Asymmetric induction through metalation of chiral dithioacetals and oxathioacetals

Article abstract of DOI:10.1080/00397910701471337

The work presented in this article consists of synthesis of chiral dithioacetals and oxathioacetals using pure chiral auxiliaries, such as, (+) camphor, (-) menthol, and L-cysteine. Metalation of these chiral dithioacetals and oxathioacetals, followed by nucleophilic addition to benzaldehyde and removal of chiral auxiliary, furnished scalemic mandelic acid with various enantiomeric purities. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701471337

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Asymmetric Induction through Metalation of
Chiral Dithioacetals and Oxathioacetals
Javid H. Zaidi a & Naseem Iqbal Gunjial a
a Department of Chemistry, Quaid‐i‐Azam University, Islamabad, Pakistan
Version of record first published: 30 Aug 2007.
To cite this article: Javid H. Zaidi & Naseem Iqbal Gunjial (2007): Asymmetric Induction through Metalation
of Chiral Dithioacetals and Oxathioacetals, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:17, 2835-2845
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Synthetic Communicationsw, 37: 2835–2845, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701471337
Asymmetric Induction through Metalation
of Chiral Dithioacetals and Oxathioacetals
Javid H. Zaidi and Naseem Iqbal Gunjial
Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan
Abstract: The work presented in this article consists of synthesis of chiral dithioacetals
and oxathioacetals using pure chiral auxiliaries, such as, (þ) camphor, (2) menthol,
and L-cysteine. Metalation of these chiral dithioacetals and oxathioacetals, followed
by nucleophilic addition to benzaldehyde and removal of chiral auxiliary, furnished
scalemic mandelic acid with various enantiomeric purities.
Keywords: dithioacetals, metalation, oxathioacetals
INTRODUCTION
Many methods of synthesizing dithioacetals and oxathioacetals are documen-
ted in literature.[1–5] However, reaction conditions often vary in convenience
and yield, and many procedures for their synthesis have resulted in optimiz-
ation problems. The use of dithioacetals as a formyl anion synthon is fairly
common in organic synthesis.[6] Thus dithioacetals and oxathioacetals with
tagged chiral auxiliaries were used for asymmetric induction via metalation
because sulfur-stabilized anions might be suitable as masked nucleophilic
acylating equivalents.[7–9]
Metalation of oxathiane tagged with chiral auxiliaries has been used for
diastereoslective synthesis of carbinols, which (after hydrolysis followed by
oxidation) yielded enantioselectively a-hydroxy carboxylic acids.
Received in India January 22, 2007
Address correspondence to Javid H. Zaidi, Department of Chemistry, Quaid-
i-Azam University, Islamabad, Pakistan. E-mail: javid_zaidi@yahoo.com
2835

2836
J. H. Zaidi and N. I. Gunjial
RESULTS AND DISCUSSION
Several chiral dithioacetals and oxathioacetals were synthesized using (þ)
camphor, (2) menthol, and L-cysteine as chiral auxiliaries. For example,
camphor 1 was converted into the thiol derivative 3, which was converted
into the chiral dithioacetals 4 and 5.[10] Similarly N-Cbz L-cysteine derivative
6 transformed into the dithioacetal derivative 7 (Scheme 1). On the other hand,
thiomethylmethylation of (2) menthol afforded the oxathioacetal 11.
Moreover, (2) menthol was converted into menthoxymethyl chloride[10]
and then reacted with the N-Cbz derivative of L-cystiene 6 to get the oxathioa-
cetal 14 (Scheme 2). Because of an undesired reactivity of the carbonyl groups
of ester functionalities of dithioacetal 7 and oxathioacetal 14 toward metala-
tion, it was appropriate to convert them into the alcohols 8 and 15 and then
protect them as the methoxymethyl ethers 9 and 16[11,12] (Schemes 1 and 2).
The dithioacetals 4, 5, and 9 and oxathioacetals 11 and 16 were metalated in
dry tetrahydofuran (THF) under nitrogen at 2788C, and the resulting anions
were quenched with benzaldehyde to afford the carbinols 17–21. After deprotec-
tion[13] and oxidation,[14] mandelic acid was isolated and scrutinized (Scheme 3).
