An L-proline-based β-amino tertiary thiol: Synthesis and use as a catalyst in the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/S0957-4166(99)00151-2

Two independent routes for the synthesis of the novel β-amino tertiary thiol 1 have been developed. Utilisation of this thiol in the enantioselective addition of diethylzinc to aldehydes provided (R)-secondary alcohols in ees of up to 64%.

Full text of DOI:10.1016/S0957-4166(99)00151-2

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1551–1561
An L-proline-based β-amino tertiary thiol: synthesis and use as a
catalyst in the enantioselective addition of diethylzinc to
aldehydes
Colin L. Gibson ∗
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UK
Received 23 March 1999; accepted 19 April 1999
Abstract
Two independent routes for the synthesis of the novel β-amino tertiary thiol 1 have been developed. Utilisation
of this thiol in the enantioselective addition of diethylzinc to aldehydes provided (R)-secondary alcohols in ees of
up to 64%. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The observation that amino sulfur catalysts offer improvements in enantioselectivity over their amino
alcohol counterparts is known for a number of transition metal mediated carbon–carbon bond forming
processes.1–7 This has led to the development of a wide range of chiral sulfur/nitrogen chelate catalysts
for the enantioselective 1,2-addition of dialkylzinc reagents to aldehydes.1,2,5,8,9 Consequently, a number
of years ago we initiated a programme for the development of syntheses of chiral β-amino disulfides
from α-amino acids and investigated their use in a number of transition metal mediated processes.5–8,10
In these previous studies, α-amino acids were identified as attractive starting points because such entities
offer ready access to sterically demanding systems and also because of their low toxicity. In these earlier
studies we concentrated on the synthesis and use of β-amino disulfides in line with the observations of
Kellogg1 that β-amino disulfides are far more stable than their β-amino thiol counterparts, the latter are
readily oxidised to the former, even under carefully controlled conditions.
The active catalytic species in dialkylzinc promoted reactions using β-amino disulfides has been
elegantly established by Kellogg.1 Thus, the disulfide bond is cleaved by the dialkylzinc to give the
catalytically productive zinc thiolate complex A (in a dimer/monomer manifold) together with a cataly-
tically unproductive thioether B (Scheme 1).11 In terms of stereochemical economy the use of disulfides is
∗
E-mail: c.l.gibson@strath.ac.uk
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00151-2

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inefficient because 50% of the stereochemical information is lost as the stable thioether B. Consequently,
this led us to the postulation that β-amino tertiary thiols, e.g. 1, may be better catalyst systems since
we anticipated that they would be more resistant to auto oxidation in comparison with their primary
counterparts. This would lead to stable β-amino thiols and so improve the stereochemical economy over
β-amino disulfides. Also, we hoped that the so-called ‘magic diphenylmethanol effect’12,13 would apply
equally to the diphenylmethane thiol group in 1 and so lead to greatly enhanced enantioselectivities.
Scheme 1.
To our knowledge, β-amino tertiary thiols have not been prepared previously. However, Kellogg has
reported the preparation of chiral pyridine tertiary thiols from thiofenchone.14 In contrast, Chelucci et
al. have recently tried, unsuccessfully, to prepare tertiary thiol pyridine ligands from the corresponding
tertiary alcohols.4 Seebach et al.,15 have elegantly shown that the TADDOL systems can be converted into
δ-amino tertiary thiols which were effective catalysts in enantioselective conjugate addition reactions.16
Therefore, we set out to establish if β-amino tertiary thiol 1 could be prepared as well as assessing its use
as a chiral catalyst in the enantioselective addition of dialkylzinc reagents to aldehydes.
2. Results and discussion
2.1. Synthesis of thiol 1
Initially, we anticipated that the β-amino tertiary thiol 1 could be accessed from L-proline 2 using
our previously developed methodology for the synthesis of β-amino primary disulfides from amino
acids.5,8,10 Thus, treatment of L-proline 2 with ethyl chloroformate and potassium carbonate in methanol
(89% after distillation) followed by reaction with excess phenylmagnesium bromide afforded the tertiary
alcohol 3 in 90% yield after purification (Scheme 2).17 Attempts to convert the tertiary alcohol 3 into the
tosylate 4, using a variety of bases (pyridine, DMAP, NaH or MeLi) in conjunction with tosyl chloride,
resulted in recovery of starting material. Consequently, the N-carbamate moiety in 3 was reduced with
lithium aluminium hydride in THF at reflux to afford the corresponding N-methyl derivative 5 in 88%
recrystallised yield. Attempted conversion of the N-methyl tertiary alcohol 5 into the corresponding
mesylate 6a (X=OMe) gave starting material upon treatment with mesyl chloride or mesic anhydride
and various bases (Et3N, DMAP, MeLi or BuLi). In contrast, reaction of the N-methyl tertiary alcohol
5 with thionyl chloride under conditions developed by Deyrup et al. for the chlorination of aziridine
tertiary alcohols18 led to complete decomposition. Alternatively, treatment of N-methyl tertiary alcohol
5 with HCl gas in dichloromethane failed to yield the chloride 6b (X=Cl) but afforded recovered starting
material. Studies aimed at accessing the tertiary thiol 1 by conversion of the known diphenyl[1,3]oxazol-
3-one 7a (X=Y=O)17b,c into the [1,3]thiazol-3-thione 7b (X=Y=S) using a variety of thionation reagents

C. L. Gibson / Tetrahedron: Asymmetry 10 (1999) 1551–1561
1553
either led to low yields of the required 7b (P4S10 or Davy’s reagent ethyl) or to the generation of the
[1,3]oxazol-3-thione 7c (X=O, Y=S) (Lawesson’s reagent).
