Solid-support synthesis of 1,2-diols and γ-lactones through addition of α-(benzoyloxy)crotylindium reagents to aldehydes

Article abstract of DOI:10.1055/s-2001-13367

A procedure for the solid phase synthesis of 1,2-diols and γ-lactones from α-(hydroxy)crotylstannane has been developed through transmetalation with InBr₃. A variety of 1,2-diols and γ-lactones were synthesized in satisfactory yields and, in some cases, with excellent diastereoselectivity. The products are formed free of tin contamination.

Full text of DOI:10.1055/s-2001-13367

LETTER
629
Solid-Support Synthesis of 1,2-Diols and -Lactones Through Addition of
-(Benzoyloxy)crotylindium Reagents to Aldehydes
Janine Cossy,*,a Chrystelle Rasamison,a Domingo Gomez Pardo,a James A. Marshallb
a Laboratoire de Chimie Organique associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Fax 33-1-40-79-46-60; E-mail: janine.cossy@espci.fr
b Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, USA
Received 5 February 2001
Initial studies were conducted with the racemic u3SnLi
adduct4 of crotonaldehyde 1 and a polystyrene resin with
an attached chloropyran group.5 However, the tetrahydro-
pyranyl ethers of 1 could not be prepared. We therefore
Abstract: A procedure for the solid phase synthesis of 1,2-diols and
-lactones from -(hydroxy)crotylstannane has been developed
through transmetalation with InBr3. A variety of 1,2-diols and -lac-
tones were synthesized in satisfactory yields and, in some cases,
with excellent diastereoselectivity. The products are formed free of elected to esterify the hydroxyl group and explore the
tin contamination.
transmetalation/addition of the acylated material. As this
chemistry was previously unexplored, we first conducted
solution phase studies on the benzoate derivative in order
to establish experimental conditions and, if possible, de-
termine the probable scope of the additions. Thus, ben-
zoylation of the hydroxy stannane 16 with benzoyl
chloride, in the presence of i-Pr2NEt, 4-(dimethylami-
no)pyridine (DMAP) in CH2Cl2, afforded benzoate 27 in
90% yield from crotonaldehyde (Scheme 2).
Key words: solid-phase synthesis, diols, lactones, -(benzoyloxy)-
crotylindium, -(benzoyloxy)-crotylstannane
Combinatorial organic synthesis on solid supports has
emerged as an important tool in lead structure identifica-
tion and optimization in drug discovery.1 Within this field,
considerable effort has been made to establish the feasibil-
ity of adapting established solution phase reactions to sol-
id supports. Nonetheless, methods for stereoselective
construction of carbon-carbon bonds on solid supports re-
main highly underdeveloped. In that connection, we be-
came interested in extending the applicability of solid
support technology to additions of -oxygenated allylic
indium reagents to afford stereochemically defined 1,2-
diols. Specifically, we wished to explore the synthesis and
transformations of -oxygenated allylic stannanes teth-
ered to the support through an ether linkage analogous to
known reactions of the corresponding OMOM or OBOM
derivatives.2 The chemistry of interest involved transmet-
alation of the stannane with InBr3 to form the indium de-
rivative (Scheme 1) and in situ addition of these reagents
to aldehydes.3
When stannane 2 was treated with InBr3 (3 equiv.) at
–78 °C followed by the addition of 3 equivalents of cyclo-
hexanecarboxaldehyde, the expected hydroxy ester 4a
was not formed to an appreciable extent. However, when
20 equivalents of aldehyde and only 1.2 equivalents of
InBr3 were employed the addition product, admixed with
inseparable tin by-products, was obtained. Treatment with
NaOMe in MeOH/THF (1:4) produced the anti 1,2-diol
5a (Scheme 2). Unfortunately, despite efforts to effect pu-
rification by chromatography, the diol remained contami-
nated with stannane by-products and the yield could not
be determined. This experiment led us to conclude that the
solid-support protocol may be particularly well suited for
these additions and no further work was conducted in so-
lution.
