167.4 (C]O).
nmax (thin film/cmꢀ1): 3401 (br), 2941 (s), 2868 (m), 1703 (s),
(CDCl3, 75 MHz, minor diastereoisomer) d 18.8 (H2C]CCH3), 19.7
(CHCH3), 25.9 (CH2), 26.4 (CH2), 28.0 (CHCH3), 30.2 (CH2), 39.2
(CCH2CH2CHO), 42.8 (OCH2CH2CHO), 44.5 (C), 58.0 (C(O)OCH2),
115.2 (H2C]C), 135.4 (CH]CC(O)), 143.7 (CH]CC(O)), 146.9
(H2C]C), 166.8 (C(O)OCH2), 199.4 (CHO), 201.8 (CHO). nmax (thin

M.D. Helm et al. / Tetrahedron 65 (2009) 10816–10829
10825
film/cmꢀ1): 2934 (m), 1707 (s, C]O), 1451 (w), 1246 (m), 1039 (w).
MS (ESþ) m/z (%): 310 (50, MþNH4), 315 (100, MþNa). HRMS: calcd
for C17H28O4N (MþNH4): 310.2013. Found: 310.2010.
(m), 2858 (w), 2725 (w), 1717 (s, C]O), 1710 (s, C]O), 1645 (w),
1458 (w), 1384 (w), 1268 (m), 1241 (s), 1083 (m). Mass spectra for
this compound were not informative.
3.5.3. 3-Oxopropyl 3-(but-3-enyl)-3-(3-oxopropyl)cyclohex-1-ene-
carboxylate 3c. General procedure 4 using 3-hydroxypropyl 3-(but-
3-enyl)-3-(3-hydroxypropyl)cyclohex-1-enecarboxylate (35.0 mg,
0.118 mmol), DMP (150 mg, 0.354 mmol) and CH2Cl2 (1.2 mL), after
4 h, gave 3c (33.0 mg, 0.113 mmol, 96%) as a colourless oil. 1H NMR
3.5.6. 3-Oxopropyl 6,6-dimethyl-3-(3-oxopropyl)-3-(prop-1-en-2-
yl)cyclohex-1-enecarboxylate 3f. General procedure 4 using 3-
hydroxypropyl 3-(3-hydroxypropyl)-6,6-dimethyl-3-(prop-1-en-
2-yl)cyclohex-1-enecarboxylate (237 mg, 0.763 mmol), DMP
(972 mg, 2.29 mmol) and CH2Cl2 (7.5 mL), after 6 h, gave 3f
(154 mg, 0.503 mmol, 66%) as a colourless oil. 1H NMR (CDCl3,
(CDCl3, 500 MHz)
d 1.37–1.52 (4H, m, CH2), 1.66 (2H, quintet,
J¼6.1 Hz, CH2CH2CC(O)), 1.71 (2H, ddd, J¼9.5, 6.5, 2.8 Hz,
CCH2CH2CHO), 1.97–2.04 (2H, m, CH2CH]CH2), 2.17–221 (2H, m,
CH2CC(O)), 2.35–2.47 (2H, m, CCH2CH2CHO), 2.82 (2H, td, J¼6.1,
1.7 Hz, CH2CH2OC(O)), 4.48 (2H, t, J¼6.0 Hz, CH2OC(O)), 4.95 (1H,
dd, J¼10.3, 1.7 Hz, cis CH]CH2), 5.01 (1H, dd, J¼17.2, 1.7 Hz, trans
CH]CH2), 5.77 (1H, ddt, J¼17.2, 10.3, 6.4 Hz, CH]CH2), 6.64 (1H, s,
C(O)C]CH), 9.77 (1H, s, CHO), 9.81 (1H, s, CHO). 13C NMR (CDCl3,
400 MHz) d 1.14 (3H, s, CCH3), 1.20 (3H, s, CCH3), 1.32–1.57 (4H, m,
CH2), 1.67–1.76 (1H, m, CCH2CH2CHO), 1.70 (3H, s, H2C]CCH3),
1.80–1.93 (1H, m, CCH2CH2CHO), 2.29–2.41 (1H, m, CCH2CH2CHO),
2.42–2.55 (1H, m, CCH2CH2CHO), 2.83 (2H, td, J¼6.1, 1.5 Hz,
OCH2CH2CHO), 4.48 (2H, t, J¼6.2 Hz, CH2OC(O)), 4.62 (1H, s,
C]CH2), 4.93 (1H, s, C]CH2), 6.62 (1H, s, C(O)C]CHC), 9.78 (1H, s,
C(CH2)2), 9.83 (1H, t, J¼1.5 Hz, O(CH2)2). 13C NMR (CDCl3,
125 MHz)
d
18.7 (CH2CH2CC(O)), 24.1 (CH2(CH2)2CC(O)), 28.1
100 MHz) d 18.8 (H2C]CCH3), 27.2 (C(CH3)2), 28.1 (C(CH3)2), 28.2
(CH2CH]CH2), 30.8 (CCH2CH2CHO), 31.1 (CH2), 37.5 (C), 38.5 (CH2),
39.0 (CCH2CH2CHO), 42.8 (OCH2CH2CHO), 58.1 (C(O)OCH2), 114.7
(CH2]CH), 130.3 (CH]CC(O)), 138.4 (CH2]CH), 146.0 (CH]CC(O)),
167.0 (C(O)OCH2), 199.6 (CHO), 202.0 (CHO). nmax (thin film/cmꢀ1):
2933 (m), 2854 (w), 1717 (s, C]O), 1711 (s, C]O), 1642 (m), 1456
(w), 1389 (w), 1243 (s). MS (ESþ) m/z (%): 379 (100), 374 (20). Mass
ion not observed.
(CH2), 30.0 (CH2), 33.4 (C(CH3)2), 36.3 (CH2), 39.2 (CCH2CH2CHO),
42.8 (OCH2CH2CHO), 44.5 (C), 57.8 (C(O)OCH2), 114.8 (H2C]C),
138.5 (CH]CC(O)), 143.3 (CH]CC(O)), 147.2 (H2C]C), 167.0
(C(O)OCH2), 200.0 (CHO), 202.0 (CHO). nmax (thin film/cmꢀ1): 2952
(m), 1712 (s, C]O), 1634 (w), 1454 (w), 1388 (w), 1255 (m). Mass
spectra for this compound were not informative.