Scheme 2. Reagents and conditions: (i) EtOCOCl, MeOH, K2CO3; (ii) PhMgBr, THF; (iii) TsCl, base (pyr. or DMAP or NaH
or MeLi); (iv) LiAlH4, THF, 4; (v) MsCl or Ms2O, base (Et3N or DMAP or MeLi or BuLi); (vi) SOCl2; (vii) HCl–CH2Cl2;
(viii) KOH, MeOH; (ix) Lawesson’s or P4S10 or Davy’s reagent ethyl ((EtSPS2)2), toluene, 4
The failure to introduce a suitable leaving group or efficiently insert a sulfur at the tertiary position
of alcohols 3 or 5 led to a reassessment of the synthetic protocol. In this context, Nishio has shown
that tertiary alcohols can be converted directly into tertiary thiols using Lawesson’s reagent.19 However,
dehydration products can predominate when the tertiary alcohol contains a β hydrogen. Indeed, exclusive
dehydration was observed by Chelucci et al. upon treatment of diphenylhydroxymethyl or dimethylhy-
droxymethyl tetrahydroquinolines with Lawesson’s reagent.4 However, treatment of N-methyl tertiary
alcohol 5 with Lawesson’s reagent under precisely controlled conditions (toluene, ∆, 7 min) gave,
reproducibly, the requisite tertiary thiol 1 in 42% yield (24.6% overall yield, four steps from L-proline
2) (Scheme 3). The tertiary thiol 1 appeared to be stable to auto oxidation and showed no evidence of
disulfide formation, however, it was unstable to visible light showing rapid decomposition.
Scheme 3. Reagent and conditions: (i) 0.53 equiv. Lawesson’s reagent, toluene, 4
Although the tertiary thiol 1 had been successfully prepared, the final Lawesson’s reaction (Scheme 3)
led to moderate yields for the conversion of 5 into 1. Consequently, alternative routes to tertiary thiol
1 were assessed. In this context, Gauthier et al. have shown that SN1 active alcohols can be converted
into the corresponding thiol esters upon treatment with zinc iodide and a thiol acid.20 Thus, reaction of
carbamate tertiary alcohol 3 with zinc iodide and thioacetic acid afforded the carbamate thioacetate 7 in
55% yield. Lithium aluminium hydride reduction5 of carbamate thioacetate 7 followed by acid treatment
gave the tertiary thiol 1 in 36% yield (15.9% overall yield, four steps from L-proline 2) (Scheme 4) which
was identical to that prepared above.

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C. L. Gibson / Tetrahedron: Asymmetry 10 (1999) 1551–1561
Scheme 4. Reagents and conditions: (i) 1 equiv. ZnI2, 2.15 equiv. AcSH, ClCH2CH2Cl; (ii) LiAlH4, THF, 4; (iii) 1.2 M HCl
2.2. Enantioselective catalytic addition of diethylzinc to aldehydes
Successful access to the β-amino tertiary thiol 1 allowed an investigation of its ability to act as a
catalyst in the enantioselective 1,2-addition of diethylzinc to aldehydes. As a result of the photolability
of thiol 1 all reactions were carried out using freshly prepared material and were conducted at 0°C in
toluene for a variety of aldehydes (Scheme 5, Table 1).
Scheme 5. Reagents and conditions: (i) Et2Zn (2 equiv.), 1 (5 mol%), toluene, 0°C, 48–72 h; (ii) 1 M HCl
Initial studies on the catalytic efficiency of thiol 1 in the diethylzinc addition to benzaldehyde, indicated
no variation in the enantioselectivity on increasing the concentration of the thiol 1 from 2.5 to 5 mol%
(entries 1 and 2) but perhaps improved the efficiency. The lack of sensitivity of the enantioselectivity to
the thiol concentration suggests the complete formation of an active catalyst, in contrast to an equilibrium
arrangement.1,5 Consequently, the remaining studies were carried out using 5 mol% of 1.
