Double conjugate addition of dithiols to propargylic carbonyl systems to generate protected 1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/jo052514s

The work describes the efficient double conjugate addition of ethane and propane dithiols in the presence of sodium methoxide to a wide variety of propargylic carbonyl containing compounds. The products of these reactions are differentiated, 1,3-dicarbony

Full text of DOI:10.1021/jo052514s

Double Conjugate Addition of Dithiols to Propargylic Carbonyl
Systems To Generate Protected 1,3-Dicarbonyl Compounds
Helen F. Sneddon, Alexandra van den Heuvel, Anna K. H. Hirsch, Richard A. Booth,
David M. Shaw, Matthew J. Gaunt, and Steven V. Ley*
Department of Chemistry, UniVersity of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K.
sVl1000@cam.ac.uk
ReceiVed December 6, 2005
The work describes the efficient double conjugate addition of ethane and propane dithiols in the presence
of sodium methoxide to a wide variety of propargylic carbonyl containing compounds. The products of
these reactions are differentiated, 1,3-dicarbonyl systems useful for various synthesis programs. By
judicious use of hydroxylated substrates tandem cyclization occurs to afford tetrahydropyran lactols or,
in the case of hydroxy-substituted propargylic esters, lactones. The corresponding amino-substituted
propargylic aldehydes gives piperidine derivatives upon double conjugate addition tandem cyclization.
Introduction
others. The cyanohydrin acetonide methodology developed by
Rychnovsky also allows a quick and stereoselective preparation
of 1,3-polyol chains.13,14 Other commonly applied approaches
to generate 1,3-oxygenation patterns are the use of isoxazo-
lines,15,16 the rearrangement of epoxyalcohols,17,18 and the
opening of epoxides with dithiane anion,19 all of which generate
latent â-hydroxy carbonyl compounds. During the course of
synthetic studies within our laboratory we required a robust and
efficient route to orthogonally protected 1,3-dicarbonyl precur-
sors for use in polyketide assembly programs. Our efforts
focused on the preparation of â-keto dithiane derivatives, which
could act as orthogonally protected 1,3-dicarbonyl precursors.
Polyketide-derived natural products have been the subject of
synthetic interest for some time, and designing general methods
to selectively generate the structural elements embedded in these
compounds remains an important goal.1-3 The most widely used
method to obtain a 1,3-polyketide framework is the aldol
reaction,4-6 which has been extensively developed by Evans,7
Heathcock,8 Masamune,9 Mukaiyama,10 and Paterson11,12 among
(1) Norcross, R. D.; Paterson, I. Chem. ReV. 1995, 95, 2041-2114.
(2) Schneider, C. Angew. Chem., Int. Ed. 1998, 37, 1375-1378.
(3) Koskinen, A. M. P.; Karisalmi, K. Chem. Soc. ReV. 2005, 34, 677-
690.
(4) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: San Diego, 1984; Vol. 3, pp 111-212.
(5) Mukaiyama, T. Org. React. 1982, 28, 203-331.
(6) Cowden, C. J.; Paterson, I. In Organic Reactions; Paquette, L. A.,
Ed.; John Wiley & Sons: New York, 1997; Vol. 51, pp 1-200.
(7) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127-2129.
(12) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996,
37, 8585-8588.
(13) Rychnovsky, S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994, 116,
1753-1765.
(14) Rychnovsky, S. D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997,
119, 2058-2059.
(15) Curran, D. P. J. Am. Chem. Soc. 1982, 104, 4024-4026.
(16) Torssell, K.; Zeuthen, O. Acta Chem. Scand., Ser. B 1978, 32, 118-
124.
(17) Jung, M. E.; D′Amico, D. C. J. Am. Chem. Soc. 1997, 119, 12150-
12158.
(18) Jung, M. E.; van den Heuvel, A. Org. Lett. 2003, 5, 4705-4707.
(19) Smith, A. B.; Pitram, S. M.; Boldi, A. M.; Gaunt, M. J.; Sfoug-
gatakis, C.; Moser, W. H. J. Am. Chem. Soc. 2003, 125, 14435-14445.
(8) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.;
Sohn, J. E.; Lampe, J. J. Org. Chem. 1980, 45, 1066-1081.
(9) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119,
2586-2587.
(10) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011-
1014.
(11) Paterson, I. Pure Appl. Chem. 1992, 64, 1821-1830.
10.1021/jo052514s CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/02/2006
J. Org. Chem. 2006, 71, 2715-2725
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Sneddon et al.
SCHEME 1. Dithiol Conjugate Addition
Results and Discussion
The work begins by establishing a general and practical
method, for a wide range of applications, through the conjugate
addition of dithiols. However, it is pertinent to comment first
on the possible mechanisms of the process, since intermediate
10 is formed that could lead profitably to the desired product 3
or, alternatively, undergo dimerization to lead to isomers 13.
We believe the addition of a dithiol into the ynone initially
involves mono-deprotonation followed by addition to the ynone
1 (Scheme 3). After proton transfer occurs, both cis and trans
isomers 9 of the R,â-unsaturated carbonyl are formed from the
allenic-enolate intermediate 8. The R,â-unsaturated carbonyl
thiols 9 are themselves substrates for a second conjugate
addition, now an intramolecular reaction, which gives the desired
â-keto-1,3-dithianes 3 (path a). However, this second addition
competes with the reaction of substrate 10 with another molecule
of ynone to give undesired dimeric side products 13 (path b),
which are observed in some cases (see later discussion).
The addition of a dithiol, either ethane or propane dithiol, to
an ynone in a 1:1 mixture of dichloromethane and methanol at
ambient temperature using a stoichiometric quantity of sodium
methoxide as the base were our initially chosen conditions.
However, conducting the reaction at ambient temperature led
to significant formation of a dimeric byproduct 13 (Scheme 3).
To minimize dimer formation we found that decreasing the
concentration of the reaction helped but did not completely
eliminate the problem.
Next, a more effective and practical solution was found by
varying the reaction temperature. Addition of dithiol at -10
°C minimized dimer formation during the rapid first reaction
of the ynone, and subsequently the slower intramolecular
conjugate addition was facilitated by allowing the reaction to
warm to ambient temperature. Maintaining the reaction tem-
perature at -10 °C, or lower throughout, resulted in the reaction
failing to go to completion within 24 h. The intramolecular
process is therefore much slower than the first addition process,
typically it takes between 1 and 18 hours at ambient temperature,
depending on the degree of steric hindrance of the ynone, and
is presumably due to the increased electron density imparted
by the first sulfur substituent on the enone acceptor.
In earlier communications we have shown that ethane and
propane dithiol can be added conjugatively to ynones, ynals,
terminal ynoates, and bisynones to give protected 1,3-dicarbonyl
systems.20,21 For example, with ynones of type 1 using ethane
or propane dithiol in the presence of methoxide in dichlo-
romethane and methanol, high yields of â-keto dithiolanes 2
and â-keto dithianes 3 are produced, respectively (Scheme 1).
The products of these reactions constitute especially useful
building blocks for various synthesis programs.22,23 Other
groups, most notably Ranu24 and Endo,25 have previously
devised alternative conditions to effect these transformations,
but we felt that their conditions would not be compatible with
the wide range of transformations and protective group se-
quences we had planned in our studies.
In addition, we have recently shown in the case of other
functionalized derivatives such as a 5-hydroxy bisynone 4 that
the dithiol addition to form 5 was further followed by tandem
in situ cyclization leading to tetrahydropyran derivative 7a
(Scheme 2).21 Here the versatility of the reaction process was
demonstrated using a wide range of both simple and highly
functionalized dithiol acceptors such as ynones, ynals, ynoates,
and bisynones (Scheme 2).
SCHEME 2. Tandem Dithiol Conjugate Addition
Cyclization
Following screening of various bases, sodium methoxide was
the most effective, giving good to excellent yields while being
compatible with a wide variety of functionalities and protecting
groups. Methanol or ethanol was used to aid the solubility of
the sodium alkoxide, whereas addition of tetrahydrofuran or
dichloromethane as cosolvent improves the solubility of the
substrate.
With optimized reaction conditions now available, improved
general methods for the synthesis of the ynal and ynone
precursors were needed. Two routes were principally investi-
gated (Scheme 4). First, ynals of type 15 were easily prepared
by addition of the corresponding terminal alkyne anion to a
formylating agent, N-formylmorpholine (eq 1). Second, advan-
tage could be taken of the Corey-Fuchs protocol for the
Compatibility with many different protecting groups such as
silyl ethers, acetals, and ethers in these reactions was also
examined. Furthermore the tandem dithiol addition-cyclization
method was extended to the preparation of piperidine derivatives
by incorporating nitrogen substituents.
(22) Gaunt, M. J.; Hook, D. F.; Tanner, H. R.; Ley, S. V. Org. Lett.
2003, 5, 4815-4818.
(23) Gaunt, M. J.; Jessiman, A. S.; Orsini, P.; Tanner, H. R.; Hook, D.
F.; Ley, S. V. Org. Lett. 2003, 5, 4819-4822.
(24) Ranu, B. C.; Bhar, S.; Chakraborti, R. J. Org. Chem. 1992, 57,
7349-7352.
(20) Gaunt, M. J.; Sneddon, H. F.; Hewitt, P. R.; Orsini, P.; Hook, D.
F.; Ley, S. V. Org. Biomol. Chem. 2003, 1, 15-16.
(21) Sneddon, H. F.; Gaunt, M. J.; Ley, S. V. Org. Lett. 2003, 5, 1147-
1150.
(25) Kuroda, H.; Tomira, I.; Endo, T. Synth. Commun. 1996, 26, 1539-
1543.
