Influence of chiral thiols on the diastereoselective synthesis of γ-lactams from cyclic anhydrides

Article abstract of DOI:10.1016/j.tet.2012.03.027

The synthesis of γ-lactams from both four-component and imine-anhydride reactions is reported. The synthesis of 2-phenylcyclohexanethiol is described and this compound was evaluated along with an additional seven chiral thiols. A range of selectivity and yields was observed and comparisons to established reactions are made in order to account for the observed reactivity.

Full text of DOI:10.1016/j.tet.2012.03.027

Tetrahedron 68 (2012) 4320e4327
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Influence of chiral thiols on the diastereoselective synthesis of g-lactams from
cyclic anhydrides
*
Ashkaan Younai, James C. Fettinger, Jared T. Shaw
Department of Chemistry, University of California, One Shields Ave, Davis, CA 95616, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of g-lactams from both four-component and imine-anhydride reactions is reported. The
Received 21 January 2012
Received in revised form 5 March 2012
Accepted 8 March 2012
synthesis of 2-phenylcyclohexanethiol is described and this compound was evaluated along with an
additional seven chiral thiols. A range of selectivity and yields was observed and comparisons to es-
tablished reactions are made in order to account for the observed reactivity.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 28 March 2012
Keywords:
Thiol
Chiral auxiliary
Lactam
Multi-component reaction
1. Introduction
thiol auxiliaries are ones derived from norephedrine6 and cam-
phor.7 In both of these cases, the scaffolds have been previously
The control of absolute configuration in multi-component re-
actions (MCRs) is often challenging, especially in the case of four-
component reactions (4CRs) with broad substrate reactivity, i.e.,
where all of the components can be independently varied. For ex-
ample, commonly used MCRs, such as the Ugi, Hantzsch, and
Biginelli reactions have been employed successfully with only
a small number of chiral substrates.1,2 Studies in our laboratory are
utilized in the form of chiral alcohol auxiliaries by Abiko8a,b and
Helmchen,9a,b respectively. As a result, known chiral thiols repre-
sent a small number of structural motifs based on the analogous
chiral alcohols. One of the most important chiral alcohols, 2-
phenylcyclohexanol, was first reported by Whitesell.10 The superb
selectivity of this substrate in many different reactions suggested
that the sulfur analog might be similarly useful.11 Herein we report
the first synthesis of 2-phenyl-cyclohexane thiol and the assess-
ment of this compound along with seven other chiral thiols in
aimed at controlling the absolute configuration of
g-lactams
formed by our labs recently disclosed 4CR (Fig.1A)3 or by the formal
cycloaddition of imines with cyclic anhydrides.4 Although both
reactions exhibit superb diastereoselectivity for the formation of
two or three stereogenic centers on the lactam center, there is
currently no method to prepare enantiomerically enriched prod-
ucts by either route.
stereoselective g-lactam syntheses (Fig. 1B).
2.2. Why chiral thiols?
Because the thio-substituted enolate intermediate (5) immedi-
ately precedes the formation of both the lactam stereocenters, we
envisioned a chiral thiol auxiliary as the best strategy for asym-
metric induction. This thiol auxiliary-based strategy was also viable
due to both the ease with which the sulfur moiety can be removed
2. Results and discussion
2.1. Thiols as chiral auxiliaries
from the g-lactam products as well as the potential to access both
the syn and anti isomers of lactam product after removal of the
auxiliary. We sought to use the ‘thio-Whitesell’ specifically due to
high diastereoselectivity observed at the same temperature
(>100 ꢀC) required for our 4CR using the Whitesell in an
azomethine-ylide cycloaddition.12
We elected to start our search for control of absolute stereo-
induction in these two lactam-forming reactions with chiral
thiols. Chiral auxiliaries have frequently been used as a means of
synthesizing enantiomerically enriched compounds,5 however, the
use of chiral thiols in this capacity is rare. The only reported chiral
In selecting additional potential structural motifs for chiral thiol
auxiliaries, we wanted a diverse array of scaffolds that were also
synthetically accessible. To accomplish this, we started with chiral
* Corresponding author. E-mail address: jtshaw@ucdavis.edu (J.T. Shaw).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.027

A. Younai et al. / Tetrahedron 68 (2012) 4320e4327
4321
A
4CR
Imine-Anhydride
O
R1
O
R2
N
N
1 + 3
O
O
R2
H
OH
1) toluene, 110°C
(D/S Trap)
R1
H
R1
S
6
1) toluene, 110°C
R3
O
O
O
2) K2CO3, CH3I,
acetone
2) K2CO3, CH3I,
acetone
1
R2NH2
3
2
5
2 + 4
O
R3SH
4
SR3
O
7
O
R1
N
CO2CH3
R2
SR3
8
Previous work: R3SH = ACHIRAL
(e.g. PhSH, p-TolSH, n-BuSH)
O
O
R1
R1
TTMSS, AIBN
toluene, 90°C
NaOCH3
CH3OH, 60 °C
CO2CH3
N
N
R2
R2
CO2H
9
10
This Work: R3SH = CHIRAL
B
Ph
SH
H3C
CH3
H3C
SH
SH
SH
Ph
XH
SH
O
Bn
O
SH
H3C
N
S
NHBz
OCH3
O
O
t-Bu
n
OCH3
H3C
Mes
11
15 (n = 1)
16 (n = 2)
18a (X = O)*
18b (X = S)*
12
13
14
17
Fig. 1. (A) Four component reaction (4CR) and imine-anhydride reaction leading to
g
-lactam product 8 followed by de-sulfurization and epimerization. (B) Chiral thiol auxiliaries
(Mes¼2,4,6-trimethylphenyl, Bz¼benzoyl, *Whitesell auxiliary shown for comparison).
thiols that have been previously synthesized and, if possible, al-
ready used in asymmetric synthesis.
available alcohols. Thiols 15e17 were prepared via identical two-
step synthetic sequences from 1-indanol (21a), 1,2,3,4-tetrahydro-
1-naphthol (21b), and 1-(1-naphthyl)ethanol (21c), respectively,
(Scheme 2). The alcohols were each treated with thiourea18 under
acidic conditions to give the corresponding isothiouronium salts.
Hydrolysis of these salts using sodium hydroxide19 gave in-
separable mixtures of the target thiols (15e17) and their corre-
sponding disulfides20 (22aec). In order to convert these mixtures
to the target thiols, a variety of disulfide cleavage conditions17,21aef
were attempted (Table 1) on a small sample of disulfide 22b.
2.3. Thiols derived from the chiral pool
Thiol 11 has been utilized as an auxiliary in the formation of
anti-aldol products and was obtained via a reported six-step se-
quence6 from (1S,2R)-(þ)-norephedrine. Thiol 12 has been utilized
as an auxiliary in the reduction of
a
-sulfinyl ketones13a and the
alkylation of sulfinimines13b and was obtained via a reported four-
step sequence7 from (þ)-camphor. The synthesis of binaphthyl
thiol 13 has been reported,14 but to this point has never been used
for asymmetric synthesis. However, the binaphthyl structural motif
has been used in a wide variety of auxiliaries and ligands for ca-
talysis.15 Thiol 13 was obtained via the reported four-step sequence
from (S)-BINOL. The last of our chiral pool derived thiols (14) was
LiAlH4, THF, 0 °C
(see TABLE 1)
R2
a) Thiourea, 5 N HCl,
SH
R2
OH
R2
21a-c
H2O/acetone, 12 h
R1
S
+
S
R1
R1
R1
b) NaOH (s), reflux, 3 h
R2
22a-c
15-17
derived from
L-cystine (19, the disulfide dimer of L-cysteine) in
(inseparable mixture)
a two-step synthesis (Scheme 1). L-Cystine dimethyl ester dihy-
drochloride (19) was benzoylated16 under biphasic conditions to
give the corresponding N,N0-dibenzoyl product (20), which was
H3C
SH
SH
SH
subjected to disulfide cleavage conditions17 to give N-Benzoyl-
cysteine methyl ester (14).
