Stereocontrolled preparation of 1,2-diol with quaternary chiral center

Article abstract of DOI:10.1016/S0040-4039(02)01946-9

Development of an enantio- and stereoselective construction of 1,2-diols including a quaternary chiral center was achieved by a titanium-mediated aldol reaction of lactates bearing chiral oxazolidine-2-ones. anti-Aldol and syn-aldol were selectively obtained by the choice of a benzyl and TBS protecting group, respectively. Plausible transition states are also shown based on the stereochemistry of the enolate anion.

Full text of DOI:10.1016/S0040-4039(02)01946-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8121–8123
Stereocontrolled preparation of 1,2-diol
with quaternary chiral center
Yoshihisa Murata, Tomoyuki Kamino, Seijiro Hosokawa and Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 12 Ichigaya-Funagawara-machi, Shinjuku-ku, Tokyo 162-0826,
Japan
Received 31 July 2002; revised 2 September 2002; accepted 6 September 2002
Abstract—Development of an enantio- and stereoselective construction of 1,2-diols including a quaternary chiral center was
achieved by a titanium-mediated aldol reaction of lactates bearing chiral oxazolidine-2-ones. anti-Aldol and syn-aldol were
selectively obtained by the choice of a benzyl and TBS protecting group, respectively. Plausible transition states are also shown
based on the stereochemistry of the enolate anion. © 2002 Elsevier Science Ltd. All rights reserved.
1,2-Diol unit including a quaternary chiral center is
seen in many natural products such as macrolide and
polyether antibiotics, and the stereocontrol of this func-
tionality is an interesting subject in organic synthesis.1
One most practical methodology is an enantioselective
dihydroxylation of substituted olefin developed by
Sharpless et al.2 High enantioselectivity is generally
attained for the preparation of a syn-diol, however,
relatively low e.e. is observed in the case of an anti-diol.
Further, stereoselective construction of the substituted
olefin is needed prior to the enantioselective dihydroxyl-
ation, and thus the development of a general and highly
stereoselective methodology is still demanded.3 We
recently reported a stereoselective aldol reaction of the
titanium enolate generated from a lactate derivative
bearing Evans’ chiral auxiliary.4 We also observed that
the stereochemical course of the aldol reaction was
found to differ depending on the protective group of
the hydroxy group as shown in Scheme 1.4,5 However,
this methodology is not suitable for the preparation of
an anti-aldol because the resulting adduct underwent a
simultaneous cyclization affording the ketocarbamate 2
which requires a forced condition for hydrolysis. In this
paper we describe an improvement of the methodology
by employing the SuperQuats6 instead of Evans’ chiral
auxiliary.
SuperQuats derivative 5 was prepared from (S)-benzyl-
oxypropionic acid and the corresponding SuperQuats
derived from L-valine. In a similar manner to the case
of 1, SuperQuats 5 was treated with LDA followed by
TiCl(O-i-Pr)3, and the resulting titanium enolate was
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01946-9