Scheme 2
OR
InBr2
O
O
OH
InBr3, EtOAc
-78 ºC
Cl
O
Me
SnBu3
a
Me
OCOPh
i-Pr2NEt
Bu3Sn
Me
Bu3Sn
Me
1
1 R = H
3
RCHO
InBr3
2 R = PhCO
c-C6H11CHO
O
O
R
OR
c-C6H11
Me
Me
OH
OH
4a R = COPh
5a R = H
b
Scheme 1
Scheme 2 a) PhCOCl, i-Pr2NEt, DMAP, CH2Cl2; b) NaOMe,
MeOH/THF (1/4)
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630
J. Cossy et al.
LETTER
O
O
O
HO
O
InBr2
O
O
InBr3, EtOAc
RCHO
R1
1
Me
O
Me
SnBu3
Me
EDCl, DMAP
-78 ºC
7
6
8
OH
NaOMe, MeOH
THF, 40 ºC
OH
OH
+
R
R
Me
Me
OH
OH
9
5
Scheme 3
The supported -(benzoyloxy)crotylstannane 68 was
readily prepared from a commercially available carboxy-
lic polystyrene resin.9,10 The resin was swirled with the
-(hydroxy)crotylstannane 1, 1-(3-dimethylaminopro-
pyl)-3-ethylcarbodiimide hydrochloride (EDCI) and
OH
OTBDMS
R
TBDMSCl (1 equiv.)
R
Me
Me
imidazole (2.5 equiv.)
CH2Cl2
OH
OH
5a R = hexyl
5b R = cyclohexyl
10a R = hexyl
10b R = cyclohexyl
11
DMAP in CH2Cl2 at room temperature for 16 h. After
Scheme 4
consecutive alternate washings with CH2Cl2 and ether, the
resin was dried in vacuo. A suspension of dried resin in
EtOAc was added to a solution of aldehyde (20 equiva-
lents) and InBr3 (1.2 equiv.) in EtOAc at –78 °C and the
reaction mixture was allowed to reach room temperature.
After 5 h, the resin was washed alternately with CH2Cl2
and ether. It was then suspended in MeOH/THF (1/4) and
treated with NaOMe12 after which, simple filtration led to
the 1,2-diols 513 (Scheme 3). The results are summarized
in Table 1.
O
O
Me
O
SnBu3
6
InBr3
O
O
O
Br2In
Me
Br2In
Me
+
O
Table 1 Synthesis of 1,2-Diols 5a-e and 9a-e.
E-7
Z-7
RCHO
RCHO
H
O
O
H
H
O
H
Me
In
Me
R
O
O
Br
Br
R
In
Br
H
H
Br
A
B
slow for R = alkyl
fast for aryl and vinyl
fast for R = alkyl
fast for aryl and vinyl
anti adducts
syn adducts
(a) The yields are reported for the three-step process (from 1).
Figure 1 Possible pathways for addition of allylic indium reagents
to aldehydes
The syn/anti ratio of the 1,2-diols, synthesized from aro-
matic aldehydes, was determined by 1H NMR analysis.18
For the 1,2-diols, synthesized from aliphatic aldehydes,
this ratio was determined after selective silylation of the
allylic alcohols 5a and 5b to 10a20,21 and 10b21,22 as these
are known compounds (Scheme 4).
