A formal convergent synthesis of (+)-trans-solamin

Article abstract of DOI:10.1016/j.tetlet.2008.01.046

A formal convergent synthesis of solamin is disclosed. The synthetic strategy exploits the potential of the sulfinyl group as an auxiliary, nucleophile and in C-C bond formation. The synthetic route can be adapted to the synthesis of stereoisomers of sola

Full text of DOI:10.1016/j.tetlet.2008.01.046

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Tetrahedron Letters 49 (2008) 1601–1604
A formal convergent synthesis of (+)-trans-solamin
Sadagopan Raghavan *, S. Ganapathy Subramanian, K. A. Tony
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 23 November 2007; revised 1 January 2008; accepted 10 January 2008
Available online 15 January 2008
Abstract
A formal convergent synthesis of solamin is disclosed. The synthetic strategy exploits the potential of the sulfinyl group as an
auxiliary, nucleophile and in C–C bond formation. The synthetic route can be adapted to the synthesis of stereoisomers of solamin,
analogs with variable carbon side chains, and other members of mono-THF acetogenins.
Ó 2008 Published by Elsevier Ltd.
Keywords: trans-Solamin; Sulfoxide; NBS; Bromohydrin; Pummerer ene reaction
Annonaceous acetogenins,1 isolated from 37 different
species of Annonaceae family, are metabolites that possess
a wide range of bioactivity including antitumor, antimal-
arial, pesticidal, immunosuppressive properties and inhibit
multi-drug resistant cancer cells.2 They are characterized
by the presence of one to three tetrahydrofuran (THF)
ring(s) with varying stereochemistries along a lengthy
hydrocarbon chain having terminal a,b-unsaturated c-lact-
one moiety. trans-Solamin,3 1, is a representative of the
mono-THF class of acetogenins (Fig. 1).
asymmetric dihydroxylation,4 Sharpless asymmetric epoxi-
dation,5,6 chiral pool starting material,7 or start from muri-
catacin,8 a natural product. We report herein a modular
formal synthesis of solamin, taking advantage of the nucleo-
philicity of the sulfinyl moiety to oxidatively functionalize
an alkene regio- and stereoselectively.9
The retrosynthetic analysis is depicted in Scheme 1. Dis-
connection at C2–C3, C17–C18, and C16–O bonds would
afford subunits 2 and 3. The latter was planned to be
obtained by C17–C18 bond formation using Horner–
Emmons–Wadsworth reaction employing aldehyde 4 and
keto-phosphonate 5. The aldehyde can be traced to bromo-
acetonide 6 and keto-phosphonate to oxazolidinone 7.
The synthesis of aldehyde 4 commenced with bromo-
acetonide10 6 that was readily obtained from acryloyl imid-
azole 8 in 4 steps. Acetonide 6 was subjected to Pummerer
reaction using trifluoroacetic anhydride, and the resulting
intermediate without isolation was reacted with 1-undecene
and anhydrous SnCl411 to afford the ene reaction product12
9 (60% yield). Proceeding ahead, the bromine was replaced
by a hydroxy group by reaction with sodium nitrite13
in DMF to furnish 10 (80% yield). Swern oxidation14
furnished aldehyde 4 (90% yield) which corresponds to
the C18–C32 subunit, Scheme 2.
The bioactivity, architecture, and the potential use of a
synthetic route to prepare other members have been the
major stimulants for synthetic activity toward acetogenins.
The synthesis of solamin reported to date utilizes Sharpless
O
O
1
19
20
OH
16
15
Me
11
11
O
Me
32
OH
1
Fig. 1.
The synthesis of 5 began with the coupling of the known
tetradecanoic acid derivative15 11 with oxazolidinone16 12
following Ho’s protocol17 to afford imide 7 (90% yield,
*
Corresponding author. Tel.: +91 040 27160123; fax: +91 040
27160512.
E-mail address: sraghavan@iict.res.in (S. Raghavan).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.01.046