L-
15
(55% yield)
16
(63% yield)
17
(50% yield)
O
S
S
SH
Ph3P, AcOH
NaOAc, MeOH
2
2
Ph
Cl
O
O
O
Scheme 2. Synthesis of thiols 15e17.
Cl
NH3
NHBz
NHBz
NaOAc,
H2O/Et2O
5 h; 47%
H2O, 100°C
12 h; 75%
OCH3
19
OCH3
20
OCH3
14
Ultimately, LiAlH4 in THF was found to effect complete conver-
sion of 22b to the target thiol 16, and so was used for conversion of
the other disulfide mixtures to their respective thiols. The harsh
conditions necessary for these substrates when compared to 14
probably originate from the steric congestion of bulky secondary
carbons at the point of sulfur attachment. Although thiols 15e17
were prepared in racemic form, assessment of diastereoselectivity
Scheme 1. Synthesis of thiol 14.
2.4. Thiols derived from commercially available alcohols
In addition to our chiral pool derived thiols, we targeted a set of
chiral thiols that could be easily derived from commercially

4322
A. Younai et al. / Tetrahedron 68 (2012) 4320e4327
Table 1
S
O
OH
Attempted disulfide cleavage conditions of 22b to thiol 16
CeCl3 7H2O
Cl
OPh
Ph
Ph
Entry
Conditions
Conversion
NaBH4, MeOH,
2h; 99%
C5H5N, DMAP (cat),
CH2Cl2, 0°C to rt,
3 h; 66%
1
2
3
4
5
6
7
8
Ph3P, NaOAc, AcOH, H2O/CH3OH, reflux, 12 h
LiBH4, THF, 0 ꢀC to rt, 12 h
<5%
<5%
<5%
<5%
<5%
<5%
w50%
>95%
28
29
NaBH4, THF, 0 ꢀC to rt, 12 h
NaBH4, THF, reflux, 12 h
Ph
S
Ph
S
OPh
Mg0, CH3OH/benzene, rt, 12 h
In0, NH4Cl, EtOH, reflux, 12 h
LiAlH4, Et2O, 0 ꢀC to rt, 12 h
LiAlH4, THF, 0 ꢀC to rt, 12 h
(see Supporting
Information)
O
S
PhO
O
PhO
31
O
Ph
32
30
Scheme 4. Attempted route to thiol 18b via 3,3-sigmatropic rearrangement.
is still possible and each can be prepared as a single enantiomer if
needed.
The successful synthesis of 18b was achieved by introducing
sulfur to the cyclohexyl scaffold by conjugate addition of benzyl
mercaptan to a cyclohexenone (Scheme 5). Although the reaction
was successful with benzyl mercaptan, the extreme stench of this
reagent prompted us to employ odorless30,31 benzyl thiol 33, which
2.5. Synthesis of 2-phenyl-cyclohexane thiol (18b)
We initially sought to synthesize 18b by a simple sulfur nucle-
ophile displacement route (Scheme 3). Starting from the commer-
cially available alkene 23, hydroboration/oxidation22 to 18a,
oxidation to 24, and diastereoselective reduction23 provided cis
alcohol 25 in high yield for the three steps. Although formation of
the corresponding mesylate24 26 was uneventful, attempted dis-
placement with KSAc to produce 27 resulted in complete elimina-
tion to yield starting alkene 23. This result is consistent with facile
E2 elimination from anti-periplanar arrangement of the axial
underwent conjugation addition to a-phenyl enone 28 in nearly
quantitative yield. Thiol 33 was synthesized in four steps from
veratraldehyde.30 NMR analysis of the crude conjugate addition
product showed only the anti isomer formed under reaction con-
ditions, but epimerization at the
a-stereocenter occurred during
column chromatography. The ratio of the inseparable syn and anti
isomers of 34 after chromatography was slightly variable and
hovered around 75:25 in favor of anti-34. Upon reaction with tosyl
hydrazide the desired anti-35 could be isolated as a single isomer at
both the carbon stereogenic centers and with respect to hydrazone
geomerty.32 Reduction of 35 using sodium-cyanoborohydride
yielded cyclohexyl compound 36, which after de-protection by
dissolving metal reduction gave target thiol 18b.
mesylate and benzylic hydrogen at the b-position. Although the
ease with which elimination occurred was surprising with such
a week base, divergent reactivity of similarly substituted cis- and
trans-cyclohexyl tosylates has been reported for attempted dis-
placement reactions with KOAc.25
Ph
Ph
a) BH3 THF, 0°C
a) IBX, EtOAc, 80°C
R
b) NaOH, H2O2
H2O; 73%
H3CO
b) Na2S2O3, Na2CO3;
H2O; 97%
OH
SH
O
TsNHNH2,
O
18a
23
Ph
O
H3CO
33
CH2Cl2, 48 h
Ph
SR
Ph
Et3N (10 mol%)
CH2Cl2, 18 h; 99%
(77:23 anti:syn)
59% isolated
yield of anti
H
24
34
28
Ph
K-Selectride
THF; 77%
H
N
NaBH3CN
ZnCl2, EtOH,
Na°, NH3 (l),
THF, -78°C,
Ts
N
Ph
SH
Ph
SR
MsO
Ph
Ph
Ph
SR
E
2 elimination
MsCl, C5H5N,
0°C; 48%
AcSK
DMF
12 h, 80 °C; 71%
30 min; 94%
OMs
OH
18b
36
Ph
35
26
25
Scheme 5. Completed synthesis of thiol 18b.
SAc
27
Scheme 3. Attempted route to thiol 18b via nucleophilic displacement.
2.6. Evaluation of thiols as chiral auxiliaries
Chiral thiols 11e17 and 18b were examined in both lactam-
forming reactions and exhibited a range of yield and diaster-
eoselectivity. Although high syn/anti selectivity was still observed
In order to avoid elimination, we envisioned a route to 18b in
which we attach sulfur to the cyclohexyl scaffold by a 3,3-
sigmatropic rearrangement,26 which affects a similar swap of ox-
for the formation of the two
g-lactam stereogenic centers, the
ygen for sulfur (Scheme 4). Reduction of
a
-phenyl enone27 28 under
products were isolated in universally low yield and with modest
stereoselectivity with respect to the thiol chirality (Table 2). For
compounds 40aee, the same diastereomeric ratio was observed
regardless of whether they were obtained by the 4CR or imine-
anhydride reaction. These results are most likely due to both re-
actions proceeding through the same thio-substituted enolate in-
termediates in the proposed penultimate step of each reaction
(Fig. 2).