tion. It is known that (E)-allylic stannanes are more reac-
tive than the (Z)-isomers in additions to aldehydes.23
Thus, if the energy of transition state of type B was signif-
icantly higher than that of transition state A, we could ex-
plain the high selectivity and lower yields of adducts 5a
and 5b. The lower selectivities observed for adducts 5c-e
could be explained by a high reactivity for aryl and conju-
gated aldehydes with both (E)-7 and (Z)-7. The reactivity
difference was confirmed by a competition experiment. A
The formation of the anti-1,2 diols 5a and 5b from the two
aliphatic aldehydes is suggestive of a reaction pathway in-
volving a cyclic transition state of type A (Figure 1). Con-
ceivably both (E)- and (Z)-allylic indium intermediates
(E)-7 and (Z)-7 are produced in the transmetalation reac-
Synlett 2001, No. 5, 629–633 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Solid-Support Synthesis of 1,2-Diols and γ-Lactones
631
1:1 mixture of benzaldehyde and cyclohexanecarboxalde- to the -oxygenated indium species 11 which produces
hyde gave rise to a 1.0/1.1/1.2 mixture of adducts 5b, 5d, adduct 12 and thence the lactols after cleavage. Such
and 9d after exposure to the supported crotyltin reagent 6 adducts are not observed in reactions involving the
to InBr3 and subsequent treatment with NaOMe thus con- OMOM analogs of stannane 2 and InBr3.2 Presumable
firming the enhanced reactivity of benzaldehyde vs. cy- chelation between the ester carbonyl and the InBr2
clohexanecarboxaldehyde.
moiety, as in 11, favors this regioisomer.
We considered the possibility of a chelated cyclic transi- The diastereoselectivity of these additions was high with
tion state C for additions involving the presumed (Z)-7 in- the exception of 12d and 12f, the adducts of heptanal and
dium reagent (Figure 2). However, this possibility was dodecanal. The major products of the four-step sequence
discounted as the expected product would contain a (Z) were the trans lactones 14 (Table 2). Unlike the previous
double bond and the diol products were exclusively (E).
additions (Table 1) high anti:syn ratios were observed
both with aromatic aldehydes and cyclohexanecarboxal-
dehyde. The trend is suggestive of a transition state in
which steric factors play a major role (Figure 3). The rel-
atively larger size of aryl and cyclohexyl R groups would
favor D relative to E.
Br
O
Br
O
In
Me
O
O
R
Me
O
O
Br2In
Me
RCHO
H
Table 2 Synthesis of Lactones 14a-f and 15a-f
H
R
O
OH
H
Z-7
H
C
Figure 2 Hypothetical chelation transition state for addition of
(Z)-7 to aldehydes.
The foregoing analysis (Fig. 1) assumes that a mixture of
(E)-7 and (Z)-7 are formed in the transmetalation reaction.
As this reaction is conducted in the presence of aldehyde,
we also assume that these intermediates are formed under
kinetic control. To further probe this assumption we con-
ducted experiments in which the resin-bound stannane 6
and InBr3 were premixed at 78 °C and allowed to reach
room temperature before addition of the aldehyde at
78 °C. It was expected that this protocol would allow the
allylic indium intermediates (E)-7 and (Z)-7 to equilibrate
before reacting with the aldehyde. When the adducts of
these reactions were cleaved from the resin with NaOMe
they were found to be the lactols 13 rather than the previ-
ously obtained 1,2-diols. To simplify the analysis, these
adducts were converted to the lactones 14 and 15 (Scheme
5).24 Obviously, equilibration of (E)-7 and (Z)-7 gives rise
(a) The yields are reported for the four-step process (from 1)
Br
Br
O
Br
Br
In
O
In
O
Me
Me
O
7
RCHO
O
H
H
H
H
O
Me
Me
O
O
R
H
O
Br
Br
O
In
Br
In
Br
E
D
H
R
anti adducts
syn adducts
O
O
Me
O
O
InBr3
R
RCHO
Figure 3 Possible transition states for addition of -acyl allylic in-
dium reagents
6
Me
In Br
Br
-78 °C
-78 to 25 ºC
OH
11
12
NaOMe, MeOH
These studies confirm the feasibility of employing solid
phase synthesis with resin-bound oxygenated allylic indi-
um reagents to produce either 1,2-diols or -lactols
through a change in reaction protocol. These adducts can
be produced in satisfactory yields and, in some cases,
with excellent diastereoselectivity. The products are
formed free of contamination by tin and other by-
THF, 40 ºC
Me
Me
Me
R
R
R
PCC, NaOAc
+
O
O
O
O
OH
O
13
15
14
Scheme 5
Synlett 2001, No. 5, 629–633 ISSN 0936-5214 © Thieme Stuttgart · New York

632
J. Cossy et al.
LETTER
(14) 5a: IR (neat): 3398, 1654, 1577, 1458, 1378, 1071, 968 cm-1.