2716 J. Org. Chem., Vol. 71, No. 7, 2006

Protected 1,3-Dicarbonyl Compounds
SCHEME 3. Proposed Mechanism for the Formation of â-Keto-1,3-dithianes
SCHEME 4. General Methods for the Synthesis of Ynals 15
the reaction conditions (entries 5 and 6). Both aldehyde 1g and
ketoester 1h proved to be stable under the applied conditions
and were good substrates for this methodology (entries 7 and
8). These more challenging examples amply demonstrated the
compatibility of the dithiol addition reaction conditions with a
wide range of functional groups and protecting groups. In the
case of ynoates, dimerization was responsible for low yields of
the desired product. Therefore new reaction conditions were
developed where it was shown that by running the reaction in
tetrahydrofuran instead of dichloromethane reduced the amount
of dimer formed (entries 9-11). Furthermore with 1,2-
ethanedithiol as the nucleophilic component the reactions
progressed well (entries 8, 11, and 12).
As rapid generation of protected 1,3-polycarbonyl systems
is a significant goal in synthesis,2 the dithiane addition chemistry
also constitutes a useful general and versatile method to generate
protected 1,3,5-triketone fragments. Consequently double con-
jugate addition of a dithiol to a bisynone 20 at the â- and â′-
alkyne carbon atoms would provide a masked trione of general
structure 21 (Table 2). This intermediate could then be used as
a highly versatile unit for the synthesis of structural motifs often
found in polyketide and 1,3-polyol natural products. Therefore
the bisynone substrates must be accessible in a mild and reliable
manner, suitable for the convergent coupling of complex
fragments. Generation of the ynals 15 according to the
procedures previously described (Scheme 3) and addition of a
second alkyne anion, followed by oxidation formed the bisyn-
ones 20 in 69-92% yield over three steps (Scheme 6).
synthesis of alkynes,21,26 with interception of the resulting
acetylide anion with the same formylating agent (eq 2). The
intermediate 17 in the Corey-Fuchs reaction was generated,
and standard metalation with n-BuLi followed by reaction with
N-formylmorpholine furnished the desired ynals 15 in good yield
(70-73%).21
The ynones of type 1 were readily available in two steps from
the corresponding ynals 15. Treatment of 15 with Grignard
reagents and subsequent oxidation of the ynols 18 with
tetrapropylammonium perruthenate27 (TPAP) or Dess-Martin
periodinane28 (DMP) afforded the ynones 1 in high yields
ranging from 75% to 88% (Scheme 5).
SCHEME 5. General Method for the Synthesis of Ynones 1
SCHEME 6. Preparation of Bisynones 20
With various ynals and ynones now available, the scope of
the dithiol addition reaction was then studied in detail. The
reaction using sodium methoxide as base and propanedithiol
occurred equally successfully with ynones, ynals, and ynoate
(Table 1). The addition tolerated substitution of the alkyne (entry
1) or of the carbonyl (entry 2) with an aromatic group. Moderate
yields could be obtained even in the case of sterically hindered
alkynes (entries 5, 8, and 12). When an R stereogenic center
was present in the initial ketone, it was pleasingly retained under
The bis-addition of dithiols proceeded in high yields for both
terminal and internal acetylene moieties. The conjugate addition
of 1,3-propanedithiol to a terminal alkyne (entries 4-7) led to
a terminal dithiane, a very useful unit since it can be deproto-
nated and added to other electrophiles and later unmasked as a
carbonyl group.23
Furthermore we have shown that the products of these
reactions can be readily transformed to structurally more
complex structures.21,22 For example, the 1,5-hydroxyketone 22
(26) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769-3772.
(27) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem.
Soc., Chem. Commun. 1987, 1625-1627.
(28) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
J. Org. Chem, Vol. 71, No. 7, 2006 2717

Sneddon et al.
TABLE 1. Addition of 1,3-Propanedithiol into Ynones, Ynals, and Ynoates
a With NaOEt. b Reaction run in THF.
upon removal of the protecting group cyclized to the tetrahy-
dropyranyl ring 23 in very high yield (Scheme 7). This latter
functional fragment is present in many natural products, and
devising methods that allow quick access to these chiral
tetrahydropyrans is a useful application of this work.
However, further elimination in some cases to the enol was
observed using 1,3-propanedithiol (entry 5), and therefore 1,2-
ethanedithiol was the preferred nucleophile for the tandem
process if the uneliminated hemiketal was the target product
(Table 4). The reaction was applicable further to the cyclic
system 30c whenever the hydroxyl internal nucleophile was part
of a ring and was transformed correspondingly to more complex
tricyclic systems 31c and 32c (Table 3, entry 4 and Table 4,
entry 4). The ketoester 30g also readily underwent cyclization
to give the desired hemiketal 32g (entry 6).
The thermodynamically favored R-anomer of the tetrahydro-
pyranyl hemiketal was isolated as the major isomer in most cases
as proven by NOE experiments.
With 5-hydroxy-ynones and ynals the tandem dithiol double
addition cyclization readily occurred, leading to tetrahydro-
pyrans 31 and 32. However, ynoates proved more challenging;
indeed the yields were low and mostly uncyclized or dimerized
products were isolated using the previously optimized condi-
tions.
Therefore to display the generality of this process we prepared
a number of precursors that could be subsequently converted
to pyran derivatives. As an alternative to employing the Corey-
Fuchs methodology described above, we found that opening of
an epoxide such as 24 with TMS-acetylide anion gives 25 in
excellent yield. This was then progressed via ynal 28 to either
an ynone or bisynone 29 using standard methods (Scheme 8).
Substrates 29, after deprotection to 30 are readily transformed
by the tandem dithiol conjugate addition followed by cyclization
to pyran derivatives 31 and 32. These reactions were initially
conducted with 1,3-propanedithiol (Table 3) and subsequently
with 1,2-ethanedithiol as the thiol source (Table 4). Ynones,
ynals, and bisynones proved to be good candidates for the
tandem process.
2718 J. Org. Chem., Vol. 71, No. 7, 2006

Protected 1,3-Dicarbonyl Compounds
TABLE 2. Addition of 1,3-Propanedithiol into Bisynones
TABLE 3. Tandem 1,3-Propanedithiol Conjugate
Addition-Cyclization
SCHEME 7. Cyclization
SCHEME 8. Preparation of 1,5-Hydroxyketone Derivatives
To obtain high yields of the desired lactone, the second
intramolecular addition needs to be faster than the intermolecular
dimerization process: increasing the dilution and lowering the
concentration of methanol was expected to favor this process.
To test this idea, both linear and cyclic ynoates of general
structure 35 and 38 were prepared using selective opening of
an epoxide 33 or 36 with a propiolate anion in the presence of
BF3‚THF (Scheme 9).
Both ethyl- and methyl-ynoates proved to be good substrates
for the tandem double addition cyclization process using
modified reaction conditions (Table 5). However, the bulkier
tert-butylynoates afforded mostly the uncyclized product.
Indeed, lowering the concentration of methanol and increasing
the dilution resulted in improved yields, but dimerization and
mono-addition were still observed to some extent. It was then
found that dimerization could be avoided by using tetrahydro-
furan as solvent without any added methanol (entries 1 vs 2).
In addition, this method has allowed a quick access to trans
bicyclic substrates (entries 6 and 7) easily obtained in two steps
from the corresponding epoxides. However, in the case of the
cyclopentanol derivative 35e the reaction was performed in
dichloromethane at very low concentration and an acidic workup
was necessary to induce the cyclization to 39e (entry 7) as only
the uncyclized product was isolated under the usual reaction
conditions.
Based on the successful preparation of tetrahydropyran
derivatives, the methods were expanded to provide access to
J. Org. Chem, Vol. 71, No. 7, 2006 2719

Sneddon et al.
TABLE 5. Tandem Conjugate Addition-Cyclization of Ynoates
TABLE 4. Tandem 1,2-Ethanedithiol Conjugate
Addition-Cyclization
SCHEME 9. Preparation of the Ynoates
a Reaction run in CH2Cl2/MeOH. b Reaction run in CH2Cl2/MeOH with
acid quench.
SCHEME 10. Synthesis of Amino Derivatives 43 and 44
piperidines. The desired 1,5-amino carbonyl precursor was
readily prepared from l-leucine via aziridine 41. The intramo-
lecular attack of an amine into a carbonyl was envisaged to
occur after the dithiol addition to the acetylene, causing the ring
closure and formation of piperidine.
The aziridine was prepared from l-leucine29 and the aziridine
ring opening was carried out with the anion of tetrahydro-2-
(2-propynyloxy)-2H-pyran in 52% (Scheme 10). After acidic
hydrolysis of the tetrahydropyranyl moiety of 42, the primary
alcohol was oxidized using Dess-Martin periodinane in excel-
lent yield. The ynone derivative 44 was obtained by ethyl
Grignard addition to the aldehyde 43 followed by oxidation.
The 1,5-amino ynal 43 was treated with either 1,2-
ethanedithiol or 1,3-propanedithiol, which successfully under-
went a conjugate addition followed by a cyclization (Table 6).
As in the oxygen series, elimination to the dihydropyridine 45
was observed with the dithiane, but with dithiolane the hemi-
aminal 46 was stable. In the presence of methanol and
pyridinium 4-toluenesulfonate the aminal 48 was formed, and
its X-ray crystallographic structural parameters revealed that
the â-anomer was formed preferentially with both groups
being in the axial position (Scheme 11). On the basis of
TABLE 6. Nitrogen as Nucleophile for Cyclization
(29) Berry, M. B.; Craig, D. Synlett 1992, 41-44.
(30) Piva, O.; U.M.R. U.C.B.L. C.N.R.S., 5622 Domaine Scientifique
de la Doua, Baˆtiment 305 4eme e´tage 43 Blvd, 69622 Villeurbanne, Cedex,
France.