The general lack of reactivity observed for branched alkyl thiols
seems to be consistent, which is a deviation from the high yields
previously observed for aryl thiols, such as thiocresol.3 That said, no
attempt was made to optimize the yields of these reactions on
Luche conditions28 to yield allylic alcohol 29 was achieved in
quantitative yield. Acylation with O-phenyl chlorothionoformate
gave allylic O-thiocarbonate intermediate 30, which upon warming
to room temperature underwent a 3,3-sigmatropic rearrangement
to S-thiocarbonate 31, which was isolated in good yield. Un-
fortunately, all attempts at hydrogenation of 31 were unsuccessful,
even under forcing conditions, such as increased pressure of H2,
elevated temperature, and an excess of catalyst in a flow reactor at
pressures that exceeded 100 bar.29 This lack of reactivity is most
likely due to the high steric demand of the trisubstituted olefin with
allylic substitution.

A. Younai et al. / Tetrahedron 68 (2012) 4320e4327
4323
Table 2
90% yield with an 83% recovery of auxiliary 18b. As a point of
comparison, norephedrine-derived thiol 11 was reported to give
a 93:7 diastereomeric mixture in the same reaction. It is clear that
the stereo-differentiating environment provide by 18b when at-
tached to a pro-stereogenic enolate center is slight.
Thiols as chiral auxiliaries in 4CR and imine-anhydride reaction
Entry
R3SH
Product
4CR yield
Imine-anhydride yield
dra
1
2
3
4
5
6
7
12
13
14
15
16
17
18b
40a
eb
21%
eb
31%
eb
62:38
eb
40b
40c
40d
40e
eb
41%
44%
23%
17%
eb
41%
42%
20%
38%
eb
54:46
51:49
64:36
64:36
eb
Ph
a) Cy2BCl, Et3N
CH2Cl2, -78 °C
O
Ph
SH
propionyl-Cl
S
C5H5N, CH2Cl2,
0 °C to rt; 85%
b) PhCHO; 71%
59:41 dr
CH3
a
Relative to chiral thiol auxiliary (>95:5 syn/anti selectivity observed for the
18b
41
stereocenters of the lactam).
b
No discernable products in the reaction mixture.
Ph
O
OH
Ph
NaOCH3,
CH3OH, rt
O
OH
Ph
18b
(83% recovered)
+
H3CO
S
a substrate-by-substrate basis and we have previously observed
lower yields with benzyl mercaptan when compared to thio-
phenols. In the cases for the most sterically demanding thiols (13
and 18b), no discernable products were observed in both the 4CR
and imine-anhydride reaction. In the case of norephedrine-derived
CH3
CH3
42
43 (90% - known
anti-aldol adduct)
Scheme 6. Aldol addition using thiol-Whitesell analog 18b.
thiol 11, no product was observed in the g-lactam forming 4CR and
the imine-anhydride reaction gave irreproducible results and low
mass recovery.33 Based on low yields seen with the other alkyl
thiols as well as the high molecular weight of this thiol relative to
the others, we chose not to pursue this thiol further.
Thiol 16 is notable in that the major isomer formed by this re-
action crystallized from the mixture of the two isomers initially
isolated. The structure was determined by X-ray diffraction and it is
clear that the long CeS bonds result in a significant distance be-
tween the stereogenic center of the thioether the newly formed
The lack of reactivity of this thiol in the 4CR paired with the lack
of selectivity of less sterically demanding substrates suggests that
the structural requirements for a thiol to exhibit high selectivity
and reactivity is exceedingly narrow. Alkyl thiols exhibit markedly
lower reactivity in this 4CR even when they are unbranched, so it is
unlikely that the right balance will be found with a branched chiral
thiol. On the other hand, the BINOL-derived chiral thiophenol 13
also exhibited low reactivity, presumably solely from the increased
steric demand. The long CeS bond lengths add a layer of difficulty
by increasing the distance between the resident stereogenic center
of the thiol and the nascent center during enolate attack on the
iminium ion. The ideal chiral controller for this reaction would
maintain the high reactivity of aromatic thiols and still provide
a chiral environment that dictates the facial selectivity of the
enolate, which may not be possible with the thiol component.
These studies have helped focus our future efforts on using chiral
amines, developing chiral catalysts and on new and chemically
distinct MCRs.
centers of the g-lactam. Given the ease with which this compound
can be prepared in enantiomerically pure34 form and the pro-
pensity for the major isomer to separate by crystallization, it is
possible that this route could eventually be optimized for the
production of useful quantities of enantiomerically pure g-lactams.
In addition to evaluating thiol 18b in the 4CR and imine-
anhydride reaction, we wanted to ascertain its effectiveness in re-
actions reported with other chiral thiol auxiliaries. Since
norephedrine-derived thiol 11 has been used previously in an anti-
aldol reaction with high diastereoselectivity, we wanted a direct
comparison to the ‘thio-Whitesell’ auxiliary 18b in the same re-
action (Scheme 6). Acylation of thiol 18b with propionyl chloride
yielded thio-ester 41 in high yield. E-selective enolization (Cy2BCl/
Et3N)35 at ꢁ78 ꢀC followed by addition of benzaldehyde yielded the
anti-aldol product (42) as a 59:41 mixture of diastereomers in 71%
yield. trans-Esterification of aldol adduct 42 was readily achieved
by treatment with sodium methoxide, affording methyl ester 43 in
3. Conclusion
In summary, we have synthesized a series of structurally diverse
chiral thiols and examined their utility as auxiliaries in our lab’s
recently disclosed 4CR and in a related imine-anhydride reaction.
These studies required a diastereoselective route to the sulfur
A
B
O
4CR
Imine-Anhydride
Bn
Ph
N
O
Bn
Na2SO4
N
37 + 38
O
CH2Cl2
25°C
O
Ph
O
H
1) toluene, 110°C
Ph
H
39
(D/S Trap)
1) toluene, 110°C
O
40d
2) K2CO3, CH3I,
acetone
2) K2CO3, CH3I,
acetone
37
2
Et3N (cat)
2 + 4
O
R3SH
4
BnNH2
38
Dioxane
60°C
SR3
O
O
7
Bn
Ph
N
CO2CH3
SR3
40a-e
X-ray structure
of 40d
(see Table 2)
Fig. 2. (A) Chiral thiols in 4CR and imine-anhydride reactions. (B) X-ray crystal structure of the major isomer of lactam 40d.

4324
A. Younai et al. / Tetrahedron 68 (2012) 4320e4327
analog of Whitesell’s auxiliary (18), which was achieved after sig-
nificant effort on three potential routes. This thiol exhibited poor
reactivity in our lactam syntheses and poor diastereo-control in
a boron-mediated aldol reaction that was executed in order to draw
direct comparison to the influence of another thiol-based auxiliary.
Although a viable reagent for controlling the absolute stereo-
4.2.1. Indanol derived thiol (15). Yield (55% over two steps) 1H NMR
(600 MHz, CDCl3) 7.51e7.48 (m, 1H), 7.36e7.29 (m, 3H), 4.48 (dd,
d
J¼7.1, 13.5 Hz, 1H), 3.21e3.15 (m, 1H), 3.00e2.93 (m, 1H), 2.75e2.68
(m,1H), 2.17e2.10 (m,1H),1.97 (d, J¼7.4 Hz,1H). 13C NMR (150 MHz,
CDCl3)
d 146.3, 142.9, 127.8, 127.2, 124.9, 124.7, 43.3, 38.4, 31.2. IR
(neat) 2557, 635 cmꢁ1. HRMS (ESI) m/z calcd for C9H9S (MꢁH)ꢁ
chemistry of
g
-lactam synthesis by the imine anhydride reaction or
149.0430, found 149.0440.
