Attempted enantiotopic group selective cyanohydrin formation from α-alkoxy aldehydes by double stereodifferentiation

Article abstract of DOI:10.1139/v01-151

Enantiotopic group selectivity can result from the competition between substrate and reagent double stereodifferentiation. We have examined this approach for enantioselective hydrocyanation of racemic α-alkoxy aldehydes (e.g., 2-(phenylmethoxy)heptanal (1)). Reaction of 1 with TMSCN mediated by chiral nonracemic alkoxy Ti(IV) reagents under conditions known to be reasonably enantioface selective in reactions with achiral aldehydes, proceeded with very low enantiotopic group selectivity (<2:1). It was established that TMSCN can react with Ti(IV) reagents to produce "TiCN" adducts that are capable of hydrocyanation but with low substrate-controlled diastereoselectivity in reactions with 1. The poor enantiotopic group selectivity observed can be rationalized to result from this low diastereoselectivity despite the respectable levels of enantioface selectivity associated with these reagents in hydrocyanation of achiral aldehydes. Highly diastereoselective hydrocyanation of α-alkoxy aldehydes can be achieved with TMSCN in the presence of excess MgBr₂·OEt₂. High diastereoselectivity was also observed using achiral and chiral TiCN adducts in place of TMSCN. Although the putative TiCN adducts obtained from nonracemic alkoxy Ti(IV) reagents are implicated in enantioface selective hydrocyanation, these reagents were not enantiotopic group selective under these conditions and showed no evidence of double stereodifferentiation. The use of nonracemic bisoxazoline ligands for Mg(II) was also ineffective.

Full text of DOI:10.1139/v01-151

1
775
Attempted enantiotopic group selective
cyanohydrin formation from -alkoxy aldehydes by
double stereodifferentiation
Dale E. Ward, Marcelo Sales, and Matthew J. Hrapchak
Abstract: Enantiotopic group selectivity can result from the competition between substrate and reagent double
stereodifferentiation. We have examined this approach for enantioselective hydrocyanation of racemic a-alkoxy
aldehydes (e.g., 2-(phenylmethoxy)heptanal (1)). Reaction of 1 with TMSCN mediated by chiral nonracemic alkoxy
Ti(IV) reagents under conditions known to be reasonably enantioface selective in reactions with achiral aldehydes,
proceeded with very low enantiotopic group selectivity (<2:1). It was established that TMSCN can react with Ti(IV)
reagents to produce “TiCN” adducts that are capable of hydrocyanation but with low substrate-controlled
diastereoselectivity in reactions with 1. The poor enantiotopic group selectivity observed can be rationalized to result
from this low diastereoselectivity despite the respectable levels of enantioface selectivity associated with these reagents
in hydrocyanation of achiral aldehydes. Highly diastereoselective hydrocyanation of a-alkoxy aldehydes can be
achieved with TMSCN in the presence of excess MgBr ·OEt . High diastereoselectivity was also observed using achiral
2
2
and chiral TiCN adducts in place of TMSCN. Although the putative TiCN adducts obtained from nonracemic alkoxy
Ti(IV) reagents are implicated in enantioface selective hydrocyanation, these reagents were not enantiotopic group
selective under these conditions and showed no evidence of double stereodifferentiation. The use of nonracemic
bisoxazoline ligands for Mg(II) was also ineffective.
Key words: cyanohydrin, 2-alkoxyalkanal, double stereodifferentiation, enantiotopic group selective reaction,
kinetic resolution.