The optical rotations of mandelic acid samples were compared with those
of commercially available (2) mandelic acid, and the enantiomeric excesses
were determined.
The values of enantiomeric excess (Table 1) show that asymmetric
induction was appreciable. It can also be observed that in the dithioacetals
and oxathioacetals, to which bulky chiral auxiliaries such as N-Cbz
Scheme 1.

Chiral Dithioacetals and Oxathioacetals
2837
Scheme 2.
Scheme 3.

2838
J. H. Zaidi and N. I. Gunjial
Table 1. Standard
S
(2) Mandelic Acid [a]2D5 ¼ 22.98
(c ¼ 1.16 g/100 cm3 MeOH)
Carbinol
Mandelic acid
[a]2D5a
Ee (%)
17
18
19
20
21
a
b
c
22.45
22.35
22.81
22.21
22.86
82%
78%
94%
74%
95%
d
e
aOptical rotation of Mandelic acid from carbinols taken in
MeOH with conc. c ¼ 1.16 g/100 cm3.
protected L-cysteine were attached, higher values of enantiomeric excess were
observed.
EXPERIMENTAL
All the reactions were carried out in anhydrous conditions and under static
pressure of nitrogen using rubber septa and three-way stopcocks. Solvents
were dried and distilled by standard methods. All the reactions were
monitored by thin-layer chomatography (TLC) on precoated silica-gel glass
plates (layer thickness 0.25 mm, HF-254, E. Merck) and detected using ultra-
violet light (lmax 254 and 365 nm). Column chomatography was performed on
E. Merck silica-gel (0.063–0.200 mm). IR spectra were recorded on a
Schimadzu Fourier transform infrared spectrophotometer model 270. The
1H NMR and 13C NMR spectra were recorded in CDCl3 on a Bru¨ker instru-
ment at a frequency of 300 MHz and 75 MHz respectively. Tetramethylsilane
(TMS) was used as internal reference. Electron impact mass spectra were
performed on a VG 70 SE mass spectrometer. The optical rotation of the
compounds was measured with Atago AP-100 automatic polarimeter.
Synthesis of Camphor Thiol (3)
(þ) Camphor was converted into thiocamphor 2, which, in turn, was reduced
to camphor thiol 3 with sodium borohydride using a reported procedure.[10]
Thiocamphor (2). Orange red solid (13.5 g, 80%). Mp 1378C (lit.[15] 136–
1388C). [a]2D5 þ2.75 (c ¼ 1.07 CHCl3); FTIR (KBr): 2960, 1450, 1410,
1390, 1360, 1300, 1260, 1210, 1130, 1090 cm21 1H NMR (300 MHz,
.
CDCl3): d 2.81–2.74 (m, 1H), 2.40 (d, J ¼ 2.1 Hz, 1H), 2.16 (t, J ¼ 4.4 Hz,
1H), 2.05–1.94 (m, 1H), 1.79–1.71 (m, 1H), 1.41–1.22 (m, 2H), 1.09
(s, 3H), 1.03 (s, 3H) 0.78 (s, 3H). 13C NMR (75 MHz, CDCl3): d 267.0

Chiral Dithioacetals and Oxathioacetals
2839
(C-2), 69.3 (C-1), 55.5 (C-3), 48.9 (C-4), 145.1 (C-5), 33.9 (C-6), 26.2 (C-5),
21.7 (C-8), 19.8 (C-9), 13.1 (C-10); EIMS (m/z, % rel. abund.): 168 (Mþ,
100), 153 (35), 125 (55), 113 (60), 93 (15), 85 (52), 79 (76), 69 (45). Anal.
calcd. for C10H16S: C, 71.36; H, 9.58. Found: C, 71.40; H, 9.56.