8122
Y. Murata et al. / Tetrahedron Letters 43 (2002) 8121–8123
Table 1. Preparation of (2S,3S)-diol
then reacted with crotonaldehyde. Different from the
previous case, aldol adduct 6 was isolated in 96% yield
in the present reaction, and none of the recyclized
ketocarbamate was formed.7 Stereoselectivity of the
reaction is high, affording the anti-aldol 6 and syn-
aldol 7 in a ratio of 11:1. Stereochemistry of the
anti-aldol 6 was unambiguously established by correlat-
ing to the stereochemically established acetonide 9 via
diol 8, and the minor isomer 7 was tentatively assigned
as shown in analogy to the case of Evans’ oxazolidine-
2-one 1 (Scheme 2).4 Encouraged with this result,
SuperQuats (10 and 12) were prepared from the corre-
Entry
R1
R2
Yield (%)
Selectivity
1
2
3
4
5
6
i-Pr
i-Pr
i-Pr
CH3CHꢀCH
(CH3)2CH
CH3(CH2)3CH2
96
94
85
96
94
85
11:1
\99:1
\99:1
11:1
14:1
\99:1
sponding chiral oxazolidine-2-ones derived from
phenylalanine and -phenylglycine, respectively. Then
L-
D
the titanium-mediated aldol reactions with crotonalde-
hyde, isobutyraldehyde, and hexanal were examined.
The results are summarized in Tables 1 and 2. As
shown in Tables 1 and 2, both enantiomers of the
anti-diols (2S,3S-11 and 2R,3R-13) were obtained with
excellent stereoselectivities. It should be mentioned
again that ketocarbamates were not formed by employ-
ing SuperQuats.
PhCH2 CH3CHꢀCH
PhCH2 (CH3)2CH
PhCH2 CH3(CH2)3CH2
Table 2. Preparation of (2R,3R)-diol
Although the t-butyldimethylsilyl lactate derivative
with Evans’ oxazolidine-2-one afforded the syn-aldol
without accompanying formation of undesirable keto-
carbamate (preparation of (2R,3S)-4 in Scheme 1), the
aldol reaction of the corresponding SuperQuats 14 was
also examined. As expected, syn-aldol (2S,3R)-15 was
obtained in high yield and stereoselectivity (91% yield
and >10:1 selectivity) as shown in Scheme 3.
Entry
R
Yield (%)
Selectivity
1
2
3
CH3CHꢀCH
(CH3)2CH
CH3(CH2)3CH2
85
96
93
24:1
57:1
\99:1
Thus both relative and absolute stereocontrol of the
1,2-diol with a quaternary chiral center became possible
by the choice of the protecting groups (TBS or benzyl)
and appropriate chiral oxazolidine-2-ones. Addition-
ally, it should be noted that aldol adducts were
afforded with protected tertiary alcohol.
In order to understand the stereochemical course of the
reaction, trapping of the enolate was next attempted.
The enolate anion derived from benzyl-protected
SuperQuats 12 was treated with TESCl to afford the
silyl enol ether 16 in 70% yield as a single isomer.
Stereochemistry of the E-O-enolate of 16 was deter-
mined by NOE experiment. In contrast, generation of
the Z-O-enolate from TBS-protected SuperQuats 14
Scheme 3. Preparation of (2S,3R)-diol.
Scheme 2. Reagents and conditions: (a) (i) BnOH, BuLi, THF, −20°C, 72%; (ii) LAH, THF, 71%; (b) (i) TBSCl, i-Pr2NEt, DMAP,
CH2Cl2, 70%; (ii) Li, NH3, 64%; (iii) dimethoxypropane, CSA, CH2Cl2, 91%.