Résumé : La sélecti vWi t aé r dé n ea tn t ai ol .topique de groupe peut découler d’une compétition entre la stéréodifférenciation double
entre le substrat et le réactif. On a examiné cette approche pour l’hydrocyanuration énantiosélective d’a-
alkoxyaldéhydes racémiques (par exemple, le 2-(phénylméthoxy)heptanal (1)). Lors de la réaction avec le TMSCN,
sous l’influence de réactifs chiraux non racémiques de type alkoxy Ti(IV), dans des conditions reconnues pour être
énantiosélectives au cours de réactions avec les faces d’aldéhydes achiraux, la sélectivité énantiotopique de groupe était
très faible (< 2:1). Il a été établi que le TMSCN peut réagit avec les réactifs du Ti(IV) pour conduire à la production
d’adduits “TiCN” qui, lors de réactions avec le composé 1, peuvent donner lieu à une hydrocyanuration pour laquelle
la diastéréosélectivité contrôlée par le substrat est faible. On peut imaginer que la faible sélectivité énantiotopique de
groupe observée résulte de cette faible diastéréosélectivité malgré les niveaux respectables de énantiosélectivité par
rapport aux faces qui sont associées à ces réactifs dans l’hydrocyanuration d’aldéhydes achiraux. On peut réaliser des
hydrocyanurations hautement diastéréosélectives d’a-alkoxyaldéhydes à l’aide de TMSCN, en présence d’un excès de
MgBr ·OEt . On a aussi observé une diastéréosélectivité lorsqu’on a utilisé des adduits TiCN achiraux et chiraux à la
2
2
place du TMSCN. Les adduits TiCN présumés, obtenus à partir de réactifs non racémiques de type alkoxy Ti(IV), sont
impliqués dans des hydrocyanurations énantiosélectives par rapport aux faces; toutefois, dans ces conditions, ces
réactifs ne donnent pas lieu à de la sélectivité énantiotopique de groupe et ne présentent pas de signe de double
stéréodifférenciation. L’utilisation de ligands bisaxozolines non racémiques pour des composés de type Mg(II) est aussi
inefficace.
Mots clés : cyanohydrine, 2-alkoxyalcanal, double stéréodifférenciation, réaction avec sélectivité énantiotopique de
groupe, dédoublement cinétique.
[
Traduit par la Rédaction] 1785
Received March 22, 2001. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on November 20, 2001.
This paper is dedicated to Professor Victor Snieckus in celebration of his numerous contributions to chemistry and to the chemistry
community in Canada.
1
D.E. Ward, M. Sales, and M.J. Hrapchak. Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon
SK S7N 5C9, Canada.
1Corresponding author (telephone: (306) 966-4656; fax: (306) 966-4730; e-mail: Dale.Ward@usask.ca).
Can. J. Chem. 79: 1775–1785 (2001)
DOI: 10.1139/cjc-79-11-1775
© 2001 NRC Canada

1
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Can. J. Chem. Vol. 79, 2001
Scheme 1
Introduction
1
S)-2s R =n-C H , R =H
2
(
OBn
S)
5
11
The development of new methods for asymmetric synthe-
sis continues to attract considerable attention (1). Although
the majority of known methods involve enantioselective ad-
dition to a ꢀ-bond of an achiral substrate (i.e., an enanti-
otopic face selective reaction), the use of enantiotopic group
1
(S)-3s R =n-C
2
11, R =(S)-MTPA
(
5
H
1
CN
R
1
(S)-5s R =t-Bu, R = H
2
(
S)
2
1
S)-6s R =t-Bu, R = (S)-MTPA
2
OBn
OR
(
kS
1
H
R
1
2
(S)-2a R =n-C H , R = H
selective reactions for desymmetrization of achiral C (or C )
O
s
i
OBn
(R)
(S)
5 11
1
(S)-3a R =n-C H , R = (S)-MTPA
2
symmetric substrates has recently emerged as an alternative
strategy (2). This approach is particularly effective when the
enantiotopic groups can react sequentially thereby coupling
an asymmetric synthesis with a kinetic resolution and pro-
ducing products with high stereoisomeric purity (3). We
have previously shown that such processes can yield prod-
ucts with very high stereoisomeric purity from reactions
with modest enantioselectivity (4) and even from mixtures
of substrate stereoisomers (5). Both the efficiency and effi-
cacy of these processes are improved with recycling, espe-
cially if the enantioselectivity is modest (4, 5). Because
recycling requires that the product(s) (or byproducts) be effi-
ciently converted back into the starting material(s), enanti-
otopic group selective reactions that are easily “reversed” are
desirable. We have previously targeted enantioselective re-
duction of chiral aldehydes (reversed by oxidation of the
product alcohols) (4) and enantioselective enolization (re-
versed by protonation of the enolate derivative) (6) as reac-
tions for development. The potential for stereoselective
formation of cyanohydrins from aldehydes (vide infra) and
the facile loss of HCN from such cyanohydrins prompted us
to examine enantiotopic group selective cyanohydrin forma-
tion from a-alkoxy aldehydes.