NOESY experiments we could conclude that the â anomer
was the favored anomer for both the hemiaminal 46 and the
aminal 48. The preferential formation of the diaxial com-
2720 J. Org. Chem., Vol. 71, No. 7, 2006

Protected 1,3-Dicarbonyl Compounds
SCHEME 11. Formation of Aminal 48
(3R,2′S)-1-{2-[2′-(Triethylsilanyloxy)-3′-(4-methoxybenzyloxy)-
propyl]-[1,3]dithian-2-yl}-4-(tert-butyldiphenylsilanyloxy)-3-
methyl-butan-2-one (2e). Compound 2e was prepared using
procedure A in 51% yield. [R]2D5 -13.0 (c 0.53, CHCl3). IR (neat)
2932, 1709, 1512, 1247, 1105 cm-1. 1H NMR (400 MHz, CDCl3)
δ 7.66 (3 H, m), 7.40 (7 H, m), 7.26 (2 H, d, J ) 8.6 Hz), 6.86 (2
H, d), 4.45 (2 H, d, J ) 2.4 Hz), 4.25-4.22 (1 H, m), 3.80 (3 H,
s), 3.80 (1 H, dd, J ) 9.9, 7.4 Hz), 3.63 (1 H, dd, J ) 9.9, 5.8 Hz),
3.40 (1 H, dd, J ) 12.5, 3.3 Hz), 3.38 (1 H, d, J ) 15.7 Hz), 3.37
(1 H, dd, J ) 12.5 Hz), 3.09 (1 H, d, J ) 15.7 Hz), 2.97 (1 H,
sextet, J ) 6.8 Hz), 2.88-2.70 (4 H, m), 2.44 (1 H, dd, J ) 15.2,
3.2 Hz), 2.33 (1 H, dd, J ) 14.4, 7.2 Hz), 1.91 (2 H, m), 1.06 (9
H, s), 1.04 (3 H, d, J ) 6.9 Hz), 0.94 (9 H, t, J ) 7.9 Hz), 0.62 (6
H, q, J ) 7.9 Hz). 13C NMR (100 MHz, CDCl3) δ 209.3, 159.1,
135.7, 135.6, 134.7, 133.4, 133.3, 130.5, 129.7, 129.3, 127.7, 113.7,
74.9, 72.9, 69.6, 66.5, 55.2, 51.3, 49.74, 49.67, 42.6, 26.9 (2 C),
26.6 (3 C), 26.4, 24.8, 19.2, 12.8, 7.0 (3 C), 5.4 (3 C). HRMS
(+ESI) m/z 789.3475 [(M + Na)+; calcd for C42H62O5S2Si2Na
789.3475].
pound over the axial-equatorial compound is presumed to be
due to the shielding of one face of the piperidine by the tosyl
group.
Following this success, the reaction was carried out on the
ynone derivative; however, only the uncyclized product 47 was
formed. This result could be explained by the steric hindrance
caused by the tosyl group on the nitrogen atom clashing with
the ethyl group and preventing the cyclization. Nevertheless the
method may find further applications for other acyclic amine-
substituted arrangements.
(2R)-4-[2-(3-Benzyloxy-2-triethylsilanyloxy-propyl)-[1,3]dithi-
olan-2-yl]-3-oxo-butyric Acid Methyl Ester (3h). Compound 3h
was prepared using procedure A in 85% yield. [R]2D5 +12.4 (c
The piperidines successfully prepared using these methods
potentially could be further functionalized to lead to natural
products containing piperidine groups.
1
0.95, CHCl3). IR (neat) 2953, 2875, 1748, 1718, 1238 cm-1. H
NMR (600 MHz, CDCl3) δ 7.32 (5 H, m), 4.50 (2 H, m), 4.11 (1
H, dddd, J ) 5.4, 5.4, 5.4, 5.4 Hz), 3.72 (3 H, s), 3.53 (1 H, d, J
) 17.6 Hz), 3.45 (2 H, m), 3.39 (2 H, d, J ) 5.3 Hz), 3.31 (1 H,
d, J ) 17.6 Hz), 3.25 (4 H, m), 2.39 (2 H, d, J ) 6.0 Hz), 0.95 (9
H, t, J ) 7.9 Hz), 0.62 (6 H, q, J ) 7.9 Hz). 13C NMR (150 MHz,
CDCl3) δ 199.6, 167.3, 138.1, 128.3 (2 C), 127.7 (2 C), 127.5,
75.1, 73.2, 71.0, 64.7, 55.6, 52.3, 49.8, 46.5, 39.4, 38.7, 6.8 (3 C),
5.3 (3 C). HRMS (+ES) m/z 499.2009 [(M + H)+; calcd for
C24H39O5S2Si 499.2008].
Conclusions
This work has developed particularly efficient and high-
yielding procedures for the double conjugate addition of ethane
and propane dithiols to a wide variety of propargylic carbonyl
compounds. The products of the reaction constitute differentiated
and protected 1,3-dicarbonyl and 1,3,5-tricarbonyl systems for
potential application in organic synthesis. Of particular interest
is the tolerance of the procedure to a large range of substituent
group protection. Also when further hydroxyl or amino substitu-
tion is present, addition and tandem cyclization occurs to give
useful lactols, lactones, and aminols as products depending upon
the initial substitution patterns. The methods reported are now
being employed in various natural product synthesis programs.
2-(2-Propyl-[1,3]dithian-2-yl)-acetic Acid Methyl Ester (2j).
Compound 2j was prepared using procedure B in 71% yield. IR
1
(neat) 2960, 1732, 1436, 1194, 1179 cm-1. H NMR (600 MHz,
CDCl3) δ 3.68 (3 H, s), 3.06 (2 H, s), 3.01 (2 H, m), 2.72 (2 H,
m), 2.08 (1 H, m), 2.01 (2 H, m), 1.86 (1 H, m), 1.58 (2 H, m),
0.95 (3 H, t, J ) 7.3 Hz). 13C NMR (150 MHz, CDCl3) δ 169.3,
51.6, 50.2, 42.7, 41.7, 26.4 (2 C), 25.0, 17.2, 14.2. HRMS (+ESI)
m/z 235.0837 [(M + H)+; calcd for C10H19O2S2 235.0826].
2-(2-Propyl-[1,3]dithiolan-2-yl)-acetic Acid Methyl Ester (3j).
Compound 3j was prepared using procedure B in 90% yield. IR
Experimental Section
1
(neat) 2957, 1736, 1434, 1343, 1193, 1170 cm-1. H NMR (600
MHz, CDCl3) δ 3.67 (3 H, s), 3.27 (4 H, m), 3.02 (2 H, m), 2.05
(2 H, m), 1.49 (2 H, m), 0.91 (3 H, t, J ) 7.3 Hz). 13C NMR (150
MHz, CDCl3) δ 170.5, 66.8, 51.7, 47.7, 44.7, 39.5 (2 C), 20.4,
14.0. HRMS (+ESI) m/z 243.0485 [(M + Na)+; calcd for
C9H16O2S2Na 243.0489].
(5R)-6-Benzyloxy-3-(1,2-dithiolan-2-yl)-5-triethylsilanyloxy-
hexanoic Acid Methyl Ester (3k). Compound 3k was prepared
using procedure A in 55% yield. [R]2D5 +23.4 (c 0.795, CHCl3). IR
(neat) 2952, 2875, 1739 cm-1. 1H NMR (600 MHz, CDCl3) δ 7.33
(4 H, m), 7.26 (1 H, m), 4.52 (1 H, d, J ) 12.0 Hz), 4.49 (1 H, d,
J ) 12.0 Hz), 4.14 (1 H, m), 3.67 (3 H, s), 3.40 (2 H, m), 3.26 (5
H, m), 3.06 (1 H, d, J ) 16.6 Hz), 2.48 (1 H, dd, J ) 14.8, 7.5
Hz), 2.44 (1 H, dd, J ) 14.8, 3.8 Hz), 0.94 (9 H, t, J ) 8.0 Hz),
0.62 (6 H, q, J ) 8.0 Hz). 13C NMR (150 MHz, CDCl3) δ 170.7,
138.2, 128.3, 127.7, 127.5, 75.1, 73.2, 70.9, 65.3, 51.4, 47.9, 46.3,
39.5, 38.8, 6.9, 5.3. HRMS (+ESI) m/z 457.1904 [(M + H)+; calcd
for C22H37O4S2Si 457.1903].
All reactions were performed under an argon atmosphere and
carried out using oven-dried glassware. Anhydrous solvents were
dried over standard drying agents and freshly distilled prior to use.
All other commercially available reagents were used as received.
Reactions were monitored by TLC on silica gel and detected by
UV fluorescence or by staining with acidic ammonium molybdate-
(IV) or potassium permanganate(VII). Flash column chromatog-
raphy was performed on silica gel. Optical rotations were measured
with a sodium lamp and are reported as follows: [R]2D5 (c (g/100
mL), solvent). 1H NMR spectra were recorded at 400, 500, or 600
MHz. Chemical shifts are recorded in ppm (δ) in CDCl3 with the
internal reference set to δ 7.26 ppm. 13C NMR spectra were
recorded at 100, 125, or 150 MHz. Chemical shifts are recorded in
ppm (δ) in CDCl3 with the internal reference set to δ 77.0 ppm.
High-resolution mass spectra were obtained using electron impact
(EI) or electrospray (+ESI). The general procedures can be found
in the Supporting Information.
1-(2-Pentyl-[1,3]dithian-2-yl)-butan-2-one (2d). Compound 2d
(2′R,8S,10R)-8-[1′-(tert-Butyldiphenylsilyloxy)prop-2′-yl]-10-
(p-methoxybenzyloxymethyl)-9-oxa-1,5-dithia-spiro[5.5]undecan-
8-ol (23). To a solution of dithiane 22 (37 mg, 0.048 mmol) in
MeOH and CH2Cl2 (1:1, 2 mL) at 0 °C was added HClO4 (1 drop,
70% aq soln). After stirring at 0 °C for 20 min, the reaction was
quenched by the slow addition of saturated aqueous NaHCO3 (2
mL). The layers were separated, and the aqueous phase was
extracted with Et2O (2 × 15 mL). The combined organic extracts
was prepared using procedure A in 69% yield. IR (neat) 2953, 1708
1
cm-1. H NMR (400 MHz, CDCl3) δ 3.04 (2 H, s), 2.89-2.79 (4
H, m), 2.54 (2 H, q, J ) 7.2 Hz), 2.08-1.89 (4 H, m), 1.37-1.07
(6 H, m), 1.05 (3 H, t, J ) 7.2 Hz), 0.86 (3 H, t, J ) 7.2 Hz). 13
C
NMR (150 MHz, CDCl3) δ 207.4, 50.3, 48.6, 38.6, 38.4, 31.8, 26.4
(2 C), 25.0, 23.8, 22.5, 14.1, 7.5. HRMS (+ESI) m/z 260.1276
[(M)+; calcd for C13H24OS2 260.1269].