Camphor thiol (3). White solid (5.6 g, 92%). Mp 2208C; [a]2D5 þ 0.83
(c ¼ 0.32 CHCl3); IR (KBr) 2950, 2890, 2720, 2590, 1500, 1390,
1
1110 cm21. H NMR (300 MHz, CDCl3): d 2.94–2.84 (m, 1H), 2.02–1.94
(m, 2H), 1.73–1.60 (m, 3H), 1.28–1.11 (m, 2H), 1.02 (s, 3H), 0.89 (s, 3H)
0.805 (s, 3H). 13C NMR (75 MHz, CDCl3): d 48.8 (C), 46.3 (C), 42.9 (CH),
44.2 (CH), 35.2 (CH2), 31.6 (CH2), 27.5 (CH2), 20.8 (CH3), 18.7 (CH3),
13.7 (CH3). EIMS (m/z, % rel. abund.): 170 (Mþ, 15%), 155 (34), 137
(56), 121 (55), 107 (68), 93 (100), 81 (10). Anal. calcd. for C10H18S:
C, 70.52; H, 10.65. Found: C, 70.46; H, 10.68.
Synthesis of Dithioacetal (4) from Camphor Thiol
To a mixture of a solution of 3 (4.0 g, 23.5 mmol) in dry benzene (150 mL)
and excess paraformaldehyde (8.0 g), p-toluenesulphonic acid (100 mg) was
added as a catalyst. The reaction mixture was subjected to azeotropic distilla-
tion under static pressure of nitrogen. The reaction mixture was cooled to
room temperature, and excess of benzene was removed. The residue was
dissolved in ether; washed with saturated solution of NaHCO3, water, and
brine, and dried (MgSO4). The organic layer was evaporated to give a
residue, which was purified on silica-gel column chomatography using
n-hexane as an eluent to give 4 (3.2 g 73%). Mp 1688C. [a]2D5þ0.74
1
(c ¼ 0.25 CHCl3). IR (KBr): 2945, 1640, 1260 cm21. H NMR (300 MHz,
CDCl3): d 3.15 (s, 2H), 2.94–2.89 (m, 2H), 1.93–1.82 (m, 3H), 1.70–1.63
(m, 5H), 1.27–1.13 (m, 4H), 0.98 (s, 6H), 0.95 (s, 6H), 0.94–084
(m, 2H), 0.82 (s, 6H).13C NMR (75 MHz, CDCl3): d 52.2 (C-1/C-10), 49.4
(C-2/C-20), 45.3 (C-7/C-70), 42.9 (C-4/40), 35.5 (C-3/30), 33.6 (CH2), 33.0
(C-7/70), 28.0 (C-8/80), 23.4 (2CH3), 21.1 (2CH3), 13.6 (2CH3); EIMS
(m/z, % rel. abund.): 352 (Mþ, 15) 155 (34), 137 (56), 121 (55), 107 (68),
93 (100), 81 (10). Anal. calcd. for C21H36S2: C, 71.52; H, 10.29. Found:
C, 71.50; H, 10.30.
Synthesis of Dithioacetal (5) from Chloromethyl Methyl Suldide
To compound 4 (2 g, 11.9 mmol) in dry chloroform (75 mL) under nitrogen
under reflux, triethylamine (8.3 mL, 60 mmol) and chloromethyl methylsul-
fide (10.61 mL, 60 mmol) were added. After 8 h, the reaction mixture was
diluted with chloroform, washed sequentially with water and brine, dried
(MgSO4), and concentrated. The residue was purified on silica-gel using

2840
J. H. Zaidi and N. I. Gunjial
n-hexane as eluent to afford product 5 as colorless oil (1.8 g, 71%).
[a]2D5 þ 1.33 (c ¼ 0.72 CHCl3). FTIR (NaCl): 2945, 1459, 1364, 1271,
1027 cm21 1H NMR (300 MHz, CDCl3): d 3.60 (s, 2H), 2.94–2.84
.
(m, 1H), 2.15 (s, 3H), 1.95–1.57 (m, 3H), 1.26–1.12 (m, 2H), 0.98 (s, 3H),
0.95 (s, 3H), 0.90–0.88 (m, 2H). 0.82 (s, 3H). 13C NMR (75 MHz, CDCl3):
d 50.7 (C-2), 49.6 (C-1), 45.3 (C-7), 44.0 (C-5), 36.9 (SCH2), 35.0 (C-6),
33.0 (C-3), 26.6 (C-4), 21.4 (CH3), 19.4 (CH3). 14.2 (SCH3), 12.6 (CH3).