1
S)-1 R =n-C H
1
S)-4 R =t-Bu
(
(
1
R
5 11
5
11
CN
1
2
(S)-5a R =t-Bu, R = H
2
OR
1
2
(S)-6a R =t-Bu, R = (S)-MTPA
1
(R)-2a R = n-C H , R =H
2
OBn
S)
5 11
1
2
(R)-3a R = n-C H , R =(S)-MTPA
(
5 11
1
R
CN
1
(R)-5a R = t-Bu, R = H
2
(R)
2
1
(R)-6a R = t-Bu, R = (S)-MTPA
2
OBn
OR
kR
1
R
H
1
(R)-2s R = n-C
2
O
OBn
(R)
(R)
H
5
11, R =H
1
2
(R)-3s R = n-C H , R =(S)-MTPA
1
R)-1 R =n-C H
1
R)-4 R =t-Bu
(
(
1
R
5 11
5
11
CN
1
(R)-5s R = t-Bu, R =H
2
2
OR
1
R)-6s R = t-Bu, R = (S)-MTPA
2
(
be quite useful for the chain extension of monosaccharides
11). Cyanohydrins are generally recognized as versatile
(
synthetic intermediates for the preparation of a variety of
useful compounds (12, 13). As a consequence, the develop-
ment of methods for enantioselective formation of cyano-
hydrins from achiral aldehydes has attracted considerable
attention (13) and several highly enantioselective methods
using chiral Lewis acid catalysts have been reported recently
Few design elements are available to guide the develop-
ment of enantiotopic group selective reactions and many of
the successful examples (2) involve application of previously
(
14). By contrast, cyanohydrins are often formed with poor
diastereoselectivity from chiral aldehydes (15), even in en-
zyme-mediated processes (16). For example, diastereo-
selectivities of only 1.5–5:1 in favor of the syn isomer have
been reported for cyanohydrin formation from a-alkoxy al-
dehydes using trimethylsilylcyanide (TMSCN) in the pres-
ence of various Lewis acids (17). Because the predicted
selectivity (E) is limited by the lower of r and s (eq. [1]), the
low substrate diastereoselectivity noted above suggested that
cyanohydrin formation from a-alkoxy aldehydes would re-
sult in poor enantiotopic group selectivity even using meth-
ods with excellent enantioface selectivity. We now report
several experiments which support this hypothesis and on
our efforts to improve on the substrate diastereoselectivity in
an attempt to achieve enantiotopic group selective cyano-
hydrin formation by double stereodifferentiation.
established “reagent-controlled” enantioface selective reac-
2
tions to chiral or C symmetric substrates that impart signif-
s
3
icant “substrate-controlled” diastereoface selectivity (7). In
such cases, enantiotopic group selectivity can be rationalized
to result from the matching and mismatching of substrate
diastereotopic face selectivity with reagent enantiotopic face
selectivity (4, 8, 9). The magnitude of the enantiotopic group
selectivity (E) can be estimated from eq. [1] where r is the
enantiotopic face selectivity associated with the chiral re-
agent acting on a “model” achiral substrate and s is the
diastereotopic face selectivity of the chiral substrate with a
4
model achiral reagent (4, 9).