Y. Murata et al. / Tetrahedron Letters 43 (2002) 8121–8123
8123
References
1. Recent Progress in the Chemical Synthesis of Antibiotics;
Lukacs, G.; Ohno, M., Eds.; Springer: Berlin, 1990.
2. Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.;
Xu, D.; Sharpless, K. B. J. Org. Chem. 1993, 58, 3785–
3786.
3. Corey, E. J.; Jardine, P. D.; Virgil, S.; Yuen, P.-W.;
Connell, R. D. J. Am. Chem. Soc. 1989, 111, 9243–9244.
4. Kamino, T.; Murata, Y.; Kawai, N.; Hosokawa, S.;
Kobayashi, S. Tetrahedron Lett. 2001, 42, 5249–5252.
5. Mukaiyama et al. also reported a similar stereocontrolled
preparation of syn- and anti-1,2-diol by choice of the
protecting group of the E-O-enolate derived from glycolic
acid. Benzyloxy derivative afforded an anti isomer through
the coordination of the benzyloxy group to a Lewis acid,
whereas the t-butyldimethylsiloxy derivative gave a syn
isomer through an extended transition state. Therefore, the
aldol reaction proceeds in a stereoselective manner regard-
less the stereochemistry of an enolate; Mukaiyama, T.;
Shiina, I.; Uchiro, H.; Kobayashi, S. Bull. Chem. Soc. Jpn.
1994, 67, 1708–1716.
Scheme 4. Trapping of enolate by silylation or alkylation.
6. Davies, S. G.; Sangnee, H. J.; Szolcsanyi, P. Tetrahedron
1999, 55, 3337–3354.
Figure 1.
7. General procedure: To a solution of LDA (prepared from
DIPA (46.7 ml, 356 mmol), and BuLi (2.6 M in hexane, 129
ml, 335 mmol) at −78°C for 15 min) was added a solution
of 5 (71.1 mg, 223 mmol) at −78°C. After stirring for 30
min at −78°C, Ti(O-i-Pr)3Cl (1.0 M in hexane, 0.89 ml,
892 mmol) was added and the resulting mixture was stirred
for 1 h at −40°C. After cooling to −78°C, crotonaldehyde
(21.6 ml, 268 mmol) was added to the mixture which was
additionally stirred at −40°C for 2 h. The reaction mixture
was quenched with satd NH4Cl and stirred with Celite for
1 h at rt. Filtration and evaporation gave a crude oil,
which was purified by column chromatography (hex-
ane:AcOEt=10:1) to yield 6 (71.1 mg, 88%) and 7 (6.4 mg,
8%). 6: Rf=0.43 (hexane:AcOEt=2:1); [h]2D3 +33.7 (c 2.11
was confirmed by NMR study of isolated 17. Thus,
NOE was observed between OMe and t-BuMe2Si.
NOE between olefinic Me and Ph was also observed
(Scheme 4).8 Although the precise mechanism is not
clear, we assume that the E-O-enolate is thermodynam-
ically favored considering an electronic repulsion
between the a-alkoxyl group and the enolate anion,
thus affording E-O-enolate 16 in the case of benzyloxy
derivative 12. On the other hand, the selective forma-
tion of Z-O-enolate 17 might be due to the serious
steric repulsion between the TBS group and the oxazo-
lidine moiety in the E-O-enolate.
1
CHCl3); H NMR (500 MHz, CDCl3): l (ppm) 0.98 (3H,
Based on these results, plausible transition states of the
present titanium-mediated aldol reaction are shown in
Fig. 1. Thus, carbonyl oxygen of the oxazolidine-2-one
coordinates to titanium, and an aldehyde approaches
from the less hindered side (opposite to the phenyl
group in 18 and 19). Both relative and stereochemical
course of the present aldol reaction could be rationally
explained by transition states 18 and 19.
d, J=7.0 Hz), 1.02 (3H, d, J=6.7 Hz), 1.32 (3H, s), 1.48
(3H, s), 1.67 (3H, dd, J=1.2, 6.4 Hz), 1.79 (3H, s),
2.12–2.16 (1H, m), 3.67 (bs, 1H), 4.26 (1H, d, J=3.7 Hz),
4.58 (1H, d, J=10.4 Hz), 4.63 (1H, d, J=10.7 Hz), 4.89
(1H, t, J=7.3 Hz), 5.62 (1H, ddd, J=1.53, 8.2, 15.4 Hz),
5.77 (1H, dq, J=6.4, 15.6 Hz), 7.26–7.41 (5H, m); 13C
NMR (100 MHz, CDCl3): l (ppm) 17.0, 17.6, 17.7, 21.2,
21.5, 28.3, 30.0, 66.3, 68.2, 74.4, 82.6, 86.6, 127.4, 127.5,
128.2, 129.5, 129.6, 138.1, 152.5, 173.0; IR (neat) 3518,
2976, 1778, 1695, 1497, 1359, 1125, 971, 735, 698; HR-
FABMS: calcd for C22H32O5N ([M−H]+) 389.2281, found
389.2286.
In conclusion, we were able to develop a general and
stereoselective route to 1,2-diols including a quaternary
chiral center. Particularly noteworthy is that all the
chiral center could be controlled by the proper choice
of a protecting group and an oxazolidin-2-one. The
present methodology could be applicable to the synthe-
sis of various biologically interesting compounds, and
further studies along this line are now in progress.
8. 16: 1H NMR (400 MHz, CDCl3) l (ppm) 0.76 (6H, q,
J=1.95 Hz), 0.88 (3H, s), 1.00 (9H, t, J=1.94 Hz), 1.48
(3H, s), 4.76 (1H, d, J=11.0 Hz), 4.81 (1H, s), 4.89 (1H, d,
J=11.0) 7.25–7.45 (10H, m); 13C NMR (100 MHz,
CDCl3) l (ppm) 4.86, 6.72, 13.15, 23.80, 27.49, 69.68,
71.02, 81.71, 127.54, 127.63, 127.75, 128.16, 128.24, 128.24,
1
128.26, 134.79, 136.46, 137.96, 155.49. 17: H NMR (400
Acknowledgements
MHz, CDCl3) l (ppm) 0.00 (3H, s), 0.12 (3H, s), 0.98 (9H,
s), 1.15 (3H, s), 1.97 (3H, s), 3.52 (3H, s), 4.85 (1H, s),
7.31–7.50 (5H, m); 13C NMR (100 MHz, CDCl3) l (ppm)
−5.21, −4.76, 17.98, 18.34, 23.69, 25.53, 27.97, 58.06,
69.00, 81.74, 127.71, 128.39, 128.58, 131.68, 134.67, 136.65,
155.88.
This work was financially supported in part by Grant-
in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology.