Nucleophilic addition reactions of 1,4-diketones derived from tartaric acid: Synthesis of TADDOL analogues

Article abstract of DOI:10.1055/s-2006-942422

A systematic investigation of the reduction and Grignard reagents addition to 1,4-diketones derived from tartaric acid was carried out. It was found that the reduction proceeded with high selectivity using K-Selectride as the reducing agent; while Grignar

Full text of DOI:10.1055/s-2006-942422

PAPER
2159
Nucleophilic Addition Reactions of 1,4-Diketones Derived from Tartaric Acid:
Synthesis of TADDOL Analogues
S
ynthesis of TADD
a
O
L
A
nalo
v
gues irayani R. Prasad,* Appayee Chandrakumar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Fax +91(80)23600529; E-mail: prasad@orgchem.iisc.ernet.in
Received 19 April 2006
Respectfully dedicated to Prof. Dr. Dieter Hoppe on the occasion of his 65th birthday
Ph Ph
R
R
Ph
Abstract: A systematic investigation of the reduction and Grignard
reagents addition to 1,4-diketones derived from tartaric acid was
carried out. It was found that the reduction proceeded with high se-
lectivity using K-Selectride as the reducing agent; while Grignard
O
O
O
OH
*
*
OH
OH
OH
O
Ph Ph
Ph
reagent addition was highly dependent on structure of the dione as
well as on the Grignard reagent. The resultant 1,4-diols represent a
series of novel TADDOL analogues.
TADDOL (1)
R = H, alkyl
Figure 1 TADDOL and its analogues
Key words: asymmetric synthesis, TADDOL, stereoselective addi-
tion
MeO
O
Me
R
R
N
Nu
O
O
O
O
Nu
RMgX
OH
OH
O
O
O
O
Synthesis of biologically active compounds in enantio-
merically pure form is of pivotal importance in organic
chemistry.1 There has been a surge to develop chiral pro-
cesses based either on chiral auxiliaries or with the aid of
chiral catalysts derived from cheap chiral pool sources.2
In the context of asymmetric catalysis, TADDOL (1)
ligand developed by Seebach et al. has attracted much at-
tention.3 The varied utility and ability of TADDOL as a
catalyst in a number of asymmetric reactions established
TADDOL as one of the most privileged ligands.4 Howev-
er, many of the TADDOL ligands have limited variations
and the synthesis and structural diversity of their ana-
logues have been limited to simple variations around the
aromatic ring in the core structure.5 As a part of our pro-
gram in asymmetric catalysis, we were interested in a gen-
eral approach for the synthesis of diverse TADDOL
analogues and their possible use in asymmetric catalysis.
New feature of the proposed TADDOL analogues is the
synthesis of diastereomerically different 1,4-diols (re-
placement of one of the aryl groups of TADDOL with an
alkyl group), possessing varied sense of chirality at the
1,4-positions, keeping the inherent tartrate backbone in-
tact (Figure 1). The availability of a number of analogues
of TADDOL is expected to have application in fine tuning
of the existing catalysts.
O
R
Nu
R
N
Me
OMe
3a–h
2
3a R = Ph; 3b R = 4-MeO-C6H4; 3c R = 4-Me-C6H4
3d R = 3,4-Me-C6H3; 3e R = Me; 3f R = Et
3g R = i-Pr; 3h R = c-C6H11
Scheme 1 Synthesis of TADDOL analogues by addition of nucleo-
philes to 1,4-diketones derived from L-(+)-tartaric acid
the reduction and addition of Grignard reagents to the 1,4-
diketones leading to the synthesis of TADDOL analogues.
We initiated our study by the synthesis of 1,4-diketones
3a–h which are obtained by respective Grignard reagent
addition to the bis-Weinreb amide 2 derived from tartaric
acid.7 Reduction of the 1,4-diaryl diketones 3a–d with K-
Selectride pre-complexed with 18-C-6 proceeded with
good diastereoselectivity (dr = 91:9) affording the C2-
symmetric alcohols 4a–d as the major product. Use of K-
Selectride as the reducing agent without 18-C-6 decreased
the dr to 71:29. Reduction with other reducing agents such
as NaBH4, LiAlH4, DIBAL-H and L-Selectride lowered
the diastereomeric ratio. While the reduction of diaryl
diketones 3a–d is in acceptable diastereomeric ratios, re-
duction of 1,4-dialkyldiones 3e,f either with K-Selectride
or with L-Selectride furnished a single diastereomer of the
product alcohols 4e,f (Scheme 2, Table 1).
We reasoned that the addition of nucleophiles (hydride
and Grignard reagents) to the diketones 3a–h should pro-
duce the corresponding secondary or tertiary alcohols
(Scheme 1). In this context, we have recently disclosed a
high diastereoselective reduction of 1,4-diketones 3a–d.6
Herein, we report the detailed investigation concerning
R
R
O
O
O
O
K-Selectride
–78 °C, 4 h
OH
OH
OH
OH
K-Selectride
18-C-6, THF
–78 °C, 4.5 h
3a–f
R
R
4e–f (dr >99:1)
4a–d
SYNTHESIS 2006, No. 13, pp 2159–2166
x
x.
x
x
.
2
0
0
6
Scheme 2 Stereoselective reduction of 1,4-diketones 3a–f derived
from L-(+)-tartaric acid
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-942422; Art ID: C02806SS
© Georg Thieme Verlag Stuttgart · New York

2160
K. R. Prasad, A. Chandrakumar
PAPER
Table 1 Reduction of 1,4-Diketones Derived from L-(+)-Tartaric Acid
1,4-Diol
dr
4a
4b
4c
4d
4e
4f
91:9
86:14
89:11
91:9
>99:1
>99:1
Interestingly, reduction of diketones 3g,h possessing a
bulky isopropyl and cyclohexyl group produced the corre-
sponding hydroxy ketones 4g,h as a single diastereomer
under similar conditions (Scheme 3).
