Double and triple asymmetric induction in phosphaaldol reactions

Article abstract of DOI:10.1016/j.tetasy.2004.05.022

A multiple asymmetric induction synthesis was applied to increase the stereoselectivity of the phosphaaldol reaction. The double stereoselectivity was achieved in the reaction of chiral di(1R,2S,5R)-menthyl phosphite 3 with chiral 2,3-D-isopropyliden-(R)-glyceraldehyde 2. The reaction of aldehyde 2 with phosphite 1 in the presence of chiral (R)-ALB catalyst proceeding under stereochemical control of three chiral auxiliaries was the most stereoselective to support the conception of multiplicativity of facial selectivities of chiral reactants involved into the reaction. The stereochemistry of the phosphaaldol reaction was in agreement with Cram's rule. The absolute configuration of the new chiral compounds was established on the basis of NMR and X-ray analysis.

Full text of DOI:10.1016/j.tetasy.2004.05.022

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1961–1963
Double and triple asymmetric induction in phosphaaldol reactions
Anastasia O. Kolodiazhna,a, Valery P. Kukhar,a Alexander N. Chernegab and
Oleg I. Kolodiazhnyia,*
aInstitute of Bioorganic Chemistry, National Academy of Sciences of Ukraine, Murmanskaia Street, 1, Kiev 02094, Ukraine
bInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanskaia Street, 5, Kiev 02094, Ukraine
Received 20 April 2004; accepted 18 May 2004
Available online 24 June 2004
Dedicated in honour of Professor Przemyslaw Mastalerz on the occasion of his 80th birthday
Abstract—A multiple asymmetric induction synthesis was applied to increase the stereoselectivity of the phosphaaldol reaction. The
double stereoselectivity was achieved in the reaction of chiral di(1R,2S,5R)-menthyl phosphite 3 with chiral 2,3-D-isopropyliden-(R)-
glyceraldehyde 2. The reaction of aldehyde 2 with phosphite 1 in the presence of chiral (R)-ALB catalyst proceeding under ste-
reochemical control of three chiral auxiliaries was the most stereoselective to support the conception of multiplicativity of facial
selectivities of chiral reactants involved into the reaction. The stereochemistry of the phosphaaldol reaction was in agreement with
Cram’s rule. The absolute configuration of the new chiral compounds was established on the basis of NMR and X-ray analysis.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Stereoselectivity and stereoselective methods in organic
synthesis are a problem of fundamental importance.1
One of the more effective methods for increasing the
stereoselectivity of reactions is multiple stereoselectivity,
when the stereochemical process proceeds under the
control of more than one chiral auxiliary.2 Proceeding
with these studies, we have applied multiple asymmetric
induction to increase the stereoselectivity of a phos-
phaaldol reaction.3 Initially we were interested in the
additivity of several chiral inductors participating in the
asymmetric synthesis. With this in mind we studied
an inseparable mixture of diastereomers (1R,2R)-3a,b/
(1S,2R)-3a,b in a 45:55 ratio (Table 1). As a result we
introduced additional asymmetric centres into the
reacting system to increase the stereoselectivity of the
reaction. The chiral di(1R,2S,5R)-menthyl phosphite 1c
reacted with the chiral aldehyde 2 in the presence of
DBU with the double asymmetric induction increasing
the stereoselectivity of reaction up to de 60%. The dia-
stereomers (R,R)-3c/(S,R)-3c were easily separated by
crystallisation or column chromatography with silica
gel; a mixture of hexane–ethyl acetate in a 3:1 ratio
served as eluent. The stereoselectivity of the reaction
depended on the solvent, nature of the base and tem-
perature (Table 1).
the stereoselectivity of the reaction of 2,3-D-isopropyl-
idene-(R)-glyceraldehyde 2 with dialkyl phosphites. It
has previously been reported, that the reaction of
dimethyl phosphite with aldehyde 2 in the presence
of sodium hydroxide as catalyst, proceeded with low
stereoselectivity (ꢀ5–10% de), to give an inseparable
mixture of (2R)-glycerol diastereomers.4–6
The reaction of chiral phosphite 1c with chiral aldehyde
2 in the presence of the chiral (S)-ALB catalyst [alu-
minium–lithium bis(binaphthoxide)]7 involving three
chiral auxiliaries proceeded with high stereoselectivity
(85% de). At the same time the (R)-ALB catalyst did not
increase the stereoselectivity (55% de). Hence the highest
stereoselectivity in the phosphaaldol reaction was
achieved in the reaction involving three chiral auxilia-
ries, which reinforced one another in matched asym-
metric induction as in the case of (R)-glyceraldehyde/
(1R,2S,5R)-menthyl/(S)-binol. The stereoselectivity did
not increase, if the absolute configurations of chiral
auxiliaries were mismatched as in the case of (R)-glyc-
eraldehyde/(1R,2S,5R)-menthyl/(R)-binol.
We studied the reaction of achiral diethyl- and diiso-
propyl phosphites 1a and b with the chiral 2,3-D-iso-
propylidene-(R)-glyceraldehyde 2 in the presence of
diazabicycloundecene (DBU) and found that this reac-
tion proceeded with very low stereoselectivity to furnish
* Corresponding author. Tel.: +380-44-573-2555; fax: +380-44-573-
2552; e-mail: oikol123@bpci.kiev.ua
Kolodiazhna Anastasia is the student of the KievState University of
Taras Shevchenko.
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.05.022

1962
A. O. Kolodiazhna et al. / Tetrahedron: Asymmetry 15 (2004) 1961–1963
Table 1. Single, double and triple asymmetric induction in the phosphaaldol reaction
HO
O
HO
O
RO
RO
O
Cat
O
O
O
P
+
O
O
+
O
O
P
P
H
OR
RO
RO
OR
1a-c
2
(1R,2R)-3a-c
(a) R = Et, (b) i-Pr, (c) Mnt = (1R,2S,5R)-Menthyl
(1S,2R)-3a-c
T (ꢁC)
Entry
R
Cat
Solvent
(1R,2R)-3/(1S,2R)-3
a
a
a
1
Et
i-Pr
DBUb
DBU
DBU
20
20
45:55
45:55
20:80
25:75
20:80
26:74
28:72
35:65
30:70
5:95
2
3
Mnt
Mnt
Mnt
Mnt
Mnt
Mnt
Mnt
Mnt
Mnt
20
20
4
DBU
DBU
Toluene
Toluene
Benzene
THF
5
)10
20
6
DBU
DBU
DBU
7
20
20
8
CH2Cl2
THF
THF
9
NaOH
(S)-ALBc
(R)-ALB
20
20
10
11
THF
20
22:78
a Without solvent.
b DBU ¼ diazabicycloundecene.
c ALB ¼ Al–Li-bis(binaphthoxide).
The hydrolysis of compound 3c with dilute hydrochloric
acid at room temperature followed by deacetonisation
produced triol 4, whereas subsequent hydrolysis of 4
with concentrated hydrochloric acid in dioxane with
heating resulted in the formation of the phosphorus
analogue of threonic acid 5, representing an important
metabolite of ascorbic acid (Scheme 1).8
The absolute configurations of compounds 3–5 were
established on the basis of NMR and X-ray analysis.9–12
HO
OH
HO
P
O
HO
OH
HCl
20oC
HCl
O
O
O
O
OH
P
OH
P
80oC
MntO
OMnt
MntO
OMnt
HO
OH
(1S,2R)-(-)-3c
(1S,2R)-(-)-4
(1S,2R)-(+)-5
Scheme 1. Synthesis of phosphorus analogue of threonic acid.
Figure 1. (a) MOPAC-8 modelling of aldehyde 2; (b) Cram modelling of the reacting system; (c) a perspective view and labelling scheme for the
independent molecule a of compound 3c; (d) a perspective view and labelling scheme for the independent molecule b of the compound 3c.