In general terms the enantioselectivities achieved using the tertiary thiol 1 in the enantioselective
addition of diethylzinc to aldehydes (6–64% ee, Scheme 5, Table 1) are disappointing. Indeed, the tertiary
Table 1
Enantioselective addition of diethylzinc to aldehydes in the presence of 1

C. L. Gibson / Tetrahedron: Asymmetry 10 (1999) 1551–1561
1555
thiol 1 shows a marked decrease in enantioselectivity in comparison to our related β-amino disulfide
derived from L-proline (68–99% ee).5 These observations indicate that the ‘magic diphenylmethanol
effect’ cannot be directly applied to the corresponding sulfur analogues. A possible explanation for these
differences is to consider the alternative transition states for the formation of the (R)- and (S)-alcohols.
The currently accepted mechanism for the β-amino alcohol catalysed addition of dialkylzinc to
aldehydes has been reviewed22 and applied directly to amino thiols2c and zinc arene thiolate catalysts.9e
Transition state modelling has been carried out on amino alcohols at the ab initio level23 and semi
emperically.24,25 The core structural features from the ab initio calculations have been used as the basis
for PM3 calculations of the transition states for an azabornylmethanethiol catalyst.3
Based on the foregoing body of evidence it can be presumed that the active catalytic species for
our proline derived disulfide5 and thiol 1 are the tricoordinate thiazazincolidines 10a (R1=H) and
10b (R1=Ph), respectively. The tricoordinate thiazazincolidines 10a,b act as bifunctional catalysts that
assemble the aldehyde and dialkylzinc, leading to the product forming transition states. By analogy
with the PM3 calculations on azabornylmethanethiol catalysts by Hongo and co-workers3 and the
rationalisation of azanorbornylmethanol enantioselectivities by Andersson and co-workers,26 we propose
that structures 11a,b and 12a,b are the two product forming transition states. The major anti anti Re
transition states 11a,b lead to alkyl addition to the Re face of the aldehyde to afford the (R)-alcohol while
the minor syn anti Si transition states lead to the formation of the (S)-alcohol.27 In the case of the active
catalyst 10b (R1=Ph), the major transition state 11b (R1=Ph) is destabilised by steric interaction between
the pro-S R1 group and Zn*. In the minor transition state 12b, such destabilisation does not occur and
so the energies of the two transition states converge with concomitant reduction of enantioselectivity. In
the case of the catalytic species 10a (R1=H), steric repulsion between the pro-S hydrogen and Zn* in
the major transition state 11a is less significant, so the differences in free energies between 11a and 12a
is maintained. Consequently, catalyst 10a produces much higher enantioselectivities in the diethylzinc
addition to aldehydes.5
As sterically demanding aldehydes would lead to a destabilisation of transition state 12b (R1=Ph)
relative to transition state 11a (R1=Ph) then it would be expected that such aldehydes would lead to
higher enantioselectivities. This is the experimental observation, thus, ortho anisaldehyde (entry 5, 64%
ee) and naphthaldehyde (entry 6, 56% ee) furnish the highest enantiomeric excesses. In contrast, the non-
α-branched aldehydes cinnamaldehyde (entry, 7, 16% ee) and dihydrocinnamaldehyde (entry 8, 8% ee)
provide the poorest enantioselectivities.
3. Conclusions
Although the synthesis of proline-based β-amino tertiary thiol 1 proved, initially, to be problematic,
two independent syntheses were successfully carried out. The first route involved the Lawesson’s reagent
mediated conversion of a β-amino tertiary alcohol into β-amino tertiary thiol 1. The second route required

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C. L. Gibson / Tetrahedron: Asymmetry 10 (1999) 1551–1561
the zinc iodide-promoted SN1 conversion of a tertiary alcohol into a tertiary thioester, followed by
subsequent reduction. The β-amino tertiary thiol 1 appeared to be stable to auto-oxidation with no
evidence for disulfide formation, however, it was degraded by visible light. Utilisation of β-amino tertiary
thiol 1 as a catalyst in the enantioselective addition of diethylzinc to aldehydes led to disappointing
enantiomeric excesses (8–64% ee). These results were rationalised in terms of a consideration of the
two likely transition states in conjunction with our previously reported results for a β-amino primary
disulfide.5
The observations and rationalisations reported in this study are being utilised to design novel improved
catalysts for transition metal mediated asymmetric reactions with a view to providing an experimental
basis for our conclusions.21
4. Experimental
4.1. Instrumentation
Melting points were determined on a Reichert 7905 hot stage and are uncorrected. Optical rotations
were measured at 20°C in a 1 mL cell with a pathlength of 10 cm using a Perkin–Elmer 341 polarimeter.
