Rapid synthesis of macrocycles from diol precursors

Article abstract of DOI:10.1016/j.tetlet.2008.11.100

A method for the formation of synthetic macrocycles with different ring sizes from diols is presented. Reacting a simple diol precursor with electrophilic reagents leads to a cyclic carbonate, sulfite, or phosphate in a single step in 25-60% yield. Conver

Full text of DOI:10.1016/j.tetlet.2008.11.100

Tetrahedron Letters 50 (2009) 693–695
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Tetrahedron Letters
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Rapid synthesis of macrocycles from diol precursors
*
Magnus J. Wingstrand, Charlotte M. Madsen, Mads H. Clausen
Department of Chemistry, Technical University of Denmark, Kemitorvet Building 201, DK-2800 Kgs. Lyngby, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the formation of synthetic macrocycles with different ring sizes from diols is presented.
Reacting a simple diol precursor with electrophilic reagents leads to a cyclic carbonate, sulfite, or phos-
phate in a single step in 25–60% yield. Converting the cyclization precursor to a bis-electrophilic iodide or
aldehyde enables preparation of a cyclic sulfide and amine, respectively, the latter using a double-reduc-
tive amination to induce ring closure.
Received 11 September 2008
Revised 14 November 2008
Accepted 26 November 2008
Available online 30 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to the memory of Magnus John
Wingstrand, 1975–2006
Keywords:
Macrocyclization
Cyclic esters
Reductive amination
In connection with an ongoing program to produce libraries of
macrocyclic compounds from simple building blocks, we were
interested in the possibility of forming large rings from bifunc-
tional precursors.
and enabled isolation of the desired product. Optimized conditions
called for slow addition of separate solutions of DMAP and the car-
An important challenge in forming large ring molecules is the
fact that it is often necessary to tailor reaction conditions to indi-
vidual substrates,1 which can render the generation of libraries
impractical. With this in mind, we decided to investigate the cycli-
zation in one to two synthetic steps with the added potential for
diversity in the ring-forming step. Our initial efforts, reported here,
have been focused on using a diol and its electrophilic derivatives
as cyclization precursors, and reacting them with bifunctional re-
agents in a single cyclization step.
OH
O
TBDMSO
MeLi
O
TBDPSCl
Imidazole
TBDMSO
O
CH2Cl2
62%
THF
62%
1
TBDPSO
TBDPSO
In order to test different cyclization methods, we synthesized
the simple precursor 7 (Scheme 1). Addition of lithium 3-(tert-
1) NaBH4, CeCl3, MeOH
2) MeI, Ag2O, Et2O
TBDMSO
TBDMSO
butyldimethylsilyloxy)propynide to
c-butyrolactone followed by
TBDPS protection of the resulting alcohol afforded the acetylenic
ketone 2. Reduction of the alkynone2 followed by neutral methyl-
ation3 gave 3, which could be selectively monodeprotected by
acidic solvolysis. Esterification with the known4 acid 5 and depro-
tection with TBAF yielded the desired diol 7.
Our first macrocyclic target was the carbonate 8 (Scheme 2 and
Table 1). Treatment of the precursor 7 with carbonyl diimidazole
(entry 1) or phosgene,5 either as a solution (entry 2) or prepared
in situ from triphosgene (entries 3 and 4), all resulted in no or
low conversion. Using p-nitrophenyl chlorocarbonate (PNPCC)
with DMAP as the base led to a 19% yield of 8 by NMR (entry 6),
OMe
O
2
3
93%
OR1
OTBDMS
OMe
TBDPSO
PPTS
EtOH
COOH
5
OR2
HO
EDC, DMAP
CH2Cl2
88%
O
OMe
4
O
95%
: R1 = TBDPS, R2 = TBDMS
6
TBAF, THF
70%
7: R1 = R2 = H
* Corresponding author. Tel.: +45 45252131; fax: +45 45933968.
E-mail address: mhc@kemi.dtu.dk (M.H. Clausen).
Scheme 1. Synthesis of the cyclization precursor.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.100

694
M. J. Wingstrand et al. / Tetrahedron Letters 50 (2009) 693–695
OMe
OMe
OMe
OMe
O
HO HO
X
See text
HO
HO
8: X = -OC(O)O-
9: X = -OS(O)O-
(45%)
(55%)
HO
HO
7
O
for details
10: X = -OP(O)(OPNP)O- (50%)
O
O
O
O
O
O
Scheme 2. Formation of macrocycles from diol precursors.
11
12
13
60%
48%
25%
bonate to a methylene chloride solution of the diol over 24 h with a
final concentration of 25 mM (entry 7). This protocol gave the de-
sired product in 45% yield. By-products were of an oligomeric nat-
ure; we did not isolate any larger cyclic structures in any of the
experiments.
Encouraged by the results of the one-pot approach to the car-
bonate, we next prepared a cyclic sulfite.6 Dropwise addition of
thionyl chloride to a 10 mM solution of 7, triethylamine and DMAP
in methylene chloride led to the isolation of cyclic sulfite 9 in 55%
yield as a 1:1 mixture of inseparable diastereoisomers. Similarly,
we were able to prepare the macrocyclic phosphate 10 by reaction
with p-nitrophenyl phosphorodichloridate (PNPOPOCl2) in 50%
yield.
O
S
OMe
O
OMe
O
OMe
O
O
O
O
O
O
S
S
O
O
O
O
O
O
14
15
16
Scheme 3. 17-Membered cyclic sulfites.
Due to the large influence of the conformations of the precur-
sors on macrocyclizations,7 it was important to test other sub-
strates under the standard conditions for cyclization. To elucidate
whether the approach was general, we studied the formation of
cyclic sulfites from other diols (Scheme 3).8 Gratifyingly, partial
(substrate 11) or full (precursor 12) reduction of the triple bond
did not negatively affect the yield of the cyclization under our stan-
dard conditions in a significant manner. On the other hand, com-
bining 4 with a sorbic acid derivative to form precursor 13 did
result in a decreased yield for the cyclization—perhaps not surpris-
ing, considering that the resulting 17-membered macrocycle 16
contains 5 sp2 and 2 sp-hybridized carbon atoms. Substrates that
cyclize reluctantly under these conditions generally led to oligo-
mers or eventually conversion of the alcohols into chlorides, which
was also the case for the reaction of 13. Overall, we were pleased
that identical conditions led to a reasonable isolated yield for all
the cyclizations without the need for optimization of the individual
reactions.
OMe
X
OMe
X
X
17: PPh3, I2,
19: (Bu3Sn)2S
imidazole
CsF, 18-C-6
7
O
or
or
O
18: Dess-Martin
20: BnNH2,
Na(AcO)3BH
O
O
19: X = -S-
(56%)
20: X = -N(Bn)- (48%)
17: X = CH2I (63%)
18: X = CHO (83%)
Scheme 4. Electrophilic precursors and their reactions with nucleophiles.
cyclic sulfide 19 in 56% yield. To the best of our knowledge, the
use of double-reductive amination of dialdehydes with a mono-
amine to prepare macrocyclic compounds has never been re-
ported.10 It was therefore with great pleasure we noted that
benzylamine reacted with 18 in the presence of sodium triacet-
oxyborohydride to give the product 20, proving that cyclization
is also feasible when nucleophilic reagents are reacted with
bis-electrophiles.
In conclusion, we have demonstrated that a simple diol and its
electrophilic derivatives can serve as precursors for cyclic mole-
cules formed in a single step under standard conditions. We be-
lieve that this method will help gain easy access to large ring
To investigate the potential of macrocyclizations involving
reactions with nucleophiles, we prepared two bis-electrophilic
derivatives of 7, the diiodide 17 and the dialdehyde 18 (Scheme
4). Reaction of 17 with sodium or lithium sulfide in a range of
solvents did not afford the desired product. However, using the
organic sulfide equivalent bis(tributyltin)sulfide in the presence
of CsF and 18-crown-69 led to the isolation of the 15-membered
Table 1
Conditions for the formation of cyclic carbonate 8 from diol 7
Entry
CDIa (equiv)
COCl2 (equiv)
Triphosgene (equiv)
PNPCCb (equiv)
Pyridine (equiv)
Et3N (equiv)
DMAP (equiv)
Concn of 7 (mM)
Yield of 8c (%)
1
1
—
1.2
—
—
—
—
—
—
—
—
—
1.2
1.35
1
—
—
3
—
1.4
3
—
—
—
—
0.1
0.2
0.05
0.05
2.4
10
10
20
10
25
12.5
25
No conv.
<5
<5
<5
<10
19
2d
3d
4d
5
—
—
—
—
—
—
0.5e
0.6f
—
5
—
—
—
6
—
—
—
—
2.4
1.3
7g
45
a
Carbonyl diimidazole.
b
c
d
e
f
p-Nitrophenyl chlorocarbonate.
Determined by 1H NMR of the crude after aqueous work-up.
Reagents added at À78 °C.
0.05 equiv of LiCl added.
0.02 equiv of Aliquot 336 added.
Separate CH2Cl2 solutions of DMAP and PNPCC added over 24 h.
g

M. J. Wingstrand et al. / Tetrahedron Letters 50 (2009) 693–695
695
molecules, and we are currently pursuing libraries of macrocycles
References and notes
based on this strategy.
1. Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. Rev. 2006, 106, 911–939;
Gradillas, A.; Pérez-Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086–6101; Wipf,
P. Chem. Rev. 1995, 95, 2115–2134.
Acknowledgments
2. Caine, D.; Arant, M. E. Tetrahedron Lett. 1994, 35, 6795–6798.
3. Trost, B. M.; Gunzner, J. L. J. Am. Chem. Soc. 2001, 123, 9449–9450.
4. Aristoff, P. A.; Johnson, P. D.; Harrison, A. W. J. Org. Chem. 1983, 48, 5341–5348.
5. For an example of successful formation of an 11-membered ring, see:
Nuss, J. M.; Murphy, M. M. Tetrahedron Lett. 1994, 35, 37–40.
6. Van Woerden, H. F. Chem. Rev. 1963, 63, 557–571.
We are grateful to the Lundbeck Foundation, the Torkil Holm
Foundation, and the Augustinus Foundation for financial support
of this work.
7. Blankenstein, J.; Zhu, J. Eur. J. Org. Chem. 2005, 1949–1964.
8. Conditions: diol (10 mM in CH2Cl2), SOCl2 (1.4 equiv), Et3N (3 equiv), DMAP
(0.1 equiv), 20 °C, 4 h.
Supplementary data
9. Harpp, D. N.; Gingras, M.; Aida, T.; Chan, T. H. Synthesis 1987, 1122–1124;
Harpp, D. N.; Gingras, M. J. Am. Chem. Soc. 1988, 110, 7737–7745.
10. For the use of dialdehydes and diamines see, for example: Farrell, J. R.; Stiles,
D.; Bu, W.; Lippard, S. J. Tetrahedron 2003, 59, 2463–2469.
Supplementary data (experimental procedures, characterization
data and copies of NMR spectra) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.11.100.