3.5.7. rac-(3R,6R)-4-Oxobutyl 6-methyl-3-(3-oxopropyl)-3-(prop-1-
3.5.4. rac-(3S,6R)-3-Oxopropyl 3-(but-3-enyl)-6-methyl-3-(3-oxo-
propyl)cyclohex-1-enecarboxylate 3d. General procedure 4 using
rac-(3S,6R)-3-hydroxypropyl 3-(but-3-enyl)-3-(3-hydroxypropyl)-
6-methylcyclohex-1-enecarboxylate (67.0 mg, 0.216 mmol, dr 3:1),
DMP (275 mg, 0.647 mmol) and CH2Cl2 (2.2 mL), after 4 h, gave 3d
(60.0 mg, 0.196 mmol, 91%, dr 3:1) as a colourless oil. 1H NMR
en-2-yl)cyclohex-1-enecarboxylate 3g. General procedure 4 using
rac-(3R,6R)-4-hydroxybutyl
3-(3-hydroxypropyl)-6-methyl-3-
(prop-1-en-2-yl)cyclohex-1-enecarboxylate (160 mg, 0.515 mmol,
dr 3:1), DMP (656 mg, 1.55 mmol) and CH2Cl2 (6.8 mL), after 4 h,
gave 3g (105 mg, 0.343 mmol, 67%, dr 3:1) as a colourless oil. 1H
NMR (CDCl3, 300 MHz, major diastereoisomer)
d 1.02 (3H, d,
(CDCl3, 500 MHz)
d
1.03 (3H, d, J¼6.8 Hz, CH3), 1.04 (d, J¼7.1 Hz,
J¼6.8 Hz, CHCH3), 1.21–1.94 (6H, m, CH2), 1.70 (3H, s, H2C]CCH3),
2.03 (2H, quintet, J¼6.8 Hz, OCH2CH2CH2CHO), 2.25–2.76 (5H, m,
CH2C(O) and CHCH3), 4.17 (2H, t, J¼6.3 Hz, CH2OC(O)), 4.68 (1H, s,
C]CH2), 4.90 (1H, s, C]CH2), 6.75 (1H, s, C(O)C]CHC), 9.76 (1H,
br s, CHO), 9.80 (1H, br s, CHO). 13C NMR (CDCl3, 75 MHz, major
CH3, minor diastereoisomer), 1.31–1.49 (4H, m, CH2), 1.58–1.76 (4H,
m, CH2), 1.88–2.07 (2H, m, CH2CH]CH2), 2.42 (2H, td, J¼8.1, 1.8 Hz,
CCH2CH2CHO), 2.61–2.65 (1H, m, CHCH3), 2.81 (2H, td, J¼6.0,1.8 Hz,
OCH2CH2CHO), 4.53–4.41 (2H, m, CH2OC(O)), 4.94 (1H, dd, J¼10.1,
1.5 Hz, cis CH2]CH), 5.00 (1H, dd, J¼17.1, 1.8 Hz, trans CH2]CH),
5.70–5.82 (1H, m, CH]CH2), 6.55 (1H, s, C(O)C]CH), 9.75 (1H, t,
J¼1.8 Hz, CHO), 9.81 (1H, t, J¼1.8 Hz, CHO). 13C NMR (CDCl3,
diastereoisomer)
d 19.0 (H2C]CCH3), 20.0 (CHCH3), 21.5 (CH2),
27.2 (CH2), 29.0 (CHCH3), 29.7 (CH2), 30.1 (CH2), 39.1
(CCH2CH2CHO), 40.7 (O(CH2)2CH2CHO), 44.1 (C), 63.5 (C(O)OCH2),
113.8 (H2C]C), 135.7 (CH]CC(O)), 143.0 (CH]CC(O)), 148.0
(H2C]C), 167.3 (C(O)OCH2), 201.3 (CHO), 201.9 (CHO). 1H NMR
125 MHz) d 20.0 (CHCH3), 26.5 (CH2), 26.9 (CH2), 27.9 (CHCH3), 28.3
(CH2CH]CH2), 30.7 (CH2), 37.6 (C), 38.4 (CH2), 38.9 (CCH2CH2CHO),
42.8 (OCH2CH2CHO), 58.0 (C(O)OCH2), 114.7 (CH2]CH), 135.3
(CH]CC(O)), 138.4 (CH2]CH), 145.6 (CH]CC(O)), 166.9
(C(O)OCH2), 199.5 (CHO), 201.9 (CHO). nmax (thin film/cmꢀ1): 2928
(m), 2849 (w), 1716 (s, C]O), 1708 (s, C]O), 1451 (w), 1249 (m),
1118 (w), 1058 (m), 1046 (m), 908 (w). MS (ESþ) m/z (%): 307 (100,
MþH). HRMS: Calcd for C18H27O4 (MþH): 307.1904. Found:
307.1900.
(CDCl3, 300 MHz, minor diastereoisomer)
d
1.05 (3H, d, J¼8.3 Hz,
CHCH3), 1.21–1.94 (10H, m, CH2 and H2C]CCH3), 2.03 (2H, quin,
J¼6.8 Hz, OCH2CH2CH2CHO), 2.25–2.76 (4H, m, CH2C(O) and
CHCH3), 4.17 (2H, t, J¼6.3 Hz, CH2CH2OC(O)), 4.57 (1H, s, C]CH2),
4.93 (1H, s, C]CH2), 6.71 (1H, s, C(O)C]CHC), 9.76 (1H, br s,
CHO), 9.78 (1H, br s, CHO). 13C NMR (CDCl3, 75 MHz, minor di-
astereoisomer)
d 18.8 (H2C]CCH3), 19.8 (CHCH3), 22.2 (CH2), 26.4
(CH2), 28.0 (CHCH3), 30.0 (CH2), 30.2 (CH2), 39.2 (CCH2CH2CHO),
40.7 (O(CH2)2CH2CHO), 44.5 (C), 63.4 (C(O)OCH2), 115.1 (H2C]C),
135.6 (CH]CC(O)), 143.3 (CH]CC(O)), 147.0 (H2C]C), 167.0
(C(O)OCH2), 201.5 (CHO), 201.9 (CHO). nmax (thin film/cmꢀ1):
2934 (m), 2951 (m), 2873 (m), 1728 (s, C]O). 1422 (w), 1259 (m).
MS (ESþ) m/z (%): 307 (10, MþH), 324 (100, MþNH4), 329 (50,
MþNa). HRMS: calcd for C18H26O4Na (MþNa): 329.1723. Found:
329.1720.
3.5.5. 3-Oxopropyl 3-methyl-3-(3-oxopropyl)cyclohex-1-enecarbo-
xylate 3e. General procedure
hydroxypropyl)-3-methylcyclohex-1-enecarboxylate
4
using 3-hydroxypropyl 3-(3-
(93.0 mg,
0.363 mmol), DMP (462 mg, 1.09 mmol) and CH2Cl2 (3.6 mL), after
4 h, gave 3e (68.0 mg, 0.270 mmol, 74%) as a colourless oil. 1H NMR
(CDCl3, 500 MHz)
d 1.01 (3H, s, CH3), 1.38–1.42 (2H, m,
CH2(CH2)2CC(O)), 1.57–1.63 (2H, m, CH2CH2CC(O)), 1.67 (2H, t,
J¼8.1 Hz, CCH2CH2CHO), 2.07–2.14 (1H, m, 1H from CH2CC(O)), 2.24
(1H, dt, J¼17.1, 4.8 Hz, 1H from CH2CC(O)), 2.35–2.48 (2H, m,
CCH2CH2CHO), 2.80 (2H, td, J¼6.2, 1.9 Hz, OCH2CH2CHO), 4.46 (2H,
t, J¼6.0 Hz, CH2OC(O)), 6.61 (1H, s, C(O)C]CHC), 9.76 (1H, s, CHO),
3.5.8. Formation of rac-(3R,6R)-2-(formyloxy)ethyl 3-(3-hydroxy-
propyl)-6-methyl-3-(prop-1-en-2-yl)cyclohex-1-enecarboxylate
9. To solution of rac-(3R,6R)-2-hydroxyethyl 3-(3-(tert-butyldime-
thylsilyloxy)propyl)-6-methyl-3-(prop-1-en-2-yl)cyclohex-1-ene-
carboxylate 8h (350 mg, 0.882 mmol, dr 3:1), diethyl
azodicarboxylate (0.280 mL, 1.76 mmol) and PPh3 (463 mg,
9.80 (1H, s, CHO). 13C NMR (CDCl3, 125 MHz)
d 18.8 (CH2CH2CC(O)),
24.2 (CH2CC(O)), 26.4 (CH3), 33.4 (CH2(CH2)2CC(O)), 33.5
(CCH2CH2CHO), 34.9 (C), 39.1 (CCH2CH2CHO), 42.8 (OCH2CH2CHO),
58.0 (C(O)OCH2), 129.3 (C(O)C]CH), 146.8 (C(O)C]CH), 167.2
(C(O)OCH2), 199.6 (CHO), 202.1 (CHO). nmax (thin film/cmꢀ1): 2935
1.76 mmol) in toluene (15 mL) was added formic acid (68.0
mL,
1.76 mmol) at 23 ꢁC. The mixture was then stirred for 16 h before

10826
M.D. Helm et al. / Tetrahedron 65 (2009) 10816–10829
concentration in vacuo and purification bychromatography on silica
gel to give rac-(3R,6R)-2-(formyloxy)ethyl 3-(3-(tert-butyldime-
thylsilyloxy)propyl)-6-methyl-3-(prop-1-en-2-yl)cyclohex-1-ene-
carboxylate (302 mg, 0.711 mmol, 81%, dr 3:1) as a yellow oil that
was used in the next step without further purification. To a solution
of rac-(3R,6R)-2-(formyloxy)ethyl 3-(3-(tert-butyldimethylsily-
loxy)-propyl)-6-methyl-3-(prop-1-en-2-yl)cyclohex-1-enecarbox-
ylate (302 mg, 0.711 mmol, dr 3:1) in pyridine (5 mL) and MeCN
(10 mL) at 0 ꢁC was added dropwise aqueous 60% HF (0.710 mL,
21.3 mmol). After 3 h, the reaction was quenched with the dropwise
addition of an excess of aqueous saturated NaHCO3 (20 mL). After
theeffervescence hadsubsided, themixturewas extractedwith Et2O
(20 mLꢂ3). The combined organic extracts were washed with
aqueous saturated CuSO4 (10 mLꢂ2) and then with brine (10 mLꢂ2)
before being dried (Na2SO4). Concentration in vacuo and purifica-
tion by chromatography on silica gel gave 9 (169 mg, 0.544 mmol,
1699 (s, C]O), 1694 (s, C]O), 1634 (m), 1455 (m), 1377 (w), 1253
(s), 1179 (w).