J. Org. Chem, Vol. 71, No. 7, 2006 2721

Sneddon et al.
were washed with saturated brine (10 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. Flash column
chromatography (petroleum ether/Et2O, 90:10) afforded 23 (29 mg,
94%) as a clear, colorless oil. [R]2D5 -36 (c 0.075, CHCl3). IR
2.21 (1 H, d, J ) 13.8 Hz), 2.12 (1 H, dd, J ) 14.7, 7.2 Hz), 2.07
(1 H, m), 2.05 (1 H, dd, J ) 14.7, 5.3 Hz), 1.95-1.85 (3 H, m),
1.80 (1 H, t, J ) 12.2 Hz). 13C NMR (150 MHz, CDCl3) δ 138.3,
128.3 (2 C), 127.6 (2 C), 127.5, 96.8, 73.4, 72.5, 69.0, 65.3, 47.7,
46.3, 40.8, 39.8, 30.4, 30.2, 26.4, 26.0, 25.4, 25.0. HRMS (+ESI)
m/z 463.0870 [(M + Na)+; calcd for C21H28O2S4Na 463.0870].
1
(neat) 2929, 1654, 1513, 1248, 1173 cm-1. H NMR (400 MHz,
CDCl3) δ 7.65 (4 H, m), 7.35 (6 H, m), 7.24 (2 H, d, J ) 8.9 Hz),
6.87 (2 H, d, J ) 8.5 Hz), 4.68 (1 H, s), 4.50 (2 H, AB quartet),
4.23 (1 H, m), 3.80 (3 H, s), 3.70 (1 H, dd, J ) 9.6, 5.9 Hz), 3.62-
3.55 (3 H, m), 3.03-2.95 (2 H, m), 2.75 (2 H, m), 2.69 (1 H, d, J
) 13.8 Hz), 2.60 (1 H, m), 2.37 (1 H, m), 2.03 (3 H, m), 1.84 (1
H, m), 1.09 (3 H, d, J ) 7.0 Hz), 1.04 (9 H, s). 13C NMR (100
MHz, CDCl3) δ 159.2, 135.7, 135.6, 134.8, 133.94, 133.93, 130.3,
129.5, 129.3, 127.6, 113.8, 99.6, 73.1, 73.0, 71.4, 66.1, 55.3, 45.3,
40.9, 38.6, 30.3, 27.5, 27.2, 26.9 (3 C), 24.6, 19.3, 14.7. HRMS
(+ESI) m/z 635.2684 [(M - OH)+; calcd for C36H47O4S2Si
634.9655].
(8R,10S,11S)-8-([1,3]Dithian-2-yl)methyl-11-methyl-10-(1-
methyl-allyl)-9-oxa-1,5-dithia-spiro[5.5]undecan-8-ol (31e).21 Com-
pound 31e was prepared using procedure E in 65% yield. [R]D25
+3.8 (c 1.00, CHCl3). IR (neat) 3350, 2900, 1638, 1413, 1019 cm-1
.
1H NMR (600 MHz, CDCl3) δ 6.02 (1 H, ddd, J ) 17.2, 10.4, 7.5
Hz), 5.95 (1 H, s), 5.04 (1 H, d, J ) 17.2 Hz), 4.98 (1 H, d, J )
10.4 Hz), 4.40 (1 H, t, J ) 6.2 Hz), 3.77 (1 H, dd, J ) 10.4, 2.1
Hz), 3.16 (1 H, dt, J ) 14.7, 2.4 Hz), 3.09 (1 H, app. d, J ) 14.6
Hz), 2.93 (2 H, dt, J ) 11.2, 2.5 Hz), 2.80 (3 H, m), 2.68 (1 H, m),
2.40 (1 H, app. t, J ) 7.1 Hz), 2.14 (1 H, m), 2.08 (2 H, m), 2.03
(2 H, app. dq, J ) 14.6, 5.8 Hz), 1.84 (3 H, m), 1.18 (3 H, d, J )
6.8 Hz), 0.99 (3 H, d, J ) 7.0 Hz). 13C NMR (150 MHz, CDCl3)
δ 142.5, 113.5, 95.9, 72.1, 53.4, 47.9, 43.5, 42.0, 41.4, 38.6, 30.7,
30.7, 25.8, 25.7, 25.5, 25.1, 11.9, 11.8. HRMS (+ESI) m/z 429.1026
[(M + Na)+; calcd for C18H30O2S4Na 429.1019].
(8R,10R)-10-Benzyloxymethyl-8-ethyl-9-oxa-1,5-dithia-spiro-
[5.5]undecan-8-ol (31a). Compound 31a was prepared using
procedure D in 58% yield. [R]2D5 +18.0 (c 0.31, CHCl3). IR (neat)
1
3381, 2906 cm-1. H NMR (500 MHz, CDCl3) δ 7.31 (5 H, m),
5.47 (1 H, s), 4.58 (2 H, d, J ) 6.2 Hz), 4.28 (1 H, m), 3.58 (1 H,
dd, J ) 10.2, 4.7 Hz), 3.50 (1 H, dd, J ) 10.2, 5.1 Hz), 3.11 (1 H,
ddd, J ) 14.5, 11.6, 2.8 Hz), 2.99 (1 H, ddd, J ) 14.1, 11.5, 2.7
Hz), 2.80 (1 H, m), 2.74 (1 H, m), 2.68 (1 H, dd, J ) 14.3, 2.2
Hz), 2.13 (2 H, m), 1.92 (2 H, m), 1.77 (1 H, dd, J ) 13.5, 2.2
Hz), 1.65 (2 H, q, J ) 7.4 Hz), 0.98 (3 H, t, J ) 7.4 Hz). 13C
NMR (125 MHz, CDCl3) δ 138.2, 128.3, 127.7, 127.6, 97.6, 73.4,
72.6, 64.7, 46.3, 41.7, 40.2, 35.2, 26.3, 25.9, 25.1, 7.3. HRMS
(+ESI) m/z 377.1205 [(M + Na)+; calcd for C18H26O3S2Na
377.1221].
(7R,9R)-9-Benzyloxymethyl-7-ethyl-8-oxa-1,4-dithia-spiro[4.5]-
decan-7-ol (32a). Compound 32a was prepared using procedure
D in 63% yield. [R]2D5 +8.5 (c 0.42, CHCl3). IR (neat) 3422, 2919
cm-1. 1H NMR (500 MHz, CDCl3) δ 7.30 (5 H, m), 4.57 (2 H, s),
4.24 (1 H, m), 3.53 (1 H, dd, J ) 10.3, 5.4), 3.47 (1 H, dd, J )
10.3, 4.5 Hz), 3.31 (4 H, m), 3.21 (1 H, d, J ) 0.9 Hz), 2.28 (1 H,
dd, J ) 14.1, 2.1 Hz), 2.12 (2 H, m), 1.92 (1 H, dd, J ) 13.4, 11.5
Hz), 1.65 (2 H, q, J ) 7.6 Hz), 0.95 (3 H, t, J ) 7.6 Hz). 13C
NMR (125 MHz, CDCl3) δ 138.3, 128.3 (2 C), 127.7 (2 C), 127.6,
97.7, 73.4, 72.7, 69.0, 60.3, 46.4, 44.0, 39.4, 37.6, 35.6, 7.4. HRMS
(+ESI) m/z 363.1035 [(M + Na)+; calcd for C17H24O3S2Na
363.1065].
(7R,9R)-9-Benzyloxymethyl-7-(2-hydroxy-ethyl)-8-oxa-1,4-
dithia-spiro[4.5]decan-7-ol (32f). Compound 32f was prepared
using procedure D in 90% yield. The â-anomer was formed in trace
amounts, therefore only the R-anomer is reported below. [R]D25
-4.3 (c 0.65, CHCl3). IR (neat) 3393, 2918, 1091 cm-1. 1H NMR
(600 MHz, CDCl3) δ 7.36-7.26 (5 H, m). 4.60 (1 H, s), 4.56 (2
H, m), 4.30 (1 H, m), 3.97 (1 H, m), 3.84 (1 H, m), 3.52 (2 H, dd,
J ) 6.8, 5.4 Hz), 3.33 (4 H, m), 2.64 (1 H, t, J ) 4.9 Hz), 2.33 (1
H, dd, J ) 13.9, 2.0 Hz), 2.19 (1 H, d, J ) 13.9 Hz), 2.14 (1 H,
d, J ) 13.5 Hz), 1.99 (1 H, m), 1.93 (1 H, ddd, J ) 14.5, 8.6, 3.6
Hz, 1 H), 1.83 (1 H, ddd, J ) 14.5, 6.2, 3.0 Hz). 13C NMR (150
MHz, CDCl3) δ 138.1, 128.4 (2 C), 127.68 (2 C), 127.65, 98.0,
73.4, 72.5, 68.9, 62.8, 58.5, 48.0, 43.7, 42.8, 39.4, 37.6. HRMS
(+ESI) m/z 379.1000 [(M + Na)+; calcd for C17H24O4S2Na
379.1014].