Ph
Ph
O
O
O
O
O
O
OH
O
K-Selectride
K
THF, –78 °C
98%
Ph
Ph
6
7
R
R
O
O
O
O
O
O
OH
O
K-Selectride (4 equiv)
THF
H
Ph
Ph
Ph
Ph
Ph
O
O
O
O
–78 °C, 5 h
O
O
O
M
OH
OH
OH
R
R
+
OH
3g R = i-Pr, 3h R = c-C6H11
O
4g R = i-Pr = 98%
4h R = c-C6H11 = 97%
Ph
H
M = Li, K
4a : 5a
70 : 30
proposed TS for the origin
of C1-symmetric isomer
Scheme 3 Stereoselective reduction of 1,4-diketones 3g–h
Ph
Ph
Although the diasteroemeric ratio was satisfactory in the
reduction of 1,4-diaryl diketones 3a–d, we were puzzled
by the origin of the C1-symmetric diastereomer 5a–d,
which can be attributed to the following. In the reduction
of diketones 3a–d, the reduction takes place via a step-
wise manner in which one of the keto groups of the dike-
O
O
OTBDMS
OTBDMS
OH
K-Selectride
THF, –78 °C
97%
O
O
O
Ph
8
Ph
9
single diastereomer
tone is reduced first to yield the potassium alkoxide 7, Scheme 4 Proposed transition state for the origin of the C1-symme-
tric isomer in the reduction of 1,4-diketones 3a–d
which exerts a 1,4-asymmetric control in the reduction of
the second keto group. Potassium ion being mild chelating
group has a little effect in the 1,4-chelation, thus leading
to a low amount of the C1-symmetric diol 5a–d.8 A con-
vincing insight in support of this postulate was provided
by the following experiment. Reduction of hydroxy ke-
tone 69 was performed under similar conditions that were
employed for the diketones 3a–d. It was anticipated that
the hydroxy ketone 6 should produce a single diastereo-
mer if the ketone reduction is independent of the hydroxy
group in 6 or should produce diastereomeric mixture of al-
cohols similar to that observed in the reduction of dike-
tone 3a–d if a 1,4-stereocontrol is present. Reduction of
hydroxy ketone 6 with K-Selectride produced a mixture of
alcohols in a ratio 70:30 (similar to that observed in dike-
tone reduction), clearly indicating the influence of the ini-
tially formed potassium alkoxide 7. In another
experiment, the silyloxy ketone 8 was subjected to reduc-
tion with K-Selectride. It was anticipated that the silyloxy
group being non-chelating in nature will exert no chela-
tion on the metal ion and hence reduction of the keto
group in 8 would be independent of stereogenic character
of the chiral center bearing the silyloxy group. This was
indeed the case and the reduction of 8 proceeded with very
high selectivity affording the alcohol 9 as a single diaste-
reomer (Scheme 4). This clearly shows that the initial re-
duction of the ketone 3a produces the alkoxide 7, which
forms a chelate with the carbonyl oxygen thus partially
forcing the approach of the nucleophile from the re face.
Diminishing the chelation partially by the addition of 18-
C-6 led to a considerable improvement in the diastereo-
meric ratio. The high selectivity observed in the case of
alkyl ketones perhaps is a result of less chelation and fast-
er reactivity of the alkyl ketones. No epimerization of the
chiral center adjacent to the keto group is observed in the
reduction of either alkyl or aryl diketones.
We then turned our attention to the addition of alkyl Grig-
nard reagents to diketone 3a. The results are summarized
in Table 2. It was found that the solvent and temperature
had a significant effect on the addition of alkylmagnesium
halides to diketone 3a. Thus addition of methylmagne-
sium bromide to ketone 3a resulted in the C1-symmetric
diastereomer 11 as the major product when the reaction
was performed in THF as solvent at –78 °C. Change of
solvent from THF to diethyl ether improved the selectivity
towards the formation of C2-symmetric diastereoemer 10.
A refinement of dr (84:16) was observed when the reac-
tion was performed in diethyl ether with the addition of
diphenyl ketone 3a to the Grignard reagent. A moderate
ratio of 75:25 was observed in the addition of EtMgBr in
dichloromethane (Scheme 5).
Ph
R
Ph
R
Ph
R
O
O
O
O
O
O
OH
OH
OH
OH
RMgX
3a
+
+
OH
OH
Ph
R
Ph
R
Ph
R
10
a R = Me, b R = Et, c R = i-Pr, d R = c-C6H11
11
12
Scheme 5 Addition of alkylmagnesium bromides to the diketone 3a
Synthesis 2006, No. 13, 2159–2166 © Thieme Stuttgart · New York

PAPER
Synthesis of TADDOL Analogues
2161
Table 2 Stereoselective Addition of Grignard Reagents to 4,5-Dibenzoyl-2,2-dimethyl-1,3-dioxolane (3a)
Entry
RMgX
Solvent
Temp (°C)
dr by 1H NMR
Yield (%)a
10
11
81
57
36
16
77
29
28
25
0
12
10
6
1
2
MeMgBr
MeMgBr
MeMgBr
MeMgBrb
EtMgBr
THF
THF
Et2O
Et2O
THF
Et2O
Et2O
CH2Cl2
Et2O
THF
–78
–15
0
9
37
91
84
95
94
95
93
94
92
21
54
3
64
0
4
0
84
0
5
–78
0
23
0
6
EtMgBr
71
0
7
EtMgBrb
EtMgBrb
i-PrMgBr
c-C6H11MgCl
0
72
0
8
0
75
0
9
0
100
100
0
10
0
0
0
a Refers to isolated yield of a mixture of all diastereomers.
b Addition of diphenyl ketone to Grignard reagent.
It is interesting to note that the addition of much bulkier ious conditions examined, THF was found be the best
isopropylmagnesium bromide and cyclohexylmagnesium solvent and at –78 °C the addition afforded the C2-sym-
chloride to diketone 3a resulted in the formation C2-sym- metric compound 12a as the major diastereomer (dr =
metric diastereomer 10c and 10d in 21 and 54% yields, re- 95:5, Table 4, entry 3). Addition of PhMgBr to the dike-
spectively (Table 2, entries 9 and 10). Other products 13 tone 3f lowered the dr to 75:25 in favor of the C2-symmet-
and 14 formed in the reaction are the reduction products ric diastereomer 12b. A dramatic reversal in the
arising from the b-hydride transfer of the Grignard re- selectivity was found with bulkier diketones 3g and 3h,
agent (Scheme 6 and Table 3).
where addition of PhMgBr led to the formation of C1-
symmetric diastereomers 11c and 11d respectively as the
exclusive product. All these results are summarized in
Table 4. Origin of the C1-symmetric diastereomer can be
attributed to a strong 1,4-stereoinduction similar to that
proposed for reduction (see above) forced by the bulky
substituents present in the system.
Ph
R
Ph
R
Ph R
O
O
O
O
O
O
RMgX
OH
OH
OH
OH
3a
+
+
OH
OH
0 °C–r.t.
Ph
R
Ph
13
c R = i-Pr, d R = c-C6H11
Ph
14
10
Ph
R
Ph
R
Ph
R
Scheme 6 Addition of isopropyl and cyclohexyl Grignard reagents
to 3a
O
O
O
O
O
O
PhMgBr
OH
OH
OH
OH
OH
OH
+
+
3e–h
Ph
R
Ph
R
Ph
R
Table 3 Addition of Isopropyl and Cyclohexyl Grignard Reagents
to 3a
12
11
10
a R = Me, b R = Et, c R = i-Pr, d R = c-C6H11
Entry RMgXa
Yield (%)b
Scheme 7 Addition of PhMgBr to alkyl diketones 3e–h
10
13
38
30
14
19
15
1
2
i-PrMgBr
21
54
Figure 2 summarizes some of the TADDOL analogues
prepared by the reduction and addition of Grignard re-
agents to the 1,4-diketones derived from L-(+)-tartaric ac-
id.
c-C6H11MgCl
a Four equiv of Grignard reagent was employed.
b Refers to isolated yield.