4CR is still lacking, we have gained valuable information about the
synthesis and reactivity of chiral thiols. With the synthetic routes
established by this study, the stage is set the exploration of chiral
thiols as chiral controllers for other useful transformations and,
potentially, for their incorporation into novel ligands for transition
metal catalysts.
4.2.2. Tetrahydro-naphthol derived thiol (16). Yield (63% over two
steps) 1H NMR (600 MHz, CDCl3)
d
7.34 (d, J¼6.8 Hz, 1H), 7.14e7.06
(m, 2H), 7.03 (d, J¼6.8 Hz, 1H), 4.33 (s, 1H), 2.85e2.79 (m, 1H),
2.76e2.69 (m, 1H), 2.18e2.10 (m, 2H), 1.95 (d, J¼6.3 Hz, 2H),
1.81e1.75 (m, 1H). 13C NMR (100 MHz, CDCl3)
d 138.9, 136.2, 129.9,
129.3, 126.8, 126.0, 38.2, 33.7, 29.1, 18.9. IR (neat) 2567, 648 cmꢁ1
.
HRMS (ESI) m/z calcd for C10H11
S
(MꢁH)ꢁ 163.0587, found
4. Experimental section
163.0584.
4.1. Materials and instrumentation
4.3. Preparation of 2-phenyl-cyclohexane thiol
Unless otherwise specified, all commercially available reagents
were used as received. All reactions using dried solvents were
carried out under an atmosphere of argon in flame-dried glassware
with magnetic stirring. Dry solvent was dispensed from a solvent
purification system that passes solvent through two columns of dry
neutral alumina. Silica gel chromatographic purifications were
performed by flash chromatography with silica gel (sigma, grade
62, 60e200 mesh) packed in glass columns; the eluting solvent for
each purification was determined by thin layer chromatography
(TLC). Analytical TLC was performed on glass plates coated with
0.25 mm silica gel using UV for visualization.
4.3.1. Allylic thio-carbonate (31). To a cooled (0 ꢀC) solution of al-
lylic alcohol 30 (85 mg, 0.49 mmol), C5H5N (0.24 mL, 2.93 mmol),
and DMAP (6 mg, 0.05 mmol) in CH2Cl2 (2.5 mL) was added O-
phenyl chlorothionoformate (0.20 mL, 1.47 mmol) as a solution in
CH2Cl2 (2.5 mL). After 2 h, the ice bath was removed, and after
stirring for 1 h at room temperature, the reaction was quenched
with H2O. The aqueous phase was extracted with CH2Cl2. The
combined organic phases were dried over MgSO4, concentrated in
vacuo, and the crude product was purified by flash chromatography
(10:90 to 15:85 CH2Cl2/hexanes) to afford the thiocarbonate as
a clear oil (103 mg, 66%). 1H NMR (600 MHz, CDCl3)
d 7.42e7.39 (m,
1H NMR spectra were obtained on a Varian UNITY INOVA
spectrometer (300 MHz) or Varian UNITY INOVA spectrometer
2H), 7.36e7.32 (m, 4H), 7.29e7.26 (m, 1H), 7.22e7.19 (m, 1H),
7.12e7.09 (m, 2H), 6.22 (dd, J¼3.0, 4.8 Hz, 1H), 4.75 (s, 1H),
2.33e2.19 (m, 3H), 2.15e2.08 (m, 1H), 1.91e1.79 (m, 2H). 13C NMR
(600 MHz). Chemical shifts (d) are reported in parts per million
(ppm) relative to residual solvent (CHCl3, s,
d
7.26). Multiplicities
(150 MHz, CDCl3)
d 170.3, 151.3, 140.2, 135.0, 131.1, 129.6, 128.6,
are given as: s (singlet), d (doublet), t (triplet), q (quartet), dd
(doublet of doublets), m (multiplet). Proton-decoupled 13C NMR
spectra were obtained on a Varian UNITY INOVA 400 spectrometer
(100 MHz) or Varian UNITY INOVA 600 spectrometer (150 MHz).
127.6, 126.2, 126.1, 121.5, 44.4, 30.7, 25.9, 18.0. IR (neat) 1719 cmꢁ1
.
HRMS (ESI) m/z calcd for C19H19O2S (MþH)þ 311.1100, found
311.1100.
13C chemical shifts are reported relative to CDCl3
(d 77.2 ppm). IR
4.3.2. Conjugate addition product (34). To a solution of 2-phenyl-2-
cyclohexene-1-one (102 mg, 0.59 mmol) and odor-free30 benzyl
thiol 33 (171 mg, 0.93 mmol) in CH2Cl2 was added triethylamine
frequencies are given in cmꢁ1 and spectra were obtained on
a Bruker Tensor 27 FT-IR spectrometer equipped with a DTGS de-
tector and Smart Orbit single bounce diamond ATR accessory. High-
resolution mass spectra were obtained on a Thermo Fisher LTQ
Orbitrap spectrometer.
(8.0 mL, 0.06 mmol). The solution was stirred for 18 h, the solvent
was removed in vacuo and the crude product was purified by flash
chromatography (50:50 CH2Cl2/hexanes to CH2Cl2 to 20:80 EtOAc/
CH2Cl2) to afford the conjugate addition product as a clear oil
(211 mg, 99%, 77:23 anti/syn; inseparable diastereomeric mixture).
4.2. General procedure for thiol formation from alcohols
Major diastereomer: 1H NMR (400 MHz, CDCl3)
d 7.01e6.96 (m, 2H),
To a solution of benzylic alcohol (7.90 mmol) and thiourea
(1.20 g, 15.80 mmol) in a 1:1 mixture of acetone/H2O (8.0/8.0 mL,
0.5 M) was added 5 N hydrochloric acid dropwise (2.4 mL,
12.00 mmol), and the solution was stirred at room temperature for
12 h. The mixture was basified with NaOH (0.96 g, 24.00 mmol) and
the solution was refluxed for 3 h. The reaction was cooled to room
temperature, acidified with 10% hydrochloric acid, and extracted
with EtOAc. The combined organic phases were dried over MgSO4
and concentrated in vacuo. Purification by flash chromatography
(hexane) afforded an inseparable mixture of the target thiol
(15e17) and the corresponding disulfide (22aec; diastereomeric
mixture) by 1H and 13C NMR.
6.70 (d, J¼7.9 Hz,1H), 6.63e6.58 (m, 2H), 3.84 (d, J¼3.7 Hz,1H), 3.82
(s, 3H), 3.76 (s, 3H), 3.54 (d, J¼11.3 Hz, 1H), 3.35 (d, J¼13.4 Hz, 1H),
3.27 (d, J¼13.4 Hz, 1H), 2.95 (td, J¼3.7, 11.3 Hz, 1H), 2.44e2.38 (m,
1H), 2.33e2.27 (m, 1H), 2.12e2.07 (m, 1H), 1.92e1.81 (m, 1H),
d 207.7, 149.0, 148.1,
136.66, 130.4, 130.1, 129.4, 128.2, 128.00, 127.27, 120.9, 111.7, 110.6,
1.74e1.61 (m, 1H). 13C NMR (100 MHz, CDCl3)
63.5, 55.91, 55.78, 48.4, 41.2, 35.4, 32.9, 25.0. Visible Peaks for Minor
Diastereomer: 1H NMR (400 MHz, CDCl3)
d 7.43e7.39 (m, 2H),
7.34e7.32 (m, 1H), 7.25e7.22 (m, 1H), 6.80e6.74 (m, 2H), 6.67 (d,
J¼8.2 Hz, 1H), 6.53e6.49 (m, 1H), 3.92 (d, J¼4.4 Hz, 1H), 3.80 (s, 3H),
3.75 (s, 3H), 3.25e3.20 (m, 1H), 3.12 (d, J¼13.3 Hz, 1H), 2.55e2.47
(m, 2H), 2.38e2.33 (m, 1H), 2.23e2.15 (m, 1H). 13C NMR (100 MHz,
To a cooled (0 ꢀC) solution of thiol/disulfide in THF (40.0 mL,
0.2 M) was added lithium aluminum hydride (0.35 g, 9.10 mmol).
After 18 h, 10% hydrochloric acid was added dropwise until a gray
amorphous solid formed. The mixture was then filtered, and the
filtrate was dried over MgSO4 and concentrated in vacuo. Purifi-
cation by flash chromatography (hexanes) afforded the thiol
product as a colorless oil.