1602
S. Raghavan et al. / Tetrahedron Letters 49 (2008) 1601–1604
O
18
O
p
-TolS
15
OP'''
3
11
O
+
Solamin
20
PhS
OP''
OP'
Me
OP
3
2
32
Me
7
18
p
-TolS
O
20
O
P
OMe
O
OP'
15
OP'''
OP'''
3
OP
+
MeO
11
OP''
32
Me
4
5
7
O
S
O
O
N
O
O
15
3
p
-Tol
11
O
7
6
Br
P = Protecting group
Ph
Scheme 1.
TFAA, CH2Cl2
0 ºC, 30 min
O
O
O
O
S
O
O
Ref 10
O
S
N
p
-Tol
p
-Tol
N
8
8
6
Br
9
Br
SnCl4, 0 ºC, 30 min
7
Me
O
(COCl)2, DMSO, -78 ºC
45 min then Et3N
O
O
NaNO2, DMF, 80 ºC
S
S
p
-Tol
p-Tol
O
OH
4
10
7
7
Me
Me
Scheme 2.
25
½aꢀD ꢁ51.0 (c 0.50, CHCl3)). The hydroxylation reaction
using Davis reagent18 13 proved tricky and it was essential
to follow the reported conditions meticulously.19 Thus
dropwise addition of a precooled (ꢁ78 °C) solution of 13
to the sodium anion of 7 generated and maintained at
ꢁ78 °C and quenching the reaction soon after the addition
followed by work up gave 14 as the sole product in 82%
Aldehyde 4 and keto-phosphonate 5 were subjected to
Horner–Emmons–Wadsworth olefination using Ba(OH)2
22
to afford unsaturated ketone 3 stereoselectively (70% yield,
25
½aꢀD +16.0 (c 2.1, CHCl3)). The carbonyl group was selec-
23
tively reduced using Zn(BH4)2 in anhydrous THF to
25
afford allyl alcohol 17 (85% yield, ½aꢀD +4.22 (c 1.85,
CHCl3)), essentially as a single isomer.24 The alcohol upon
treatment with Raney-Ni under an atmosphere of hydrogen
suffered hydrogenation and selective hydrogenolysis to
25
yield, ½aꢀD ꢁ28.0 (c 1.0, CHCl3). The auxiliary was
removed using methoxymagnesium bromide20 to afford
25
25
methyl ester 15 (80% yield, ½aꢀD ꢁ1.65 (c 2.70, CHCl3)).
afford alcohol 18 (65% yield, ½aꢀD +7.5 (c 1.0, CHCl3)).
The hydroxy group was protected as its Mom ether 16
Having introduced the oxygen functionalities, the THF ring
needed to be constructed. It was planned to convert the
hydroxyl into a good nucleofuge, deprotect the acetonide
selectively in the presence of Mom ether, and subject the
resulting diol to treatment with a mild base to form the
THF ring. Toward this end, 18 was converted to mesylate
25
(90% yield, ½aꢀD +31.27 (c 1.3, CHCl3)) and was subse-
quently reacted with the anion of dimethyl methylphospho-
25
nate21 to furnish keto-phosphonate 5 (75% yield, ½aꢀD
+12.5 (c 1.05, CHCl3)) which corresponds to the C3–C17
fragment of solamin, Scheme 3.