EIMS (m/z, % rel. abund.): 230 (Mþ, 16), 216 (43), 184 (58), 170 (66),
138 (100), 123 (12), 93 (44), 79 (24), 65 (8). Anal. calcd. for C12H22S2: C,
62.55; H, 9.62. Found: C, 62.66; H; 9.57.
Synthesis of Dithioacetal of N-Cbz-Protected Methyl Ester of
L-Cystiene (9)
The dithioacetal 7 was prepared according to the same procedure as described
for 4. Colorless oil (4.5 g, 72%). [a]2D5 þ1.80 (c ¼ 0.70 CHCl3,). FTIR (NaCl
cm21): 3400, 1750, 1711. 1H NMR (CDCl3, 300 MHz): d 7.27–7.38
(m, 10H), 5.2 (s, 2H), 4.65–4.83 (m, 2H), 3.78 (s, 6H), 3.66 (s, 2H), 3.21–
3.38 (m, 4H), 13C NMR (CDCl3, 75 MHz): d 171.6 (CO), 153.78 (CONH),
136.02 (Ar), 128.6–128.57 (Ar), 67.80 (CH2O), 61.98 (CHNH), 52.81
(OCH3), 48.04 (SCH2S), 33.24 (SCH2). EIMS (m/z, % rel. abund.): 550
(Mþ, 5), 178 (10), 147 (4), 146 (50), 91 (100), 77 (7), 65 (29), 51 (8). Anal.
calcd. for C25H30N2O8S2: C, 54.5; H, 5.4; N, 5.09. Found: C, 53.50; H,
5.30; N, 5.02.
The dithioacetal 7 (4.0 g, 7.2 mmol) was dissolved in dry THF
(100 mL) under nitrogen and cooled to 08C. The solution of diisobutyl-
aluminium hydride (DIBAL) in n-hexane (56 mL, 56.64 mmol) was
added dropwise. The reaction mixture was heated under reflux for 3 h,
quenched with saturated solution of NaF, and repeatedly extracted with
ethyl acetate. The combined organic layers were washed with water and
brine and dried over MgSO4. The solvent was evaporated, and the crude
product was purified on a silica-gel column with 10% ethyl acetate in
petroleum ether to afford
a
colorless oil (2.5 g, 70%). [a]D25
1
þ2.54(c ¼ 0.99 CHCl3,). FTIR (NaCl cm21): 3437, 3400, 1699. H NMR
(CDCl3, 300 MHz): d 7.32–7.38 (m, 10H), 5.16 (s, 4H), 4.64–4.67
(m, 2H), 4.32–4.35 (d, J ¼ 4.9 Hz, 4H), 3.71–3.78 (m, 4H), 2.98–3.17
(m, 4H). 13C NMR (CDCl3, 75 MHz); d 154.9 (CO), 135.99 (Ar),
128.63–128.10 (Ar), 67.78 (CH2O), 63.56 (CH2OH), 62.28 (CHNH),
48.05 (SCH2S), 32.61 (SCH2). EIMS (m/z, % rel. abund.): 494 (Mþ, 3),
222 (3), 178 (4), 145 (5), 91 (100), 77 (7), 65 (28). Anal. calcd. for
C23H30N2O6S2: C, 55.8; H, 6.07; N, 5.6. Found: C, 55.1; H, 6.30; N, 4.9.
The alcoholic group of 8 was protected with methoxymethyl chloride[12]
to afford compound 9 as a colorless oil (1.76 g, 75%). [a]2D5 þ4.25 (c ¼ 2.23
CHCl3,) FTIR (NaCl cm21): 1750. 1H NMR (CDCl3, 300 MHz): d 7.63–7.47

Chiral Dithioacetals and Oxathioacetals
2841
(m, 10H), 5.37 (d, J ¼ 6 Hz, 4H), 5.24 (s, 4H), 4.71–4.67 (m, 2H), 4.29–4.22
(m, J ¼ 3 Hz, 4H), 3.48 (s 2H), 3.38 (s, 3H) 2.98–3.17 (m, 4H), 13C NMR
(CDCl3, 75 MHz): d 156.1 (CO), 137.62 (Ar), 128.80–128.27 (Ar), 97.34
(OCH2O), 68.78 (CH2O), 62.16 (CH2O), 60.28 (CHNH), 55.23 (OCH3),
49.05 (SCH2S), 32.91 (SCH2). EIMS (m/z, % rel. abund.): 582 (Mþ, 6),
405 (5), 390 (8), 355 (4), 303 (6), 221 (6), 147 (15), 111 (10), 77 (15), 69
(72), 57 (100), 55 (63). Anal. calcd. for C27H38N2O8S2: C, 55.6; H, 6.5;
N, 4.8. Found: C, 55.50; H, 6.15; N, 4.5.