3.6. General procedure 5. Samarium(II) iodide-mediated
cascade cyclization of dialdehydes 3a–f
SmI2 in THF (0.1 M, 2.5 equiv) was added to degassed t-BuOH
and the resulting solution was stirred under a nitrogen atmosphere
for 20 min before being cooled to 0 ꢁC (ice bath). After cooling, the
dialdehyde 3a–f (1 equiv) was added dropwise as a solution in THF
and the reaction was stirred for 30 min before the excess SmI2 was
quenched by allowing air to reach the reaction. Once the solution
was yellow, an aqueous saturated solution of K/Na tartrate was
added and the crude reaction mixture was extracted with Et2O
(ꢂ3). The combined organic fractions were washed with water and
brine, dried (Na2SO4) and concentrated in vacuo. The crude prod-
ucts were purified by chromatography on silica gel.
76%, dr 3:1) as a colourless oil.1H NMR (CDCl3, 500 MHz)
d 1.04 (3H,
d, J¼6.6 Hz, CHCH3), 1.06 (d, J¼6.9 Hz, CHCH3, minor di-
astereoisomer), 1.21–1.83 (8H, m, CH2), 1.71 (s, H2C]CCH3, minor
diastereoisomer),1.72 (3H, s, H2C]CCH3), 1.91 (1H, br s, OH), 2.55–
2.69 (1H, m, CHCH3), 3.53–3.68 (2H, m, CH2OH), 4.27–4.48 (4H, m,
CH2OC(O)), 4.53 (s, C]CH2, minor diastereoisomer), 4.65 (1H, s,
C]CH2), 4.87 (1H, s, C]CH2), 4.89 (s, C]CH2, minor di-
astereoisomer), 6.87 (s, C(O)C]CH, minor diastereoisomer), 6.91
(1H, s, C(O)C]CH), 8.10 (1H, s, OCHO). 13C NMR (CDCl3, 75 MHz)
3.6.1. Spirocycle 5a. General procedure 5 using 3-oxopropyl 3-
(3-oxopropyl)-3-(prop-1-en-2-yl)cyclohex-1-enecarboxylate
3a
(77.0 mg, 0.277 mmol) in THF (2.00 mL), SmI2 (0.1 M in THF, 6.92 mL,
0.692 mmol) and t-BuOH (1.8 mL) gave 5a (70.0 mg, 0.250 mmol,
90%, dr>95:5) as a colourless solid. Mp 191 ꢁC (CH2Cl2/hexanes). 1H
NMR (DMSO-d6, 400 MHz)
d 1.04–1.18 (2H, m, CH2), 1.28–1.40 (1H,
m, CH2), 1.41–1.56 (3H, m, CH2), 1.58–1.69 (1H, m, CH2), 1.70–1.84
(2H, m, CH2), 1.76 (3H, s, CH3), 1.84–1.98 (1H, m, CH2), 2.01–2.14 (1H,
m, CH2), 2.14–2.28 (1H, m, CH2), 2.42 (1H, d, J¼7.8 Hz, CCHOHCH2),
3.98 (1H, m, CH2CHOH), 4.23 (1H, m, 1H from CH2OC(O)), 4.33 (2H,
m, CHCHOH and 1H from CH2OC(O)), 4.57 (2H, s, C]CH2), 5.56 (1H,
d, J¼4.0 Hz, OH), 5.75 (1H, d, J¼4.3 Hz, OH). 13C NMR (DMSO-d6,
d
18.8 (H2C]CCH3, minor diastereoisomer), 19.1 (H2C]CCH3), 19.7
(CHCH3, minor diastereoisomer), 20.0 (CHCH3), 25.9 (CH2, minor
diastereoisomer), 26.3 (CH2, minor diastereoisomer), 27.3 (CH2),
27.4 (CH2), 27.4 (CH2, minor diastereoisomer), 28.0 (CHCH3, minor
diastereoisomer), 29.1 (CHCH3), 30.2 (CH2), 34.4 (CH2), 34.9 (CH2,
minor diastereoisomer), 44.6 (C), 44.9 (C, minor diastereoisomer),
61.6 (C(O)OCH2, minor diastereoisomer), 61.7 (C(O)OCH2), 61.8
(C(O)OCH2), 61.8 (C(O)OCH2, minor diastereoisomer), 63.3
(CH2OH), 113.2 (H2C]C), 114.5 (H2C]C, minor diastereoisomer),
134.5 (H2C]C, minor diastereoisomer), 134.6 (H2C]C), 145.1
(C(O)C]CH), 145.3 (C(O)C]CH, minor diastereoisomer), 147.7
(C]CH, minor diastereoisomer), 148.7 (C]CH), 160.8 (OCHO),
167.0 (C(O)CH2, minor diastereoisomer),167.3 (C(O)CH2). nmax (thin
film/cmꢀ1): 3421 (br), 2920 (w), 2848 (w),1718 (m, C]O),1647 (m),
1538 (w), 1438 (w), 1321 (w), 1253 (w). MS (ESþ) m/z (%): 328 (20,
MþNH4), 333, (100, MþNa). HRMS: calcd for C17H30O5N (MþNH4):
328.2118. Found: 328.2117.
100 MHz) d 18.4 (CH2), 19.9 (H2C]CCH3), 25.5 (CH2), 28.7 (CH2), 29.7
(CH2), 31.4 (CH2), 37.9 (CH2), 49.2 (C), 49.7 (C), 50.0 (CCHCHOH), 65.0
(CH2OC(O)), 71.0 (CCHOH), 72.9 (CHCHOH), 107.2 (C]CH2), 150.0
(C]CH2), 173.9 (C]O). nmax (thin film/cmꢀ1): 3335 (br), 2924 (s),
2862 (m), 2849 (m), 1715 (s), 1632 (w), 1451 (w), 1257 (m). MS (ESþ)
m/z (%): 303 (100, MþNa), 281 (42, MþH). HRMS: calcd for
C16H24O4Na (MþNa): 303.1567. Found: 303.1566.