The [α]D values are given in 10−1 deg cm2 g−1 and the concentrations are given in g/100 cm3. 1H NMR
spectra were recorded on Brucker WM-250, Jeol 270, or Brucker 400 spectrometers in the indicated
solvents operating at 250, 270 or 400 MHz, respectively. 13C NMR spectra were obtained on the same
instruments operating at 62.89, 67.80, and 100 MHz, respectively. Infra red (IR) spectra were recorded
on a Nicolet Impact 400D FTIR spectrometer either as liquid films or as 1–2% solutions in CCl4. Mass
spectra were recorded on a Jeol JMS AX505 spectrometer. Chiral HPLC analysis was performed using
an Applied Chromatography Systems (ACS) Model 351 isocratic pump with the indicated flow rates and
solvents. The columns used were either Daicel Chiralcel OB or OD columns (250×4.6 mm). The peaks
were detected with an ACS Model 750/12 UV detector set at 254 nm and an ACS Chiramonitor. The
data was collected on a Viglen computer fitted with a SUMMIT data card and the chromatograms were
integrated using COMUS SUMMIT software.
4.2. General methods
All reactions were carried out under an atmosphere of nitrogen in oven dried glassware (140°C).
Anhydrous solvents were obtained using standard procedures: methanol (Mg(OMe)2), THF (K metal),
toluene (Na metal) and dichloroethane (NaH). Flash column chromatography was performed according
to the procedure of Still et al.28 using silica gel (230–400 mesh) or neutral alumina where specified.
4.3. (S)-Proline-N-ethyl carbamate methyl ester17
This compound was prepared according to literature procedures except that it was purified by
distillation before use to afford a colourless oil (89%), bp 78–82°C @ 0.13 mmHg (found: C, 53.60;
H, 7.56; N, 6.81; calculated for C9H15NO5: C, 53.72; H, 7.51; N, 6.96); [α]=−75.1 (c 1.03, CHCl3);
νmax (liq. film)/cm−1 1747 (ester C_O), 1700 (carbamate C_O); δH (400 MHz, CD3NO2, 80°C) 1.24
(t, J=7, 3H, CH3CH2O), 1.87–2.02 (m, 3H, C-4 CH2+H-3), 2.25–2.32 (m, 1H, H-3), 3.44–3.51 (m, 2H,
C-5 CH2), 3.72 (s, 3H, CH3O), 4.07–4.15 (m, 2H, CH3CH2O), 4.29–4.34 (m, 1H, H-2); δC (100 MHz,

C. L. Gibson / Tetrahedron: Asymmetry 10 (1999) 1551–1561
1557
CD3NO2, 80°C) 15.28 (CH3), 25.14 (CH2), 31.63 (CH2), 48.01 (C-5), 52.79 (C-2), 60.76 (OCH3), 62.43
(CH2O), 156.49 (NC_O), 175.13 (CO2) (found: MH+ 202.1096; calculated for C9H15NO5: 202.1080).
4.4. Ethyl (S)-(−)-2-[hydroxy(diphenyl)methyl]-1-pyrrolidinecarboxylate17
This compound was prepared according to literature procedures except that it was purified before use
by flash column chromatography eluting with 28% ethyl acetate–hexane which afforded white needles
(90%), mp 115–116.5°C (hexane) (found: C, 73.65; H, 7.33; N, 4.6; calculated for C20H23NO3: C, 73.82;
H, 7.12; N, 4.3); [α]=−146 (c 1.04, CHCl3); νmax (CCl4)/cm−1 3540–3200 (OH), 1674, 700; δH (270
MHz, CDCl3) 0.68–0.9 (m, 1H, H-5), 1.19 (t, J=7, 3H, CH3), 1.41–1.53 (m, 1H, H-4), 1.88–1.97 (m,
1H, H-3), 1.99–2.17 (m, 1H, H-3), 2.91–1.99 (m, 1H, H-5), 3.42 (dd, J=18.4, 7.8, 1H, H-4), 4.04–4.17
(m, 2H, CH2O), 4.93 (dd, J=8.9, 3.5, 1H, H-2), 7.21–7.42 (m, 10H, ArH); δC (100 MHz, CDCl3) 15.05
(CH3), 23.34 (CH2), 30.04 (CH2), 48.13 (C-5), 62.32 (OCH2), 66.30 (C-2), 81.99 (COH), 127.28, 127.57,
127.75, 127.99, 128.29, 128.85, 129.05, 129.54 (all ArC-H), 144.07, 146.76 (both ArC), 158.77 (C_O)
(found: MH+ 326.1758; calculated for C20H23NO3: 326.1756).