Synthesis of Oxathioacetal (11) with Chloromethyl Methyl Suldide
The oxathioacetal 11 was synthesized by the same procedure as for 5 and
obtained as white crystalline solid (3.4 g, 70%). Mp 478C: [a]2D5 þ 4.74
1
(c ¼ 1.85 CDCl3), FTIR (KBr cm21): 2959. H NMR (300 MHz, CDCl3): d
4.82 (s, 2H), 3.31–3.23 (m, 1H), 2.19 (s, 3H), 2.21–2.24 (m, 1H) 2.14–
2.16 (m, 1H), 1.61–1.67 (m, 2H), 1.30–1.44 (m, 4H), 0.94 (d, J ¼ 6.5 Hz
6H), 0.834 (d, J ¼ 7 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 72.3 (OCH2),
79.1 (OCH), 48.6 (CH), 42.4 (CH), 34.3 (CH2), 31.4 (CH2), 25.3 (CH), 23.1
(CH2), 21.3 (CH3), 21.2 (CH3), 14.12 (CH3). EIMS (m/z, % rel. abund.):
216 (Mþ, 11), 185 (3), 138 (44), 83 (100), 69 (42), 57 (40), 55 (65). Anal.
calcd. for C12H24SO: C, 66.6; H, 11.1. Found: C, 65.8; H, 10.57.
Synthesis of Acetal of (2) Menthol (12)
Compound 12 was prepared using a reported procedure[10] as a white crystal-
1
line solid (5.2 g, 80%). Mp 588C. [a]2D5 26.4 (c ¼ 0.2 CHCl3). H NMR
(300 MHz CDCl3) d 4.75 (s, 2H), 3.25–3.16 (m, 2H), 2.18–2.06 (m, 4H),
1.61–0.75 (m, 14H), 0.852 (d, J ¼ 7 Hz 6H), 0.841 (d, J ¼ 7 Hz, 6H),
0.706 (d, J ¼ 7 Hz, 6H). 13C NMR (75 MHz, CDCl3): d 95.29 (OCH2),
79.1 (C-1/C-10), 48.6 (C-2/C-20), 42.4 (C-6/C-60), 34.4 (C-4/C-40), 31.6
(2C), 25.3 (C-5/C-50). 23.1 (CH3), 21.2 (2CH3), 16.1 (2CH3). EIMS (m/z,
% rel. abund.): 324 (Mþ, 31), 309 (13), 294 (18), 266 (7), 238 (22), 186
(56), 170 (19), 156 (100), 140 (68). Anal. calcd. for C21H40O2: C, 77.72; H,
12.42. Found: C, 77.60; H, 12.54.
Synthesis of Menthoxymethyl Chloride (13)
Freshly distilled acetyl chloride (0.88 mL, 12.06 mmol) was added dropwise to
a mixture of 12 (3.5 g, 10.8 mmol) and 2–3 drops of dry methanol at room
temperature under nitrogen. The reaction mixture was allowed to stand at
room temperature for 36 h. Compound 13 was ready to use without purification.

2842
J. H. Zaidi and N. I. Gunjial
Synthesis of Oxathioacetal of N-cbz-Protected Methyl Ester of
L-Cysteine with Menthol (16)
The oxathioacetal 14 was synthesized by reacting N-Cbz L-cysteine 6 with
[10]
13.