(8RS,10R)-10-Benzyloxymethyl-9-oxa-1,5-dithia-spiro[5.5]-
undecan-8-ol (31b). Compound 31b was prepared using procedure
D. The lactol was obtained as an inseparable mixture of anomers
1
(10:7) in 41% yield. IR (neat) 3411, 2907 cm-1. H NMR (500
MHz, CDCl3) δ 7.31 (10 H, m), 5.28 (1 H, m), 5.13 (1 H, ddd, J
) 9.3, 6.1, 2.1 Hz), 4.57 (4 H, m), 4.36 (1 H, tdd, J ) 9.4, 4.6, 2.5
Hz), (1 H, tdd, J ) 7.8, 4.1, 2.1 Hz), 3.51 (4 H, m), 3.19 (1 H, d,
J ) 6.1 Hz), 3.04 (2 H, m), 2.83 (7 H, m), 2.56 (1 H, app. dt, J )
13.4, 2.1), 2.12 (4 H, m), 1.98 (4 H, m), 1.68 (2 H, m), one OH
not observed. 13C NMR (125 MHz, CDCl3) δ 138.0, 137.9,128.41,
128.38,128.2, 127.8, 127.74, 127.67, 92.49, 92.46, 73.6, 73.5, 72.41,
72.39, 70.6, 63.5, 47.4, 45.4, 43.6, 39.9, 39.4, 39.0, 26.4, 26.0,
25.91, 25.86, 25.5, 25.0. HRMS (+ESI) m/z 349.0903 [(M + Na)+;
calcd for C16H22O3S2Na 349.0908].
trans-(2′RS)-[1,3]-Dithian-2-spiro-4′-octahydro-chromen-2′-
ol (31c). Compound 31c was prepared using procedure D. The lactol
was obtained as an inseparable mixture of anomers (10:3.7) in 53%
yield. The structure was confirmed by X-ray crystallography. IR
(neat) 3380, 2929, 2856 cm-1. Mp ) 133-137 °C. 1H NMR (500
MHz, CDCl3) δ 5.88 (1 H, d, J ) 11.5 Hz), 5.20 (1 H, ddd, J )
12.5, 3.9, 1.0 Hz), 5.12 (1 H, ddd, J ) 11.1, 6.6, 1.9 Hz), 3.82 (1
H, app. dt, J ) 10.2, 4.7 Hz), 3.60 (1 H, app. dt, J ) 10.4, 4.3 Hz),
3.45 (1 H, d, J ) 6.6 Hz), 3.13 (3 H, m), 3.04 (3 H, m), 2.81 (1 H,
td, J ) 14.4, 3.6 Hz), 2.66 (1 H, td, J ) 14.4, 7.8 Hz), 2.15 (5 H,
m), 1.97 (2 H, m), 1.80 (7 H, m), 1.60 (1 H, m), 1.32 (9 H, m),
one OH not observed. 13C NMR (125 MHz, CDCl3) δ 92.8, 92.3,
73.0, 66.7, 52.7, 51.2, 51.1, 50.7, 44.4, 40.1, 32.92, 32.90, 25.76,
25.73, 25.67, 25.63, 25.58, 25.49, 25.41, 25.34, 25.14, 24.5, 24.3.
HRMS (+ESI) m/z 283.0799 [(M + Na)+; calcd for C12H20O2S2-
Na 283.0802].
(9R)-9-Benzyloxymethyl-8-oxa-1,4-dithia-spiro[4.5]decan-7-
ol (32b). Compound 32b was prepared using procedure D. The
lactol was obtained as a mixture of anomers (10:6.5) in 64% yield.
1
IR (neat) 3402, 2919, 2862 cm-1. H NMR (500 MHz, CDCl3) δ
7.31 (10 H, m), 5.34 (1 H, m), 4.88 (1 H, ddd, J ) 9.3, 6.0, 2.0
Hz), 4.57 (4 H, m), 4.32 (1 H, m), 3.88 (1 H, m), 3.50 (4 H, m),
3.32 (8 H, m), 2.99 (1 H, d, J ) 6.0 Hz), 2.36 (4 H, m), 2.01 (4 H,
m), one OH not observed. 13C NMR (125 MHz, CDCl3) δ 138.0,
137.9, 128.40, 128.38, 127.83, 127.77, 127.72, 127.67, 95.2, 92.0,
73.8, 73.5, 73.4, 72.5, 72.3, 67.7, 64.0, 61.8, 48.1, 43.9, 43.7, 43.5,
39.6, 39.5, 38.0, 37.8. HRMS (+ESI) m/z 335.0744 [(M + Na)+;
calcd for C15H20O3S2Na 335.0752].
(10R)-10-Benzyloxymethyl-8-([1,3]dithian-2-yl)methyl-9-oxa-
1,5-dithia-spiro[5.5]undec-7-ene (31d). Compound 31d was pre-
pared using procedure E in 91% yield. [R]2D5 +16.3 (c 1.035,
trans-(2′RS)-[1,3]-Dithiolan-2-spiro-4′-octahydro-chromen-2′-
ol (32c). Compound 32c was prepared using procedure D. The lactol
was obtained as a mixture of anomers (10:4) in 58% yield. The
structure was confirmed by X-ray crystallography. IR (neat) 3384,
2929, 2857 cm-1. Mp ) 109-111 °C. 1H NMR (500 MHz, CDCl3)
δ 5.25 (1 H, m), 4.86 (1 H, m), 4.08 (1 H, m), 3.70 (1 H, app. td
J ) 10.2, 4.4 Hz), 3.24 (9 H, m), 2.46 (3 H, m), 2.14 (2 H, m),
2.03 (1 H, dd, J ) 13.0, 9.3 Hz), 1.96 (2 H, m), 1.92 (1 H, m),
1
CHCl3). IR (neat) 3346, 2901, 1421, 1091, 1020 cm-1. H NMR
(600 MHz, CDCl3) δ 7.34 (4 H, m), 7.28 (1 H, m), 5.63 (1 H, s),
4.81 (2 H, AB quartet), 4.39 (1 H, dd, J ) 6.9, 5.4 Hz), 4.33 (1 H,
m), 3.60 (1 H, dd, J ) 10.3, 4.7 Hz), 3.53 (1 H, dd, J ) 10.3, 4.9
Hz), 3.06 (1 H, ddd, J ) 13.8, 10.8, 2.5 Hz), 2.98-2.76 (7 H, m),
2722 J. Org. Chem., Vol. 71, No. 7, 2006

Protected 1,3-Dicarbonyl Compounds
1.75 (4 H, m), 1.65 (1 H, m), 1.53 (1 H, m), 1.32 (8 H, m). 13C
NMR (125 MHz, CDCl3) δ 94.6, 92.1, 77.3, 71.5, 69.5, 67.3, 51.9,
51.5 (2 C), 47.7, 40.3 (2 C), 38.8, 38.6, 32.8, 32.7, 26.0, 25.6, 25.5,
25.4, 24.6. HRMS (+ESI) m/z 269.0650 [(M + Na)+; calcd for
C11H18O2S2Na 269.0646].
MHz, CDCl3) δ 4.07 (1H, ddd, J ) 10.6, 10.6, 4.2 Hz), 3.36 (3 H,
m), 3.30 (1 H, d, J ) 17.5 Hz), 3.20 (1 H, m), 3.02 (1 H, d, J )
17.7 Hz), 2.31 (1 H, m), 2.18 (1 H, m), 1.83 (3 H, m), 1.32 (4 H,
m). 13C NMR (100 MHz, CDCl3) δ 167.2, 82.5, 66.6, 50.3, 49.3,
40.3, 40.2, 32.9, 25.8, 24.9 24.3. HRMS (+ESI) m/z 267.0478 [(M
+ Na)+; calcd for C11H16O2S2Na 267.0489].
(()-trans-[1,3]-Dithiolan-2-spiro-4′-hexahydro-cyclopenta[b]-
pyran-2′-one (39e). Compound 39e was prepared using a modified
procedure F. The reaction was quenched with concentrated HCl
and allowed to stir for 7 h. The reaction was neutralized with
saturated NaHCO3 and then worked up following procedure G. The
lactone was obtained in 50% yield. The structure was confirmed
by X-ray crystallography. IR (neat) 2977, 2921, 1729, 1219, 1094
cm-1. Mp ) 79-86 °C. 1H NMR (400 MHz, CDCl3) δ 4.21 (1 H,
ddd, J ) 10.1, 9.9, 7.7 Hz), 3.4-3.2 (4 H, m), 3.37 (1 H, d, J )
18.1 Hz), 3.16 (1 H, d, J ) 18.3 Hz), 2.27 (1 H, td, J ) 10.8, 7.1
Hz), 2.17 (1 H, m), 1.95 (1 H, m), 1.89 (1 H, m), 1.73 (3 H, m).
13C NMR (125 MHz, CDCl3) δ 169.2, 82.9, 64.7, 52.2, 49.4, 40.7,
39.8, 29.3, 22.3, 18.4. HRMS (+ESI) m/z 231.0511 [(M + H)+;
calcd for C10H15O2S2 231.0513].
(()-10-Benzyloxymethyl-9-oxa-1,5-dithia-spiro[5.5]undecan-
8-one (40a). Compound 40a was prepared using procedure F in
73% yield. IR (neat) 2906, 1731, 1238, 1098, 1060 cm-1. 1H NMR
(600 MHz, CDCl3) δ 7.31 (5 H, m), 4.80 (1 H, dddd, J ) 11.9,
4.0, 4.0, 4.0 Hz), 4.60 (1 H, d, J ) 12 Hz), 4.56 (1 H, d, J ) 12
Hz), 3.68 (1 H, dd, J ) 10.6, 4.4 Hz), 3.65 (1 H, dd, J ) 10.6, 4.2
Hz), 3.21 (1 H, d, J ) 17.4 Hz), 3.0-2.8 (4 H, m), 2.86 (1 H, d,
J ) 17.2 Hz), 2.50 (1 H, ddd, J ) 14.4, 2.7, 2.7 Hz), 2.16 (1 H,
dd, J ) 14.4, 12.0 Hz), 2.00 (2 H, m). 13C NMR (125 MHz, CDCl3)
δ 167.4, 137.6, 128.4 (2 C), 127.8, 127.7 (2 C), 75.7, 73.7, 71.1,
44.8, 43.3, 37.3, 26.6, 26.5, 24.5. HRMS (+ESI) m/z 325.0947 [(M
+ H)+; calcd for C16H21O3S2 325.0947].