In a preliminary investigation of the prepared TADDOL
analogues in asymmetric catalysis, four representative
TADDOLs I–IV (Figure 2) were examined in enantiose-
lective vinylogous Mukaiyama aldol addition reaction of
silyldienol ethers to aldehydes reported by Rawal et al.10
It was found that TADDOL analogue I catalyzed the ad-
dition of silyldienol ether 15 to ethyl glyoxalate (16) af-
To prepare the C2-symmetric diastereomer 12 as the major
product, addition of PhMgBr to 1,4-dialkyl diketones 3e,f
was undertaken (Scheme 7). Unlike the addition of alkyl
Grignard reagents to the diaryl diketones 3a–d, addition
of PhMgBr to dialkyl diketones 3e,f was strongly depen-
dent on the temperature as well as the solvent. Of the var-
Synthesis 2006, No. 13, 2159–2166 © Thieme Stuttgart · New York

2162
K. R. Prasad, A. Chandrakumar
PAPER
Table 4 Addition of PhMgBr to 1,4-Dialkyldiketones 3e–h Derived from Tartaric Acid
Entry
R
Solvent
Temp (°C)
dr by 1H NMR
Yield (%)a
12
11
35
10
30
11
0
1
2
3
4
5
6
7
8
9
Me
Me
Me
Et
Et2O
THF
THF
Et2O
Et2O
THF
THF
THF
Et2O
0
0
35
67
95
18
40
44
75
0
84
62
89
81
87
31
57
94
95
22
5
-78
0
51
31
4
Et
-78
0
56
Et
56
0
Et
-78
0 to r.t.
0 to r.t.
25
0
i-Pr
c-C6H11
100
100
0
0
0
a Refers to isolated yield of a mixture of all diastereomers.
Ar
(Figure 2) represent a new class of analogues of TAD-
DOL ligands. Further application of these ligands in cata-
lytic asymmetric reactions is under way.
Ph Me
Ph Me
O
O
OH
OH
O
O
O
O
OH
OH
OH
OH
Ar
Ph Me
II
Ph Me
Column chromatography was performed on silica gel, Acme grade
100–200 mesh. TLC plates were visualized either with UV, in an io-
dine chamber, or with phosphomolybdic acid spray, unless other-
wise noted. Unless stated otherwise, all reagents were purchased
from commercial sources and used without additional purification.
THF was freshly distilled over Na-benzophenone ketyl. Melting
points were uncorrected. Petroleum ether used had bp range 60–80
°C. Unless stated otherwise, all the reactions were performed under
an inert atmosphere.
I
III
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
OH
OH
OH
OH
OH
OH
O
(4R,5R)-4,5-Diacyl-2,2-dimethyl-1,3-dioxolanes 3a–h;
General Procedure
IV
V
VI
Figure 2 TADDOL analogues prepared by reduction and Grignard
reagent addition to 1,4-diketones derived from tartaric acid
In an oven-dried two-neck, 100-mL, round-bottom flask equipped
with a magnetic stir bar, rubber septum, and argon inlet, was placed
(4R,5R)-N,N¢-dimethoxy-N,N¢,2,2-tetramethyl-1,3-dioxolane-4,5-
dicarboxamide (2; 0.55 g, 2.0 mmol) dissolved in THF (10 mL).
The solution was cooled to –78 °C and a THF (or Et2O) solution of
RMgX (8 mmol) was added slowly and stirred at the same temper-
ature. After the reaction was complete (disappearance of starting di-
amide was monitored by TLC), it was cautiously quenched by
addition of cold aq sat. solution of NH4Cl (10 mL). It was then
poured into H2O (15 mL) and extracted with Et2O (3 × 20 mL). The
combined Et2O extracts were washed with brine (20 mL) and dried
(Na2SO4). After removal of the solvent, the residue was purified by
silica gel column chromatography using petroleum ether and
EtOAc as an eluent to yield 3a–h.
O
O
O
O
O
OH
CO2Et
OEt
II, toluene
+
H
–78 °C, 2 h
TBSO
O
O
17
15
16
23% ee
Scheme 8 Vinylogous Mukaiyama aldol reaction catalyzed by
TADDOL analogues
fording product 17 in 10% ee, while III and IV afforded
the product with 5% ee. TADDOL analogue II yielded the
product with 23% ee (Scheme 8).
(4R,5R)-4,5-Dibenzoyl-2,2-dimethyl-1,3-dioxolane (3a)
25
Yield: 86%; mp 57–58.5 °C; [a]D –78.3 (c = 1.2, CHCl3) [Lit.5a
In summary, a systematic investigation of the nucleophilic
addition reactions to the 1,4-diketones derived from L-(+)-
tartaric acid was examined. Reduction of these diketones
proceeded with very high selectivity with Selectride as the
reducing agent. Addition of alkylmagnesium halides to
the 1,4-diaryl diketones was strongly dependent on sol-
vent, temperature, while the addition of PhMgBr on 1,4-
[a]D25 –78.4 (c = 1, CHCl3)].
IR (KBr): 3060, 2989, 1686, 1598, 1449, 1210, 1153 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.12–8.10 (m, 4 H), 7.62–7.46 (m,
6 H), 5.85 (s, 2 H), 1.43 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 196.3, 134.8, 133.8, 129.5, 128.6,
113.3, 79.0, 26.7.
dialkyl diketones derived from tartaric acid is dependent HRMS: m/z calcd for C19H18O4 + Na: 333.1103; found: 333.1098.
on alkyl group of the ketone. The diastereomeric 1,4-diols
Synthesis 2006, No. 13, 2159–2166 © Thieme Stuttgart · New York

PAPER
Synthesis of TADDOL Analogues
2163
(4R,5R)-4,5-Bis(4-methoxybenzoyl)-2,2-dimethyl-1,3-dioxo-
lane (3b)
13C NMR (75 MHz, CDCl3): d = 212.3, 112.2, 80.1, 37.1, 26.1, 18.3,
17.5.
Yield: 83%; mp 118.7–120 °C; [a]D25 –60 (c = 1.1, CHCl3).
HRMS: m/z calcd for C13H22O4 + Na: 265.1416; found: 265.1396.
IR (neat): 3066, 2988, 2936, 1678, 1599, 1511, 835, 735, 619 cm–1.
(4R,5R)-4,5-Bis(cyclohexylcarbonyl)-2,2-dimethyl-1,3-dioxo-
lane (3h)
1H NMR (300 MHz, CDCl3): d = 8.11 (d, 4 H, J = 9 Hz), 6.95 (d, 4
H, J = 9 Hz), 5.79 (s, 2 H), 3.87 (s, 6 H), 1.44 (s, 6 H).
Yield: 6%; [a]D25 +20 (c = 1, CHCl3).
13C NMR (75 MHz, CDCl3): d = 194.7, 164.0, 131.9, 127.8, 113.8,
78.8, 55.4, 26.6.
IR (neat): 2931, 2854, 1707, 1450, 1375, 1259, 1211, 1078, 860
cm–1.
Anal. Calcd for C21H22O6 (370.4): C, 68.10; H, 5.99. Found: C,
68.22; H, 6.12.