3.6.2. Spirocycle 5b. General procedure 5 using rac-(3R,6R)-3-
oxopropyl 6-methyl-3-(3-oxopropyl)-3-(prop-1-en-2-yl)cyclohex-
1-enecarboxylate 3b (140 mg, 0.479 mmol, dr 3:1) in THF (2 mL),
SmI2 (0.1 M in THF, 12.0 mL, 1.20 mmol) and t-BuOH (2.80 mL) gave
a major spirocycle 5b (74 mg, 0.251 mol, 52%, dr>95:5) and a minor
3.5.9. Formation of rac-(3R,6R)-2-(formyloxy)ethyl 6-methyl-3-
(3-oxopropyl)-3-(prop-1-en-2-yl)cyclohex-1-enecarboxylate 10. To
spirocycle (26 mg, 88.3
isolated as yellow solid. Mp 170 ꢁC (CH2Cl2/hexanes). 1H NMR
(CDCl3, 300 MHz)
mmol, 18%, dr>95:5). Major spirocycle 5b
a solution of oxalyl chloride (45.0
m
L, 0.534 mmol) in CH2Cl2
d
1.05 (3H, d, J¼6.6 Hz, CHCH3), 1.22–1.47 (4H, m,
(1 mL) at ꢀ78 ꢁC was dropwise added DMSO (63.0
m
L,
CH2), 1.63 (1H, m, CH2), 1.74 (3H, s, H2C]CCH3), 1.81–1.97 (2H, m,
CH2), 2.10–2.37 (2H, m, CH2), 2.46 (1H, m, CHCH3), 2.56 (1H, d,
J¼8.5 Hz, CHCHOH), 2.59–2.77 (1H, m, CH2), 4.08–4.29 (2H, m,
CCHOHCH2 and 1H from CH2CH2OC(O)), 4.43 (1H, ddd, J¼11.9, 8.0,
4.4 Hz, CH2CH2OC(O)), 4.90–4.66 (3H, m, C]CH2 and CHCHOHCH2).
0.889 mmol). After 20 min, rac-(3R,6R)-2-(formyloxy)ethyl 3-
(3-hydroxypropyl)-6-methyl-3-(prop-1-en-2-yl)cyclohex-1-ene-
carboxylate 9 (138 mg, 0.445 mmol, dr 3:1) in CH2Cl2 (1 mL) was
dropwise added and the mixture stirred for 45 min before tri-
ethylamine (0.245 mL, 1.76 mmol) was added and the reaction
allowed to warm to 23 ꢁC. Upon warming, the reaction was stirred
for 3 h before quenching with aqueous saturated NaHCO3 (10 mL)
and extracted with Et2O (5 mLꢂ3). After drying (Na2SO4) and
concentration in vacuo, 10 (133 mg, 0.431 mmol, 97%, dr 3:1) was
isolated as a yellow oil that was used without further purification.
13C NMR (CDCl3, 75 MHz):
d 14.2 (CHCH3), 16.0 (H2C]CCH3), 27.0
(CH2), 28.5 (CH2), 29.4 (CH2), 30.1 (CHCH3), 30.8 (CH2), 38.6 (CH2),
48.7 (CCHCHOH), 50.6 (CCHCHOH), 53.1 (CC(O)), 64.5 (CH2OC(O)),
69.0 (CCHOH), 73.5 (CHCHOH), 110.4 (C]CH2), 147.7 (C]CH2), 171.6
(C]O). nmax (thin film/cmꢀ1): 3311 (br), 2935, (m), 1706 (s, C]O),
1263 (w), 1065 (m). MS (ESþ) m/z (%): 295 (5, MþH), 317 (100,
MþNa). HRMS: calcd for C17H27O4 (MþH): 295.1904. Found:
295.1902. Minor spirocycle isolated as a yellow gum. 1H NMR
1H NMR (CDCl3, 300 MHz)
d
1.04 (3H, d, J¼7.0 Hz, CHCH3), 1.06 (d,
J¼7.5 Hz, CHCH3, minor diastereoisomer), 1.20–1.50 (2H, m, CH2),
1.54–1.93 (4H, m, CH2), 1.71 (3H, s, H2C]CCH3), 2.27–2.53 (2H, m,
CH2CHO), 2.55–2.70 (1H, m, CHCH3), 4.25–4.47 (4H, m, CH2O),
4.58 (s, C]CH2, minor diastereoisomer), 4.69 (1H, s, C]CH2), 4.91
(1H, s, C]CH2), 6.78 (s, HC]CC(O), minor diastereoisomer), 6.81
(1H, s, HC]CC(O)), 8.09 (1H, s, OCHO), 9.76 (1H, t, J¼1.2 Hz,
CH2CHO), 9.79 (t, J¼1.3 Hz, CH2CHO, minor diastereoisomer). nmax
(thin film/cmꢀ1): 2938 (s), 2873 (w), 1732 (s, C]O), 1738 (s, C]O),
(CDCl3, 300 MHz)
d
1.02 (3H, d, J¼7.0 Hz, CHCH3), 1.19–2.37 (11H, m,
CH2 and CHCH3), 1.91 (3H, s, H2C]CCH3), 2.80 (1H, d, J¼6.8 Hz,
CHCHOH), 4.09–4.21 (1H, m, CCHOHCH2), 4.36 (1H, dt, J¼11.6,
5.9 Hz, CH2CH2OC(O)), 4.41–4.50 (1H, m, CHCHOHCH2), 4.51–4.63
(1H, m, CH2CH2OC(O)), 4.81–4.90 (1H, m, C]CH2), 5.00 (1H, s,
C]CH2). 13C NMR (CDCl3, 75 MHz):
d
18.8 (CHCH3), 20.2
(H2C]CCH3), 27.3 (CH2), 27.7 (CH2), 28.1 (CH2), 32.1 (CHCH3), 32.7

M.D. Helm et al. / Tetrahedron 65 (2009) 10816–10829
10827
(CH2), 37.8 (CH2), 49.6 (CCHCHOH), 51.0 (CCHCHOH), 54.8 (CC(O)),
65.4 (CH2OC(O)), 70.3 (CCHOH), 76.4 (CHCHOH), 109.4 (C]CH2),
152.7 (C]CH2), 174.2 (C]O). nmax (thin film/cmꢀ1): 3311 (br), 2935,
(m), 1706 (s, C]O), 1263 (w), 1065 (m). MS (ESþ) m/z (%): 295 (7,
MþH), 317 (100, MþNa). HRMS: calcd for C17H30O4 (MþNH4):
312.2169. Found: 312.2163.
(3H, s, CH3), 1.28–1.29 (1H, m, 1H from CH2), 1.39–1.54 (4H, m, 1H
from CCH2CH2CHOH, 1H from CCH2CH2CHOH, CH2), 1.71–1.76 (1H,
m, 1H from CCH2CH2CHOH), 1.83–1.91 (2H, m, 1H from
CH2CH2OC(O), 1H from CH2), 2.08–2.15 (2H, m, CCHCHOH, 1H from
CCH2CH2CHOH), 2.24–2.33 (1H, m, 1H, from CH2CH2OC(O)), 4.08
(1H, t, J¼3.9 Hz, CCHOH), 4.29–4.36 (2H, m, 1H from CH2OC(O),
CHCHOH), 4.59 (1H, td, J¼11.0, 5.9 Hz, 1H from CH2OC(O)). 13C
3.6.3. Spirocycle 5c. General procedure 5 using 3-oxopropyl 3-(but-
3-enyl)-3-(3-oxopropyl)cyclohex-1-enecarboxylate 3c (33.0 mg,
0.113 mmol) in THF (1 mL), SmI2 (0.1 M in THF, 2.82 mL, 0.282 mmol)
NMR (CDCl3, 125 MHz) d 19.0 (CH2), 26.0 (CH2CH2OC(O)), 28.5
(CH2), 28.9 (CH3), 32.2 (CCH2CH2CHOH), 33.1 (CH2), 40.4
(CCH2CH2CHOH), 41.8 (CCHCHOH), 50.6 (CC(O)), 53.8 (CCHCHOH),
66.2 (CH2OC(O)), 72.8 (CCHOH), 75.6 (CHCHOH), 176.1 (C]O). nmax
(thin film/cmꢀ1): 3397 (br), 2929 (s), 2859 (m), 1723 (s, C]O),
1460 (m), 1265 (w), 1158 (m), 1078 (w), 1006 (w). MS (ESþ) m/z (%):
277 (100, MþNa). HRMS: Calcd for C14H22O4Na (MþNa): 277.1410.
Found: 277.1404.
and t-BuOH (0.760 mL) gave 5c (23.0 mg, 78.1
m
mol, 69%, dr>95:5)
as a colourless oil. 1H NMR (CDCl3, 300 MHz)
d
1.05–1.12 (1H, m, 1H
from CH2), 1.30–1.38 (4H, m, 1H from 3ꢂCH2, 1H from
CCH2CH2CH]CH2), 1.49–1.54 (2H, m, 1H from CCH2CH2CHOH, 1H
from CH2), 1.71–1.74 (1H, m, 1H from CCH2CH2CHOH), 1.79–1.82 (1H,
m, 1H from CCH2CH2CHOH), 1.83–1.89 (4H, m, CCH2CH2CH]CH2, 1H
from CCH2CH2CH]CH2, 1H from CH2CH2OC(O)), 2.08–2.13 (2H, m,
1H from CCH2CH2CHOH, 1H from CH2), 2.19 (1H, d, J¼8.6 Hz,
CCHCHOH), 2.36 (1H, dddd, J¼14.3, 11.0, 7.7, 3.5 Hz, 1H from
CH2CH2OC(O)), 4.07 (1H, t, J¼4.3 Hz, CCHOH), 4.28–4.37 (2H, m, 1H
from CH2OC(O), CCHCHOH), 4.52 (1H, td, J¼11.1, 5.8 Hz, 1H from
CH2OC(O)), 4.85 (1H, dd, J¼10.1, 2.2 Hz, cis CH]CH2), 4.97 (1H, dd,
J¼17.1, 2.2 Hz, trans CH]CH2), 5.82 (1H, ddt, J¼17.1, 10.4, 6.6 Hz,
3.6.6. Spirocycle 5f. General procedure 5 using 3-oxopropyl 6,6-
dimethyl-3-(3-oxopropyl)-3-(prop-1-en-2-yl)cyclohex-1-enecarbo-
xylate 3f (28.0 mg, 91.4
2.28 mL, 0.228 mmol) and t-BuOH (0.900 mL) gave spirocycle 5f
(21.0 mg, 68.1 mol, 75%, dr>95:5) as a light yellow solid. Mp 159–
160 ꢁC (CH2Cl2/hexanes). 1H NMR (CDCl3, 400 MHz)
0.96 (1H, m,
mmol) in THF (2 mL), SmI2 (0.1 M in THF,
m
d
CH2), 1.00 (3H, s, C(CH3)2), 1.04 (3H, s, C(C)2), 1.26 (1H, m, CH2),
1.35–1.48 (2H, m, CH2), 1.52–1.67 (1H, m, CH2), 1.74–1.82 (1H, m,
CH2), 1.88 (3H, s, H2C]CCH3), 1.98–2.25 (2H, m, CH2), 2.33 (1H,
dddd, J¼13.7, 8.2, 5.1, 3.3 Hz, CHOHCH2CH2O), 2.57 (1H, td, J¼12.7,
7.8 Hz, CH2), 2.76 (1H, br s, CHCHOH), 3.58 (1H, br s, OH), 4.15 (1H,
ddd, J¼8.1, 5.9, 2.1 Hz, CHCHOH), 4.23 (1H, dd, J¼7.7, 3.2 Hz,
CCHOH), 4.32 (1H, dt, J¼11.4, 5.6 Hz, CH2OC(O)), 4.59 (1H, ddd,
J¼11.4, 7.9, 5.0 Hz, CH2OC(O)), 4.92 (1H, s, C]CH2), 5.07 (1H, s,
CH]CH2). 13C NMR (CDCl3, 125 MHz)
d 18.6 (CH2), 26.1
(CH2CH2OC]O), 29.1 (CH2), 29.2 (CH2), 31.8 (CH2), 32.4
(CCH2CH2CHOH), 35.6 (CH2CH]CH2), 38.4 (CCH2CH2CHOH), 44.6
(CCHOH), 50.6 (CCH2CH2CH]CH2), 51.7 (CC]O), 66.0 (CH2OC]O),
72.7 (CCHOH), 75.3 (CCHCHOH), 113.8 (HC]CH2), 139.9 (HC]CH2),
176.0 (C]O). nmax (thin film/cmꢀ1): 3402 (br), 2938 (s), 2864 (m),
1718 (s, C]O),1639 (w),1458 (m),1399 (w),1259 (w),1152 (m),1052
(m), 908 (w). MS (ESþ) m/z (%): 317 (100, MþNa). HRMS: Calcd for
C17H26O4Na (MþNa): 317.1723. Found: 317.1715.
C]CH2). 13C NMR (CDCl3, 100 MHz)
d 20.1 (H2C]CCH3), 23.5
(C(CH3)2), 28.7 (CH2), 29.3 (C(CH3)2), 29.2 (CH2), 33.9 (CH2), 34.0
(two signals, CH2), 36.0 (C(CH3)2), 49.2 (CCHCHOH), 50.7
(CCHCHOH), 59.7 (C(C(O))), 65.3 (CH2OC(O)), 71.9 (CCHOH), 82.0
(CHCHOH), 110.0 (C]CH2), 153.8 (C]CH2), 173.3 (C]O). nmax (thin
film/cmꢀ1): 3389 (br), 2953 (s), 2925 (s), 2858 (m), 1715 (s, C]O),
1631 (w), 1459 (w), 1108 (w). MS (ESþ) m/z (%): 326 (10, MþNH4),
331 (100, MþNa). HRMS: calcd for C18H28O4Na (MþNa): 331.1880.
Found: 331.1879.
3.6.4. Spirocycle 5d. General procedure 5 using rac-(3S,6R)-3-oxo-
propyl 3-(but-3-enyl)-6-methyl-3-(3-oxopropyl)cyclohex-1-ene-
carboxylate 3d (50.0 mg, 0.163 mmol, dr 3:1) in THF (1 mL), SmI2
(0.1 M in THF, 4.08 mL, 0.408 mmol) and t-BuOH (1.02 mL) gave
a major spirocycle 5d (33.0 mg, 0.106 mmol, 66%, dr>95:5) as
a colourless oil. 1H NMR (CDCl3, 300 MHz)
d
1.10 (3H, d, J¼6.8 Hz,
CH3), 1.22–1.32 (2H, m, 1H from CH2CHCH3, 1H from CH2), 1.40–1.47
(2H, m, 1H from CH2, 1H from CCH2CH2CHOH), 1.50–1.68 (2H, m, 1H
from CH2, 1H from CCH2CH2CHOH), 1.70–1.80 (1H, m, 1H from
CH2CHCH3), 1.86–1.98 (4H, m, CH2CH]CH2, CCH2CH2CHOH), 2.13
(1H, d, J¼8.8 Hz, CCHCHOH), 2.17–2.25 (2H, m, 1H from
CH2CH2OC(O), CHCH3), 2.30–2.41 (1H, m, 1H from CH2), 2.58–2.68
(1H, m, 1H from CH2CH2OC(O)), 4.15–4.27 (2H, m, 1H from
CH2OC(O), CCHOH), 4.47 (1H, ddd, J¼11.7, 8.1, 4.9 Hz, 1H from
CH2OC(O)), 4.73 (1H, td, J¼9.1, 6.3 Hz, CHCHOH), 4.90 (1H, dd,
J¼10.1, 2.0 Hz, cis CH2]CH), 4.99 (1H, dd, J¼17.1, 2.0 Hz, trans
CH2]CH), 5.78 (1H, ddt, J¼17.1, 10.1, 6.5 Hz, CH2]CH). 13C NMR
3.6.7. Attempted cascade cyclization of rac-(3R,6R)-4-oxobutyl 6-
methyl-3-(3-oxopropyl)-3-(prop-1-en-2-yl)cyclohex-1-enecarbox-
ylate 3g. SmI2 (0.1 M in THF, 5.30 mL, 0.530 mmol) was added to
degassed t-BuOH (1.46 mL) and the resulting complex was stirred
under a nitrogen atmosphere for 20 min before being cooled to
0 ꢁC (ice bath). After cooling, rac-(3R,6R)-4-oxobutyl 6-methyl-3-
(3-oxopropyl)-3-(prop-1-en-2-yl)cyclohex-1-enecarboxylate 3g
(65.0 mg, 0.212 mmol, dr 3:1) was added dropwise as a solution in
THF (2 mL) and the reaction was stirred for 30 min before the
excess SmI2 was quenched by allowing air to reach the reaction.
