Improved method for the synthesis of β-carbonyl silyl-1,3-dithianes by the double conjugate addition of 1,3-dithiol to propargylic carbonyl compounds

Article abstract of DOI:10.1021/jo901950e

(Chemical Equation Presented) Base-mediated double conjugate addition of 1,3-propane dithiol to various silylated propargylic aldehydes and ketones allows for an efficient and scalable synthesis of β-carbonyl silyl-1,3-dithianes.

Full text of DOI:10.1021/jo901950e

pubs.acs.org/joc
of polyketides, we desired to take advantage of the capacity of
Improved Method for the Synthesis of β-Carbonyl
Silyl-1,3-Dithianes by the Double Conjugate Addition
of 1,3-Dithiol to Propargylic Carbonyl Compounds
olefin metathesis.5 Thus, allylation or a crotylation product
derived from bifunctional aldehyde 1 can be directly joined with
another polyketide motif without any functional group manip-
ulation. Also, it was envisioned that these processes could be
further streamlined by a tandem allylation (crotylation)-
epoxide opening via 1,4-Brook rearrangement, further improv-
ing the economy of polyketide synthesis (eq 1). Such a stream-
lined synthesis can also be envisaged for the corresponding
ketones 2 via an asymmetric aldol,6 Evans-Tishchenko reduc-
tion7 and anion relay chemistry (ARC)4 sequence (eq 2).
Sumit Mukherjee, Dimitra Kontokosta, Aditi Patil,
Sivakumar Rallapalli, and Daesung Lee*
Department of Chemistry, University of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607
dsunglee@uic.edu
Received September 10, 2009
Base-mediated double conjugate addition of 1,3-propane
dithiol to various silylated propargylic aldehydes and
ketones allows for an efficient and scalable synthesis of
β-carbonyl silyl-1,3-dithianes.
The effectiveness of this concept was amply demonstrated in
our recent formal synthesis of cochleamycin A (Scheme 1),8
where triethylsilyldithiane aldehyde 1b was converted to the
β-hydroxy dithiane by Leighton’s asymmetric allylation.9 A
subsequent alkylation with bromoacetaldehyde dimethyl-
acetal under basic conditions in the presence of HMPA
afforded a product, which later takes part in a tandem enyne
RCM to afford an advanced intermediate in the formal
synthesis of cochleamycin A.
Polyketide-based natural products show a tremendous vari-
ety of biological activity and structural diversity, and thus the
development of new synthetic methods for their efficient
syntheses has been a highly pursued goal in organic chemistry.1
Most general and effective methods for the construction of
typical polyketide motifs include an aldol reaction between
enolates and aldehydes,2 asymmetric allylation and crotylation
of aldehydes,3 and opening of epoxides with 2-lithiodithianes.4
In our plan to develop a modular approach for the construction
(5) For reviews on alkene metathesis, see: (a) Grubbs, R. H. Tetrahedron
2004, 60, 7117. (b) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, Germany, 2003. (c) Schrock, R. R.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2003, 42, 4592. (d) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001,
34, 18. (e) F€urstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (f) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413. (g) Armstrong, S. K. J. Chem. Soc.,
Perkin Trans. 1 1998, 371. (h) Schusterand, M.; Blechert, S. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2037. (i) Schmalz, H. G. Angew. Chem., Int. Ed. Engl. 1995,
34, 1833. (j) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
(6) (a) Evans, D. A.; Cee, V. J.; Siska, S. J. J. Am. Chem. Soc. 2006, 128,
(1) (a) Shang, S.; Tan, D. S. Curr. Opin. Chem. Biol. 2005, 9, 248. (b)
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Wang, X.; Meng, W.; Perl, N. R.; Xu, Y.; Leighton, J. L. J. Am. Chem. Soc.
2005, 127, 12806. (c) Hu, T.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc.
2002, 124, 12806. (d) Zacuto, M. J.; O’Malley, S. J.; Leighton, J. L. J. Am.
Chem. Soc. 2002, 124, 7890. (e) de Lemos, E.; Poree, F.-H.; Bourin, A.;
Agouridas, E.; Lannou, M.-I.; Commercon, A.; Betzer, J.-F.; Pancrazi, A.;
Ardisson, J. Chem.;Eur. J. 2008, 14, 11092. (f) Herber, C.; Breit, B. Chem.;
Eur. J. 2006, 12, 6684. (g) Nicolaou, K. C.; Kim, D. W.; Baati, R. Angew.