(9R)-9-Benzyloxymethyl-7-([1,3]dithiolan-2-yl)methyl-8-oxa-
1,4-dithia-spiro[4.5]decan-7-ol (32d). Compound 32d was pre-
pared using procedure E in 81% yield. [R]2D5 -8.0 (c 0.24, CHCl3).
IR (neat) 3398, 2919, 1423, 1091, 1038 cm-1. 1H NMR (600 MHz,
CDCl3) δ 7.35 (4 H, m), 7.28 (1 H, m), 4.81 (1 H, dd, J ) 8.7, 5.4
Hz), 4.58 (2 H, d, J ) 3.1 Hz), 4.44 (1 H, s), 4.28 (1 H, m), 3.56
(1 H, dd, J ) 10.3, 5.1 Hz), 3.51 (1 H, dd, J ) 10.3, 4.5 Hz), 3.48
(4 H, m), 3.30 (3 H, m), 3.17 (1 H, m), 2.35 (1 H, dd, J ) 11.8,
9.0 Hz), 2.24 (1 H, dd, J ) 14.4, 9.0 Hz), 2.14 (2 H, m), 2.13 (1
H, d, J ) 14.4 Hz), 1.95 (1 H, dd, J ) 13.4, 11.6 Hz). 13C NMR
(150 MHz, CDCl3) δ 138.3, 128.3 (2 C), 127.6 (2 C), 127.6, 96.4,
73.4, 72.6, 69.0, 62.8, 49.9, 48.3, 47.3, 44.1, 39.5, 38.0, 37.9, 37.6.
HRMS (+ESI) m/z 453.0654 [(M + Na)+; calcd for C19H26O3S4-
Na 453.0663].
(()-(9-Benzyloxymethyl-7-hydroxy-8-oxa-1,4-dithia-spiro[4.5]-
dec-7-yl)-acetic Acid Methyl Ester (32g). Compound 32g was
prepared using procedure D in 83% yield. IR (neat) 3452, 2921,
1717, 1437, 1168, 1092, 1022 cm-1. 1H NMR (400 MHz, CDCl3)
δ 7.32 (4 H, m), 7.27 (1 H, m), 5.07 (1 H, d, J ) 2.0 Hz), 4.55 (2
H, m), 4.35 (1 H, dddd, J ) 11.3, 4.8, 4.8, 1.9 Hz), 3.71 (3 H, s),
3.49 (2 H, m), 3.30 (4 H, m), 2.67 (1 H, d, J ) 15.4 Hz), 2.60 (1
H, d, J ) 15.4 Hz), 2.42 (1 H, dd, J ) 13.7, 1.9 Hz), 2.18 (1 H,
dd, J ) 13.7, 1.8 Hz), 2.12 (1 H, ddd, J ) 13.5, 1.8, 1.8 Hz), 1.91
(1 H, dd, J ) 13.5, 11.4 Hz). 13C NMR (100 MHz, CDCl3) δ 171.9,
138.4, 128.3 (2 C), 127.6 (2 C), 127.5, 95.4, 73.2, 72.4, 69.1, 62.6,
51.9, 47.6, 44.7 (2 C), 39.8, 37.7. HRMS (+ESI) m/z 407.0963
[(M + Na)+; calcd for C18H24O5S2Na 407.0963].
(()-10-[Hex-5-enyl]-9-oxa-1,5-dithia-spiro[5.5]undecan-8-
one (40b). Compound 40b was prepared using procedure F in 65%
yield. IR (neat) 2931, 2858, 1728, 1238, 1052 cm-1. 1H NMR (400
MHz, CDCl3) δ 5.79 (1 H, dddd, J ) 16.9, 10.1, 6.7, 6.7 Hz), 5.00
(1 H, dd, J ) 17.1, 1.6 Hz), 4.95 (1 H, bd, J ) 10.2 Hz), 4.61 (1
H, m), 3.21 (1 H, dd, J ) 17.2, 1.7 Hz), 3.02-2.80 (4 H, m), 2.92
(1 H, d, J ) 17.0 Hz), 2.43 (1 H, ddd, J ) 14.5, 2.6, 2.2 Hz), 2.04
(4 H, m), 1.90 (1H, dd, J ) 14.4, 11.8 Hz), 1.63 (1 H, m), 1.43 (2
H, m), 1.25 (3 H, m). 13C NMR (100 MHz, CDCl3) δ 168.0, 138.4,
114.6, 76.4, 44.8, 43.4, 41.3, 35.0, 33.5, 28.5, 26.7, 26.6, 24.5, 24.2.
HRMS (+ESI) m/z 287.1133 [(M + H)+; calcd for C14H23O2S2
287.1139].
(()-9-Benzyloxymethyl-8-oxa-1,4-dithia-spiro[4.5]decan-7-
one (39a). Compound 39a was prepared using procedure A in 60%
yield. Compound 39a was prepared using procedure F in 84% yield.
IR (neat) 2922, 1730, 1368, 1231, 1095, 1062 cm-1. 1H NMR (600
MHz, CDCl3) δ: 7.33 (5 H, m), 4.67 (1 H, m), 4.59 (1 H, d, J )
12.0 Hz), 4.56 (1 H, d, J ) 12.1 Hz), 3.69 (1 H, dd, J ) 10.5, 4.2
Hz), 3.64 (1 H, dd, J ) 10.5, 4.0 Hz), 3.40 (5 H, m), 3.17 (1 H,
dd, J ) 17.6, 2.3 Hz), 2.98 (1 H, d, J ) 17.6 Hz), 2.42 (1 H, dd,
J ) 13.8, 11.5 Hz), 2.35 (1 H, m). 13C NMR (100 MHz, CDCl3)
δ: 167.7, 137.6, 128.5 (2 C), 127.9, 127.7 (2 C), 78.3, 73.7, 71.2,
61.3, 47.0, 40.6, 39.9, 39.7. HRMS (+ESI) m/z 333.0587 [(M +
Na)+; calcd for C15H18O3S2Na 333.0595].
(()-10-Allyloxymethyl-9-oxa-1,5-dithia-spiro[5.5]undecan-8-
one (40c). Compound 40c was prepared using procedure F in 58%
yield. IR (neat) 2907, 1730, 1422, 1239, 1060 cm-1. 1H NMR (400
MHz, CDCl3) δ 5.86 (1 H, dddd, J ) 17.0, 10.6, 5.6, 5.3 Hz), 5.25
(1 H, bd, J ) 17.2 Hz), 5.17 (1 H, bd, J ) 10.3 Hz), 4.76 (1 H,
m), 4.02 (2 H, AB quartet), 3.99 (1 H, d, J ) 13.4 Hz), 3.61 (2 H,
m), 3.17 (1 H, d, J ) 17.3 Hz), 2.98-2.78 (5 H, m), 2.49 (1 H, bd,
J ) 14.4 Hz), 2.12 (1 H, m), 2.00 (2 H, m). 13C NMR (100 MHz,
CDCl3) δ 167.3, 134.1, 117.4, 75.6, 72.5, 71.0, 44.8, 43.3, 37.3,
26.5, 26.4, 24.4. HRMS (+ESI) m/z 275.0763 [(M + H)+; calcd
for C12H19O3S2 275.0776].
(S)-1-Isobutyl-5-(tetrahydro-pyran-2-yloxy)-N-toluensulfonyl-
pent-3-ynylamine (42). To a solution of tetrahydro-2-(2-propyny-
loxy)-2H-pyran (2.25 mL, 16 mmol) in THF (9 mL) at -10 °C
was added dropwise n-BuLi (1.6 M in hexanes, 10 mL, 16 mmol).
The resulting solution was stirred at ambient temperature for 30
min. The aziridine 41 (1.0 g, 4 mmol) in THF (4.4 mL) was added
dropwise, and the reaction was stirred for 22 h. The mixture was
quenched with saturated NaHCO3 and extracted with Et2O. The
combined organic phases were dried (MgSO4), filtered, and
concentrated under reduced pressure to yield a yellow oil, which
was purified by gradient flash column chromatography (hexanes/
AcOEt 86:14 f 75:25) to yield compound 42 as a mixture of
diastereomers (0.797 g, 52%). IR (neat) 3269, 2952, 2869, 1598
cm-1. 1H NMR (500 MHz, CDCl3) δ 7.76 (2 H, d, J ) 8 Hz), 7.75
(()-9-Hex-5-enyl-8-oxa-1,4-dithia-spiro[4.5]decan-7-one (39b).
Compound 39b was prepared using procedure F in 79% yield. IR
(neat) 2927, 1732 cm-1. 1H NMR (400 MHz, CDCl3) δ 5.78 (1 H,
m), 5.00 (1 H, dd, J ) 17.1, 1.5 Hz), 4.95 (1 H, app. d, J ) 10.2
Hz), 4.47 (1 H, dddd, J ) 11.6, 7.6, 4.8, 3.4 Hz), 3.39 (4 H, m),
3.17 (1 H, dd, J ) 17.6, 2.3 Hz), 2.96 (1 H, d, J ) 17.6 Hz), 2.34
(1 H, app. ddd, J ) 14.1, 2.7, 2.7 Hz), 2.14 (1 H, app. dd, J )
14.0, 11.7 Hz), 2.06 (2 H, app. dd, J ) 13.3, 6.6 Hz)), 1.73 (1 H,
m), 1.65 (1 H, m), 1.55 (1 H, m), 1.44 (3 H, m). 13C NMR (100
MHz, CDCl3) δ 168.1, 138.5, 114.7, 79.5, 61.4, 47.3, 44.3, 39.9,
39.7, 35.5, 33.5, 28.6, 24.2. HRMS (+ESI) m/z 295.0807 [(M +
Na)+; calcd for C13H20O3S2Na 295.0802].