1H NMR (300 MHz, CDCl3) : 5.74 (dq, J = 6.2 and 15.4 Hz,
1H), 5.56 (ddd, J = 1.5, 7.4 and 15.5 Hz, 1H), 4.00 (dd, J = 3.3
and 7.4 Hz, 1H), 3.72-3.60 (m, 1H), 1.72 (dd, J = 1.1 and 6.2
Hz, 3H), 1.50-1.20 (m, 10H), 0.92-0.83 (m, 3H). 13C NMR (75
MHz, CDCl3) : 129.5 (d), 128.8 (d), 75.7 (d), 74.1 (d), 32.1
(t), 31.6 (t), 29.2 (t), 25.7 (t), 22.5 (t), 17.8 (q), 14.0 (q). MS
(CI, NH3) m/z: 204 (MH++NH3), 202 (4), 187 (2), 186 (18),
175 (5), 174 (48), 172 (5), 169 (7), 141 (3), 123 (100), 109
(12), 107 (2). HRMS (CI) calculated for C11H26O2N
(MH++NH3): 204.1964, found: 204.1970.
(15) (5b: IR (neat): 3369, 1718, 1449, 1377, 1262, 1084, 968, 800,
739 cm-1. 1H NMR (300 MHz, CDCl3) : 5.87-5.73 (m, 1H),
5.62 (ddd, J = 1.5, 7.3 and 15.4 Hz, 1H), 4.17 (m, 1H), 3.41
(dd, J = 3.7 and 8.1 Hz, 1H), 2.10-0.80 (m, 11H), 1.75 (dd,
J = 1.1 and 5.9 Hz). 13C NMR (75 MHz, CDCl3) : 129.9 (d),
128.5 (d), 78.0 (d), 73.2 (d), 39.6 (d), 28.7 (t), 28.6 (t), 26.3 (t),
25.8 (t), 25.6 (t), 17.8 (q). MS (EI) m/z: 184 (M+, 0.07), 113
(7), 112 (6), 96 (8), 95 (100), 93 (5), 83 (8), 81 (6), 79 (3), 73
(4), 72 (70), 71 (16), 70 (4), 69 (10), 67 (16), 57 (16), 55 (16),
53 (6).
(16) Pons, J.-M.; Santelli, M. J. Org. Chem. 1989, 54, 877.
Schobert, R. Angew. Chem., Int. Ed. Engl. 1988, 27, 855.
Handa, Y.; Inanaga, J. Tetrahedron Lett. 1987, 28, 5717.
(17) Becker, H.; Soler, M. A.; Sharpless, K. B. Tetrahedron 1995,
51, 1345. Tanaka, S.; Yasuda, A.; Yamamoto, H.; Nozaki, H.
J. Am. Chem. Soc. 1975, 97, 3252.
(18) Dana, G.; Chuche, J.; Monot, M.-R. Bull. Soc. Chim. Fr. 1967,
3308.
(19) Dana, G.; Thuan, S. L. T. Bull. Soc. Chim. Fr. 1973, 1676.
(20) Marshall, J. A.; Welmaker, G. J. Tetrahedron Lett. 1991, 32,
2101.
products. Clearly, it should be possible to improve the
yields and reaction stoichiometry through the use of alter-
native spacer groups and resins. We hope to clarify these
issues in future studies.
References and Notes
(1) For reviews, see: Brown, R. C. D. J. Chem. Soc., Perkin
Trans. 1 1998, 3293. Booth, S.; Hermkens, P. H. H.;
Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1998, 54,
15385. Blackburn, C.; Albericio, F.; Kates, S. A. Drugs of the
Future 1997, 22, 1007. Hermkens, P. H. H.; Ottenheijm, H. C.
J.; Rees, D. C. Tetrahedron 1997, 53, 5643. Balkenhohl, F.;
Von dem Bussche-Hünnefeld, C.; Lansky, A.; Zechel, C.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2288. Hermkens, P. H.