CDCl3) d 207.2, 148.9, 136.2, 129.9, 127.26, 121.1, 112.1, 110.7, 60.7,
55.88, 49.5, 40.8, 36.1, 31.6, 23.0. IR (neat) 1713 cmꢁ1. HRMS (ESI) m/
z calcd for C21H24NaO3S (MþNa)þ 379.1344, found 379.1343.
4.3.3. Anti-hydrazone (35). To a solution of 34 (70 mg, 0.20 mmol)
in CH2Cl2 (2.0 mL, 0.1 M) was added tosyl hydrazide (44 mg,
0.24 mmol) and the reaction was stirred for 48 h. The mixture was

A. Younai et al. / Tetrahedron 68 (2012) 4320e4327
4325
concentrated in vacuo and the crude product was purified by col-
umn chromatography (15:85 to 30:70 EtOAc/hexanes) to afford the
anti-hydrazone product as a colorless solid (62 mg, 59%). Mp
Method B (Imine-Anhydride). To a solution of maleic anhydride
(98 mg, 1.0 mmol) and triethylamine (1.5 L, 0.01 mmol) in benzene
m
(1.0 mL) was added thiol (1.0 mmol) as a solution in benzene
(1.5 mL). The solution was heated to 60 ꢀC for 30 min then cooled to
room temperature. Concentration in vacuo afforded the thio-
substituted succinic anydride product, which was used without
further purification.
To a solution of benzaldehyde (0.10 mL, 1.0 mmol), and Na2SO4
(0.43 g, 3.0 mmol) in CH2Cl2 (10.0 mL, 0.1 M) was added benzyl
amine (0.11 mL, 1.0 mmol). After stirring for 3 h, the reaction
mixture was filtered through Celite, and the filtrate was concen-
trated in vacuo to afford the imine product. The imine was re-
dissolved in toluene (10.0 mL, 0.1 M) and was added to the thio-
substituted succinic anhydride. This mixture was refluxed for
18 h. After cooling to room temperature, the solvent was removed
in vacuo. The residue was methylated and purified in the same
manner as in method A.
118e126 ꢀC; 1H NMR (600 MHz, CDCl3)
d 7.81 (s, 1H), 7.38 (d,
J¼8.0 Hz, 2H), 7.30e7.25 (m, 3H), 7.06 (d, J¼8.0 Hz, 2H), 6.98e6.94
(m, 2H), 6.74e6.65 (m, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.44 (d,
J¼9.6 Hz, 1H), 3.40 (d, J¼9.6 Hz, 1H), 3.05 (td, J¼3.8, 9.2, 1H),
2.52e2.46 (m, 1H), 2.36 (s, 3H), 2.15 (s, 1H), 2.14e2.11 (m, 1H),
2.05e1.97 (m, 1H), 1.93e1.86 (m, 1H), 1.69e1.60 (m, 1H), 1.54e1.45
(m,1H). 13C NMR (150 MHz, CDCl3)
d 160.6,149.2,148.2,143.7,138.9,
135.0, 130.5, 130.0, 129.8, 129.6, 129.5, 129.3, 128.4, 128.12, 128.08,
128.0, 127.5, 126.8, 121.1, 112.0, 110.9, 56.10, 56.09, 56.0, 46.8, 35.4,
31.5, 31.2, 29.5, 26.1, 23.5, 21.8. IR (neat) 3196, 1736 cmꢁ1. HRMS
(ESI) m/z calcd for C28H33N2O4S2 (MþH)þ 525.1876, found 525.1874.
4.3.4. Tosylhydrazone reduction (36). To a solution of hydrazone 35
(197 mg, 0.38 mmol) in EtOH (15.0 mL, 0.025 M) was added
NaBH3CN (99 mg, 1.50 mmol) and a 1 N solution of ZnCl2 (0.38 mL,
0.38 mmol) in Et2O. The resulting suspension was refluxed for 12 h.
The reaction was quenched with 1 N NaOH solution and NaCl, then
extracted with EtOAc. The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The crude product was purified
by flash chromatography to afford the reduced product as a clear oil
4.4.1. Lactam from camphor derived thiol (40a). Yield (21% by
method A, 31% by method B, 62:38 dr, inseparable mixture, yellow
oil). Major diastereomer: 1H NMR (600 MHz, CDCl3)
d 7.33 (m, 2H),
7.27 (m, 3H), 7.17 (m, 2H), 7.02 (m, 3H), 5.14 (d, J¼15.1 Hz, 1H), 4.92
(s, 1H), 3.63 (s, 3H), 3.57 (d, J¼16.6 Hz, 1H), 3.45 (d, J¼15.1 Hz, 1H),
3.07 (d, J¼7.6 Hz, 1H), 3.03 (d, J¼7.7 Hz, 1H), 2.81 (d, J¼7.7 Hz, 1H),
2.70 (d, J¼7.6 Hz, 1H), 1.61 (m, 2H), 1.38 (d, J¼4.0 Hz, 1H), 1.27 (d,
J¼4.0 Hz, 1H), 0.93 (s, 1H), 0.91 (m, 1H), 0.89 (s, 3H), 0.84 (s, 3H),
(91 mg, 71%). 1H NMR (600 MHz, CDCl3)
d 7.23e7.20 (m, 1H),
7.13e7.08 (m, 2H), 6.74 (d, J¼8.1 Hz, 1H), 6.67 (d, J¼2.0 Hz, 1H), 6.64
(dd, J¼2.0, 8.1 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.34 (d, J¼13.4 Hz,
1H), 3.27 (d, J¼13.4 Hz, 1H), 2.58 (td, J¼3.8, 11.5 Hz, 1H), 2.50 (td,
J¼3.6, 11.5 Hz, 1H), 2.24e2.18 (m, 1H), 1.90e1.85 (m, 1H), 1.85e1.80
(m, 1H), 1.80e1.74 (m, 1H), 1.52e1.42 (m, 2H), 1.40e1.29 (m, 2H). 13C
0.78 (s, 3H), 0.65 (s, 9H). 13C NMR (150 MHz, CDCl3)
d 173.4, 172.1,
135.94, 135.5, 134.4, 129.04, 128.95, 128.71, 128.25, 127.82, 89.3,
83.6, 67.3, 55.3, 53.4, 53.1, 52.95, 50.3, 47.1, 44.8, 40.8, 33.4, 32.7,
28.5, 26.9, 21.17, 21.15, 11.9. Visible peaks for minor diastereomer: 1H
NMR (150 MHz, CDCl3)
d 149.1, 148.0, 145.5, 131.2, 128.4, 127.9,
126.5, 121.1, 112.1, 110.1, 56.1, 56.0, 51.4, 48.0, 36.3, 35.04, 34.96, 27.0,
26.4. IR (neat) 655 cmꢁ1. HRMS (ESI) m/z calcd for C21H26NaO2S
(MþNa)þ 365.1551, found 365.1542.