White crystalline solid (4.5 g, 70%). Mp 1078C. [a]2D5 22.38
(c ¼ 0.58 CHCl3); FTIR (KBr cm21): 3355, 1751, and 1690. 1H NMR
(300 MHz, CDCl3): d 7.34–7.24 (m, 5H), 6.13 (bd, J ¼ 8.1 Hz, 1H), 5.1
(s, 2H), 4.68–4.60 (m, 3H), 3.73 (s, 3H), 3.33–3.24 (m, 1H), 3.13 (dd,
J ¼ 14 Hz and 5.5 Hz, 1H), 3.0 (dd, J ¼ 14 Hz and 5.5 Hz 1H), 2.14–2.04
(m, 2H), 1.64–1.55 (m, 2H), 1.25–0.817 (m, 5H), 0.88 (d, J ¼ 7.1 Hz, 6H)
0.74 (d, J ¼ 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 169.1 (CO), 167.0
(CONH), 132.8 (C-1, Ar), 130.6 (C-4, Ar), 129.0 (C-2/C-6), 126.9 (C-3/C-
5), 75.9 (C-100), 56.8 (CH), 50.4 (OCH3), 48.2 (CH, C-20), 36.0 (CH2), 34.7
(CH, C-5), 34.0 (CH2S), 33.8 (CH2), 28.0 [CH(CH3)2], 26.7 (CH2), 20.6
(CH3) 18.0 (CH3), 17.0 (CH3). EIMS (m/z, % rel. abund.): 393 (Mþ, 23),
334 (27), 316 (48), 288 (68), 267 (29), 77 (100). Anal. calcd. for
C21H33NO5S: C, 61.3; H, 8.02; N, 3.4. Found C, 61.15; H, 7.88; N, 3.3.
The compound 15 was synthesized by reduction and protection as
described for synthesis of compound 9. Yellow oil (2.3 g, 74%). [a]D25
22.79 (c ¼ 1.30 CHCl3,) FTIR (NaCl cm21): 3331, 1724. 1H NMR
(300 MHz, CDCl3) d 7.38–7.34 (m, 5H), 5.54 (bd, 2H) 5.13 (s, 2H), 4.71–
4.70 (d, 2H), 4.66–4.62 (m, 1H), 3.76 (dd, 2H), 3.59 (dd, 2H), 3.36 (s, 3H),
2.92–2.87 (m, 1H), 2.1–2.19 (m, 1H), 1.65–1.59 (m, 2H), 1.41–1.27
(m, 5H), 0.89 (d, J ¼ 7.2 Hz, 6H), 0.79 (d, J ¼ 6.9 Hz, 3H). EIMS (m/z, %
rel. abund.): 453 (Mþ, 9), 253 (4), 238 (3), 139 (5), 108 (8), 91 (100), 83
(36), 69 (13), 57 (15), 55 (25). Anal. calcd. for C22H37NO5S: C, 61.8; H,
8.6; N, 3.2. Found: C, 61.50; H, 8.15; N, 3.1.
General Procedure for Metalation of Dithioacetals
A solution of dithioacetal (2 mmol) in anhydrous THF (20 mL) was cooled to
2788C under nitrogen and treated with a solution of n-butyllithium (2.5 M
solution in hexane) (2.4 mmol). After stirring for 2 h at 2788C the reaction
mixture was warmed to 2258C and quenched with benzaldehyde (4 mmol)
dropwise. After 8 h, it was diluted with water (50 mL) and extracted with
ethyl acetate. The organic layers were washed sequentially with water and
brine and dried (MgSO4). The product was purified on a silica-gel column
using ethyl acetate–hexane mixtures as eluent to afford pure carbinols.
Carbinol (17). Yellow oil (0.84 g, 65%). [a]2D5 þ 0.85 (c ¼ 0.45 CHCl3).
FTIR (NaCl): 3429, 2945, 1459, 1364, 1271, 1027 cm21 1H NMR
.
(300 MHz, CDCl3): d 7.39–7.28 (m, 5H), 4.70 (d, J ¼ 4.5 Hz, 1H), 4.68
(d, J ¼ 4.7 Hz, 1H), 4.10 (d, J ¼ 4.1 Hz, 1H), 4.06 (d, J ¼ 3.7 Hz, 1H),
2.99–2.86 (m, 2H), 2.64–2.59 (m, 4H), 1.45–1.42 (m, 4H), 1.36–1.31

Chiral Dithioacetals and Oxathioacetals
2843
(m, 2H), 1.28–1.27 (m, 4H), 0.93 (s, 6H), 0.91 (s, 6H), 0.88 (s, 6H). 13C NMR
(75 MHz, CDCl3): d 140.88 (Ar0), 127–128 (Ar), 65.35 (CHOH), 36.53 (CH),
34.53 (C), 33.84 (CH), 33.95 (CH), 30.32 (CH2), 29.72 (CH2), 29.29, (CH2),
28.65 (CH3), 25.93 (CH3). Anal. calcd. for C28H41OS2: C, 73.3, H, 9.1. Found:
C, 72.50; H, 9.30.