H.; Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1996, 52,
4527. Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96,
555. Früchtel, J. S.; Jung, G. Angew. Chem., Int. Ed. Engl.
1996, 35, 17. Terrett, N. K.; Gardner, M.; Gordon, D. W.;
Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135.
Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.;
Gallop, M. A. J. Med. Chem. 1994, 37, 1233.
(2) Marshall, J. A. Chem. Rev. 1996, 96, 31.
(3) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1996, 61, 105.
(4) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481.
(5) Cossy, J.; Rasamison, C.; Gomez Pardo, D. Unpublished
results.
(6) Pratt, A. J.; Thomas, E. J. J. Chem. Soc., Chem. Commun.
1982, 1115.
(7) Pratt, A. J.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1989,
1521.
(21) Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1996, 61,
8732. Marshall, J. A.; Welmaker, G. J. J. Org. Chem. 1992,
57, 7158.
(22) Marshall, J. A.; Jablonowski, J. A.; Welmaker, G. J. J. Org.
Chem. 1996, 61, 2904. Marshall, J. A.; Jablonowski, J. A.;
Elliott, L. M. J. Org. Chem. 1995, 60, 2662.
(8) Preparation of support-bound -(benzoyloxy)crotylstannane
6: To a suspension of carboxypolystyrene (1.0 g, 2 mmol/g, 2
mmol) in CH2Cl2 (20 mL) at r.t., were added successively
EDCI (1.9 g, 10 mmol, 5 equiv.), DMAP (0.74 g, 6 mmol, 3
equiv.) and 1 (3.6 g, 10 mmol, 5 equiv.). After 16 h, the resin
was filtered, alternately thoroughly washed with CH2Cl2 and
Et2O and then dried in vacuo to give the crotylstannane
supported reagent 6. IR (KBr): 3022, 2922, 2844, 1728, 1700,
1350 cm-1. 13C NMR (75 MHz, CDCl3) : 130.6 (d), 127.8 (m,
polystyrene), 119.4 (d), 71.9 (d), 40.3 (m, polystyrene), 28.8
(t), 27.2 (t), 17.7 (q), 13.6 (q), 9.5 (t).
(9) The carboxylic polystyrene resin (1% DVB cross-linked) with
a loading of 2 mmol/g was purchased from Advanced
Chemtech.
(10) Leznoff, C. C.; Dixit, D. M. Can. J. Chem. 1977, 55, 3351.
(11) The principal drawback in the use of dicyclohexyl-
carbodiimide (DCC) is the formation of the dichloromethane-
insoluble dicyclohexylurea (DCU) during acylation. The
EDCI urea is soluble in dichloromethane.
(23) Keck, G. E.; Savin, K. A.; Cressman, E. N. K.; Abbott, D. E.
J. Org. Chem. 1994, 59, 7889.
(24) General conditions for the preparation of lactones: To a
solution of InBr3 (253 mg, 0.72 mmol, 3 equiv.) in EtOAc at
78 °C, was added resin 6 (200 mg, 0.24 mmol, 1 equiv.). The
resulting slurry was allowed to reach r.t. before addition of
RCHO (0.72 mmol, 3 equiv.) at 78 °C. After 5 h at r.t., the
resin was filtered, alternately thoroughly washed with CH2Cl2
and Et2O and then dried in vacuo. The resin was then
suspended in MeOH/THF (1/4) (5 mL) at r.t. After addition of
NaOMe (259 mg, 4.80 mmol, 20 equiv.), the resulting slurry
was stirred at 40 °C for 1 h, before neutralization by an
aqueous solution of HCl (1.2 M). The solution was collected
by filtration, dried over MgSO4 and the solvent was removed
in vacuo to give lactols 13. To a solution of lactol (0.24 mmol,
1 equiv.) in CH2Cl2 (5 mL) at r.t., were added successively
molecular sieves (310 mg), NaOAc (9 mg, 0.12 mmol, 0.5
equiv.) and PCC (155 mg, 0.72 mmol, 3 equiv.). The mixture
was stirred at r.t. for 6 h before filtration through silica gel
(EtOAc/cyclohexane: 70/30). The solvent was then removed
in vacuo to give lactones.