Chem., Int. Ed. 2002, 41, 3701. (h) Bouzbouz, S.; Cossy, J. Org. Lett. 2003, 5,
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9206 J. Org. Chem. 2009, 74, 9206–9209
Published on Web 10/30/2009
DOI: 10.1021/jo901950e
r
2009 American Chemical Society

Mukherjee et al.
JOCNote
SCHEME 1
TABLE 1. Synthesis of Silyl-Substituted Propargylic Aldehydesa
entry
R3Si
Me3Si
yield (%)b
yield (%)b
1
2c
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
100
71
78
89
74
100
72
66
65
d
Et3Si
(tBu)Me2Si
(allyl)Me2Si
(vinyl)Ph2Si
(vinyl)Me2Si
(benzyl)Me2Si
(Me)Ph2Si
(tBu)Ph2Si
iPr3Si
98
94
52
55
61
77
72
74
65
SCHEME 2
100
68
85
10
11
j
k
(H)tBu2Si
aReagents and conditions: (I) (i) n-BuLi, THF, -78 °C, 1 h; (ii)
R3Si-Cl, -78 °C to rt; (iii) PPTS, MeOH; (II) IBX, DMSO. bIsolated
yields after column chromatography. cAldehyde was synthesized by
formylation with DMF of the lithium acetylide generated with n-BuLi.
dNot applicable.
Through this streamlined sequence, various polyketide
motifs are expected to be synthesized in an unusually effective
manner, which, however, is contingent upon a secure supply
of carbonyl compounds 1 and 2 (Scheme 2) containing γ-1,3-
dithiane and trialkylsilyl moieties. Conceptually, two general
approaches (Paths A and B) to these compounds are envi-
sioned, and along these lines, several procedures10-13 were
already reported in the literature. From the standpoint of
substrate scope and functional group tolerance,11,12 the latter
involving a double Michael addition of 1,3-propanedithiol to
R,β-acetylenic aldehydes and ketones seems to be most attrac-
tive. However, the isolation of a silylated hemiacetal by Ley
and co-workers under their base-mediated conjugate addition
to silyl-substituted propargylic aldehydes (eq 3) calls for an
alternative procedure for silyl-substituted acetylenic alde-
hydes. Herein, we report the development of a general,
efficient, and scalable method for the synthesis of β-carbonyl
silyl-1,3-dithianes (1 and 2) carrying various silyl groups.
It was expected that the aldehyde 4 and ketone 6 could be
garnered via formylation14 or acylation15 of the correspond-
ing silyl acetylides. However, this route gave poor yields
when lithium acetylide and silyl chlorides were employed.16
An alternative approach involves the silylation of the lithium
acetylide of the commercially available THP-protected prop-
argyl alcohol, deprotection of the THP group generating
alcohols 3a-k with PPTS, and their oxidation with IBX.
This three-step sequence afforded aldehydes 4a-k in good to
excellent overall yields (Table 1).17 Other oxidation proto-
cols such as Swern,18 Parikh-Doering,19 or PCC oxidation
led to much lower yields. Since triethylsilylacetylene is
readily available at low price, the corresponding aldehyde 4b
(entry 2) was synthesized according to our initial plan
involving formylation of the lithium acetylide.
Silyl-substituted methyl propargylic ketones 6a-j were
also obtained in good to excellent yields by the silylation of
commercially available TMS-protected 3-butyn-2-ol,20 fol-
lowed by desilylation with 1 M HCl and MnO2 oxidation21 of
the precursor allylic alcohols 5a-j (Table 2).
With these aldehydes and ketones 4 and 6 in hand, we
attempted the addition of 1,3-propane dithiol using NaOMe
as the base according to Ley’s conditions.11c,12 As shown in
Table 3, the desired dithiane aldehydes 1a and 1b with a
trimethylsilyl (entry 1) and triethylsilyl group (entry 3) were
obtained in 61 and 62% yields, respectively, whereas t-butyl
dimethylsilyl-substituted aldehyde 1c (entry 2) was generated
in only moderate yield (42%). Further, this procedure is
unlikely to be amenable to a large-scale synthesis due to the
necessity of large amounts (0.05 M) of solvents, which is
(10) (a) Stossel, D.; Chan, T. H. J. Org. Chem. 1988, 53, 4901. (b) Taylor,
E. C.; LaMattina, J. L. Tetrahedron Lett. 1977, 2077. (c) Hatanaka, K.;
Tanimoto, S.; Sugimoto, T.; Okano, M. Tetrahedron Lett. 1981, 22, 3243. (d)
Gammill, R. B.; Sobieray, D. M.; Gold, P. M. J. Org. Chem. 1981, 46, 3555.