Carbinol (18). Yellow viscous oil (0.52 g, 69%). [a]2D5 þ 1.95 (c ¼ 0.76
1
CHCl3). IR (NaCl): 3407, 2927, 1451, 1380, 1260, 1081, 1028 cm21. H
NMR (300 MHz, CDCl3): d 7.42–7.26 (m, 5H), 4.79 (d, J ¼ 4.4 Hz, 1H),
4.75 (d, J ¼ 4.1 Hz, 1H), 3.86 (d, J ¼ 3.5 Hz, 1H), 3.84 (d, J ¼ 3.9 Hz,
1H), 2.67–2.90 (m, 1H), 2.10 (s, 3H), 2.02 (d, J ¼ 3 Hz, 2H), 1.36–1.21
(m, 2H), 0.98 (s, 3H), 0.95 (s, 3H), 0.87–0.84 (m, 2H), 0.81 (s, 3H). 13C
NMR (75 MHz, CDCl3): d 142.38, 127–128, 68.39, 37.73, 35.63, 33.94,
33.65, 31.32, 30.10, 30.2, 26.42, 24.23, 18.3. Anal. calcd. for C19H27OS2:
C, 67.8; H, 8.3. Found: C, 67.50; H, 8.1.
Carbinol (19.) Yellow oil (0.34 g, 58%).[a]2D5 þ 3.14 (c ¼ 1.22 CHCl3), FTIR
(NaCl cm21): 3402, 3345. 1H NMR (CDCl3, 75 MHz): d 7.45–7.27 (m, 15H),
5.51 (d, J ¼ 4.5 Hz, 4H), 5.16 (s, 4H), 4.89 (d, J ¼ 7.3 Hz, 1H), 4.87
(d, J ¼ 7.9 Hz, 1H), 4.71 (d, J ¼ 3.9 Hz, 1H) 4.70 (d, J ¼ 3.4 Hz, 1H),
4.64–4.55 (m, 2H), 4.33–4.28 (d, J ¼ 6.6 Hz, 4H), 3.49 (s, 3H), 3.05–3.18
(m, 4H), 13C NMR (CDCl3. 75 MHz): d 158.2 (CO), 142.1 (Ar), 128.8–
128.2 (Ar), 98.3 (OCH2O), 78.7 (CHOH) 68.7 (CH2O), 64.3 (CH2O), 59.8
(CHNH), 57.6 (SCHS), 55.2 (OCH3), 32.8 (SCH2). Anal. calcd. for
C34H44N2O9S2: C, 59.3; H, 6.3; N, 4.06. Found: C, 59.50; H, 6.15; N, 4.5.
General Procedure for Metalation of Oxathioacetals
Oxathioacetal (2.31 mmol) solution in (15 mL) dry THF was treated with
n-butyllithium (2.5 M solution in hexane, 2.4 mmol) at 2788C under
nitrogen, allowed to warm to 08C, and then immediately recooled to
2788C. Benzaldehyde (6.46 mmol) was then added dropwise. After 2 h of
stirring at 2788C, the reaction mixture was allowed to stand overnight at
2258C. It was diluted with a saturated solution of NH4Cl (20 mL),
extracted with ethyl acetate, washed with water and brine, and dried
(MgSO4). The product was purified on a silica-gel column by eluting with
8% ethyl acetate in n-hexane.