4.5. (S)-(+)-Diphenyl(1-methylpyrrolidin-2-yl)methanol
To a stirred solution of ethyl (S)-(−)-2-[hydroxy(diphenyl)methyl]-1-pyrrolidinecarboxylate (1.55 g,
4.77 mmol) in anhydrous THF at 0°C under a nitrogen atmosphere was added, portionwise, lithium
aluminium hydride (0.364 g, 9.59 mmol). The resulting suspension was heated under reflux for 2 h,
whereupon it was cooled to 0°C and water (20 mL) was added. The mixture was acidified to pH 3
with 1 M HCl and washed with ether (20 mL). The resulting aqueous layer was made alkaline with 11
M NaOH, filtered and the filtrate was washed with ethyl acetate (20 mL). The layers were separated
and the aqueous phase was washed with dichloromethane (×2, 20 mL). The combined organic extracts
were dried (Na2SO3), filtered and evaporated to afford colourless plates (1.12 g, 4.19 mmol, 88%),
mp 70–71°C (hexane) (literature mp 68.5–68.9°C13) (found: C, 81.06; H, 7.93; N, 5.16; calculated for
C18H21NO: C, 80.86; H, 7.92; N, 5.21); [α]=+56.7 (c 1.04, CHCl3) (literature [α]=+57 (c 1, CHCl3)13);
νmax (CCl4)/cm−1 3550–3200 (OH), 2790, 704; δH (270 MHz, CDCl3) 1.56–1.75 (m, 3H, H-3 and C-4
CH2), 1.81 (s, 3H, NCH3), 1.84–1.99 (m, 1H, H-3), 2.37–2.48 (m, 1H, H-5), 3.08–3.13 (m, 1H, H-5),
3.62 (dd, J=9.2, 4, 1H, H-2), 4.79 (bs, 1H, OH), 7.09–7.16 (m, 2H, Ar-H), 7.23–7.29 (m, 4H, Ar-H),
7.51–7.65 (m, 4H, Ar-H); δC (67.8 MHz, CDCl3) 24.24 (CH2), 30.09 (CH2), 43.18 (CH3N), 72.21 (C-
2), 77.75 (COH), 125.65, 125.69, 126.34, 128.22, 146.91, 148.43 (all ArC) (found: MH+ 268.1698;
calculated for C18H21NO: 268.1701)
4.6. (S)-(+)-Diphenyl(1-methylpyrrolidin-2-yl)methanethiol
A stirred suspension of (S)-(+)-diphenyl(1-methylpyrrolidin-2-yl)methanol (99.5 mg, 0.373 mmol)
and Lawesson’s reagent (80.9 mg, 0.2 mmol) in anhydrous toluene (12 mL) was heated to reflux for 7
min. The resulting solution was cooled to 0°C and the solvent removed in vacuo. The resulting residue
was filtered through a short plug of neutral alumina eluting with dichloromethane, evaporation of the
solvent afforded a blue oil. Column chromatography of this residue on neutral alumina eluting with
dichloromethane afforded a light yellow oil (44.7 mg, 0.158 mmol, 42%); [α]=+260 (c 0.955, CHCl3);
ν
max (liq. film)/cm−1 2956, 2847, 2785, 2785, 2570–2360 (SH), 748, 699; δH (270 MHz, CDCl3) 1.62 (s,
3H, NCH3), 1.64–1.86 (m, 2H, H-3/4), 2.04–2.13 (m, 1H, H-4), 2.16–2.25 (m, 1H, H-3), 2.34–2.41
(m, 1H, H-5), 3.07 (t, J=7.6, 1H, H-5), 3.53 (dd, J=9.2, 3.2, 1H, H-2), 7.11–7.27 (m, 8H, Ar-H),

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C. L. Gibson / Tetrahedron: Asymmetry 10 (1999) 1551–1561
7.39 (d, J=7, 2H, Ar-H), 7.56 (d, J=7, 2H, Ar-H); δC (67.8 MHz, CDCl3) 25.39 (CH2), 32.76 (CH2),
44.59 (NCH3), 59.89 (C-5), 66.09 (C-S), 74.3 (C-2), 126.72, 127.01, 128.12, 128.49, 129.17, 129.41 (all
ArC-H), 146.79, 147.61 (both ArC); m/z (CI) 284 (MH+, 75%), 250 (MH+–H2S, 100%) (found: MH+
284.1467; C18H22NS requires: 284.1473)
4.7. Ethyl (S)-(−)-2-[(acetylsulfanyl)(diphenyl)methyl]-1-pyrrolidinecarboxylate
To a stirred suspension of zinc iodide (225.3 mg, 0.706 mmol) in anhydrous dichloroethane (7 mL)
was added a solution of ethyl (S)-(−)-2-[hydroxy(diphenyl)methyl]-1-pyrrolidinecarboxylate (207.1 mg,