1H NMR (300 MHz, CDCl3): d = 4.72 (s, 2 H), 2.89–2.81 (m, 2 H),
1.94–1.19 (m, 20 H), 1.42 (s, 6 H).
(4R,5R)-2,2-Dimethyl-4,5-bis(4-methylbenzoyl)-1,3-dioxolane
(3c)
13C NMR (75 MHz, CDCl3): d = 211.4, 112.2, 80.1, 46.9, 28.6, 27.7,
26.2, 25.8, 25.7, 25.3.
Yield: 89%; mp 127–129 °C; [a]D25 –70 (c = 1, CHCl3).
HRMS: m/z calcd for C19H30O4 + Na: 345.2042; found: 345.2039.
IR (neat): 2986, 1680, 1603, 1321, 1284, 1144, 1091, 840, 724 cm–1.
(4S,5S)-4,5-Bis[(R)-hydroxy(aryl)methyl]-2,2-dimethyl-1,3-di-
oxolanes 4a–d; General Procedure
1H NMR (300 MHz, CDCl3): d = 8.00 (d, 4 H, J = 8.4 Hz), 7.48 (d,
4 H, J = 8.4 Hz), 5.81 (s, 2 H), 2.41 (s, 6 H), 1.42 (s, 6 H).
To a solution of 18-C-6 (793 mg, 3 mmol) in THF (5 mL) was added
K-Selectride (444.5 mg, 2 mmol, 2 mL of 1 M solution in THF) at
r.t. and the mixture was stirred for 5 min. Then, a solution of 4,5-
di(aroyl)-2,2-dimethyl-1,3-dioxolane (0.5 mmol) in THF (5 mL)
was added at –78 °C dropwise under argon. The mixture was stirred
for 4.5 h at the same temperature and quenched with aq 2 N NaOH
(2 mL) and 30% (w/v) H2O2 in H2O (1 mL). It was then allowed to
warm up to r.t. and stirred for 3 h. The suspension was filtered
through a pad of Celite and the Celite pad was washed with Et2O (20
mL). The filtrate was washed with brine and dried (Na2SO4). After
evaporation of the solvent, the residue was purified by silica gel col-
umn chromatography using petroleum ether and EtOAc as an eluent
to afford 4a–d.
13C NMR (75 MHz, CDCl3): d = 195.9, 144.8, 132.3, 129.6, 129.3,
113.2, 79.0, 26.7, 21.8.
Anal. Calcd for C21H22O4 (338.4): C, 74.54; H, 6.55. Found: C,
74.79; H, 6.68.
(4R,5R)-2,2-Dimethyl-4,5-bis(3,4-dimethylbenzoyl)-1,3-dioxo-
lane (3d)
Yield: 85%; mp 137.2–138.4 °C; [a]D25 –66.9 (c = 1.3, CHCl3).
IR (neat): 2983, 2931, 1681, 1606, 1454, 1211, 862 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.84–7.81 (m, 4 H), 7.21 (d, 2 H,
J = 7.5 Hz), 5.81 (s, 2 H), 2.30 (s, 12 H), 1.43 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 196.0, 143.4, 137.0, 132.7, 130.3,
129.8, 127.2, 113.1, 78.9, 26.7, 20.1, 19.7.
(4S,5S)-4,5-Bis[(R)-hydroxy(phenyl)methyl]-2,2-dimethyl-1,3-
dioxolane (4a)
Yield: 82%; mp 110.5–112.3 °C; [a]D25 –3.8 (c = 1.3, CHCl3).
Anal. Calcd for C23H26O4 (366.5): C, 75.38; H, 7.15. Found: C,
75.37; H, 7.03.
IR (neat): 3426, 2985, 2911, 1454, 1078, 766, 702 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.31–7.17 (m, 10 H), 4.16–4.13
(m, 4 H), 2.79 (br s, 2 H), 1.48 (s, 6 H).
(4R,5R)-4,5-Diacetyl-2,2-dimethyl-1,3-dioxolane (3e)
Yield: 93%; [a]D25 +30 (c = 1.5, CHCl3).
IR (neat): 2991, 1726, 1377, 1358, 1259, 1095, 860 cm–1.
13C NMR (75 MHz, CDCl3): d = 139.9, 128.5, 128.2, 126.6, 110.4,
81.5, 74.1, 27.5.
1H NMR (300 MHz, CDCl3): d = 4.56 (s, 2 H), 2.31 (s, 6 H), 1.44
(s, 6 H).
HRMS: m/z calcd for C19H22O4 + Na: 337.1416; found: 337.1384.
13C NMR (75 MHz, CDCl3): d = 206.5, 112.5, 81.7, 26.5, 26.1.
(4S,5S)-4,5-Bis[(R)-hydroxy(4-methoxyphenyl)methyl]-2,2-
dimethyl-1,3-dioxolane (4b)
Yield: 71%; [a]D25 +24 (c = 0.5, CHCl3).
HRMS: m/z calcd for C9H14O4 + Na: 209.0790; found: 209.0788.
(4R,5R)-2,2-Dimethyl-4,5-dipropionyl-1,3-dioxolane (3f)
Yield: 89%; [a]D25 +32 (c = 1, CHCl3).
IR (neat): 3453, 2928, 1612, 1513, 1248, 1032, 833, 621cm–1.
1H NMR (300 MHz, CDCl3): d = 7.08 (d, 4 H, J = 8.7 Hz), 6.79 (d,
4 H, J = 8.7 Hz), 4.16 (dd, 2 H, J = 3.8, 1.6 Hz), 4.07 (dd, 2 H,
J = 3.8, 1.6 Hz), 3.78 (s, 6 H), 2.74 (br s, 2 H), 1.49 (s, 6 H).
IR (neat): 2981, 2885, 1721, 1462, 1381, 1215, 1088, 1025, 977
cm–1.
1H NMR (300 MHz, CDCl3): d = 4.58 (s, 2 H), 2.82–2.57 (m, 4 H),
1.43 (s, 6 H), 1.10 (t, 6 H, J = 7.2 Hz).
13C NMR (75 MHz, CDCl3): d = 159.4, 131.9, 127.9, 113.8, 110.5,
81.8, 73.9, 55.2, 27.8.
13C NMR (75 MHz, CDCl3): d = 209.2, 112.3, 81.4, 32.4, 26.1, 7.1.
HRMS: m/z calcd for C21H26O6 + Na: 397.1627; found: 397.1604.
HRMS: m/z calcd for C11H18O4 + Na: 237.1103; found: 237.1105.
(4S,5S)-4,5-Bis[(R)-hydroxy(4-methylphenyl)methyl]-2,2-
dimethyl-1,3-dioxolane (4c)
Yield: 65%; [a]D25 +18 (c = 1, CHCl3).
(4R,5R)-4,5-Di(isobutyryl)-2,2-dimethyl-1,3-dioxolane (3g)
Yield: 17%; [a]D25 +64 (c = 0.5, CHCl3).
