Stereoselective synthesis of syn,syn-2-methyl-1,3-diols through one-pot aldol-reduction sequence

Article abstract of DOI:10.1016/S0040-4039(02)01289-3

Chx₂BCl-mediated syn-aldol reaction of the α-OTBS lactate-derived ketone 1 followed by in situ reduction of the resulting boron aldolate with LiBH₄ lead to complete stereoselectivity for the boronates 2 in 80-95% yields. Then, a very

Full text of DOI:10.1016/S0040-4039(02)01289-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6145–6148
Stereoselective synthesis of syn,syn-2-methyl-1,3-diols through
one-pot aldol–reduction sequence
Marta Galobardes, Marisa Mena, Pedro Romea,* Fe`lix Urp´ı* and Jaume Vilarrasa
Departament de Qu´ımica Orga`nica, Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain
Received 17 June 2002; revised 1 July 2002; accepted 2 July 2002
Abstract—Chx2BCl-mediated syn-aldol reaction of the a-OTBS lactate-derived ketone 1 followed by in situ reduction of the
resulting boron aldolate with LiBH4 lead to complete stereoselectivity for the boronates 2 in 80–95% yields. Then, a very mild
oxidative work-up of 2 (H2O2/NaOAc in THF–H2O) allows isolation of syn,syn-2-methyl-1,3-diols 3 in yields up to 95% without
migration of the TBS group. © 2002 Elsevier Science Ltd. All rights reserved.
Stereoselective synthesis of acyclic 1,3-diols has
attracted much attention since these units are embed-
ded in the structure of a large array of polyketide
natural products. In view of the easy availability of
b-hydroxyketones, most of the strategies addressed to
the synthesis of 1,3-diols rely on a two-step process: (i)
stereoselective aldol reaction1,2 and (ii) stereoselective
We have recently disclosed that the Chx2BCl-mediated
aldol reaction of a-OTBS ketones9 affords syn aldol
adducts in excellent yields and diastereoselectivities up
to 99:1.10 Then, we envisioned that the boron aldolates
involved in this reaction might be reduced in situ to
afford the syn,syn-2-methyl-1,3-diols shown in Eq. (2)
(see Scheme 1), which would improve the scope of the
above-mentioned methodology.
reduction of the corresponding b-hydroxyketone.3–5
A
noteworthy exception is the boron mediated one-pot
anti aldol–reduction sequence developed by Paterson6,7
which, taking advantage of the structurally rigid boron
aldolate intermediate, favours the addition of the
hydride ion from an external source yielding the
anti,anti-2-methyl-1,3-diols shown in Eq. (1) (see
Scheme 1).8
In preliminary studies, we observed that aldol reaction
of (S)-2-tert-butyldimethylsilyloxy-3-pentanone (1)11
with benzaldehyde (a) followed by reduction (LiBH4) of
the resulting aldolate afforded a reaction mixture con-
taining boronate 2a. However, oxidative work-up under
the reported conditions (H2O2 in MeOH/aqueous 2.5 M
Chx Chx
BChx2
O
O
OH OH
O
O
B
Chx
O
O
see Refs. 6–7
this Letter
B
O
O
(1)
(2)
+
+
R'
R
R
R'
R
R
Chx
H
H
R'
R'
R
R'
H–
Chx Chx
B
O
O
BChx2
OH OH
R'
Chx
B
O
O
R'
Chx
R
R'
H–
Scheme 1.
Keywords: aldol reactions; asymmetric reactions; diols; stereocontrol.
* Corresponding authors. Fax: +34 93 339 78 78; e-mail: promea@qo.ub.es; furpi@qo.ub.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01289-3

6146
M. Galobardes et al. / Tetrahedron Letters 43 (2002) 6145–6148
O
NaOH 1:1) afforded non-reproducible yields and, more
1
disappointingly, a mixture (3:1 by H NMR) of two
inseparable diols, 3a and 4a.12,13
TBSO
1
Given that the TBS protecting group is prone to
migrate14 under the basic conditions used along the
overall process, we decided to carry out a careful
analysis of the reaction sequence.
a
Chx
B
O
O
First of all, boronates 2 were prepared from ketone 1
and several aldehydes (a–e) and purified by chromato-
R
TBSO
1
graphy.15,16 The yields are summarised in Table 1. H
2
NMR (500 MHz) spectra of 2 showed the presence of
just one diastereomer, which proves the high level of
stereocontrol attained in the aldol–reduction sequence.