Once the solution was yellow, an aqueous saturated solution of K/
Na tartrate (10 mL) was added and the crude reaction mixture was
extracted with Et2O (10 mLꢂ3). The combined organic fractions
were washed with water (5 mL) and brine (5 mL), dried (Na2SO4)
and concentrated in vacuo. The crude products were purified by
(CDCl3, 125 MHz)
d 15.6 (CHCH3), 26.6 (CH2), 27.5 (CH2CH2OC(O)),
28.1 (CH2), 28.8 (CH2CH]CH2), 29.7 (CHCH3), 30.9 (CH2), 35.0
(CH2CHCH3), 35.9 (CH2CH2CHOH), 45.1 (CCHOH), 51.7 (CHCHOH),
52.9 (CC(O)), 64.4 (CH2OC(O)), 68.7 (CCHOH), 73.3 (CCHCHOH),
113.6 (CH]CH2), 138.7 (CH]CH2), 173.5 (C]O). nmax (thin film/
cmꢀ1): 3381 (br), 2933 (s), 2868 (m), 1711 (s, C]O), 1640 (w), 1253
(w), 1175 (m), 1064 (m), 909 (m), 733 (w). MS (ESþ) m/z (%): 331
(100, MþNa). HRMS: Calcd for C18H28O4Na (MþNa): 331.1880.
Found: 331.1882.
chromatography on silica gel to give 11 (10.0 mg, 32.2
mmol, 15%)
as colourless oil. 1H NMR (CDCl3, 300 MHz)
d
0.90 (3H, d, J¼7.2 Hz,
CHCH3), 1.15–1.36 (2H, m, CH2), 1.40–1.84 (8H, m, CH2), 1.86 (3H, s,
H2C]CCH3), 1.89 (s, H2C]CCH3, minor diastereoisomer), 2.03–
2.27 (2H, m, CH2), 2.27–2.37 (1H, m, CHC(O)), 2.45 (d, J¼10.7 Hz,
CHCHOH minor diastereoisomer), 2.55 (1H, d, J¼10.7 Hz,
CHCHOH), 3.69 (2H, t, J¼6.1 Hz, CH2OH), 3.81–3.93 (1H, m,
CHCHOH), 4.03–4.33 (2H, m, CH2OC(O)), 4.89–4.98 (1H, m,
C]CH2), 4.99–5.12 (1H, m, C]CH2). 13C NMR (CDCl3, 75 MHz)
3.6.5. Spirocycle 5e. General procedure 5 using 3-oxopropyl 3-
methyl-3-(3-oxopropyl)cyclohex-1-enecarboxylate 3e (50.0 mg,
0.198 mmol) in THF (1.50 mL), SmI2 (0.1 M in THF, 4.95 mL,
0.495 mmol) and t-BuOH (1 mL) gave 5e (39.0 mg, 0.153 mmol,
77%, dr>95:5) as a colourless oil. 1H NMR (CDCl3, 300 MHz)
d
1.03–
d
13.8 (CHCH3), 19.1 (H2C]CCH3), 19.3 (H2C]CCH3, minor di-
1.037 (1H, m, 1H from CH2), 1.18–1.21 (1H, m, 1H from CH2), 1.23
astereoisomer), 24.1 (CH2), 24.3 (CH2, minor diastereoisomer),

10828
M.D. Helm et al. / Tetrahedron 65 (2009) 10816–10829
26.5 (CH2), 27.3 (CH2), 28.2 (CH2), 28.4 (CH2, minor di-
astereoisomer), 28.7 (CH2, minor diastereoisomer), 29.0 (CHCH3),
30.8 (CH2), 30.9 (CH2), 31.9 (CH2, minor diastereoisomer), 32.2
(CH2, minor diastereoisomer), 45.7 (CHCHCHOH), 46.2
(CHCHCHOH), 48.2 (C), 48.9 (minor diastereoisomer), 51.2 (minor
diastereoisomer), 51.3 (minor diastereoisomer), 61.2 (CH2OH),
63.2 (CH2OC(O)), 77.7 (CHCHOH, minor diastereoisomer), 78.8
(CHCHOH), 109.6 (C]CH2), 109.8 (C]CH2, minor di-
astereoisomer), 150.3 (C]CH2), 151.6 (C]CH2, minor di-
astereoisomer), 174.0 (C]O), 174.6 (C]O, minor diastereoisomer).
MS (ESþ) m/z (%): 311 (18, MþH), 328 (10, MþNH4), 333 (100,
MþNa).
(CHOH), 110.7 (C]CH2), 151.1 (C]CH2), 160.6 (OCHO), 174.6 (C(O)).
nmax (thin film/cmꢀ1): 2996 (m), 2955 (m), 2873 (w), 1723 (s),
1460 (w), 1442, (w), 1251 (w), 1168 (m). MS (ESþ) m/z (%): 328 (40,
MþNH4), 333 (100, MþNa). HRMS: calcd for C17H26O5Na (MþNa):