IR (neat): 3424, 2984, 2923, 1514, 1379, 1235, 1051, 818, 658 cm–1.
IR (neat): 2974, 2875, 1716, 1467, 1383, 1259, 1211, 1072, 864
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.11–7.04 (m, 8 H), 4.14–4.09 (m,
4 H), 2.72 (br s, 2 H), 2.32 (s, 6 H), 1.47 (s, 6 H).
1H NMR (300 MHz, CDCl3): d = 4.74 (s, 2 H), 3.12 (sept, 2 H,
J = 6.9 Hz), 1.43 (s, 6 H), 1.70 (d, 6 H, J = 6.9 Hz), 1.20 (d, 6 H,
J = 6.9 Hz).
13C NMR (75 MHz, CDCl3): d = 137.8, 136.9, 129.1, 126.5, 110.4,
81.7, 74.0, 27.6, 21.1.
HRMS: m/z calcd for C21H26O4 + Na: 365.1729; found: 365.1727.
Synthesis 2006, No. 13, 2159–2166 © Thieme Stuttgart · New York

2164
K. R. Prasad, A. Chandrakumar
PAPER
(4S,5S)-4,5-Bis[(R)-hydroxy(3,4-dimethylphenyl)methyl]-2,2-
dimethyl-1,3-dioxolane (4d)
IR (neat): 3460, 2927, 1707, 1450, 1380, 1373, 1213, 1161, 1078,
877 cm–1.
Yield: 82%; [a]D25 +25.7 (c = 0.7, CHCl3).
1H NMR (300 MHz, CDCl3): d = 4.46 (d, 1 H, J = 7.2 Hz), 4.21 (dd,
1 H, J = 7.5, 1.8 Hz), 3.32 (t, 1 H, J = 5.1 Hz), 2.93–2.84 (m, 1 H),
2.00–0.97 (m, 22 H), 1.47 (s, 3 H), 1.37 (s, 3 H).
IR (neat): 3441, 2923, 1505, 1455, 1381, 1238, 1062, 818 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.05–6.89 (m, 6 H), 4.13–4.08 (m,
4 H), 2.82 (br s, 2 H), 2.22 (s, 6 H), 2.21 (s, 6 H), 1.48 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 213.4, 110.2, 80.4, 77.6, 74.3, 46.6,
41.7, 29.2, 28.9, 28.7, 27.3, 26.7, 26.3, 26.1, 26.0, 25.9, 25.8, 25.2.
13C NMR (75 MHz, CDCl3): d = 137.3, 136.6, 136.4, 129.6, 127.7,
124.0, 110.4, 81.9, 74.1, 27.7, 19.7, 19.5.
HRMS: m/z calcd for C19H32O4 + Na: 347.2198; found: 347.2211.
HRMS: m/z for C23H30O4 + Na: 393.2042; found: 393.2066.
Addition of RMgX to (4R,5R)-4,5-Dibenzoyl-2,2-dimethyl-1,3-
dioxolane (3a); General Procedure
(4S,5S)-4,5-Bis[(R)-1-hydroxyalkyl)-2,2-dimethyl-1,3-dioxo-
lanes 4e,f and Ketones 4g,h; General Procedure
In a two-neck 100-mL, round-bottom flask equipped with a magnet-
ic stir bar, rubber septum, and argon inlet was placed 3a (0.77 g, 2.5
mmol). This was dissolved in THF (10 mL) and cooled to the tem-
perature as mentioned in the Table 2. A THF (or Et2O) solution of
RMgX (10 mmol) was added slowly and the mixture was stirred un-
til the reaction was complete (disappearance of starting diketone
was monitored by TLC). It was then cautiously quenched by addi-
tion of aq sat. cold solution of NH4Cl (10 mL). The mixture was
then poured into H2O (20 mL) and extracted with Et2O (3 × 25 mL).
The combined Et2O extracts were washed with brine (30 mL) and
dried (Na2SO4). After evaporation of the solvent, the crude residue
was subjected to silica gel column chromatography to yield a,a¢-di-
alkyl-2,2-dimethyl-a,a¢-diphenyl-1,3-dioxolane-4,5-dimethanols
10–14 listed below.
To a solution of 3e–h (1 mmol) in THF (5 mL) was added K-Selec-
tride (4 mL, 1 M solution in THF) dropwise at –78 °C over 5 min
under argon. The mixture was stirred for 4 h (for 4e,f and 5 h for
4g,h) at the same temperature and quenched with aq 2 N NaOH (2
mL) and 30% (w/v) H2O2 in H2O (1 mL). It was then allowed to
warm up to r.t. and stirred for 3 h. The suspension was filtered
through a pad of Celite and the Celite pad was washed with Et2O (20
mL). The filtrate was washed with brine and dried (Na2SO4). After
evaporation of the solvent, the residue was purified by silica gel col-
umn chromatography using petroleum ether and EtOAc as an eluent
to afford 4e–h.
(4S,5S)-4,5-Bis[(R)-1-hydroxyethyl]-2,2-dimethyl-1,3-dioxo-
lane (4e)
Yield: 92%; [a]D25 –26 (c = 0.5, CHCl3) [Lit.11 [a]D +26.1 (c = 0.44,
CHCl3) for the enantiomer].
(aS,a¢S,4R,5R)-a,a¢,2,2-Tetramethyl-a,a¢-diphenyl-1,3-dioxo-
lane-4,5-dimethanol (10a)
Yield: 76%; mp 131–133 °C [Lit.5a mp 131–133 °C]; [a]D –24.5
25
IR (neat): 3413, 2985, 1373, 1234, 1074, 1014, 883 cm–1.
(c = 2, CHCl3) [Lit.5a [a]D25 –24.6 (c = 0.618, CHCl3)].
1H NMR (300 MHz, CDCl3): d = 3.91–3.75 (m, 4 H), 2.32 (br s, 2
H), 1.44 (s, 6 H), 1.25 (d, 6 H, J = 6 Hz).
IR (KBr): 3232, 2985, 1495, 1377, 1240, 1068 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.43–7.18 (m, 10 H), 4.18 (s, 2 H),
3.76 (br s, 2 H), 1.46 (s, 6 H), 1.31 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 109.4, 81.3, 67.0, 27.4, 20.1.
13C NMR (75 MHz, CDCl3): d = 146.1, 127.9, 127.0, 125.7, 109.6,
83.4, 74.1, 27.7, 24.3.
(4S,5S)-4,5-Bis[(R)-1-hydroxypropyl]-2,2-dimethyl-1,3-dioxo-
lane (4f)
Yield: 98%; [a]D25 –16.2 (c = 0.8, CHCl3).
Anal. Calcd for C21H26O4 (342.4): C, 73.66; H, 7.65. Found: C,
73.65; H, 7.66.
IR (neat): 3460, 2967, 2933, 1460, 1379, 1241, 1072, 977, 860 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.94 (s, 2 H), 3.43 (t, 2 H, J = 6.6
Hz), 2.02 (br s, 2 H), 1.60–1.51 (m, 4 H), 1.43 (s, 6 H), 1.02 (t, 6 H,
J = 7.2 Hz).