(
r)(s) +1
r + s
[
1]
E =
Results and discussion
The stereoselective formation of cyanohydrins from alde-
hydes dates back to the late 19th century when Emil Fischer
reported that addition of HCN to L-arabinose gave a 2:1 mix-
ture of cyanohydrins in favor of the manno (i.e., 2,3-anti)
diastereomer (10). Subsequently, this reaction has proven to
We selected the racemic a-alkoxy aldehydes 1 and 4 as
substrates to investigate enantiotopic group selective cyano-
hydrin formation. Under the influence of a chiral nonracemic
reagent or catalyst, the individual enantiomers of the aldehyde
2
Enantiotopic group selective reaction of chiral substrates is equivalent to kinetic resolution. In this case, groups on enantiomeric substrates
are enantiotopic by external comparison.
For a discussion and definition of reagent- and substrate-controlled stereoselectivity, see ref. 8.
The face selectivity for one group will be (r)(s):1 (i.e., “matched”); total reactivity is (r)(s) + 1. The face selectivity for the enantiotopic
group will be (r):(s) (i.e., “mismatched”); total reactivity is (r) + (s). The accuracy of this estimation depends on the suitability of the mod-
els used for the determination of r and s. For a detailed discussion of the derivation, assumptions, and sources of error in the above
multiplicativity rule, see ref. 8.
3
4
©
2001 NRC Canada

Ward et al.
1777
a
Table 1. Enantiotopic group selective hydrocyanation of 1 and 4 with TMSCN–(i-Pr-O) TiCl –TADDOL at –23°C.
2
2
Entry
Aldehyde
Time (h)
(C)b,c
(R)-2sc,d (%)
(R)-2ac,d (%)
(S)-2sc,d (%)
(S)-2ac,d (%)
kS/kRe
1
2
3
4
5
a
1
1
1
4
1
3
8
3
3
0.31
0.68
0.87
0.71
0.20
27
33
35
20f
46
10
11
12
25f
6
42
39
37
43f
23
21
16
17
13f
25
2.0
1.5
1.6
1.5
0.91
g
1
Reagent preparation: TADDOL (1.5 equiv) was added to a toluene solution of (i-Pr-O) TiCl (1.5 equiv) at room temperature. After 1 h, MS4A and
2
2
TMSCN were added.
b
c
1
Determined by H NMR of the crude reaction mixture.
Estimated relative error of ±10%.
d
1
Determined by H NMR of the corresponding Mosher’s esters.
e
f
Calculated according to footnote 5.
Refers to cyanohydrins 6 (not 2).
g
(
+)-BINOL was used instead of TADDOL.
(
e.g., 1) should form cyanohydrins at different rates (i.e., a ki-
Scheme 2.
netic resolution) and with different diastereoselectivities to
OBn
OBn syn
OBn anti
produce the four possible stereoisomeric products (e.g., (R)-
1
H
1
CN
+
1
CN
R
R
R
2
a, (R)-2s, (S)-2a, and (S)-2s) (18).
The relative amounts of the product stereoisomers from a
2
OR
2
OR
O
1
1 R = n-C H
1
R = t-Bu
1
2
1
2
reaction of low or known conversion can be used to calcu-
late the relative rates of hydrocyanation of the individual
substrate enantiomers (i.e., the enantiotopic group selectiv-
2s R = n-C H , R = H
2a R = n-C H , R = H
5
11
5
11
2
5
11
2
1
1
4
5s R = t-Bu, R = H
5a R = t-Bu, R = H
1
2
1
2
7
8
s R = n-C H , R = TMS 7a R = n-C H , R = TMS
5
11
2
5
11
2
5
1
1
ity). Alternatively, the enantiomeric purity of the recovered
s R = t-Bu, R = TMS
8a R = t-Bu, R = TMS
a-alkoxy aldehyde from a hydrocyanation reaction of known
6
conversion can be used to determine the selectivity. Thus, a
method to analyze the composition of the four stereoi-
someric cyanohydrins was required.