333.1678. Found: 333.1661.
3.6.9. Reduction of spirocyclic lactone 5c with SmI2–H2O to give rac-
(1R)-1-[(3S,3aR,4S,7aS)-3-hydroxy-4-(hydroxymethyl)-7a-(but-3-
en-1-yl)octahydro-1H-inden-4-yl]propane-1,3-diol 18c. Degassed,
distilled water (1.15 mL) was added to a solution of SmI2 in THF
(0.1 M, 4.60 mL, 0.460 mmol) and stirred under nitrogen until the
solution turned
a dark red. Degassed spirocycle 5c (17 mg,
57.7 mol) was added as a solution in THF (0.700 mL) and the re-
m
3.6.8. Attempted cascade cyclization of rac-(3R,6R)-2-(formyl-
oxy)ethyl 6-methyl-3-(3-oxopropyl)-3-(prop-1-en-2-yl)cyclohex-1-
enecarboxylate 10. SmI2 (0.1 M in THF, 3.65 mL, 0.365 mmol) was
added to degassed t-BuOH (1.13 mL) and the resulting complex
was stirred under a nitrogen atmosphere for 20 min before being
cooled to 0 ꢁC (ice bath). After cooling, rac-(3R,6R)-2-(for-
action was stirred for 18 h until the solution had decolourised. An
aqueous saturated solution of K/Na tartrate (10 mL) was added and
the mixture was extracted with EtOAc (5ꢂ15 mL). The combined
organic fractions were washed with water (2ꢂ15 mL) and brine
(15 mL), dried (Na2SO4) and concentrated in vacuo. The crude
products were purified by chromatography on silica gel to give 18c
myloxy)ethyl
6-methyl-3-(3-oxopropyl)-3-(prop-1-en-2-yl)cy-
(14.0 mg, 46.9
400 MHz) 1.15–1.42 (4H, m, CH2), 1.57–1.75 (7H, m, 1H from
m
mol, 81%) as a colourless oil. 1H NMR (CDCl3,
clohex-1-enecarboxylate 10 (45.0 mg, 0.146 mmol, dr 3:1) was
added dropwise as a solution in THF (2 mL) and the reaction was
stirred for 30 min before the excess SmI2 was quenched by
allowing air to reach the reaction. Once the solution was yellow,
a saturated aqueous solution of K/Na tartrate (10 mL) was added
and the crude reaction mixture was extracted with Et2O
(10 mLꢂ3). The combined organic fractions were washed with
water (5 mL) and brine (5 mL), dried (Na2SO4) and concentrated in
vacuo. The crude products were purified by chromatography
d
CH2CH2OH, 1H from CCH2CH2CHOH, 1H from CH2, 1H from
CCH2CH2CH]CH2, CH2), 1.87–1.97 (2H, m, 1H from CH2CH2OH, 1H
from CH2), 2.02–2.11 (1H, m, 1H from CCH2CH2CH]CH2), 2.17–2.23
(2H, m, 1H from CCH2CH2CHOH, 1H from CCH2CH2CH]CH2), 2.37
(1H, d, J¼7.3 Hz, CCHCHOH), 3.77 (1H, d, J¼11.4 Hz, 1H from
CCH2OH), 3.83–3.96 (4H, m, 1H from CCH2OH, CCHOH, CH2CH2OH),
4.51 (1H, td, J¼8.6, 2.8 Hz, CCHCHOH), 4.93 (1H, dd, J¼10.1, 2.0 Hz,
cis CH]CH2), 5.03 (1H, dd, J¼17.1, 2.0 Hz, trans CH]CH2), 5.84 (1H,
on silica gel to give 12 (9.00 mg, 31.9
m
mol, 21%) and 13 (10.0 mg,
ddt, J¼17.1, 10.1, 6.7 Hz, CH]CH2). 13C NMR (CDCl3, 125 MHz)
d 18.1
32.2 mol, 22%). rac-(3S,3aS,4R,5R,7aR)-2-Hydroxyethyl 3-
m
(CH2), 27.8 (CH2), 28.9 (CH2CH]CH2), 29.7 (CH2), 31.6 (CH2CH2OH),
31.8 (CH2), 36.9 (CH2), 38.2 (CH2), 41.4 (C), 44.8 (C), 50.8
(CCHCHOH), 62.8 (CH2CH2OH), 65.6 (CCH2OH), 74.6 (CCHCHOH),
81.3 (CCHOH), 114.1 (HC]CH2), 139.5 (HC]CH2). nmax (thin film/
cmꢀ1): 3324 (br OH), 2923 (s), 2855 (m), 1721 (w), 1640 (w), 1554
(m), 1434 (m), 1361 (w), 1233 (w), 1049 (m), 908 (w). MS (ESþ) m/z
(%): 321 (100, MþNa). HRMS: calcd for C17H30O4Na (MþNa):
321.2042. Found: 321.2051.
hydroxy-5-methyl-7a-(prop-1-en-2-yl)-octahydro-1H-indene-4-
carboxylate 12 was isolated as colourless oil. 1H NMR (CDCl3,
300 MHz)
d
0.92 (3H, d, J¼7.0 Hz, CHCH3), 1.18–1.96 (7H, m, CH2),
1.85 (3H, s, H2C]CCH3), 2.02–2.30 (2H, m, CHCH3 and CH2), 2.40
(1H, dd, J¼10.7, 4.5 Hz, CHC(O)), 2.61 (1H, d, J¼10.9 Hz, C(O)CH-
CHOH), 3.68–3.93 (3H, m, CH2OH and CHOH), 4.04–4.18 (1H, m,
CH2OC(O)), 4.26–4.43 (1H, m, CH2OC(O)), 4.94 (1H, s, C]CH2), 5.04
(1H, s, C]CH2). 13C NMR (CDCl3, 75 MHz)
d 14.7 (CHCH3), 20.0
(H2C]CCH3), 20.4 (H2C]CCH3, minor diastereoisomer), 27.6 (CH2),
28.5 (CH2), 29.3 (CH2, minor diastereoisomer), 30.2 (CHCH3), 30.9
(CH2, minor diastereoisomer), 31.9 (CH2, minor diastereoisomer),
32.0 (CH2), 32.3 (CH2), 32.6 (CHCH3, minor diastereoisomer), 33.0
(CH2, minor diastereoisomer), 46.5 (CHOHCHCH), 47.8 (CHCHCH),
49.1 (C), 49.6 (C, minor diastereoisomer), 52.1 (CH, minor di-
astereoisomer), 52.6 (CH, minor diastereoisomer), 61.0
(CH2OC(O)), 61.1 (CH2OC(O), minor diastereoisomer), 66.0
(CH2OH), 79.2 (CHOH, minor diastereoisomer), 79.9 (CHOH), 110.6
(C]CH2), 110.8 (C]CH2, minor diastereoisomer), 151.4 (C]CH2),
152.0 (C]CH2, minor diastereoisomer), 175.0 (C]O), 175.9 (C]O,
minor diastereoisomer). nmax (thin film/cmꢀ1): 3401 (br), 3085
(w), 2955 (s), 1730 (s, C]O), 1635 (m), 1454 (m), 1384 (w), 1248
(w), 1217 (w), 1171 (w). MS (ESþ) m/z (%): 265 (25, [MþH]ꢀH2O),
283 (10, MþH), 300 (35, MþNH4), 305 (100, MþNa). HRMS: calcd
for C16H26O4Na (MþNa): 305.1729. Found: 305.1715. rac-
(3S,3aS,4R,5R,7aR)-2-(Formyloxy)ethyl 3-hydroxy-5-methyl-7a-
(prop-1-en-2-yl)-octahydro-1H-indene-4-carboxylate 13 isolated
3.6.10. Reduction of spirocyclic lactone 5e with SmI2–H2O to give rac-
(1R)-1-[(3S,3aR,4S,7aS)-3-hydroxy-4-(hydroxymethyl)-7a-methyl-
octahydro-1H-inden-4-yl]propane-1,3-diol 18e. Degassed, distilled
water (1.73 mL) was added to a solution of SmI2 in THF (0.1 M,
6.90 mL, 0.690 mmol) and stirred under nitrogen until the solu-
tion turned a dark red. Degassed spirocycle 5e (22 mg, 86.5 mmol)
was added as a solution in THF (1 mL) and the reaction was stirred
for 18 h until the solution had decolourised. An aqueous saturated
solution of K/Na tartrate (10 mL) was added and the mixture was
extracted with EtOAc (5ꢂ15 mL). The combined organic fractions
were washed with water (2ꢂ15 mL) and brine (15 mL), dried
(Na2SO4) and concentrated in vacuo. The crude products were
purified by chromatography on silica gel to give 18e (21.0 mg,
81.3
1.15–1.30 (4H, m, CH2), 1.26 (3H, s, CH3), 1.40–1.46 (3H, m, 1H
m
mol, 94%) as a colourless oil. 1H NMR (CDCl3, 400 MHz)
d
from CCH2CH2CHOH, CH2), 1.55–1.62 (1H, m, 1H from
CCH2CH2CHOH), 1.68–1.74 (1H, m, 1H from CHOHCH2CH2OH),
1.86–1.92 (2H, m, 1H from CCH2CH2CHOH, 1H from CHOHCH2
-
as colourless oil. 1H NMR (CDCl3, 300 MHz)
d
0.90 (3H, d, J¼7.2 Hz,
CH2OH), 2.17–2.23 (1H, m, 1H from CCH2CH2CHOH), 2.31 (1H, d,
J¼7.8 Hz, CCHCHOH), 3.78 (1H, d, J¼11.6 Hz, 1H from CCH2OH),
3.83–3.96 (4H, m, 1H from CCH2OH, CCHOH, CH2CH2OH), 4.48 (1H,
CHCH), 1.03–1.12 (1H, m, CHCH3), 1.16–2.00 (6H, m, CH2), 1.87 (3H,
m, H2C]CCH3), 2.00–2.29 (2H, m, CH2), 2.35–2.43 (1H, m,
CHC]O), 2.50–2.59 (1H, m, CHCHCHOH), 3.87 (1H, br s, CHOH),
4.25–4.52 (4H, m, CH2OC(O)), 4.80–5.13 (2H, m, C]CH2), 8.09 (1H,
td, J¼8.8, 2.5 Hz, CCHCHOH). 13C NMR (CDCl3, 125 MHz)
d 18.4
(CH2), 26.9 (CH3), 27.6 (CH2), 29.7 (CH2), 31.5 (CH2CH2OH), 31.7
(CCH2CH2CHOH), 41.3 (CCH2CH2CHOH), 41.4 (C), 41.6 (C), 52.3
(CCHCHOH), 62.7 (CH2CH2OH), 65.1 (CCH2OH), 74.7 (CCHCHOH),
81.2 (CCHOH). nmax (thin film/cmꢀ1): 3327 (br O–H), 2929 (s), 2858
(m), 2365 (w), 2341 (w), 1458 (w), 1052 (s). MS (ESþ) m/z (%): 281
s, OCHO). 13C NMR (CDCl3, 75 MHz)
d 14.9 (CHCH), 20.3
(H2C]CCH3), 27.4 (CH2), 28.5 (CH2), 29.9 (CHCH3), 31.9 (CH2), 32.2
(CH2), 46.8 (CHCHCH or CHCHCHOH), 46.9 (CHCHCH or
CHCHCHOH), 49.1 (C), 61.6 (CH2OC(O)), 61.8 (CH2OC(O)), 79.6

M.D. Helm et al. / Tetrahedron 65 (2009) 10816–10829
10829
2. (a) Johnston, D.; McCusker, C. M.; Procter, D. J. Tetrahedron Lett. 1999, 40, 4913;
(b) Johnston, D.; McCusker, C. F.; Muir, K.; Procter, D. J. J. Chem. Soc., Perkin Trans.