(()-9-Allyloxymethyl-8-oxa-1,4-dithia-spiro[4.5]decan-7-
one (39c). Compound 39c was prepared using procedure F in 57%
1
yield. IR (neat) 2927, 1732 cm-1. H NMR (600 MHz, CDCl3) δ
5.86 (1 H, m), 5.27 (1 H, dd, J ) 17.1, 1.4 Hz), 5.19 (1 H, dd, J
) 10.4, 0.8 Hz), 4.64 (1 H, m), 4.03 (2 H, m), 3.65 (1 H, dd, J )
10.6, 4.2 Hz), 3.61 (1 H, dd, J ) 10.7, 4.0 Hz), 3.39 (4 H, m),
3.17 (1 H, dd, J ) 17.6, 2.3 Hz), 2.98 (1 H, d, J ) 17.6 Hz), 2.36
(2 H, m). 13C NMR (150 MHz, CDCl3) δ 167.7, 134.1, 117.5, 78.3,
72.6, 71.1, 61.3, 47.0, 40.6, 39.9, 39.7. HRMS (+ESI) m/z 283.0423
[(M + Na)+; calcd for C11H16O3S2Na 283.0439].
(()-trans-[1,3]-Dithiolan-2-spiro-4′-octahydro-chromen-2′-
one (39d). Compound 39d was prepared using procedure F in 54%
yield. IR (neat) 2933, 1730, 1231, 1198, 1044 cm-1. 1H NMR (400
J. Org. Chem, Vol. 71, No. 7, 2006 2723

Sneddon et al.
(2 H, d, J ) 8 Hz), 7.28 (4 H, d, J ) 8 Hz), 4.76 (2 H, m), 4.68
(2 H, m), 4.20 (4 H, m), 3.84 (2 H, m), 3.53 (2 H, m), 3.39 (2 H,
m), 2.41 (6 H, s), 2.26 (4 H, m), 1.82 (2 H, m), 1.73 (2 H, m), 1.57
(10 H, m), 1.32 (4 H, m), 0.81 (6 H, d, J ) 6 Hz), 0.73 (3 H, d, J
) 6 Hz), 0.72 (3 H, d, J ) 6 Hz). 13C NMR (125 MHz, CDCl3) δ
143.3 (2 C), 138.1 (2 C), 129.6 (4 C), 127.0 (4 C), 97.2, 97.0, 81.3
(2 C), 79.4, 79.3, 62.2, 62.1, 54.6, 54.5, 50.0 (2 C), 43.5 (2 C),
30.3 (2 C), 25.5, 25.3, 24.3 (2 C), 22.7 (2 C), 21.9 (2 C), 21.5 (2
C), 19.2 (2 C), 19.1 (2 C). HRMS (ESI) m/z 416.1891 [(M + Na)+;
calcd for C21H31NO4SNa 416.1872].
(5S)-5-(N-Toluensulfonyl-amino)-7-methyl-oct-2-ynal (43). The
protected alcohol 42 (0.571 g, 1.45 mmol) was dissolved in MeOH
(2 mL), amberlyst 15 was added (300 mg), and the reaction was
stirred overnight at ambient temperature. The mixture was filtered,
and the amberlyst was washed with Et2O. The combined organic
layers were concentrated under reduced pressure. Gradient flash
column chromatography (hexanes/AcOEt 80:20 f 75:25 f 70:
30) yielded starting material 42 (0.133 g, 23%) and the alcohol
(0.241 g, 54%). [R]2D5 -83.0 (c 1.05, CHCl3). IR (neat) 3272,
3020, 2957, 2870, 1598 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.32
(2 H, d, J ) 8.3 Hz), 7.29 (2 H, d, J ) 8.5 Hz), 5.06 (1 H, m),
4.20 (2 H, s), 3.40 (1 H, m), 2.41 (3 H, s), 2.33 (1 H, m), 2.23 (1
H, m), 2.12 (1 H, br s), 1.52 (1 H, m), 1.32 (2 H, m), 0.79 (3 H,
d, J ) 6.6 Hz), 0.71 (3 H, J ) 6.5 Hz). 13C NMR (100 MHz,
CDCl3) δ 143.4, 138.1, 129.6 (2 C), 127.0 (2 C), 81.7, 81.1, 51.1,
50.1, 43.5, 25.5, 24.5, 22.5, 21.8, 21.5. HRMS (ESI) m/z 310.1469
[(M + H)+; calcd for C16H24NO3S 310.1477].
The alcohol (119 mg, 0.35 mmol) was dissolved in CH2Cl2 (3
mL) and cooled to 0 °C. To this solution was added Dess-Martin
periodinane (225 mg, 0.53 mmol), and the resulting mixture was
stirred for 30 min at 0 °C, then allowed to warm to ambient
temperature, and stirred for 90 min. The reaction was quenched
with saturated NaHCO3 and saturated Na2S2O3 (1:1, 10 mL). The
organic and aqueous layers were separated, the aqueous phase was
extracted with Et2O, and the combined organic layers were washed
with brine, dried (MgSO4), and concentrated under reduced pressure
to yield a yellow oil. Flash column chromatography (petroleum
ether/AcOEt 80:20) yielded the ketone 44 (104 mg, 89%) as a
colorless oil. [R]2D5 -100.0 (c 0.515, CHCl3). IR (neat) 3281,
2957, 2871, 2212, 1672, 1598 cm-1. 1H NMR (500 MHz, CDCl3)
δ 7.75 (2 H, d, J ) 8.3 Hz), 7.30 (2 H, d, J ) 8.0 Hz), 4.43 (1 H,
d, J ) 8.8 Hz), 3.46 (1 H, m), 2.52 (4 H, m), 2.42 (3 H, s), 1.49
(1 H, m), 1.34 (2 H, m), 1.12 (3 H, t, J ) 7.4 Hz), 0.82 (3 H, d,
J ) 6.6 Hz), 0.67 (3 H, d, J ) 6.5 Hz). 13C NMR (125 MHz,
CDCl3) δ 188.1, 143.7, 137.7, 129.8 (2 C), 127.0 (2 C), 88.5, 82.9,
49.7, 43.5, 33.8, 26.2, 24.4, 22.7, 21.6, 21.5, 8.0. HRMS (ESI) m/z
358.1446 [(M + Na)+; calcd for C18H25NO3SNa 358.1453].
(10S)-10-Isobutyl-N-toluensulfonyl-1,5-dithia-9-aza-spiro[5.5]-
undec-7-ene (45). The aldehyde 43 (58 mg, 0.19 mmol) was
dissolved in CH2Cl2 and MeOH (1:1, 6 mL) and stirred at -10 °C
for 30 min. Then 1,3-propanedithiol (29 µL, 0.28 mmol) followed
by NaOMe (15 mg, 0.28 mmol) were added, and the reaction was
allowed to warm to ambient temperature and was stirred for 12 h.
The reaction was quenched with saturated NH4Cl, extracted with
Et2O, washed with brine, dried (MgSO4), and concentrated under
reduced pressure. Flash column chromatography (1% MeOH in
The alcohol (750 mg, 2.44 mmol) was dissolved in CH2Cl2 (1.3
mL), and the solution was cooled to 0 °C. Dess-Martin periodinane
(1.56 g, 3.7 mmol) was added, and while warming to ambient
temperature the reaction was stirred for 2 h. The reaction was then
quenched with saturated NaHCO3 and saturated Na2S2O3 (1:1, 10
mL). The organic and aqueous layers were separated, and the
aqueous layers were washed with brine, dried (MgSO4), and
concentrated under reduced pressure to yield a yellow oil. Gradient
flash column chromatography (petroleum ether/AcOEt 80:20 f
70:30) yielded the aldehyde 43 as an opaque oil (736 mg, 99%).
[R]2D5 -96.6 (c 1.1, CHCl3). IR (neat) 3272, 2957, 2870, 2203,
CH2Cl2) yielded piperidine 45 (59 mg, 78%). [R]25 +272.8 (c
D
1
1.85, CHCl3). IR (neat) 2954, 2868, 1632, 1596 cm-1. H NMR
(500 MHz, CDCl3) δ 7.65 (2 H, d, J ) 8.3 Hz), 7.28 (2 H, d, J )
8.0 Hz), 6.62 (1 H, dd, J ) 8.2, 1.0 Hz), 5.45 (1 H, dd, J ) 8.2,
1.6 Hz), 3.92 (1 H, m), 2.92 (2 H, m), 2.77 (2 H, m), 2.40 (3 H, s),
2.36 (1 H, ddd, J ) 14.7, 2.0, 2.0 Hz), 1.92 (2 H, m), 1.79 (1 H,
m), 1.70 (1 H, m), 1.54 (1 H, ddd, J ) 13.5, 6.7, 1.5 Hz), 1.52 (1
H, dd, J ) 14.8, 5.4 Hz), 0.90 (3 H, d, J ) 6.5 Hz), 0.89 (3 H, d,
J ) 6.6 Hz). 13C NMR (125 MHz, CDCl3) δ 143.8, 136.0, 129.8
(2 C), 126.9 (2 C), 122.7, 110.5, 51.6, 42.0, 41.8, 37.3, 27.8, 26.5,
24.8, 24.5, 22.7, 21.6. HRMS (ESI) m/z 398.1277 [(M + H)+; calcd
for C19H28NO2S3 398.1282].
(9S)-9-Isobutyl-N-toluensulfonyl-1,4-dithia-8-aza-spiro[4.5]-
decan-7-ol (46). The aldehyde 43 (19 mg, 0.07 mmol) was
dissolved in CH2Cl2 and MeOH (1:1, 1 mL) and stirred at -10 °C
for 30 min. Then 1,2-ethanedithiol (9.2 µL, 0.11 mmol) followed
by NaOMe (6 mg, 0.11 mmol) were added, and the reaction was
allowed to warm to ambient temperature and was stirred for 12 h.