(12) Dilley, G. J.; Durgin, T. L.; Powers, T. S.; Winssinger, N. A.;
Zhu, H.; Pavia, M. R. Mol. Div. 1995, 1, 13.
(13) General conditions for the preparation of 1,2-diols: To a
solution of InBr3 (102 mg, 0.29 mmol, 1.2 equiv.) and RCHO
(4.80 mmol, 20 equiv.) in EtOAc at 78 °C, was added resin
6 (200 mg, 0.24 mmol, 1 equiv.). The mixture was allowed to
reach r.t. After 5 h the resin was filtered, alternately
thoroughly washed with CH2Cl2 and Et2O and then dried in
vacuo. The resin was then suspended in MeOH/THF (1/4)
(5 mL) at r.t. After addition of NaOMe (259 mg, 4.80 mmol,
20 equiv.), the resulting slurry was stirred at 40 °C for 1 h
before neutralization by an aqueous solution of HCl (1.2 M).
The solution was collected by filtration, dried over MgSO4
and the solvent was removed in vacuo. Purification of the
crude material by flash chromatography (EtOAc/petroleum
ether: 20/80) afforded 1,2-diols.
(25) Satoh, M; Washida, S.; Takeuchi, S.; Asaoka, M.
Heterocycles 2000, 52, 227. Jephcote, V. J.; Pratt, A. J.;
Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1989, 1529.
(26) Fukuzawa, S.-I.; Seki, K.; Tatzuzawa, M.; Mutoh, K. J. Am.
Chem. Soc. 1997, 119, 1482.
(27) Frenette, R.; Monette, M.; Bernstein, M. A.; Young, R. N.;
Verhoeven, T. B. J. Org. Chem. 1991, 56, 3083.
Synlett 2001, No. 5, 629–633 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Solid-Support Synthesis of 1,2-Diols and γ-Lactones
633
(28) 14f and 15f: IR (mixture of two diastereomers, neat): 1781,
1458, 1205, 1160 cm-1. 1H NMR (300 MHz, mixture of two
diastereomers, CDCl3) : 4.48-4.35 (m, 0.38H), 4.06-3.97 (m,
0.62H), 2.75-2.62 (m, 1H), 2.64-2.52 (m, 1H), 2.28-2.14 (m,
1H), 1.70-1.25 (m, 20H), 1.14 (d, J = 6.25 Hz, 1.86H), 1.02 (d,
J = 7.0 Hz, 1.14H), 0.93-0.84 (m, 3H). 13C NMR (75 MHz,
mixture of two diastereomers, CDCl3) : 176.8 (s), 176.4 (s),
87.3 (d), 83.6 (d), 37.4 (t), 37.0 (t), 35.9 (d), 33.9 (t), 32.9 (d),
31.8 (t), 29.8 (t), 29.5 (t), 29.4 (t), 29.3 (t), 29.3 (t), 29.2 (t),
25.8 (t), 25.6 (t), 22.5 (t), 17.3 (q), 14.0 (q), 13.7 (q). MS for
the major diastereomer (EI) m/z: 254 (M+, 0.5), 236 (5), 195
(10), 194 (61), 142 (12), 110 (11), 99 (100), 98 (9), 97 (17), 96
(17), 83 (17), 82 (11), 71 (25), 70 (13), 69 (23), 68 (11), 57
(13), 55 (23). MS for the minor diastereomer (EI) m/z: 254
(M+, 0.7), 236 (5), 195 (11), 194 (66), 142 (14), 110 (15), 99
(100), 97 (22), 96 (18), 95 (11), 83 (21), 82 (12), 71 (25), 70
(16), 69 (27), 68 (12), 57 (16), 56 (13), 55 (25).
Article Identifier:
1437-2096,E;2001,0,05,0629,0633,ftx,en;G02601ST.pdf
Synlett 2001, No. 5, 629–633 ISSN 0936-5214 © Thieme Stuttgart · New York