Stereochemistry of boronates 2 depicted in Scheme 2 is
based on the known stereochemical outcome of boron-
mediated aldol reactions of ketone 110 and of related
reductions; 1H NMR spectra also support these
assignments.
b
OH OH
TBSO
HO
OH
+
R
R
TBSO
3
4
Conversion of 2 into the desired 1,3-diols was then
evaluated.
Scheme 2. Reagents and conditions: (a) i. Chx2BCl, Et3N,
Et2O; ii. RCHO; iii. Et3N, LiBH4. (b) See text and Table 2.
bases allowed isolation of 1,3-diols 3 in acceptable
yields. Given that poor solubility of 2 in MeOH/H2O
could be to some extent the reason of the aforemen-
tioned troubles, we considered the possibility of carry-
ing out this oxidation with perborate in THF/H2O 1.5:1
(method B).7a,17 Again, the basicity of the reagent pro-
duced the undesired migration of the TBS group (see
entries 2, 5, and 9 in Table 2). Eventually, it was found
that very pure syn 1,3-diols 3 can be obtained by means
of H2O2 in THF/H2O 3:1 using 2 equiv. of NaOAc
(method C).18 The results are summarised in Table 2.
According to the reported procedure, it was expected
1,3-diols 3 to be obtained in good yields by treatment
of 2 with H2O2 in MeOH/aqueous 2.5 M NaOH 1:1
(method A). In our case, these conditions produced the
partial migration of the TBS group observed in prelim-
inary experiments (see Scheme 2 and entries 1 and 8 in
Table 2). Our efforts to overcome this problem did not
afford good results: neither the use of neutral or
buffered media nor replacement of NaOH by other
Table 1. Preparation of boronates 2
Having sorted out the problems involved in the
sequence, it was worth trying to apply the optimal
conditions in a synthetically more useful procedure
which implies avoidance of the isolation of the
boronate intermediate. Therefore, reaction mixtures
obtained after the aldol–reduction process were treated
with H2O2 and NaOAc in THF/H2O. We were pleased
to obtain the desired 1,3-diols 3 in excellent yields;
however, their purification was often hampered by the
presence of non-identified impurities which presumably
Entry
Aldehyde
R
Boronate
Yield (%)a
1
2
3
4
5
a
b
c
d
e
Ph
2a
2b
2c
2d
2e
90
80
90
87
95
(E) CH3CHꢀCH
H2CꢀC(CH3)
(CH3)2CHCH2
(CH3)2CH
a Isolated yield.
Table 2. Oxidation of boronates 2
Entry
Boronate
Methoda
Time (h)
3:4
3:1
3:1
\95:5
\95:5
3:1
\95:5
\95:5
3:1
Yield (%)b
1
2
3
4
5
6
7
8
9
2a
A
B
C
C
B
C
C
A
B
C
1
12
2
80
92
95
92
67
86
90
90
95
89
2b
2c
2
12
3.5
3.5
1
12
7.5
2d
2e
5.5:1
\95:5
10
a Method A: H2O2, MeOH/2.5 M aq. NaOH (1:1). Method B: NaBO3·4H2O, THF/H2O (1.5:1). Method C: H2O2, NaOAc, THF/H2O (3:1).
b Isolated yield.

M. Galobardes et al. / Tetrahedron Letters 43 (2002) 6145–6148
6147
4048.
O
O
4. For diastereoselective reductions of b-hydroxy ketones
leading to syn 1,3-diols, see: (a) Narasaka, K.; Pai, F.-C.
Tetrahedron 1984, 40, 2233–2238; (b) Kiyooka, S.-i.;
Kuroda, H.; Shimasaki, Y. Tetrahedron Lett. 1986, 27,
3009–3012; (c) Chen, K.-M.; Hardtmann, G. E.; Prasad,
K.; Repic, O.; Shapiro, M. J. Tetrahedron Lett. 1987,
28, 155–158; (d) Evans, D. A.; Hoveyda, A. H. J. Org.
Chem. 1990, 55, 5190–5192; (e) Sarko, C. R.; Collibee,
S. E.; Knorr, A. L.; DiMare, M. J. Org. Chem. 1996,
61, 868–873; (f) Bartoli, G.; Bellucci, M. C.; Bosco, M.;
Dalpozzo, R.; Marcantoni, E.; Sambri, L. Chem. Eur. J.
2000, 6, 2590–2598.
5. For diastereoselective reductions of b-hydroxy ketones
leading to anti 1,3-diols, see: (a) Evans, D. A.; Chap-
man, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988,
110, 3560–3578; (b) Evans, D. A.; Hoveyda, A. H. J.
Am. Chem. Soc. 1990, 112, 6447–6449; (c) Keck, G. E.;
Wager, C. A.; Sell, T.; Wager, T. T. J. Org. Chem.
1999, 64, 2172–2173.
a, b
R
TBSO
Scheme 3. Reagents and conditions: (a) See Refs. 16 and 18.
(b) 2,2-Dimethoxypropane, CH2Cl2, PPTS cat.
Table 3. Protected 1,3-diols 5 from ketone 1
Entry
Aldehyde
R
Yield (%)a
1
2
3
a
c
e
Ph
65
71
55
H2CꢀC(CH3)
(CH3)2CH
a Isolated overall yield.
arise from the reductive step. Then, protection of 3 as a
cyclic acetal was undertaken in order to obtain pure
products and, also, to get more evidences about the
stereochemical outcome of the process through NMR
studies (see Scheme 3). Enantiopure acetals 5 were
finally obtained in 55–71% yield from 1 after chromato-
graphic purification (see Table 3).19
6. (a) Paterson, I.; Perkins, M. V. Tetrahedron Lett. 1992,
33, 801–804; (b) Paterson, I.; Perkins, M. V. Tetra-
hedron 1996, 52, 1811–1834.
7. For recent applications, see: (a) Nicolaou, K. C.; Mur-
phy, F.; Barluenga, S.; Ohshima, T.; Wei, H.; Xu, J.;
Gray, D. L. F.; Baudoin, O. J. Am. Chem. Soc. 2000,
122, 3830–3838; (b) Perkins, M. V.; Sampson, R. A.
Org. Lett. 2001, 3, 123–126; (c) Paterson, I.; Florence,
G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am.
Chem. Soc. 2001, 123, 9535–9544; (d) Paterson, I.; Chen,
D. Y.-K.; Franklin, A. S. Org. Lett. 2002, 4, 391–394.
8. For other reports dealing with aldol–reduction
sequences, see: (a) Bonini, C.; Rascioppi, R.; Righi, G.;
Rossi, L. Tetrahedron: Asymmetry 1994, 5, 173–176; (b)
Mahrwald, R.; Costisella, B. Synthesis 1996, 1087–1089;
(c) Bodnar, P. M.; Shaw, J. T.; Woerpel, K. A. J. Org.
Chem. 1997, 62, 5674–5675; (d) Mahrwald, R.; Ziemer,
B. Tetrahedron 1999, 55, 14005–14012; (e) Lu, L.;
Chang, H.-Y.; Fang, J.-M. J. Org. Chem. 1999, 64,
843–853; (f) Mascarenhas, C. M.; Duffey, M. O.; Liu,
S.-Y.; Morken, J. P. Org. Lett. 1999, 1, 1427–1429.
9. (a) Figueras, S.; Mart´ın, R.; Romea, P.; Urp´ı, F.; Vilar-
rasa, J. Tetrahedron Lett. 1997, 38, 1637–1640; (b)
Esteve, C.; Ferrero´, M.; Romea, P.; Urp´ı, F.; Vilarrasa,
J. Tetrahedron Lett. 1999, 40, 5079–5082.
In summary, the boron-mediated aldol reaction of the
a-OTBS ketone 1 followed by in situ reduction with
LiBH4 proceeds with an excellent stereochemical con-
trol. Oxidative treatment of the resulting boronates 2
under very mild conditions avoids the migration of the
TBS group and gives access to pure syn,syn-2-methyl-
1,3-diols. Application of this methodology to the syn-
thesis of natural products is currently in progress in our
laboratories and will be reported in due course.
Acknowledgements
Financial support from the Ministerio de Educacio´n y
Cultura (DGESIC, Grant PM98-1272) and the Gener-
(1998SGR00040
2000SGR00021) and a doctorate studentship (Universi-
tat de Barcelona) to M.G. are acknowledged.
alitat
de
Catalunya
and
10. Galobardes, M.; Gasco´n, M.; Mena, M.; Romea, P.;
Urp´ı, F.; Vilarrasa, J. Org. Lett. 2000, 2, 2599–2602.
11. Ferrero´, M.; Galobardes, M.; Mart´ın, R.; Montes, T.;
Romea, P.; Rovira, R.; Urp´ı, F.; Vilarrasa, J. Synthesis
2000, 1608–1614.
12. Structure of 4a is temptative. It has been assumed that
migration of TBS group proceeds to the closest free OH.
13. Treatment of a 3:1 mixture of 3a and 4a with HF 48%
-CH3CN for 45 min under standard deprotection con-
ditions affords a 86% of a single triol, which was
identified as (1R,2R,3S,4S)-2-methyl-1-phenyl-1,3,4-
pentanetriol.
References
1. For a review on stereoselective aldol reactions, see:
Cowden, C. J.; Paterson, I. In Organic Reactions;
Paquette, L. A., Ed.; John Wiley and Sons: New York,
1997; Vol. 51, pp. 1–200.
2. For recent developments on stereoselective catalytic
aldol reactions, see: Carreira, E. M. In Comprehensive
Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Heidelberg, 1999; Vol. 3,
pp. 997–1065.
14. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis; John Wiley and Sons: New York,
1999.
15. All new compounds have spectroscopic and analytical
data consistent with the assigned structure.
3. For a review on diastereoselective reduction of carbonyl
groups, see: Davis, A. P. In Stereoselective Synthesis,
Methods of Organic Chemistry (Houben-Weyl); Helm-
chen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,
Eds.; Thieme: Stuttgart, 1995; Vol. E21d, pp. 3988–

6148
M. Galobardes et al. / Tetrahedron Letters 43 (2002) 6145–6148
16. General procedure. To a cooled (−78°C) solution of 1 (108
mg, 0.5 mmol) in Et2O (2 mL) was added dropwise
Chx2BCl (0.16 mL, 0.75 mmol) followed by Et3N (0.14
mL, 1 mmol). The aldehyde (1 mmol) was added 2 h later
and the reaction mixture was further stirred at −78°C for
3 h and kept at −20°C overnight. It was cooled at −78°C,
Et3N (0.14 mL, 1 mmol) was added, and few minutes
later a 2 M LiBH4 solution in THF (1.25 mL, 2.5 mmol).
The reaction mixture was stirred at −78°C for 1.5 h and
quenched with NH4Cl sat (2.5 mL). Upon warming to rt
the mixture was partitioned between NH4Cl sat (5 mL)
and Et2O (3×15 mL). The organic extracts were washed
with brine (15 mL), dried (MgSO4) and concentrated in
vacuo. Isolation of boronates 2 was achieved by filtration
through a pad of silica gel (hexanes/EtOAc 95:5).
Angew. Chem., Int. Ed. 2001, 40, 3186–3188.
18. Method C. General procedure. To a cooled (0°C) mixture
of 2 (0.5 mmol) and NaOAc (82 mg, 1 mmol) in THF/
H2O 3:1 (2.5 mL) was added dropwise H2O2 30% (0.65
mL). The reaction mixture was stirred at rt, cooled at 0°C
and quenched with sat. Na2SO3 (10 mL). The mixture
was extracted with CH2Cl2 (3×15 mL) and the combined
extracts were dried (Na2SO4) and concentrated in vacuo.
Flash chromatographic purification (hexanes/EtOAc
95:5) afforded the desired diols.
Spectroscopic and analytical data of 3a: Colourless oil. Rf
(hexanes/EtOAc 95:5)=0.10. [h]D +17.1 (c 2.5, CHCl3).
IR (film): 3460 (br), 2923, 1250 cm−1 1H NMR (500
.
MHz, CDCl3) l 7.40–7.20 (5H, m; ArH), 5.01 (1H, d,
J=2.8 Hz; PhCH), 3.75 (1H, dq, J=8.1 Hz, J=6.2 Hz;
CHOTBS), 3.60 (1H, dd, J=8.1 Hz, J=2.3 Hz;
CH(OTBS)CHOH), 1.86–1.80 (1H, m; CHCH3), 1.10
(3H, d, J=6.2 Hz; CH3CHOTBS), 0.91 (9H, s;
(CH3)3CSi), 0.80 (3H, d, J=7.0 Hz; CHCH3), 0.11 (3H,
s; CH3Si), 0.10 (3H, s; CH3Si). 13C NMR (75.4 MHz,
CDCl3) l 143.3 (C), 128.0 (CH), 126.8 (CH), 126.0 (CH),
80.6 (CH), 77.9 (CH), 70.4 (CH), 40.8 (CH), 25.8 (CH3),
19.7 (CH3), 18.0 (C), 5.0 (CH3), −4.0 (CH3), −4.8 (CH3).
HRMS (+FAB): m/z calcd for C18H33O3Si [M+H]+
325.2198; found 325.2198.
Spectroscopic and analytical data of 2a: Colourless oil. Rf
(hexanes/EtOAc 95:5)=0.50. [h]D +45.4 (c 1.4, CHCl3).
IR (film): 2853 cm−1 1H NMR (500 MHz, CDCl3) l
.
7.30–7.10 (5H, m; ArH), 5.13 (1H, d, J=2.9 Hz; PhCH),
3.86 (1H, dd, J=8.5 Hz, J=2.3 Hz; TBSOCHCHO),
3.64 (1H, dq, J=8.5 Hz, J=6.2 Hz; CHOTBS), 2.10–
2.00 (1H, m; CH3CH(CHOB)2), 1.69–1.08 (11H, m;
C6H11), 1.04 (3H, d, J=6.2 Hz; CH3CHOTBS), 0.84 (9H,
s; (CH3)3CSi), 0.41 (3H, d, J=6.8 Hz; CH3CH(CHOB)2),
0.07 (3H, s; CH3Si), 0.03 (3H, s; CH3Si). 13C NMR (75.4
MHz, CDCl3) l 141.4 (C), 128.1 (CH), 126.9 (CH), 125.3
(CH), 80.7 (CH), 76.6 (CH), 70.3 (CH), 36.2 (CH), 28.4
(CH2), 28.3 (CH2), 27.5 (CH2), 27.4 (CH2), 27.0 (CH2),
25.9 (CH3), 19.5 (CH3), 18.3 (C), 4.1 (CH3), −4.4 (CH3),
−5.0 (CH3). HRMS (+FAB): m/z calcd for C24H42BO3Si
[M+H]+ 417.2996; found 417.2980.
1
19. Spectroscopic data of 5a. H NMR (500 MHz, CDCl3) l
7.40–7.20 (5H, m; ArH), 5.04 (1H, d, J=2.1 Hz; PhCH),
3.78 (1H, dd, J=8.1 Hz, J=2.1 Hz; TBSOCHCHO),
3.73 (1H, dq, J=8.1 Hz, J=6.0 Hz; CHOTBS), 1.75–
1.65 (1H, m; CHCH3), 1.52 (3H, s; CH3CO2), 1.49 (3H,
s; CH3CO2), 1.10 (3H, d, J=6.0 Hz; CH3CHOTBS), 0.89
(9H, s; (CH3)3CSi), 0.58 (3H, d, J=6.8 Hz; CHCH3),
0.08 (3H, s; CH3Si), 0.07 (3H, s; CH3Si). 13C NMR (75.4
MHz, CDCl3) l 141.0 (C), 128.0 (CH), 126.8 (CH), 125.6
(CH), 99.2 (C), 78.6 (CH), 74.7 (CH), 69.4 (CH), 35.2
(CH), 29.9 (CH3), 25.9 (CH3), 19.5 (CH3), 18.9 (CH3),
18.3 (C), 5.2 (CH3), −4.3 (CH3), −4.9 (CH3).
17. (a) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J.
Org. Chem. 1989, 54, 5930–5933; (b) Molander, G. A.;
Bobbitt, K. L. J. Org. Chem. 1994, 59, 2676–2678; (c)
Ramachandran, P. V.; Lu, Z.-H.; Brown, H. C. Tetra-
hedron Lett. 1997, 38, 761–764; (d) Martin, H. J.;
Drescher, M.; Ka¨hlig, H.; Schneider, S.; Mulzer, J.