0.637 mmol) in dichloroethane (4 mL) under a nitrogen atmosphere. To the resulting suspension was
added thiolacetic acid (125 µL, 1.54 mmol) and the solution was stirred for 5 h. At the completion of
this period, water (25 mL) was added and the layers were separated. The aqueous phase was extracted
with dichloromethane (×2, 15 mL) and the combined organic layers were dried (Na2SO4), filtered and
evaporated to afford a yellow oil. Purification by flash column chromatography eluting with hexane:ethyl
acetate (68:32) afforded white needles (134.8 mg, 0.35 mmol, 55%), mp 140.5–141.5°C (hexane) (found:
C, 68.61; H, 6.41; N, 3.52; C22H25NO3S requires: C, 68.9; H, 6.57; N, 3.65); [α]=−231.4 (c 0.98,
CHCl3); νmax (CCl4)/cm−1 2982, 1712 (C_O), 704, 630; δH (400 MHz, CD3NO2, 80°C) 0.37–0.51
(m, 1H, H-5), 1.26 (t, J=7, 3H, CH3CH2), 1.42–1.52 (m, 1H, H-4), 2.0–2.07 (m, 1H, H-3), 2.12 (s, 3H,
CH3C_O), 2.29–2.32 (m. 1H, H-3), 2.66–2.72 (m, 1H, H-5), 3.43–3.47 (m, 1H, H-4), 4.02–4.18 (m, 1H,
CH3CHHO), 4.32–4.34 (m, 1H, CH3CHHO), 5.67 (dd, J=8.8, 1.9, 1H, H-2), 7.24–7.4 (m, 6H, ArH),
7.41–7.42 (m, 2H, ArH), 7.59–7.6 (m, 2H, ArH); δC (100 MHz, CD3NO2, 80°C) 15.34 (CH3CH2O),
23.98 (CH2), 30.71 (CH2), 31.71 (CH3C_O), 50.16 (C-5), 62.56 (CH2O), 63.73 (C-2), 69.84 (C-S),
128.12, 128.4, 129.18, 131.56, 131.98 (all ArC-H), 142.82, 145.35 (both ArC), 158.96 (CO2), 194.47
(SC_O) (found: MH+ 384.1642; C22H26NO3S requires: 384.1633).
4.8. (S)-(+)-Diphenyl(1-methylpyrrolidin-2-yl)methane thiol via reduction of ethyl 2-[(acetyl-
sulfanyl)(diphenyl)methyl]-1-pyrrolidinecarboxylate
To a stirred suspension of lithium aluminium hydride (46.2 mg, 1.217 mmol) in anhydrous
THF (3 mL) at 0°C under a nitrogen atmosphere was added, dropwise, a solution of ethyl 2-
[(acetylsulfanyl)(diphenyl)methyl]-1-pyrrolidinecarboxylate (134.8 mg, 0.35 mmol) in dry THF (4 mL).
The resulting suspension was heated to reflux for 7 h, whereupon it was cooled to 0°C and water (90 µL,
5 mmol) was added followed by 1.2 N HCl (1.2 mL). The organic layer was decanted from the solids
and filtered through anhydrous sodium sulfate. The remaining solids were washed with dichloromethane
(×3, 15 mL). The combined organic layers were evaporated and column chromatography on neutral
alumina eluting with dichloromethane afforded a light yellow oil (36.1 mg, 0.127 mmol, 36%). The
spectroscopic properties of this material were identical to those described above.
4.9. Addition of diethylzinc to aldehydes
To a solution of the freshly prepared thiol (14.3 mg, 0.05 mmol) in anhydrous toluene (5 mL) under
a nitrogen atmosphere was added diethylzinc (2 mL, 1 M solution in hexane, 2 mmol). After stirring at
room temperature for 2 h the solution was cooled to −27°C, whereupon freshly distilled aldehyde was
added (1 mmol) and the resulting yellow solution was stirred at 0°C for 48 h. At the completion of this
period 1 M aqueous hydrochloric acid was added. The aqueous phase was extracted with dichloromethane

C. L. Gibson / Tetrahedron: Asymmetry 10 (1999) 1551–1561
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(2×10 mL) and dried over sodium sulphate. Filtration and evaporation of the solvent followed by flash
column chromatography (hexane:ethyl acetate) afforded the product alcohols.
4.9.1. 1-Phenyl-1-propanol
Colourless oil (108 mg, 0.79 mmol, 81%) after purification by flash column chromatography (hex-
ane:ethyl acetate, 82:18): νmax (liq. film)/cm−1 3680–3100 (OH), 3030, 762, 700; δH (270 MHz, CDCl3)
0.87 (t, J=7.4, 3H, CH3CH2), 1.62–1.83 (m, 2H, CH3CH2), 2.38 (s, 1H, OH), 4.51 (t, J=6.6, H-1),
7.21–7.35 (m, 5H, ArH); δC (68.7 MHz, CDCl3) 10.13 (C-3), 31.82 (C-2), 75.91 (C-1), 127.32 (C-
20,60), 127.41 (C-40), 128.06 (C-30,50), 144.61 (C-10) (found: M+· 136.0886; calculated for C9H12O:
136.0888). The ee was determined by HPLC analysis using a Daicel Chiralcel OD column with 1% 2-
propanol–hexane (flow rate 1 mL min−1): (R)-1-phenyl-1-propanol 28 min, (S)-1-phenyl-1-propanol 35.1
min.
4.9.2. 1-(4-Methylphenyl)-1-propanol
Colourless oil (120.6 mg, 0.804 mmol, 80%) after purification by flash column chromatography
(hexane:ethyl acetate, 4:1): νmax (liq. film)/cm−1 3710–3090 (OH), 3020, 816; δH (270 MHz, CDCl3)
0.86 (t, J=7.4, 3H, CH3CH2), 1.59–1.84 (m, 2H, CH3CH2), 2.31 (s, 3H, ArCH3), 2.45 (s, 1H, OH),
4.46 (t, J=6.6, 1H, H-1), 7.11 (ABd, J=8.2, 2H, H-30,50), 7.17 (ABd, J=8.2, 2H, H-20,60); δC (68.7 MHz,
CDCl3) 10.30 (C-3), 21.20 (ArCH3), 31.87 (C-2), 75.85 (C-1), 126.09 (C-20,60), 128.66 (C-30,50), 137.07
(C-40), 141.81 (C-10) (found: M+· 150.1054; calculated for C10H14O: 150.1045). The ee was determined
by HPLC analysis using a Daicel Chiralcel OB column with 1% 2-propanol–hexane (flow rate 0.7 mL
min−1): (R)-1-(4-methylphenyl)-1-propanol 28.3 min, (S)-1-(4-methylphenyl)-1-propanol 37.9 min.
4.9.3. 1-(4-Methoxyphenyl)-1-propanol
Colourless oil (153.8 mg, 0.927 mmol, 93%) after purification by flash column chromatography
(hexane:ethyl acetate, 72:28): νmax (liq. film)/cm−1 3700–3100 (OH), 2836, 831; δH (270 MHz, CDCl3)
0.93 (t, J=7.3, 3H, CH3CH2), 1.34–1.93 (m, 2H, CH3CH2), 2.66 (s, 1H, OH), 3.84 (s, 3H, OCH3), 4.54
(t, J=6.8, 1H, H-1), 6.93 (d, J=8.6, 2H, H-30,50), 7.27 (d, J=8.6, 2H, H-20,40); δC (67.8 MHz, CDCl3)
10.29 (C-3), 31.82 (C-2), 55.28 (OCH3), 75.56 (C-1), 114.15 (C-30,50), 127.73 (C-20,40), 136.93 (C-10),
158.92 (C-40) (found: M+· 166.0985; calculated for C10H14O2: 166.0994). The ee was determined by
HPLC analysis using a Daicel Chiralcel OD column with 2.5% 2-propanol–hexane (flow rate 0.7 mL
min−1): (R)-1-(4-methoxyphenyl)-1-propanol 33.4 min, (S)-1-(4-methoxyphenyl)-1-propanol 37.4 min.
4.9.4. 1-(2-Methoxyphenyl)-1-propanol
Colourless oil (143.5 mg, 0.864 mmol, 87%) after purification by flash column chromatography
(hexane:ethyl acetate, 97:3): νmax (liq. film)/cm−1 3660–3135 (OH), 2836, 754; δH (270 MHz, CDCl3)
0.92 (t, J=7.3, 3H, CH3CH2), 1.71–1.82 (m, 2H, CH3CH2), 2.85 (s, 1H, OH), 4.77 (t, J=6.5, 1 H, H-
1), 6.22 (dd, J=7.6, 1, 1H, H-30), 6.91 (td, J=7.6, 1, 1H, H-50), 7.21 (td, J=7.6, 1.6, 1H, H-40), 7.27
(dd, J=7.6, 1.6, 1H, H-60); δC (67.8 MHz, CDCl3) 10.47 (C-3), 30.26 (C-2), 55.23 (OCH3), 71.93 (C-
1), 110.47 (C-30), 120.68 (C-50), 127.4 (C-40 or 60), 128.10 (C-60 or 40), 132.59 (C-10), 156.55 (C-20)
(found: M+· 166.0995; calculated for C10H14O2: 166.0994). The ee was determined by HPLC analysis
using a Daicel Chiralcel OD column with 2.5% 2-propanol–hexane (flow rate 0.5 mL min−1): (S)-1-(2-
methoxyphenyl)-1-propanol 33.5 min, (R)-1-(2-methoxyphenyl)-1-propanol 35.5 min.