NMR (600 MHz, CDCl3) d 7.39e7.36 (m, 3H), 7.29e7.27 (m, 3H),
7.17e7.15 (m, 2H), 5.11 (d, J¼9.8 Hz, 1H), 3.66 (s, 3H), 3.43e3.39 (m,
2H), 2.49 (d, J¼7.6 Hz, 1H), 2.42 (d, J¼7.7 Hz, 1H), 0.75 (s, 3H), 0.70
(s, 9H), 0.68 (s, 3H), 0.66 (s, 3H). 13C NMR (150 MHz, CDCl3)
d 173.0,
4.3.5. 2-Phenyl-cyclohexane thiol (18b). A solution of thioether 36
(107 mg, 0.31 mmol) in THF (3.1 mL, 0.1 M) was added drop-wise to
a well-stirred solution of sodium metal (36 mg,1.56 mmol) in liquid
ammonia (w3 mL) at ꢁ78 ꢀC. After 1 h at ꢁ78 ꢀC, 5 mL of CH3OH
was added followed by 5 mL of satd NH4Cl. After warming to room
temperature, the mixture was partitioned between H2O and
CH2Cl2, and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were dried over MgSO4, concentrated in
vacuo, and the crude product was purified by flash chromatography
(0:100 to 3:97 EtOAc/hexanes) to afford the free thiol as a colorless
171.8, 135.90, 128.68, 128.31, 127.80, 88.8, 83.1, 67.0, 54.9, 53.3,
53.03, 52.9, 50.1, 47.3, 45.1, 41.1, 33.2, 32.6, 28.4, 27.0, 21.5, 21.16,
11.8. IR (neat) 1727, 1699 cmꢁ1
. HRMS (ESI) m/z calcd for
C34H46NO4S (MþH)þ 564.3142, found 564.3144.
4.4.2. Lactam from cystine derived thiol (40b). Yield (41% by
method A, 41% by method B, 54:46 dr; inseparable mixture, yellow
oil). NMR Peaks for major & minor isomers are nearly indistinguish-
able: 1H NMR (600 MHz, CDCl3)
d
7.71 (t, J¼7.5 Hz, 3H), 7.52 (s, 2H),
7.46e7.40 (m, 4H), 7.40e7.37 (m, 3H), 7.34 (s, 4H), 7.27 (s, 2H), 7.26
(s, 1H), 7.21e7.15 (m, 4H), 7.02e6.98 (m, 3H), 6.62 (d, J¼7.4 Hz, 2H),
5.14 (d, J¼14.8 Hz, 2H), 4.93 (s, 1H), 4.92 (s, 1H), 4.80e4.73 (m, 2H),
3.81 (d, J¼27.1 Hz, 1H), 3.72 (s, 3H), 3.68 (s, 3H), 3.63 (s, 3H), 3.60 (s,
3H), 3.44 (d, J¼14.8 Hz, 2H), 3.37 (d, J¼17.5 Hz,1H), 3.17 (d, J¼7.1 Hz,
1H), 2.87e2.84 (m, 1H), 2.81 (d, J¼7.1 Hz, 1H), 2.78 (d, J¼6.8 Hz, 1H),
oil (56 mg, 94%). 1H NMR (400 MHz, CDCl3)
d 7.35e7.28 (m, 2H),
7.25e7.16 (m, 3H), 3.11e3.02 (m, 1H), 2.46 (td, J¼3.6, 11.3 Hz, 1H),
2.22e2.15 (m, 1H), 1.94e1.79 (m, 3H), 1.55e1.40 (m, 4H), 1.34 (d,
J¼4.1 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 145.1, 128.7, 127.8, 126.8,
54.5, 44.0, 37.1, 36.0, 27.2, 26.6. IR (neat) 2573, 623 cmꢁ1. HRMS
(ESI) m/z calcd for C12H15S (MꢁH)ꢁ 191.0900, found 191.0896.
2.66 (dd, J¼6.2, 12.9 Hz, 1H). 13C NMR (150 MHz, CDCl3)
d 171.84,
171.83, 171.3, 171.2, 170.7, 170.6, 167.1, 167.0, 135.6, 134.4, 134.2,
133.6, 132.13, 132.11, 129.43, 129.41, 129.0, 128.9, 128.82, 128.81,
128.78, 128.77, 128.76, 128.73, 128.5, 128.4, 128.0, 127.33, 127.32,
66.82, 66.78, 55.5, 55.3, 53.59, 53.56, 53.02, 52.97, 51.9, 51.6, 45.0,
4.4. General procedure for forming g-lactams
Method A (4CR). A solution of thiol (1.00 mmol), maleic anhy-
dride (98 mg, 1.0 mmol), benzyl amine (0.11 mL, 1.0 mmol), and
benzaldehyde (0.10 mL, 1.0 mmol) in toluene (10.0 mL, 0.1 M) was
refluxed with a DeaneStark trap for 18 h. After cooling to room
temperature, the solvent was removed in vacuo. The residue was
then re-dissolved in acetone (10 mL, 0.1 M), followed by addition of
anhydrous K2CO3 (0.55 g, 4.0 mmol) and CH3I (0.25 mL, 4.0 mmol).
This mixture was stirred for 12 h, and then the solvent was re-
moved in vacuo. The residue was partitioned between H2O and
EtOAc, and the aqueous layer was extracted with EtOAc. The com-
bined organic layers were dried over MgSO4, concentrated in vacuo,
and the crude product was purified by flash chromatography (0:100
40.73, 40.69, 32.56, 32.54. IR (neat) 3321, 1729, 1685, 1681 cmꢁ1
.
HRMS (ESI) m/z calcd for C30H31N2O6S (MþH)þ 547.1898, found
547.1896.
4.4.3. Lactam from indanol derived thiol (40c). Yield (21% by
method A, 31% by method B, 51:49 dr; inseparable mixture, yellow
oil). NMR Peaks for major & minor isomers are nearly indistinguish-
able: 1H NMR (800 MHz, CDCl3)
d 7.42e7.38 (m, 6H), 7.32e7.27 (m,
6H), 7.24e7.21 (m, 4H), 7.12e6.98 (m, 12H), 5.20 (d, J¼14.8 Hz, 1H),
5.17 (d, J¼14.8 Hz, 1H), 5.13 (s, 1H), 4.95 (s, 1H), 4.09 (s, 2H), 3.98 (s,
1H), 3.95 (s, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 3.67 (d, J¼17.1 Hz, 1H),
3.52 (d, J¼17.1 Hz, 1H), 3.46 (dd, J¼4.3, 14.5 Hz, 2H), 2.97 (d,
to 60:40 EtOAc/hexanes) to afford the g-lactam.