(aS,a¢R,4R,5R)-a,a¢,2,2-Tetramethyl-a,a¢-diphenyl-1,3-dioxo-
lane-4,5-dimethanol (11a)
Yield: 15%; [a]D25 +2 (c = 2, CHCl3).
13C NMR (75 MHz, CDCl3): d = 109.2, 79.6, 71.5, 27.8, 27.3, 10.2.
IR (KBr): 3263, 2985, 1495, 1373, 1244, 1219, 1173, 1066 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.57–6.96 (m, 10 H), 4.27 (d, 1 H,
J = 7.8 Hz), 3.61 (d, 1 H, J = 7.8 Hz), 1.70 (s, 3 H), 1.63 (br s, 1 H),
1.42 (s, 3 H), 1.14 (s, 3 H), 1.26 (s, 3 H), 1.08 (s, 3 H).
HRMS: m/z calcd for C11H22O4 + Na: 241.1416; found: 241.1423.
1-{(4R, 5S)-5-[(R)-1-Hydroxy-2-methylpropyl]-2,2-dimethyl-
1,3-dioxolan-4-yl}-2-methylpropan-1-one (4g)
Yield: 98%; [a]D25 +45.5 (c = 1.8, CHCl3).
13C NMR (75 MHz, CDCl3): d = 146.2, 144.0, 128.0, 127.5, 127.2,
126.8, 126.5, 125.8, 108.6, 83.7, 83.0, 73.9, 73.8, 28.5, 27.5, 27.2,
23.6.
IR (Neat): 3514, 2935, 1712, 1469, 1383, 1215, 1076, 883 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.48 (d, 1 H, J = 7.2 Hz), 4.20 (dd,
1 H, J = 7.5, 2.1 Hz), 3.32 (br s, 1 H), 3.14 (sept, 1 H, J = 6.9 Hz),
1.91 (br s, 1 H), 1.76 (sept, 1 H, J = 6.9 Hz), 1.37 (s, 3 H), 1.26 (s,
3 H), 1.15 (d, 3 H, J = 6.9 Hz), 1.09 (d, 3 H, J = 6.9 Hz), 1.02 (d, 3
H, J = 6.9 Hz), 0.09 (d, 3 H, J = 6.9 Hz).
(aS,a¢S,4R,5R)-a,a¢-Diethyl-2,2-dimethyl-a,a¢-diphenyl-1,3-
dioxolane-4,5-dimethanol (10b)
Yield: 93% (mixture of 75:25 10b and 11b); mp 128–130 °C; [a]D
–12.8 (c = 0.7, CHCl3).
25
IR (neat): 3514, 3377, 2972, 1446, 1369, 1232 cm–1.
13C NMR (75 MHz, CDCl3): d = 214.4, 110.3, 80.5, 78.0, 75.2, 36.8,
32.2, 26.7, 26.1, 22.5, 19.1, 18.5, 17.2.
1H NMR (300 MHz, CDCl3): d = 7.23–7.16 (m, 10 H), 4.30 (s, 2 H),
2.30 (br s, 2 H), 1.83–1.69 (m, 4 H), 1.38 (s, 6 H), 0.55 (t, 6 H,
J = 7.2 Hz).
HRMS: m/z calcd for C13H24O4 + Na: 267.1572; found: 267.1573.
13C NMR (75 MHz, CDCl3): d = 142.4, 128.0, 126.8, 126.3, 110.6,
84.4, 77.4, 29.9, 28.2, 7.2.
Cyclohexyl{(4R,5S)-5-[(R)-cyclohexyl(hydroxy)methyl]-2,2-
dimethyl-1,3-dioxolan-4-yl}methanone (4h)
Yield: 85%; [a]D25 +20.8 (c = 1.2, CHCl3).
Anal. Calcd for C23H30O4 (370.4): C, 74.56; H, 8.16. Found: C,
74.82; H, 8.53.
Synthesis 2006, No. 13, 2159–2166 © Thieme Stuttgart · New York

PAPER
Synthesis of TADDOL Analogues
2165
(aS,a¢S,4R,5R)-a,a¢-Diisopropyl-2,2-dimethyl-a,a¢-diphenyl-
1,3-dioxolane-4,5-dimethanol (10c)
Hz), 2.67 (s, 1 H), 2.28–2.14 (m, 1 H), 1.45 (s, 3 H), 1.09 (s, 3 H),
0.90 (d, 3 H, J = 6.9 Hz), 0.80 (d, 3 H, J = 6.9 Hz).
Yield: 21%; mp 143.5–144.8 °C; [a]D25 –10 (c = 1.2, CHCl3).
13C NMR (75 MHz, CDCl3): d = 141.1, 139.7, 128.5, 128.2, 128.0,
127.5, 126.3, 109.5, 82.6, 80.7, 76.7, 74.2, 37.4, 27.4, 27.2, 18.3,
17.3.
IR (neat): 3567, 3058, 2969, 1444, 1366, 1241 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.06–6.92 (m, 10 H), 4.72 (s, 2 H),
2.10 (s, 2 H), 2.06 (sept, 2 H, J = 7.2 Hz), 1.49 (s, 6 H), 0.79 (d, 6
H, J = 7.2 Hz), 0.48 (d, 6 H, J = 7.2 Hz).
Anal. Calcd for C22H28O4 (356.5): C, 74.13; H, 7.92. Found: C,
74.25; H, 8.02.
13C NMR (75 MHz, CDCl3): d = 139.3, 127.2, 126.4, 126.3, 109.9,
81.9, 79.4, 36.3, 28.3, 18.2, 16.7.
(aS,a¢S,4R,5S)-a-Cyclohexyl-2,2-dimethyl-a,a¢-diphenyl-1,3-
dioxolane-4,5-dimethanol (14d)
Yield: 15%; [a]D25 –11.6 (c = 2.5, CHCl3).
Anal. Calcd for C25H34O4 (398.4): C, 75.34; H, 8.60. Found: C,
75.19; H, 8.56.
IR (neat): 3419, 2929, 2852, 1495, 1448, 1381, 1242, 1163, 1070,
877, 758, 704 cm–1.
(aS,a¢S,4R,5R)-a,a¢-Dicyclohexyl-2,2-dimethyl-a,a¢-diphenyl-
1,3-dioxolane-4,5-dimethanol (10d)
Yield: 54%; mp 212.5–213.5 °C; [a]D25 +18 (c = 0.5, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.52–7.25 (m, 10 H), 4.25 (dd, 1
H, J = 8.1, 3.9 Hz), 4.02 (d, 1 H, J = 8.1 Hz), 3.39 (d, 1 H, J = 3.9
Hz), 2.70 (s, 1 H), 2.00–0.78 (m, 11 H), 1.45 (s, 3 H), 1.09 (s, 3 H).
IR (neat): 3560, 2926, 2853, 1444, 1371, 1240, 1046, 888 cm–1.