The relative stereochemical configurations of the cyano-
hydrins 2 and 5 were determined via NMR analysis of the
derived acetonides (17a). Reaction of 1 with trimethylsilyl-
OH
syn
CN
OH
anti
CN
1
1
R
R
OH
1
s R = n-C H
OH
1
9a R = n-C H
9
5
11
5
11
cyanide (TMSCN) in the presence of Et N (19) gave 7 as a
1
10s R = t-Bu
3
2
:1 mixture of racemic diastereomers in quantitative yield.
Hydrolysis of 7 (a 2:1 mixture of diastereomers) with dilute
acid gave a 2:1 mixture of cyanohydrins 2. Alternatively,
treatment of 7 with TiCl gave the diols 9, also as a 2:1 mix-
ture of diastereomers, which produced a 2:1 mixture of
acetonides 11. The minor acetonide was assigned as cis (i.e.,
O
O
4
trans
cis
4
1
R
4
1
R
O
O
5
5
CN
CN
1
1c) on the basis of an 8% nOe observed for HC-5 upon ir-
1
11t R = n-C
1
12t R = t-Bu
1
11c R = n-C
radiation of HC-4 (nOe was not observed between HC-4 and
HC-5 in the major acetonide, 11t); thus, the major
cyanohydrin formed was assigned as the syn diastereomer
5
H
11
5
H
11
2
s. Similar processing of 4 gave a separable 3:1 mixture of
cyanohydrins 5; the major diastereomer was assigned as syn
i.e., 5s) on the basis of an 18% nOe observed for HC-4
upon irradiation of the (H C) C protons in the derived
7
1
OH]. Assignment of individual signals in the H NMR
spectrum of the mixture of esters to individual diastereomers
was possible on the basis of intensity (i.e., major signals
from syn diastereomers and minor signals from anti
diastereomers), homonuclear decoupling experiments (i.e.,
(
3
3
acetonide 12t. A method for determining the absolute con-
figurations of the four stereoisomers of 2 was established by
conversion (20) of a 2.4:1 mixture of racemic 2s and 2a, re-
spectively, to a 2.6:2.6:1:1 mixture of diastereoisomeric
Mosher’s esters (21) 3 in 88% yield from excess (2S)-3,3,3-
trifluoro-2-methoxy-2-phenylpropanoic acid [(S)-MTPA-
identifying the pairs of HC-2–HC-3 and H CO signals for
individual diastereomers), and application of the advanced
Mosher’s method (22). The same strategy was successfully
applied for analysis of the four stereoisomers of 6.
2
8
5
At low conversion, k /k (= E) is closely approximated by ([(S)-2a] + [(S)-2s])/([(R)-2a] + [(R)-2s]). At higher conversions (C) with product
S
R
stereoisomeric excess (se = ([(S)-2a] + [(S)-2s] – [(R)-2a] – [(R)-2s])/([(S)–2a] + [(S)-2s] + [(R)-2a] + [(R)-2s])), E = {ln (1 – C(1 + se)}/{ln
1 – C(1 – se)}. For a discussion, see ref. 18.
(
6
If the ee of recovered 1 is ([(R)-1] – [(S)-1])/([(R)-1] + [(S)-1]) at conversion C, then k /k = E = {ln [(1 – C)(1 – ee)]}/{ln [(1 – C)
S
R
(
1 + ee)]}. For a discussion, see ref. 18.
7
8
A control experiment established that acetylation of 2 under these conditions occurred without loss of stereochemical integrity.
This method predicts that for the (S)-MTPA esters 3 (and 6), the HC-2 and H CO (and t-Bu) signals for the (1S) diastereomers will appear
2
downfield relative to the (1R) diastereomers.