(e) Choi, B.; Youn, I. K.; Pak, C. S. Synthesis 1988, 792. (f) Woessner, W.;
Ellison, R. Tetrahedron Lett. 1972, 3735. (g) Taylor, E.; LaMattina, J. J. Org.
Chem. 1978, 43, 1200.
(11) (a) Ranu, B. C.; Bhar, S.; Chakraborti, R. J. Org. Chem. 1992, 57,
7349. (b) Kuroda, H.; Tomiro, I.; Endo, T. Synth. Commun. 1996, 26, 1539.
(c) Gaunt, M. J.; Sneddon, H. F.; Hewitt, P. R.; Orsini, P.; Hook, D. F.; Ley,
S. V. Org. Biomol. Chem. 2003, 1, 15. (d) Xu, C.; Bartley, J. K.; Enache, D. I.;
Knight, D. W.; Lunn, M.; Lok, M.; Hutchings, G. J. Tetrahedron Lett. 2008,
49, 2454.
(12) (a) Gaunt, M. J.; Hook, D. F.; Tanner, H. R.; Ley, S. V. Org. Lett.
2003, 5, 4815. (b) Gaunt, M. J.; Jeissman, A. S.; Orsini, P.; Tanner, H. R.;
Hook, D. F.; Ley, S. V. Org. Lett. 2003, 5, 4819. (c) Sneddon, H. F.; Gaunt,
M. J.; Ley, S. V. Org. Lett. 2003, 5, 1147.
(13) (a) Brook, A. G.; Duff, J. M.; Jones, P. F.; Davis, N. R. J. Am. Chem.
Soc. 1967, 89, 431–434. (b) Corey, E. J.; Seebach, D.; Freedman, R. J. Am.
Chem. Soc. 1967, 89, 434–436. (c) Collins, D. J.; James, A. M. Aust. J. Chem.
1989, 42, 223–228.
(14) Journet, M; Cai, D; DiMichele, L. M.; Larsen, R. D. Tetrahedron
Lett. 1998, 39, 6427.
(15) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
(16) Michael, M. D.; Roy, J. W.; Patrick, P. Aust. J. Chem. 1989, 42,
1907–1918.
(17) Sharma, A.; Chattopdhyay, S. J. Org. Chem. 1998, 63, 6128.
(18) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(19) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505.
(20) (a) Myers, A. G.; Zheng, B. Org. Synth. 1998, 76, 178–188. (b)
Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 2000, 65, 1601.
(21) Marshall, J. A.; Eidam, P.; Hillary, S. Org. Synth. 2007, 84, 120–128.
J. Org. Chem. Vol. 74, No. 23, 2009 9207

Mukherjee et al.
JOCNote
necessary to prevent the undesired intermolecular processes.
Hence, we investigated the heterogeneous conditions em-
ploying MgO and basic Al2O3 as reported by Knight11d and
Ranu.1a Reactions with MgO purchased from Aldrich were
very slow even with 10 equiv at room temperature; only 40%
of desired dithiane formed for the triethylsilyl aldehyde after
24 h together with unreacted starting material. On the
other hand, with 10 equiv of basic alumina in CH2Cl2,
dithiane 1b was obtained in 70% yield after 24 h (entry 7).
Optimal yield was observed with 10 equiv of basic Al2O3 in
THF at 1 M concentration at room temperature. Under
these conditions, substrate aldehydes 4b and 4c afforded
dithianes 1b and 1c in 81 and 78% isolated yields, respec-
tively (entries 9 and 10).
Next, an optimization for the formation of 1,3-dithianes
via the addition of dithiol to the propargylic ketones was
carried out with ketone substrates 6f and 6g that contain
vinyl dimethylsilyl and benzyldimethylsilyl groups, respec-
tively (Table 4). As expected, the propargylic ketones were
much less reactive toward conjugate addition: even the
reaction with 30 equiv of Al2O3 gave a 1:1 mixture of double
and mono conjugate addition product for the benzyldi-
methylsilyl ketone 6g after 24 h at room temperature (entry
3). It was found that, for these ketones, homogeneous bases
such as NaOMe, NaOEt, and KOtBu were more efficient
t
(entries 5-9); addition of 0.5 equiv of KOtBu in BuOH at
0 °C, followed by warming to room temperature over 3 h,
provided the best ratio of 6:2:7.
After establishing these optimized reaction conditions, a
range of aldehyde and ketone substrates was further exam-
ined (Table 5). Substrate aldehydes 4a-h provided excellent
yields of the corresponding products 1a-h in the range of
48-93% yield (entries 1-8) under condition A (10 equiv of
Al2O3, THF, 1.5 M). Gratifyingly, reactions on 5-6 g scale
of triethylsilyl and TBS-propargyl aldehydes (4b and 4c)
showed no diminution of yields, demonstrating the utility of
these conditions. However, no conversions were observed
even with 15 equiv of Al2O3 for di-tert-butylsilyl- (4k),
TABLE 4. Optimization of Reaction Conditions for the Addition of
Dithiols to Propargylic Ketonesa
TABLE 2. Synthesis of Silyl-Substituted Propargylic Ketone\sa
entry
base (equiv)
solvent time (h) temp (°C) 6:2:7b
entry
R3Si
Me3Si
yield (%)b
yield (%)b
1
2
3
4
5
6
7
8
9
6f Al2O3 (10)
6f Al2O3 (20)
6g Al2O3 (20)
6g Al2O3 (30)
THF
THF
THF
THF
24
24
24
24
3
3
3
3
rt
rt
rt
rt
0:3:1
0:5:1c
0:1:1
1
2
3
4
5
6
7
8
9
10
a
b
c
d
e
f
g
h
i
72
85
67
74
100
80
82
75
74
78
71
78
92
94
95
65
86
85
83
82
Et3Si
(tBu)Me2Si
(allyl)Me2Si
(vinyl) Ph2Si
(vinyl)Me2Si
(benzyl)Me2Si
(Me)Ph2Si
(tBu)Ph2Si
(H)iPr2Si
0:1:1
6g NaOMe (1.5) THF
-10 to rt
-10 to rt
-10 to rt
0 to rt
0 to rt
0:0:1d
4:0:1d
0:1.5:1
0:8:1
6g NaOEt (1.5)
6g KOtBu (1.0)
6g KOtBu (0.5)
6f KOtBu (0.5)
THF
THF
tBuOH
tBuOH
3
0:1:0
aAll reactions were carried out at a concentration of 0.5 M. SM
indicates unreacted starting material. bRatios were determined from 1H
NMR spectroscopy of the crude. cObtained significant amounts of
unidentified products. dLonger reaction times led to a complex mixture
as observed on TLC.
j
aReagents and conditions: (I) (i) n-BuLi, THF, -78 °C, 1 h; (ii)
R3Si-Cl, -78 °C to rt; (iii) HCl (1 M); (II) MnO2, CH2Cl2. Isolated
yields after column chromatography.
b
TABLE 3. Optimization of Reaction Conditions for the Addition of Dithiols to Propargylic Aldehydes
entry
base (equiv)
solvent
time (h)
temp (°C)
conc (M)
yielda (%)
1
2
3
4
5
6
7
8
9
4a
4c
4b
4b
4b
4b
4b
4b
4b
4c
4c
NaOMe (1.5)
NaOMe (1.5)
NaOMe (1.5)
MgO (4)
DCM/MeOHb
DCM/MeOH
DCM/MeOH
THF
THF
DCM
DCM
THF
THF
THF
THF
1
2.5
2
10
24
24
24
10
3
-10
-10
-10
rt
rt
rt
rt
rt
rt
rt
0.05
0.05
0.05
0.5
0.5
0.5
0.5
0.5
1
61
42c
62
20c
40c
50c
70c
80
MgO (10)
Al2O3 (5)d
Al2O3 (10)
Al2O3 (10)
Al2O3 (10)
Al2O3 (10)
Al2O3 (10)
81
78
78
10
11
5
10
1
0.5
rt
b
c
1
aIsolated yields after column chromatography. DCM/MeOH = 4:1. As determined from H NMR spectroscopy of the crude. The rest of the
mixture was unconverted starting material. dBasic alumina.
9208 J. Org. Chem. Vol. 74, No. 23, 2009

Mukherjee et al.
JOCNote
TABLE 5. Dithiol Additions to Propargylic Aldehydes and Ketones
toward the alkoxide. Similar to the cases with the aldehydes,
substrates 6i and 6j with sterically bulky silyl substituents
showed either decomposition or no reaction (entries 20
and 21).
In conclusion, base-mediated conjugate addition of 1,3-
dithiols to silyl propargylic aldehydes and ketones allows for
a versatile, efficient, and scalable approach toward the
assembly of β-carbonyl silyl-1,3-dithianes.
entry substrates
R3Si
Me3Si
R1 conditiona products yield (%)b
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
H
H
H
H
H
H
Ac
A
A
A
A
A
A
A
1a
1b
1c
1d
1e
1f
89
81
78
82
48
80
88
93
Et3Si
(tBu)Me2Si
(allyl)MezSi
(vinyl)Ph2Si
(vinyl)Me2Si
Experimental Section
General Procedure for Dithiane Aldehydes 1a-h. To a well-
stirred solution of propargylic aldehydes (1 equiv) and 1,3-
propanedithiol (1 equiv) in THF (1.5 M with respect to
aldehyde) was added activated basic alumina (5-10 equiv,
4g
4h
(benzyl)Me2Si H
(Me)Ph2Si
1g
1h
H
˚
standard grade, ∼150 mesh, 58 A) in 10 portions, such that
9
6a
Me3Si
Et3Si
Me
Me
Me
Me
Me
B
B
B
B
B
B
B
B
2a
2b
2c
2d
2e
2f
35
64
100
100
100
98
the temperature did not go above room temperature. After
completion of the reaction (3-6 h, TLC), the reaction mixture
was filtered through a short plug of Celite, followed by washing
of the residue with DCM (2 Â 50 mL). The filtrate and the
washings were evaporated to give the crude product, which was
purified by column chromatography (0-5% ethyl acetate in
hexanes) to yield the aldehydes 1a-h as a light yellow oil.
General Procedure for Dithiane Ketones 6a-h. To a well-
stirred solution of propargylic ketones (1.0 equiv) and 1,3-
10 6b
11 6c
12 6d
13 6e
14 6f
15 6g
16 6h
(tBu)Me2Si
(allyl)Me2Si
(vinyl)Ph2Si
(vinyl)Me2Si Me
(benzyl)Me2Si Me
(Me)Ph2Si
2g
2h
92
98
Me
17 4i
18 4j
19 4k
20 6i
21 6j
(tBu)Ph2Si
iPr3Si
H
H
H
Me
Me
Af
Af
Ad
Bh
B
NRe
NRe
t
propanedithiol (1.0 equiv) in BuOH (0.5 M with respect to
(H)tBu2Si
(tBu)Ph2Si
(H)iPr2Si
NRe
trace
ketone) was added KOtBu (0.5 equiv) at 0 °C, and the reaction
was maintained at that temperature for 1-2 h, following which
it was warmed to room temperature and kept there until the
reaction was complete (TLC). The reaction was diluted with
H2O and extracted with ether. The combined ether layers were
washed with water and brine, dried over MgSO4, filtered,
concentrated, and subjected to column chromatography
(0-5% ethyl acetate in hexanes) to obtain the ketones 6a-h.
decompg
aCondition: (A) 10 equiv of Al2O3, THF (1.5 M); (B) 0.5 equiv of
KOtBu, tBuOH (0.5 M). bIsolated yields after column chromatography.
c5 equiv of Al2O3 was optimum. dReaction was forced with 15 equiv of
Al2O3. eNo reaction. Reaction was forced with 30 equiv of Al2O3.
f
gDecomposed. hReaction was forced with 1.5 equiv of KOtBu.
tert-butyl diphenylsilyl- (4i), and triisopropyl (4j)-substi-
tuted aldehydes (entries 17-19).
Under condition B, ketones 6a-h afforded the corres-
ponding 1,3-dithiane products 2a-h in good to excellent
yields (entries 9-16), except for trimethylsilyl-containing
substrate 6a (entry 9). The poor yield (35%) for 2a is
probably due to the instability of the trimethylsilyl group
Acknowledgment. We thank UIC and the NIH
(CA106673) for a partial support this work.
Supporting Information Available: General procedures and
characterization data of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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