13C NMR (75 MHz, CDCl3): d = 141.4, 139.9, 128.5, 128.2, 128.0,
127.9, 127.4, 126.3, 109.5, 82.3, 80.7, 74.3, 47.9, 27.8, 27.4, 27.3,
27.2, 26.8, 26.6, 26.4.
1H NMR (300 MHz, CDCl3): d = 7.05–6.93 (m, 10 H), 4.71 (s, 2 H),
2.11 (s, 2 H), 2.11 (s, 2 H), 1.75–1.37 (m, 4 H), 1.51 (s, 6 H), 1.19–
0.99 (m, 4 H), 0.91–0.76 (m, 4 H), 0.29–0.15 (m, 2 H).
HRMS: m/z calcd for C25H32O4 + Na: 419.2198; found: 419.2215.
13C NMR (75 MHz, CDCl3): d = 140.1, 127.3, 126.3, 126.1, 110.0,
81.6, 79.3, 46.9, 28.4, 28.1, 26.8, 26.7, 26.4, 26.3.
Addition of PhMgBr to 4,5-Diacyl-2,2-dimethyl-1,3-dioxolanes
3e–h; General Procedure
Anal. Calcd for C31H42O4 (478.7): C, 77.79; H, 8.84. Found: C,
77.75; H, 8.81.
In a two-neck 100-mL, round-bottom flask equipped with a magnet-
ic stir bar, rubber septum, and argon inlet was placed 3e–h (2
mmol). This was dissolved in THF (10 mL) and cooled to the tem-
perature as mentioned in Table 3. A THF (or Et2O) solution of Ph-
MgBr (8 mmol) was added slowly and the mixture was stirred for
the specified time. After the reaction was complete (disappearance
of starting diketone indicated by TLC), it was cautiously quenched
by addition of aq sat. cold solution of NH4Cl (10 mL) and poured
into H2O (20 mL). The mixture was extracted with Et2O (3 × 25
mL) and the combined Et2O extracts were washed with brine (30
mL) and dried (Na2SO4). After evaporation of the solvent, the crude
residue was subjected to silica gel column chromatography to yield
12a–d.
(aS,a¢R,4R,5S)-a-Isopropyl-2,2-dimethyl-a,a¢-diphenyl-1,3-
dioxolane-4,5-dimethanol (13c)
Yield: 38%; mp 126.0–128.2 °C; [a]D25 –10.7 (c = 1.4, CHCl3).
IR (neat): 3568, 2966, 2931, 1496, 1444, 1379, 1240, 1159, 1039,
748 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.53–6.76 (m, 10 H), 4.63 (d, 1 H,
J = 8.1 Hz), 3.95 (d, 1 H, J = 8.1 Hz), 3.36 (d, 1 H, J = 9.9 Hz), 2.61
(d, 1 H, J = 13.2 Hz), 2.58 (s, 1 H), 2.29–2.23 (m, 1 H), 1.51 (s, 3
H), 1.41 (s, 3 H), 0.94 (d, 3 H, J = 6.9 Hz), 0.90 (d, 3 H, J = 6.9 Hz).
13C NMR (75 MHz, CDCl3): d = 142.3, 140.1, 128.2, 128.0, 127.3,
127.1, 126.1, 125.6, 109.1, 80.8, 70.9, 38.1, 27.5, 27.4, 18.2, 17.2.
(aR,a¢R,4R,5R)-a,a¢,2,2-Tetramethyl-a,a¢-diphenyl-1,3-dioxo-
lane-4,5-dimethanol (12a)
Yield: 89%; mp 196.0–196.5 °C [Lit.5a mp 192–193 °C]; [a]D25 +46
(c = 1, CHCl3) {Lit.5a [a]D25 +46.4 (c = 0.627, CHCl3)}.
Anal. Calcd for C22H28O4 (356.5): C, 74.13; H, 7.92. Found: C,
74.20; H, 8.32.
(aS,a¢R,4R,5S)-a-Cyclohexyl-2,2-dimethyl-a,a¢-diphenyl-1,3-
dioxolane-4,5-dimethanol (13d)
Yield: 30%; mp 200–201 °C; [a]D25 +27.7 (c = 0.9, CHCl3).
IR (neat): 3294, 2985, 1595, 1371, 1216, 1071, 880, 773 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.57–7.25 (m, 10 H), 4.84–4.81
(m, 2 H), 3.48 (s, 2 H), 1.55 (s, 6 H), 1.01 (s, 6 H).
IR (neat): 3566, 2985, 2931, 1448, 1371, 1242, 1219, 1601, 1099,
1070, 1018, 987, 822, 756, 706 cm–1.
13C NMR (75 MHz, CDCl3): d = 143.3, 127.5, 127.0, 126.9, 108.3,
83.6, 74.1, 29.1, 27.0.
1H NMR (300 MHz, CDCl3): d = 7.52–7.10 (m, 8 H), 6.78–6.75 (m,
2 H), 4.64 (d, 1 H, J = 8.1 Hz), 3.94 (d, 1 H, J = 8.1 Hz), 3.39 (d, 1
H, J = 10.2 Hz), 2.60 (d, 1 H, J = 9.9 Hz), 2.58 (s, 1 H), 2.10–0.97
(m, 10 H), 1.51 (s, 3 H), 1.40 (s, 3 H), 0.84–0.70 (m, 1 H).
(aR,a¢R,4R,5R)-a,a¢-Diethyl-2,2-dimethyl-a,a¢-diphenyl-1,3-
dioxolane-4,5-dimethanol (12b)
25
Yield: 87% (75:25 mixture of 12b:11b); [a]D +29.2 (c = 1.2,
CHCl3).
13C NMR (75 MHz, CDCl3): d = 142.3, 140.3, 128.1, 128.0, 127.3,
127.0, 126.1, 125.6, 109.0, 80.8, 80.4, 76.7, 70.9, 48.7, 27.8, 27.5,
27.4, 27.3, 26.8, 26.7, 26.4.
IR (neat): 3346, 2983, 1446, 1242, 1072, 985, 887, 760 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.55–7.26 (m, 10 H), 4.15 (s, 2 H),
3.48 (s, 2 H), 2.19–2.06 (m, 2 H), 1.82–1.67 (m, 2 H), 1.05 (s, 6 H),
0.70 (t, 6 H, J = 7.2 Hz).
Anal. Calcd for C25H32O4 (396.5): C, 75.73; H, 8.13. Found: C,
75.65; H, 7.98.
(aS,a¢S,4R,5S)-a-Isopropyl-2,2-dimethyl-a,a¢-diphenyl-1,3-
dioxolane-4,5-dimethanol (14c)
Yield: 19%; mp 111–112 °C; [a]D25 –46.9 (c = 1.6, CHCl3).
13C NMR (75 MHz, CDCl3): d = 141.8, 127.5, 127.2, 126.9, 108.1,
82.3, 76.5, 33.3, 27.1, 7.0.
HRMS: m/z calcd for C23H30O4 + Na: 393.2042; found: 393.2035.
IR (neat): 3419, 2983, 2929, 1495, 1452, 1381, 1244, 1215, 1163,
1066, 1022, 895, 748, 704 cm–1.