The reaction was quenched with saturated NH4Cl, extracted with
Et2O, washed with brine, dried (MgSO4), and concentrated under
reduced pressure. Flash column chromatography (0.5% MeOH in
CH2Cl2) yielded a diastereomeric 6:1 mixture of piperidine 46 (19
mg, 71%). Only the major â-anomer is reported. IR (neat) 3486,
2954, 2921, 1325, 1160 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.72
(2 H, d, J ) 8.3 Hz), 7.29 (2 H, d, J ) 8.0 Hz), 5.54 (1 H, ddd, J
) 7.8, 4.9, 4.5 Hz), 4.15 (1 H, m), 3.52 (1 H, d, J ) 5.0 Hz), 3.34
(2 H, td, J ) 6.0, 2.0 Hz), 3.21 (2 H, t, J ) 6.0 Hz), 2.46 (1 H,
ddd, J ) 14.3, 2.0, 2.0 Hz), 2.41 (3 H, s), 2.33 (1 H, ddd, J )
14.3, 3.1, 1.6 Hz), 2.18 (2 H, m), 1.60 (3 H, m), 0.89 (3 H, d, J )
6.3 Hz), 0.88 (3 H, d, J ) 6.3 Hz). 13C NMR (125 MHz, CDCl3)
δ 143.5, 137.7, 129.6 (2 C), 127.3 (2 C), 76.7, 60.1, 51.7, 45.7,
44.6, 41.0, 40.2, 38.7, 25.5, 23.5, 21.5, 21.0. HRMS (ESI) m/z
402.1223 [(M + H)+; calcd for C18H28NO3S3 402.1231].
1
1662, 1598 cm-1. H NMR (500 MHz, CDCl3) δ 9.12 (1 H, s),
7.76 (2 H, d, J ) 8.3 Hz), 7.30 (2 H, d, J ) 8.0 Hz), 4.56 (1 H, d,
J ) 8.6 Hz), 3.47 (1 H, m), 2.61 (1 H, ddd, J ) 17.5, 5.9, 0.4 Hz),
2.53 (1 H, ddd, J ) 17.4, 3.8, 0.4 Hz), 2.42 (3 H, s), 1.49 (1 H,
m), 1.33 (2 H, m), 0.81 (3 H, d, J ) 6.7 Hz), 0.66 (3 H, d, J ) 6.5
Hz). 13C NMR (125 MHz, CDCl3) δ 176.6, 143.7, 137.5, 129.8 (2
C), 127.1 (2 C), 93.6, 83.5, 49.6, 43.5, 26.4, 24.4, 22.7, 21.57, 21.53.
HRMS (ESI) m/z 308.1325 [(M + H)+; calcd for C16H22NO3S:
308.1320].
(7S)-7-(N-Toluensulfonyl-amino)-9-methyl-dec-4-yn-3-one (44).
The aldehyde 43 (231 mg, 0.75 mmol) was dissolved in THF (13
mL) and cooled to -78 °C. To this stirred mixture was added
ethylmagnesium bromide (3 M in Et2O, 0.5 mL, 1.5 mmol), and
the reaction mixture was allowed to warm to -30 °C and then
stirred for 1 h. The reaction was cooled to -78 °C, EtMgBr (3 M
in Et2O, 0.25 mL, 0.75 mmol) was added, and then the reaction
was stirred at -30 °C for 2 h. The reaction was quenched with
saturated NH4Cl, extracted with Et2O, washed with brine, dried
(MgSO4), and concentrated under reduced pressure to yield a yellow
oil. Gradient flash column chromatography (petroleum ether/AcOEt
75:25 f 70:30 f 65:35) yielded the alcohol (156 mg, 62%). IR
(neat) 2961, 2253 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.76 (2 H,
d, J ) 8.1 Hz), 7.29 (2 H, d, J ) 8.1 Hz), 4.81 (1 H, d, J ) 9.1
Hz), 4.28 (1 H, br s), 3.40 (1 H, m), 2.42 (3 H, s), 2.27 (2 H, m),
2.02 (1 H, br s), 1.66 (2 H, m), 1.53 (1 H, m), 1.33 (2 H, m), 0.97
(3 H, t, J ) 7.4 Hz), 0.80 (3 H, d, J ) 6.6 Hz), 0.71 (3 H, d, J )
6.5 Hz). 13C NMR (125 MHz, CDCl3) δ 143.4, 138.1, 129.7 (2 C),
127.0 (2 C), 84.5, 80.1, 63.7, 50.1, 43.5, 31.0, 25.4, 24.3, 22.7,
21.9, 9.5. HRMS (ESI) m/z 360.1617 [(M + Na)+; calcd for C18H27-
NO3SNa 360.1609].
(2S)-1-[2-(2-(N-Toluensulfonyl-amino)-4-methyl-pentyl)-[1,3]-
dithiolan-2-yl]-butan-2-one (47). The ketone 44 (52 mg, 0.155
mmol) was dissolved in CH2Cl2 and MeOH (1:1, 2 mL) and stirred
at -10 °C for 20 min. Then 1,2-ethanedithiol (19 µL, 0.22 mmol)
followed by NaOMe (12 mg, 0.22 mmol) were added ,and the
reaction was allowed to warm to ambient temperature and was
2724 J. Org. Chem., Vol. 71, No. 7, 2006

Protected 1,3-Dicarbonyl Compounds
stirred for 12 h. The reaction was quenched with saturated NH4Cl,
extracted with Et2O, washed with brine, dried (MgSO4), and
concentrated under reduced pressure. Flash column chromatography
(petroleum ether/AcOEt 80:20) yielded ketone 47 (48 mg, 74%).
[R]2D5 +22.9 (c 0.535, CHCl3). IR (neat) 3265, 2955, 2161, 2022,
8.0 Hz), 5.23 (1 H, dd, J ) 3, 1 Hz), 3.93 (1 H, m), 3.39 (3 H, s),
3.33 (1 H, m), 3.23 (1 H, m), 3.15 (2 H, m), 2.49 (1 H, ddd, J )
14.5, 1.8, 1.8 Hz), 2.42 (3 H, s), 2.17 (1 H, ddd, J ) 14.3,2.2, 2.1
Hz), 2.02 (2 H, m), 1.76 (2 H, m), 1.68 (1 H, m), 0.92 (3 H, t, J
) 6.5 Hz), 0.88 (3 H, d, J ) 6.6 Hz). 13C NMR (125 MHz, CDCl3)
δ 143.5, 137.7, 129.8 (2 C), 126.9 (2 C), 84.5, 60.2, 55.2, 51.9,
44.8, 43.1, 41.5, 40.9, 37.8, 25.1, 23.1, 21.5, 21.3. HRMS (ESI)
m/z 438.1217 [(M + Na)+; calcd for C19H29NO3S3Na 438.1231].
1
1706, 1598 cm-1. H NMR (600 MHz, CDCl3) δ 7.74 (2 H, d, J
) 8.2 Hz), 7.30 (2 H, d, J ) 8.0 Hz), 4.73 (1 H, m), 3.50 (1 H, d,
J ) 18.1 Hz), 3.41 (1 H, m), 3.25 (2 H, m), 3.19 (2 H, m), 3.09 (1
H, d, J ) 18.1 Hz), 2.46 (2 H, m), 2.43 (3 H, s), 2.29 (2 H, m),
1.42 (1 H, m), 1.13 (1 H, ddd, J ) 13.5, 10.1, 4.2 Hz), 1.05 (3 H,
t, J ) 7.3 Hz), 0.92 (1 H, ddd, J ) 16.9, 9.9, 3.5 Hz), 0.74 (3 H,
d, J ) 6.5 Hz), 0.69 (3 H, d, J ) 6.6 Hz). 13C NMR (150 MHz,
CDCl3) δ 209.5, 143.3, 138.5, 129.6 (2 C), 127.3 (2 C), 64.8, 53.4,
52.1, 46.3, 45.7, 39.5, 38.0, 36.3, 24.6, 23.6, 21.5, 21.4, 7.5. HRMS
(ESI) m/z 430.1552 [(M + H)+; calcd for C20H32NO3S3: 430.1544].
(7S,9R)-7-Isobutyl-9-methoxy-N-toluensulfonyl-1,4-dithia-8-
aza-spiro[4.5]decane (48). The crude hemiaminal 46 (900 mg) was
dissolved in MeOH (60 mL), and then trimethylorthoformate (6
mL), THF (6 mL) and PPTS (621 mg, 2.47 mmol) were added.
The reaction mixture was stirred at ambient temperature overnight.
The reaction was quenched with saturated NH4Cl and saturated
NaHCO3 (1:1), extracted with Et2O, washed with brine, dried
(MgSO4) and concentrated under reduced pressure to yield a yellow-
white solid. Flash column chromatography (petroleum ether:AcOEt
90:10) yielded eliminated product in 2% yield and a diastereomeric
16:1 mixture of the piperidine 48 (759 mg, 89% over 2 steps). The
structure was confirmed by X-ray crystallography. [R]2D5 +52.3 (c
1.2, CHCl3). IR (neat) 2949, 1597 cm-1. Mp ) 91-98 °C. 1H NMR
(500 MHz, CDCl3) δ 7.67 (2 H, d, J ) 8.3 Hz), 7.30 (2 H, d, J )
Acknowledgment. We thank Dr. Olivier Piva for his
preliminary contribution to the dithiol addition during his study
leave with our group (1995-1996).30 We thank Peter Hewitt
for the preparation of compound 2f. We thank Dr David Hook
and Dr Paolo Orsini for their contribution to the dithiane
chemistry while they were working on the synthesis of Spong-
istatin. We thank Dr John Davis for the X-ray structures. This
work was supported by a Novartis Research Fellowship (S.V.L.),
EPSRC (M.J.G. and H.F.S.), Swiss National Science Foundation
(A.V.), AstraZeneca (D.M.S.).
Supporting Information Available: Characterization data for
the previously published compounds 2a-c, 2f-g, 2i, 21a-c, and
1
21e-g; experimental data for compounds 25-28; H NMR and
13C NMR spectra for unknown compounds; X-ray crystallographic
data file in CIF format for 31c, 32c, 39e, and 48. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO052514S
J. Org. Chem, Vol. 71, No. 7, 2006 2725