Carbinol (20). colorless oil (0.51 g, 69%). [a]2D5 2 4.75 (c ¼ 0.67 CHCl3);
FTIR (NaCl cm21): 3386, 1H NMR (300 MHz, CDCl3) d 7.39 2 7.27
(m, 5H), 4.82 (d, 1H, J ¼ 4.3 Hz), 4.79 (d, 1H, J ¼ 3.9 Hz), 4.69 (d, 1H,
J ¼ 3.7 Hz), 4.65 (d, 1H, J ¼ 3.5 Hz), 3.31 2 3.23 (m, 1H), 2.19 (s, 3H),
2.21 2 2.24 (m, 1H), 2.14 2 2.16 (m, 1H), 1.61 2 1.67 (m, 2H),
1.30 2 1.44 (m, 4H), 0.94 (d, J ¼ 6.5 Hz 6H), 0.834 (d, J ¼ 7 Hz, 3H). 13C

2844
J. H. Zaidi and N. I. Gunjial
NMR (75 MHz, CDCl3): d 135.4 (Ar), 126–129 (Ar), 95.9 (OCHS), 81.5
(CHO), 76.7 (CHOH), 47.2 (CH), 41.9 (CH), 32.3 (CH2), 31.9 (CH2), 27.3
(CH), 23.9 (CH2), 21.6 (CH3), 20.2 (CH3), 16.1 (CH3). Anal. calcd. for
C19H30O2S: C, 70.8; H, 9.3. Found: C, 69.50; H, 9.1.
Carbinol (21). Colorless oil (0.38 g, 62%) [a]2D5 2 0.43(c ¼ 0.22 CHCl3).
FTIR (NaCl cm21): 3442, 3329, 1719. 1H NMR (300 MHz, CDCl3) d
7.55–7.21 (m, 10H), 5.66 (bd, 2H), 5.12 (s, 2H), 4.88 (d, 1H, 6.5 Hz), 4.85
(d, 1H, 6.8 Hz), 4.72 (d, 1H, 4.2 Hz), 4.70 (d, 1H, 3.9 Hz), 4.64–4.61
(m, 1H), 3.86 (dd, 2H), 3.75 (dd, 2H), 3.35 (s, 3H), 2.90–2.82 (m, 1H),
2.19–2.02 (m, 1H), 1.69–1.58 (m, 2H), 1.39–1.31 (m, 5H), 0.91
(d, J ¼ 6.9 Hz, 6H), 0.85 (d, J ¼ 7.2 Hz, 3H). Anal. calcd. for
C29H42NO6S: C, 65.4; H, 7.8; N, 2.6. Found: C, 65.3; H, 7.1; N, 2.5.
General Procedure for Synthesis of Samples of Mandelic Acids from
Carbinols (17–21)
Solution of carbinol (1.0 mmol) in acetone (10 mL) was added to N-bromo-
succinimide (8 mmol) in 90–97% aqueous acetone (25 mL) at 258C. The
reaction mixture quickly turned red (bromine) but soon faded to a yellow
orange color, was stirred for 5–10 min, and was then shaken with a mixture
of saturated aqueous sodium sulphite and 1:1 dichloromethane. The organic
phase was sequentially washed with 1.0 M aqueous sodium bicarbonate,
water, and brine and dried (MgSO4).
The a-hydroxy aldehyde (1 mmol) thus obtained was oxidized to
mandelic acid by dissolving it in t-butylalcohol (10 mL) and treatment with
5% aqueous solution of KH2PO4 (3.4 mL) and 1M aqueous solution of
KMnO4 (5 mL). After 45 min, the reaction was quenched with a saturated
aqueous solution of Na2SO3. The pH of the solution was brought to 5 by
adding 4N HCl solution dropwise. The product was extracted with ethyl
acetate. The product was washed with de-ionized water and brine and dried
(MgSO4) to yield enantiomerically enriched mandelic acid as a white crystal-
line solid.
Samples of synthesized mandelic acids (a, b, c, d, e). Mp 127–1298C
1
(lit.[15] 1318C). IR (NaCl cm21): 3420–2635 (O-H), 1714 (C55O). H NMR
(300 MHz, CDCl3): d 10.9 (s, 1H) 7.35–7.25 (m, 5H) 5.01 (s, 1H) 13C
NMR (75 MHz, CDCl3): d 178.9 (COOH), 127-135 (Ar), 85.9 (CHOH).
The [a]2D5values of various samples of mandelic acids are reported in Table 1.
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