4326
A. Younai et al. / Tetrahedron 68 (2012) 4320e4327
J¼17.0 Hz, 1H), 2.92e2.83 (m, 4H), 2.77e2.68 (m, 3H), 2.44e2.40
(m,1H), 2.30e2.26 (m,1H),1.92e1.87 (m,1H),1.80e1.76 (m,1H). 13C
between H2O and CH2Cl2. The aqueous phase was extracted with
CH2Cl2. The combined organic phases were dried over MgSO4 and
concentrated in vacuo. The crude product was purified by flash
chromatography (15:85 EtOAc/hexanes) to yield the aldol adduct as
a colorless oil (25 mg, 71%, 59:41 dr, inseparable mixture). 1H NMR
(600 MHz, CDCl3; distinguishable peaks for minor diastereomer ita-
NMR (200 MHz, CDCl3)
d 173.0, 172.6, 172.0, 171.7, 143.46, 143.43,
142.3, 141.7, 135.83, 135.78, 134.77, 134.2, 129.33, 129.26, 129.0,
128.82, 128.80, 128.4, 128.3, 127.97, 127.95, 127.90, 127.88, 126.7,
126.6, 125.3, 124.63, 124.57, 67.4, 67.2, 56.4, 55.8, 53.6, 53.5, 48.61,
48.59, 45.0, 44.8, 41.5, 41.4, 35.7, 35.2, 31.1, 31.0. IR (neat) 1726,
1699 cmꢁ1. HRMS (ESI) m/z calcd for C28H28NO3S (MþH)þ 458.1785,
found 458.1784.
licized)
d 7.32e7.29 (m, 2H), 7.27 (m, 3H), 7.26e7.22 (m, 6H),
7.21e7.18 (m, 3H), 7.17e7.14 (m, 3H), 4.61 (d, J¼8.3 Hz, 1H), 4.51 (d,
J¼8.6 Hz, 1H), 3.83e3.77 (m, 1H), 3.79e3.74 (m, 1H), 2.76e2.70 (m,
2H), 2.60 (td, 3.9, 12.2 Hz, 1H), 2.55 (td, J¼3.9 Hz, 12.2, 1H), 2.21e2.14
(m, 2H), 2.02e1.93 (m, 2H), 1.89e1.80 (m, 3H), 1.66e1.49 (m, 5H),
1.45e1.33 (m, 2H), 0.82 (d, J¼7.1, 3H), 0.63 (d, J¼7.1 Hz, 3H). 13C
NMR (150 MHz, CDCl3; distinguishable peaks for minor diastereomer
4.4.4. Lactam from tetrahydro-naphthol derived thiol (40d). Yield
(23% by method A, 20% by method B, 64:36 dr). A small sample of
the major diastereomer was isolated by crystallization from semi-
pure mixture in CH3OH for characterization (colorless crystalline
italicized)
d 202.90, 202.88, 144.5, 144.4, 141.7, 141.2, 133.9, 130.4,
solid): mp 153e156 ꢀC; 1H NMR (600 MHz, CDCl3)
d
7.38e7.34 (m,
129.4, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 127.85, 127.82,
126.87, 126.81, 126.71, 126.67, 76.72, 76.69, 55.95, 55.71, 50.24, 50.03,
47.33, 47.09, 36.38, 36.29, 34.99, 34.88, 26.95, 26.93, 26.33, 26.32,
15.45, 15.43. IR (neat) 3459, 1692 cmꢁ1. HRMS (ESI) m/z calcd for
C22H27O2S (MþH)þ 355.1726, found 355.1726.
3H), 7.31e7.27 (m, 3H), 7.20e7.17 (m, 2H), 7.06e7.00 (m, 5H),
6.95e6.91 (m, 1H), 5.17 (d, J¼14.8 Hz, 1H), 4.93 (s, 1H), 3.99e3.96
(m, 1H), 3.71 (d, J¼16.7 Hz, 1H), 3.66 (s, 3H), 3.44 (d, J¼14.8 Hz, 1H),
3.04 (d, J¼16.7 Hz, 1H), 2.68e2.55 (m, 2H), 1.86e1.74 (m, 2H),
1.71e1.60 (m, 2H). 13C NMR (150 MHz, CDCl3)
d 172.8, 171.8, 137.6,
135.9, 135.8, 134.3, 130.7, 129.24, 129.21, 128.8, 128.4, 127.9, 127.1,
126.0, 67.6, 56.1, 53.3, 44.8, 44.4, 41.7, 30.5, 28.8, 19.0. IR (neat) 1724,
1698 cmꢁ1. HRMS (ESI) m/z calcd for C29H30NO3S (MþH)þ 472.1941,
found 472.1941.
Acknowledgements
This research was supported by startup funds from UC Davis and
the NSF in the form of a CAREER award to J.T.S.
4.4.5. Lactam from 1-(1-naphthyl)ethanol derived thiol (40e). Yield
(21% by method A, 38% by method B, 64:36 dr, colorless oil). A small
sample of the major diastereomer was isolated by HPLC for char-
Supplementary data
1H and 13C NMR for novel compounds, experimental procedures
for compounds 17, 29, and 43, and X-ray crystallographic data for
compounds 35 and 40d. Supplementary data related to this article
can be found online at doi:10.1016/j.tet.2012.03.027.
acterization: 1H NMR (600 MHz, CDCl3)
d
7.80 (d, J¼8.0 Hz, 2H), 7.67
(d, J¼8.0 Hz, 1H), 7.49e7.41 (m, 6H), 7.35 (t, J¼7.6 Hz, 2H), 7.24e7.18
(m, 4H), 6.98e6.92 (m, 2H), 5.09 (d, J¼14.8 Hz,1H), 4.95 (s, 1H), 4.41
(br s, 1H), 3.42 (d, J¼14.8 Hz, 1H), 3.06 (s, 3H), 2.97 (d, J¼17.3 Hz,
1H), 2.55 (d, J¼17.3 Hz, 1H), 1.27 (d, J¼6.5 Hz, 3H). 13C NMR
References and notes
(150 MHz, CDCl3)
d 171.8, 171.7, 139.5, 135.7, 134.6, 133.9, 130.3,
1. See, for example: (a) Banfi, L.; Basso, A.; Cerulli, V.; Rocca, V.; Riva, R. Beilstein J.
Org. Chem. 2011, 7, 976 and references cited therein; (b) For previous work on the
Ugi 4CR, including chiral substrates, see Doemling, A. Chem. Rev. 2006, 106, 17.
2. Biggs-Houck, J. E.; Younai, A.; Shaw, J. T. Curr. Opin. Chem. Biol. 2010, 14, 371.
3. Wei, J.; Shaw, J. T. Org. Lett. 2007, 9, 4077.
129.2, 129.1, 128.6, 128.2, 128.1, 127.8, 126.1, 125.7, 125.4, 67.2, 55.7,
52.7, 44.7, 40.8, 24.1. IR (neat) 1730, 1700 cmꢁ1. HRMS (ESI) m/z
calcd for C31H30NO3S (MþH)þ 496.1941, found 496.1941.
4. Ng, P. Y.; Masse, C. E.; Shaw, J. T. Org. Lett. 2006, 8, 3999.
5. Evans, D. A.; Helmchen, G.; Ruping, M.; Wolfgang, J. Asymmetric Synth. 2007,
p 3.
4.5. Other applications of 2-phenyl-cyclohexane thiol
6. Fanjul, S.; Hulme, A. N.; White, J. W. Org. Lett. 2006, 8, 4219.
7. Lee, D. S.; Hung, S. M.; Lai, M. C.; Chu, H. Y.; Yang, T. K. Org. Prep. Proced. Int.
1993, 25, 673.
8. (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586; (b) Abiko,
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9. (a) Helmchen, G.; Schmierer, R. Angew. Chem., Int. Ed. 1981, 20, 205; (b)
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11. Whitesell, J. K. Chem. Rev. 1992, 92, 953.