A. O. Kolodiazhna et al. / Tetrahedron: Asymmetry 15 (2004) 1961–1963
1963
(CH3)2CH–Mnt); 1.1–2.2 (m, CH2+CH–Mnt); 1.33 (c);
1.40 (c, 6H, (CH3)2C), 1.62 (d, J 11.1, 2H, CH–Mnt); 2.1–
2.27 (m, CH–Mnt, 2H); 2.65 (br, J 12, 1H, OH); 4.05 (dt, J
6.6, J 10.5, OCHCH2+PCH); 4.23 (dt, J 7, JAB 6, 2H,
CH2); 4.39 (m, 2H, CH2). 31P NMR (CDCl3), dP,
20.9 ppm.
The MOPAC-8 modelling of the reaction between the
initial compounds 1 and 2 showed, that the Re-side is
strongly shielded and the Si-side is open (Fig. 1a).
Therefore the phosphaaldol reaction should lead pref-
erentially to the formation of the (S)-diastereomer,
corresponding to the anti-aldol product. Consideration
of the models of the formed products showed, that the
stereochemistry of the phosphaaldol reaction is in the
agreement with Cram’s rule (Fig. 1b).13
(1R,2R)-3 contains small quantity of the (1S,2R)-diaste-
reomer: Yield 5–15%. 31P NMR (CDCl3), dP, 20.0 ppm.
(1S,2R)-4. Yield 90%, mp 108–109 ꢁC (needles).
20
D
1
½aŠ ¼ À60 (c 2, CHCl3). H NMR (CDCl3), d, ppm (J,
Hz): 0.78 (d, J 6.9, 3H, (CH3)2C); 0.78 (d, J 6.6, 3H,
(CH3)2C); 0.89 (d, J 6.0, 6H, CH3–Mnt); 0.89 (d, J 6.6,
6H, CH3–Mnt); 1.00–1.50 (m, CH2+CH–Mnt); 1.63 (m,
2H, H–Mnt); 1.66 (m, 2H, H–Mnt); 2.13 (m, 2H, H–Mnt);
2.23 (m, 2H, H–Mnt); 2.74 (br, 3H, OH); 3.83 (m, 2H,
POCH); 3.90 (m, 1H, PCH); 4.23 (m, 2H, CH2). 31P NMR
(CDCl3), dP 22.51 ppm.
X-ray analysis confirmed the (1S,2R)-configuration of
product 3c. It was found also that in its solid state there
are two symmetrically independent molecules a and b
connected in the chains by the O(4)–HÁ Á ÁO(7) and
O(10)–HÁ Á ÁO(1) hydrogen bonds (Fig. 1c and d).
Cyclohexylammonium salt of (1S,2R)-5: Yield 65%. Mp
>200 ꢁC (dec.). 1H NMR (CD3OD), d, ppm (J, Hz): 0.90–
1.20 (m, 2H, CH2); 1.60 (m, 4H, CH2); 1.75 (m, 4H, CH2);
2.70 (m, 2H, CH2); 3.10 (s, 4H, OH); 3.40–3.60 (m, 2H,
NH+CH). 31P NMR (CD3OD), dP 18.10 ppm. Cyclohexyl-
ammonium salt of (1S,2R+1R,2R)-5: 31P NMR (CD3OD),
dP 18.1; 17.8 ppm.
Acknowledgements
Financial support for this work from State Foundation
of Basic Researches of Ukraine (Project 03.07/00047) is
gratefully acknowledged.
10. All new compounds gave satisfactory microanalytical
data. Compound 3c: Anal. Calcd for C26H49O6P: C,
63.91; H, 10.11; P, 6.34. Found: C, 63.80; H, 10.13; P,
6.20. Compound 4: Anal. Calcd for C23H45O6P: P, 6.90.
Found: P, 6.71. Compound 5: Anal. Calcd for
C9H22NO6P: N, 5.16; P, 11.42. Found: N, 5.00; P, 11.03.
11. Crystal data for (SR)-3c: C26H49O6P, colourless prism
0.22 · 0.37 · 0.49 mm from acetonitrile, monoclinic, space
References and notes
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94.78(8), V 2924 A3, M 977.3, Z 4, dcalcd ¼ 1:11 g/cm3,
l ¼ 11:1 cmÀ1, F ð000Þ 977.3. Data collection: Enraf-No-
nius CAD-4 diffractometer. Measured reflections 9112
(hmax 68ꢁ), 5484 independent (Rint 0.024). Structure solu-
tion: direct method, anisotropic refinement on F (CRYS-
TALS program). The structure was refined over 4021
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reflections on parameter). The absolute configuration of
the compound was determined according to Flack
method. The Flack parameter12 was refined to 0.04(2)
over 6563 reflections with unaveraged Friedel equivalents.
Full details (excluding the structure factors) for the
structure have been deposited at the Cambridge Crystal-
lographic Data Centre, as supplementary publication no.
CCDC-235073 and can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: (internat.) +44-1223/336-033; e-mail:
deposit@ccdc.cam.ac.ul].
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13. Ward, R. S. Selectivity in Organic Reactions; John Wiley:
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20
1
½aŠ ¼ À65 (c 2, CHCl3). H NMR (CDCl3), d, ppm (J,
D
Hz): 0.76 (d, J 7.0, 6H, CH3–Mnt); 0.87 (d, J 6.6, 12H,