1560
C. L. Gibson / Tetrahedron: Asymmetry 10 (1999) 1551–1561
4.9.5. 1-(2-Naphthyl)-1-propanol
Off white solid (91.5 mg, 0.492 mmol, 49%) after purification by flash column chromatography
(hexane:ethyl acetate, 78:22), mp 29–31°C: νmax (CCl4 soln.)/cm−1 3615 (OH), 3059, 855, 819; δH
(270 MHz, CDCl3) 0.89 (t, J=7.4, 3H, CH3CH2), 1.70–1.99 (m, 2H, CH3CH2), 2.33 (s, 1H, OH), 4.67
(t, J=6.6, 1H, H-1), 7.39–7.51 (m, 3H, ArH), 7.70 (s, 1H, H-10), 7.76–7.81 (m, 3H, ArH); δC (68.7 MHz,
CDCl3) 10.30 (C-3), 31.89 (C-2), 76.20 (C-1), 124.32, 124.89, 126.02, 126.09, 127.83, 128.08, 128.35
(all ArC-H), 133.11, 133.4 (both ArC), 142.10 (C-20) (found: M+· 186.1045; calculated for C13H14O:
186.1045). The ee was determined by HPLC analysis using a Daicel Chiralcel OD column with 4%
2-propanol–hexane (flow rate 1 mL min−1): (R)-1-(2-naphthyl)-1-propanol 25.9 min, (S)-1-(2-naphthyl)-
1-propanol 22.9 min.
4.9.6. (E)-1-Phenyl-1-penten-3-ol
Colourless oil (145.8 mg, 0.899 mmol, 90%) after purification by flash column chromatography
(hexane:ethyl acetate, 74:26): νmax (liq. film)/cm−1 3690–3100 (OH), 3026, 965, 748, 693; δH (270
MHz, CDCl3) 0.93 (t, J=7.3, 3H, CH3CH2), 1.51–1.74 (m, 2H, CH3CH2), 2.53 (s, 1H, OH), 4.15 (q,
J=6.8, 1H, H-3), 6.17 (dd, J=15.9, 6.8, 1H, H-2), 6.52 (d, J=15.9, 1H, H-1), 7.13–7.36 (m, 5H, ArH); δH
(68.7 MHz, CDCl3) 9.88 (C-5), 30.26 (C-4), 74.38 (C-3), 126.5, 127.64, 128.64, 130.38, 132.44 (all sp2
C), 137.05 (C-10) (found: M+· 162.1030; calculated for C11H14O: 162.1045). The ee was determined by
HPLC analysis using a Daicel Chiralcel OD column with 5% 2-propanol–hexane (flow rate 1 mL min−1):
(R,E)-1-phenyl-1-penten-3-ol 16.9 min, (S,E)-1-phenyl-1-penten-3-ol 27.2 min.
4.9.7. 1-Phenyl-3-pentanol
Colourless oil (112 mg, 0.682 mmol, 68%) after purification by flash column chromatography
(hexane:ethyl acetate, 4:1): νmax (liq. film)/cm−1 3700–3100 (OH), 3026, 746, 699; δH (270 MHz,
CDCl3) 0.92 (t, J=7.4, 3H, CH3CH2), 1.39–1.57 (m, 2H, CH3CH2), 1.69–1.84 (m, 2H, C-2 CH2), 1.97 (s,
1H, OH), 2.59–2.84 (m, 2H, C-1 CH2), 3.48–3.57 (m, 1H, H-3); δC (68.7 MHz, CDCl3) 9.99 (C-5), 30.35
(C-4), 32.19 (C-2), 38.69 (C-1), 72.67 (C-3), 125.8 (C-40), 128.54 (ArC-H), 142.40 (C-10) (found: M+·
164.1204; calculated for C11H16O: 164.1201). The ee was determined by HPLC analysis using a Daicel
Chiralcel OD column with 5% 2-propanol–hexane (flow rate 1 mL min−1): (S)-1-phenyl-3-pentanol 13.3
min, (R)-1-phenyl-3-pentanol 19.2 min.
Acknowledgements
Donie Guiney is thanked for some preliminary experiments. Drs. P. Dennison and A.I. Khalaf are
warmly thanked for their spectroscopic expertise in obtaining NMR and mass spectra, respectively. The
use of the EPSRC chemical database service at Daresbury is gratefully acknowledged.29
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