4.5.1. Propionylated thiol (41). To a solution of thiol 18b (81 mg,
0.42 mmol) in CH2Cl2 (2.1 mL, 0.2 M) was added pyridine (46
0.57 mmol) followed by propionyl chloride (66 L, 0.76 mmol) at
ꢀC. The reaction mixture was warmed to room temperature and
mL,
m
0
stirred for 18 h. The reaction mixture was diluted with Et2O and was
washed with H2O and brine. The organics were dried (MgSO4) and
concentrated in vacuo to give the crude product, which was puri-
fied by flash chromatography (5:95 EtOAc/hexanes) to afford the
thio-ester as a colorless oil (89 mg, 85%). 1H NMR (600 MHz, CDCl3)
12. Cravotto, G.; Giovenzana, G. B.; Pilati, T.; Sisti, M.; Palmisano, G. J. Org. Chem.
2001, 66, 8447.
d
7.26 (t, J¼7.7 Hz, 2H), 7.20e7.17 (m, 1H), 7.15 (d, J¼7.7 Hz, 2H),
13. (a) Hung, S. M.; Lee, D. S.; Yang, T. K. Tetrahedron: Asymmetry 1990, 1, 873; (b)
Yang, T.-K.; Chen, R.-Y.; Lee, D.-S.; Peng, W.-S.; Jiang, Y.-Z.; Mi, A.-Q.; Jong, T.-T. J.
Org. Chem. 1994, 59, 914.
14. Fabbri, D.; Pulacchini, S.; Gladiali, S. Synlett 1996, 1054.
15. Brunel, J. M. Chem. Rev. 2005, 105, 857.
16. Menger, F. M.; Caran, K. L. J. Am. Chem. Soc. 2000, 122, 11679.
17. Busnel, O.; Carreaux, F.; Carboni, B.; Pethe, S.; Goff, S. V.-L.; Mansuy, D.; Boucher,
J.-L. Bioorg. Med. Chem. 2005, 13, 2373.
3.74e3.67 (m, 1H), 2.56 (td, J¼3.6, 12.0 Hz, 1H), 2.38e2.29 (m, 2H),
2.22e2.17 (m, 1H), 2.00e1.93 (m, 1H), 1.85e1.80 (m, 2H), 1.60e1.50
(m, 3H), 1.45e1.36 (m, 1H), 1.00e0.96 (m, 3H). 13C NMR (150 MHz,
CDCl3)
d 199.8, 144.5, 128.2, 127.4, 126.4, 49.3, 47.0, 37.4, 36.5, 35.2,
26.7, 26.2, 9.7. IR (neat) 1686 cmꢁ1. HRMS (ESI) m/z calcd for
C15H21OS (MþH)þ 249.1308, found 249.1305.
18. Vetter, S. Synth. Commun. 1998, 28, 3219.
19. When the isothiouronium salts were exposed to hydrolysis conditions for ex-
tended periods (>12 h) they underwent complete conversion to the disulfides,
although in very low yield (10e15%). This is the source of pure 22b for testing
disulfide cleavage conditions.
4.5.2. Thio-Whitesell aldol adduct (42). To a solution of thio-ester
41 (25 mg, 0.10 mmol), in CH2Cl2 (5.0 mL, 0.02 M) at ꢁ78 ꢀC was
added dicyclohexylboron chloride (0.20 mL, 1.0 M in hexane,
0.20 mmol), then Et3N (56
was stirred for 2 h, then freshly distilled benzaldehyde (43
20. Though thiols 15 and 16 have been reported previously, the reported 13C NMR
spectra for these compounds contained twice the expected number of signals
(Nishio, T. J. Chem. Soc., Perkin Trans. 1 1993, 1113). We attributed this to the
presence of a diastereomeric mix of disulfides. After treatment of this mixture
with LiAlH4, the 13C NMR spectrum contained the expected number of signals.
21. (a) LiBH4: Rajaram, S.; Chary, K. P.; Iyengar, D. S. Indian J. Chem. 2001, 40B, 622;
(b) NaBH4: Turos, E.; Revell, K. D.; Ramaraju, P.; Gergeres, D. A.; Greenhalgh, K.;
Young, A.; Sathyanarayan, N.; Dickey, S.; Lim, D.; Alhamadsheh, M. M.; Rey-
nolds, K. Bioorg. Med. Chem. 2008, 16, 6501; (c) Mgꢀ/MeOH: Sridhar, M.; Vadivel,
mL, 0.40 mmol). The reaction mixture
mL,
0.40 mmol) was added. The reaction mixture was stirred at ꢁ78 ꢀC
for 4 h, followed by the addition of pH 7 buffer (1 mL), CH3OH
(3 mL), and the careful addition of 30% H2O2 (1 mL). The reaction
mixture was stirred vigorously for 14 h, and then partitioned

A. Younai et al. / Tetrahedron 68 (2012) 4320e4327
4327
S. K.; Bhalerao, U. T. Synth. Commun. 1997, 27, 1347; (d) Inꢀ/NH4Cl: Reddy, G. V.
S.; Rao, G. V.; Iyengar, D. S. Synth. Commun. 2000, 30, 859; (e) LiAlH4/Et2O:
Silvestri, M. G.; Wong, C.-H. J. Org. Chem. 2001, 66, 910; (f) LiAlH4/THF: Ban-
darage, U. K.; Chen, L.; Fang, X.; Garvey, D. S.; Glavin, A.; Janero, D. R.; Letts, L.
G.; Mercer, G. J.; Saha, J. K.; Schroeder, J. D.; Shumway, M. J.; Tam, S. W. J. Med.
Chem. 2000, 43, 4005.
28. Barriault, L.; Thomas, J. D. O.; Clement, R. J. Org. Chem. 2003, 68, 2317.
29. For specific conditions of attempted hydrogenations of 31, see Table 1 in the
Supplementary data.
30. O’Byrne, A.; Murray, C.; Keegan, D.; Palacio, C.; Evans, P.; Morgan, B. S. Org.
Biomol. Chem. 2010, 8, 539.
31. For other ‘odorless’ thiols see: (a) Node, M.; Kumar, K.; Nishide, K.; Ohsugi, S.-i.;
Miyamoto, T. Tetrahedron Lett. 2001, 42, 9207; (b) Nishide, K.; Miyamoto, T.;
Kumar, K.; Ohsugi, S.-i.; Node, M. Tetrahedron Lett. 2002, 43, 8569.
32. The configuration of 35 was determined by X-ray crystallography. See
Supplementary data.
22. Jackman, H.; Marsden, S. P.; Shapland, P.; Barrett, S. Org. Lett. 2007, 9, 5179.
23. Kruger, D.; Sopchik, A. E.; Kingsbury, C. A. J. Org. Chem. 1984, 49, 778.
24. Smissman, E. E.; Pazdernik, T. L. J. Med. Chem. 1973, 16, 14.
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elimination in the presence of potassium acetate: Murahashi, S.; Moritani, I.
Bull. Chem. Soc. Jpn. 1968, 41, 1884.
33. A preliminary experiment showed low yield of an un-characterizable mixture
of diastereomers.
26. Takaku, H.; Miyamoto, Y.; Asami, S.; Shimazaki, M.; Yamada, S.; Yamamoto, K.;
Udagawa, N.; DeLuca Hector, F.; Shimizu, M. Bioorg. Med. Chem. 2008, 16, 1796.
27. Derived in two steps from commercially available 2-cyclohexen-1-one: Felpin,
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34. Peschiulli, A.; Procuranti, B.; O’Connor, C. J.; Connon, S. J. Nat. Chem. 2010, 2,
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