(aR,a¢R,4R,5S)-a,a¢-Diisopropyl-2,2-dimethyl-a,a¢-diphenyl-
1,3-dioxolane-4,5-dimethanol (11c)
Yield: 94%; mp 89.7–90.3 °C; [a]D25 –10 (c = 0.8, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.53–7.01 (m, 10 H), 4.26 (dd, 1
H, J = 8.1, 4.2 Hz), 4.00 (d, 1 H, J = 8.1 Hz), 3.37 (d, 1 H, J = 4.2
Synthesis 2006, No. 13, 2159–2166 © Thieme Stuttgart · New York

2166
K. R. Prasad, A. Chandrakumar
PAPER
IR (neat): 3554, 3305, 2976, 1446, 1378, 1242, 1171, 1063, 891,
739 cm–1.
(3) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem. Int. Ed.
2001, 40, 92.
(4) Jacobsen, E. N.; Yoon, T. P. Science 2003, 299, 1691.
(5) For the synthesis of TADDOL analogues by addition of
MeMgBr and ArMgBr to the diketone 3a, see: (a) Ito, Y.
N.; Ariza, X.; Beck, A. K.; Bohac, A.; Ganter, C.; Gawley,
R. E.; Kuhnle, F. N. M.; Tuleja, J.; Wang, Y. M.; Seebach,
D. Helv. Chim. Acta 1994, 77, 2071. (b) Haase, C.; Sarko,
C. R.; DiMare, M. J. Org. Chem. 1995, 60, 1777 . A
multistep synthesis of 1,4-diol 4f from mannitol has been
reported, see: (c) Yan, Y.-Y.; RajanBabu, T. V. Org. Lett.
2000, 2, 4137. (d) Li, W.; Zhang, Z.; Xiao, D.; Zhang, X. J.
Org. Chem. 2000, 65, 3489. (e) Horita, K.; Inoue, T.;
Tanaka, K.; Yonemitsu, O. Tetrahedron 1996, 52, 531.
(6) Preliminary communication: Prasad, K. R.; Chandrakumar,
A. Tetrahedron: Asymmetry 2005, 16, 1897.
(7) (a) Nugiel, D. A.; Jakobs, K.; Worley, T.; Patel, M.;
Kaltenbach, R. F. III; Meyer, D. T.; Jadhav, P. K.; De Lucca,
G. V.; Smyser, T. E.; Klabe, R. M.; Bacheler, L. T.; Rayner,
M. M.; Seitz, S. P. J. Med. Chem. 1996, 39, 2156.
(b) McNulty, J.; Grunner, V.; Mao, J. Tetrahedron Lett.
2001, 42, 5609.
1H NMR (300 MHz, CDCl3): d = 7.34–7.19 (m, 10 H), 4.42 (d, 1 H,
J = 8.1 Hz), 3.83 (d, 1 H, J = 8.1 Hz), 2.46 (s, 1 H), 2.34–2.17 (m,
2 H), 1.44 (s, 3 H), 1.36 (s, 3 H), 1.16 (s, 1 H), 1.01 (d, 3 H, J = 6.6
Hz), 0.75 (d, 3 H, J = 6.9 Hz), 0.68 (d, 3 H, J = 7.2 Hz), 0.41 (d, 3
H, J = 6.6 Hz).
13C NMR (75 MHz, CDCl3): d = 143.3, 140.5, 128.1, 127.6, 127.2,
126.8, 126.7, 126.6, 107.0, 82.2, 80.1, 77.7, 76.8, 37.1, 36.0, 27.4,
27.1, 18.3, 17.1, 16.6, 16.3.
Anal. Calcd for C25H34O4 (398.4): C, 75.34; H, 8.60. Found: C,
75.14; H, 8.43.
(aR,a¢R,4R,5S)-a,a¢-Dicyclohexyl-2,2-dimethyl-a,a¢-diphenyl-
1,3-dioxolane-4,5-dimethanol (12d)
Yield: 95%; [a]D25 +11 (c = 2, CHCl3).
IR (neat): 3550, 2931, 2852, 1493, 1446, 1379, 1238, 1057, 891,
758, 708 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.38–7.14 (m, 10 H), 4.43 (d, 1 H,
J = 8.1 Hz), 3.84 (d, 1 H, J = 8.1 Hz), 2.37 (s, 1 H), 1.92–0.78 (m,
21 H), 1.42 (s, 3 H), 1.38 (s, 3 H), 0.42–0.30 (m, 1 H).
(8) The low selectivity (dr 4a:5a = 67:33) observed in the
reduction of diketone 3a with L-Selectride can be explained
by the chelation of lithium ion which has a propensity to
chelate to a greater extent.
(9) Synthesis of compounds 6 and 8 (Scheme 9), see also:
Prasad, K. R.; Gholap, S. L. Synlett 2005, 2260.
13C NMR (75 MHz, CDCl3): d = 143.3, 140.8, 128.2, 127.6, 127.2,
126.8, 126.7, 126.5, 107.0, 81.5, 79.8, 77.6, 48.0, 45.7, 28.1, 27.5,
27.2, 27.1, 26.8, 26.6, 26.5, 26.4, 26.3, 26.2, 26.0.
HRMS: m/z calcd for C31H42O4 + Na: 501.2981; found: 501.2969.
Ph
Ph
Acknowledgment
O
O
O
O
OTBDMS PhMgBr (2 equiv)
OTBDMS
O
We thank DST, New Delhi for funding of this project. A.C.K.
thanks CSIR for a junior research fellowship.
THF, 0 °C, 2 h
97%
O
NMe2
Ph
8
i
References
Ph
(1) (a) Nicaloau, K. C.; Sorensen, E. J. Classics in Total
Synthesis; Wiley-VCH: Weinheim, 1996. (b) Corey, E. J.;
Cheng, X.-M. Logic of Chemical Synthesis; Wiley
Interscience: New York, 1995.
O
OH
O
TBAF (2 equiv)
THF, 0 °C to r.t.
96%
O
Ph
(2) (a) Blaser, H.-U. Chem. Rev. 1992, 92, 935. (b) Blaser, H.-
U. Chem. Commun. 2003, 293. (c) Asymmetric Catalysis on
Industrial Scale. Challenges, Approaches and Solutions;
Blaser, H.-U.; Schmidt, E., Eds.; Wiley-VCH: Weinheim,
2004, 55–70. (d) Breuer, M.; Ditrich, K.; Habicher, T.;
Hauer, B.; Keßeler, M.; Sturmer, R.; Zelinski, T. Angew.
Chem. Int. Ed. 2004, 43, 788.
6
Scheme 9
(10) Vijaya, G. B.; Gravel, M.; Rawal, V. H. Org. Lett. 2005, 7,
5657.
(11) Bayer, A.; Murszat, P.; Thewalt, U.; Rieger, B. Eur. J. Inorg.
Chem. 2002, 2614.
Synthesis 2006, No. 13, 2159–2166 © Thieme Stuttgart · New York