S. Raghavan et al. / Tetrahedron Letters 49 (2008) 1601–1604
1603
NaHMDS, THF, -78 ºC
O
O
O
O
Et3N, CH2Cl2, 0 ºC
LiCl, rt
O
Cl
O
N
SO2Ph
15
OBn
Ph
3
13
N
15
OBn
3
11
15
OBn
O
3
X
11
HO
11
O
OH
H
7
11
N
O
14, X = Auxiliary
Ph
MeOMgBr, MeOH,
CH2Cl2, 0 ºC
Ph
15, X = OMe
12
O
P
Mom-Cl,
CH2Cl2, rt
i-PrNEt2
Me
O
O
O
MeO
OMe
-BuLi, THF, -78 ºC
P
OMe
15
OBn
3
15
OBn
3
MeO
11
MeO
11
n
OMom
OMom
5
16
Scheme 3.
25
19 cleanly (100% yield, ½aꢀD +10.0 (c 0.25, CHCl3)), and
(71% yield, ½aꢀ2D5 +15.0 (c 0.75, CHCl3)) using iodine and tri-
phenylphosphine in the presence of imidazole, Scheme 4.27
Iodide 23, an intermediate in the synthesis of 1 reported by
Mioskowski and co-workers,6 had spectral characteristics
in full agreement to that reported by them, thus completing
the formal synthesis of trans-solamin.
In conclusion, we have devised a formal modular syn-
thesis of trans-solamin, 15 steps by the longest linear
sequence (0.038% overall yield), which demonstrates the
potential of the sulfinyl moiety as an auxiliary, potent
intramolecular nucleophile and in C–C bond forming reac-
tions. It is noteworthy that the reduction of the keto group
in 3 with L-selectride28 would yield the threo alcohol
(epimer of 17) which can be transformed into cis-solamin
selective deprotection of the acetonide using 70% aq
25
AcOH25 directly yielded diol 20 (65% yield, ½aꢀD +6.00 (c
0.65, CHCl3)). The diol is probably formed by the sequen-
tial deprotection of the acetonide, cyclization, promoted
by the high temperature, and Mom deprotection. The
methine protons at C16 and C19 resonated at d 3.8–3.7
and the methylene protons at C17 and C18 resonated at d
1.95–1.5 confirming the trans di-substitution of the THF
ring.26 The diol was protected as the di-TBS ether 21
25
(95% yield, ½aꢀD +14.4 (c 0.75, CHCl3)). Deprotection of
the benzyl ether by hydrogenolysis using Pd/C furnished
25
the primary alcohol 22 (95% yield, ½aꢀD +11.2 (c 0.85,
CH2Cl2)). Alcohol 22 was converted to iodo derivative 23
R2
18 R1
Raney-Ni, EtOH,
H2, rt
p-TolS
15
OBn
3
11
Ba(OH)2, Aq. THF, rt
20
4
5
+
OMom
O
O
32
Me
3, R1,R2 = O
17, R1 = H, R2 = OH
7
Zn(BH4)2, THF,
-40 ºC
Aq. 70% AcOH, 80 ºC
OBn
OBn
Me
11
11
Me
11
11
O
OP
O
OMom
O
OP
OP
Ms-Cl, Et3N, Cat. DMAP,
CH2Cl2, 0 ºC
20, P = H
TBS-OTf, 2,6-Lutidine
CH2Cl2, 0 ºC
18, P = H
21, P = TBS
19, P = SO2Me
H2, Pd/C, EtOAc, rt
Ref. 6
X
1
Me
11
11
O
OTBS
OTBS
22, X = OH
23, X = I
Ph3P, I2, THF
Imidazole, rt
Scheme 4.

1604
S. Raghavan et al. / Tetrahedron Letters 49 (2008) 1601–1604
8. Makabe, H.; Tanaka, A.; Oritani, T. J. Chem. Soc., Perkin Trans. 1
1994, 1975.
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12. The ene product indicated the presence of one major diastereomer,
however, efforts were not made to separate or assign the configuration
at the newly introduced stereogenic center of the major isomer since it
was to be destroyed subsequently.
by following the same sequence of reactions delineated for
the transformation of 17 into trans-solamin. Also other
stereoisomers of solamin can be prepared starting from
the diastereoisomer of 6 that can be obtained by DIBAL-
29
H/ZnCl2 reduction of keto sulfoxide. The methodology
should also be useful for the synthesis of analogs possessing
longer or shorter chain lengths (possessing functional
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Acknowledgments
S.R. is thankful to Dr. J. M. Rao, Head, Org. Div. I, Dr.
J. S. Yadav, Director, IICT for constant support and
encouragement. S.G.S. and K.A.T are thankful to CSIR,
New Delhi for a fellowship. Financial assistance from
DST (New Delhi) is gratefully acknowledged. We thank
Dr. A. C. Kunwar for the NMR spectra and Dr. M. Vair-
amani for the mass spectra.
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