1 2000, 681.
(100, MþNa). HRMS: Calcd for C14H26O4Na (MþNa): 281.1729.
Found: 281.1724.
3. (a) Johnston, D.; Francon, N.; Edmonds, D. J.; Procter, D. J. Org. Lett. 2001, 3,
2001; (b) Johnston, D.; Couche´, E.; Edmonds, D. J.; Muir, K.; Procter, D. J. Org.
Biomol. Chem. 2003, 328; (c) Edmonds, D. J.; Muir, K. W.; Procter, D. J. J. Org.
Chem. 2003, 68, 3190; (d) Baker, T. M.; Edmonds, D. J.; Hamilton, D.; O’Brien, C. J.;
Procter, D. J. Angew. Chem., Int. Ed. 2008, 47, 5631.
4. (a) Hutton, T. K.; Muir, K.; Procter, D. J. Org. Lett. 2002, 4, 2345; (b) Hutton, T. K.;
Muir, K. W.; Procter, D. J. Org. Lett. 2003, 5, 4811; (c) Guazzelli, G.; Duffy, L. A.;
Procter, D. J. Org. Lett. 2008, 10, 4291.
5. Sloan, L. A.; Baker, T. M.; Macdonald, S. J. F.; Procter, D. J. Synlett 2007,
3155.
6. Findley, T. J. K.; Sucunza, D.; Miller, L. C.; Davies, D. T.; Procter, D. J. Chem.dEur. J.
2008, 14, 6862.
7. For CCDC numbers, please see: Helm, M. D.; Sucunza, D.; Da Silva, M.; Helliwell,
M.; Procter, D. J. Tetrahedron Lett. 2009, 50, 3224.
8. Takahashi, S.; Kubota, A.; Nakata, T. Angew. Chem., Int. Ed. 2002, 41, 4751.
9. When the alkene is sufficiently electron-deficient, as is the case with a,b-un-
saturated esters, an alternative mechanism involving reduction of the alkene
and a subsequent radical or anionic addition to the aldehyde is also possible,
3.6.11. SmI2-mediated, dialdehyde cyclization cascade–lactone re-
duction to give 18e from 3e. SmI2 (0.1 M in THF, 3.70 mL,
0.370 mmol) was added to degassed t-BuOH (0.73 mL) and the
resulting complex was stirred under a nitrogen atmosphere for
20 min before being cooled to 0 ꢁC (ice bath). After cooling, 3-oxo-
propyl 3-methyl-3-(3-oxopropyl)cyclohex-1-enecarboxylate 3e
(37.0 mg, 0.147 mmol) was added dropwise as a solution in THF
(1.50 mL) and the reaction was stirred for 30 min. The ice bath was
removed and a solution of SmI2 (0.1 M in THF, 12.1 mL, 1.21 mmol)
and degassed, distilled water (3.02 mL) was added. The reaction was
stirred for 18 h until the solution had decolourised. An aqueous
saturated solution of K/Na tartrate (10 mL) was added and the
mixture was extracted with EtOAc (5ꢂ15 mL). The combined organic
fractions were washed with water (2ꢂ15 mL) and brine (15 mL),
dried (Na2SO4) and concentrated in vacuo. The crude products were
purified by chromatography on silica gel to give 18e (29.0 mg,
0.112 mmol, 76%) as a colourless oil.
although such
a mechanism is less frequently proposed. This alternative
mechanism could also explain the selectivity seen in our studies and those of
Takahashi and Nakata (Ref. 8).
10. For a review of the chemistry of samarium enolates, see: Rudkin, I. M.; Miller, L. C.;
Procter, D. J. Organomet. Chem. 2008, 34, 19.
11. Enholm, E. J.; Trivellas, A. Tetrahedron Lett. 1994, 35, 1627.
12. Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
13. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
Acknowledgements
14. Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380; For a recent
review, see: Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.; Pavan
Kumar, K. V. P. Chem. Rev. 2009, 109, 2551.
15. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480.
16. No other diastereoisomers formed from the major diastereoisomer of the
starting material were observed in the crude 1H NMR.
We thank the EPSRC (M.D.H. and DTA studentship to M.d.S.), the
EC (Marie–Curie Fellowship to D.S.) and The University of Man-
chester for financial support.
17. Curran, D. P.; Fevig, T. L.; Jasperse, C. P.; Totleben, M. J. Synlett 1992, 943.
18. For an illustrative example, see Ref. 3b.
References and notes
19. Duffy, L. A.; Matsubara, H.; Procter, D. J. J. Am. Chem. Soc. 2008, 130, 1136.
20. Guazzelli, G.; De Grazia, S.; Collins, K. D.; Matsubara, H.; Spain, M.; Procter, D. J.
J. Am. Chem. Soc. 2009, 131, 7214.
21. Treatment of 3e with SmI2–H2O appeared to give products resulting from
radical cyclization but not aldol cyclization. This is presumably due to rapid
protonation of the intermediate samarium enolate by H2O, thus preventing
aldol cyclization. The second aldehyde is then reduced by the reagent
system.
1. For recent reviews on the use of samarium(II) iodide: (a) Molander, G. A.;
Harris, C. R. Tetrahedron 1998, 54, 3321; (b) Kagan, H.; Namy, J. L. In Lanthanides:
Chemistry and Use in Organic Synthesis; Kobayashi, S., Ed.; Springer: Berlin,
1999; p 155; (c) Steel, P. G. J. Chem. Soc., PerkinTrans.1 2001, 2727; (d) Kagan, H. B.
´
Tetrahedron 2003, 59,10351; (e) Dahlen, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004,
3393; (f) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104, 3371;
(g) Gopalaiah, K.; Kagan, H. B. New J. Chem. 2008, 32, 607.