©
2001 NRC Canada

1
778
Can. J. Chem. Vol. 79, 2001
With an analytical method in place, we chose to examine
cyanohydrin formation using TMSCN mediated by the chiral
Although the observation of double stereodifferentiation
in the hydrocyanation of 1 was encouraging, the very low
enantiotopic group selectivity obtained suggested that both the
reagent enantioselectivity and the substrate diastereoselectivity
required improvement. The low diastereoselectivity observed
for cyanohydrin formation from a-alkoxy aldehydes on reac-
tion with TMSCN in the presence of various Lewis acids (17)
is in stark contrast to the excellent selectivity often associated
with nucleophilic additions to these aldehydes under
chelation-controlled conditions (26). For example, Reetz et
al. (17a) reported that reaction of 2-(phenylmethoxy)propanal
alkoxytitanium generated in situ by mixing (i-Pr-O) TiCl
2
2
and (2R,3R)-2,3-O-(1-phenylethylidene)-1,1,4,4-tetraphenyl-
,2,3,4-butanetetrol (13, TADDOL) in the presence of 4 Å
1
molecular sieves (MS4A) as described by Narasaka and
co-workers (23). Using this system, 3-phenylpropanal
was reported to give the (R)-cyanohydrin in high yield
and in 74–91% ee depending on the procedure employed. In
our hands, the same cyanohydrin was obtained in >80%
yield under the reported conditions but in only 60 ± 5% ee
despite numerous attempts including using alternative meth-
ods (24) for preparing the precatalyst 14a. Despite this mod-
est result (i.e., 4:1 selectivity for addition of cyanide to the si
face of the aldehyde), we attempted enantiotopic group se-
lective hydrocyanation of 1 using the Narasaka reagent; the
with TMSCN mediated by TiCl (1 equiv) at –78°C gave a
4
4:1 mixture of syn:anti cyanohydrins in good yield. We ob-
tained the same diastereoselectivity (i.e., a 4:1 mixture of 2s
and 2a) on hydrocyanation of 1 under these conditions (27).
This moderate diastereoselectivity prompted us to investigate
this reaction more closely.
9
results are presented in Table 1. Although the selectivity
1
0
(
i.e., k /k ) was predictably low, it was surprising that
Varying amounts of TMSCN were added to a solution of
TiCl in CDCl to determine if these two reagents undergo
S
R
hydrocyanation of 1 occurred without evidence of double
stereodifferentiation (8). That is, the cyanohydrins from (R)-
and (S)-1 were formed with comparable levels of syn dia-
stereoselectivity (i.e., 2–3:1; compare (R)-2s:(R)-2a with (S)-
s:(S)-2a in Table 1, entries 1–3) with the slower reacting
R)-enantiomer giving slightly higher diastereoselectivity. A
4
3
1
any reaction. The H NMR spectra of the yellow solutions ob-
tained after addition of 1, 2, or 4 equiv of TMSCN showed a
single signal (d 0.43) indistinguishable from chloro-
1
13
2
(
trimethylsilane (TMSCl); addition of 10 equiv of TMSCN
13
gave a 3:2 ratio signals assigned to TMSCN (d 0.36) and
.5–2:1 enantiotopic group selectivity for hydrocyanation of
under these conditions was observed at three different con-
TMSCl, respectively. The propensity of mixtures of TiCl and
4
TMSCN to produce cyanohydrins from benzaldehyde and
from 1 was assessed (Table 2). Clearly, excess TMSCN was
required for high conversions (Table 2, entries 1–3) although
the diastereoselectivity was unchanged (Table 2, entries 4–5).
Interestingly, the cyanohydrin 2 was produced in similar yield
and diastereoselectivity by addition of TMSCN to a solution
1
1
of 1 and TiCl or by addition of 1 to a premixed solution of
4
TiCl and TMSCN (cf. entries 5 and 6). To obtain further in-
4
3
.3:1 syn diastereoselectivity (i.e., (S)-4s/(S)-4a) whereas
the slower reacting (R)-4 was slightly anti selective (i.e.,
R)-4a/(RS)-4s = 1.25); addition of cyanide occurred pref-
formation on the nature of this reagent, solutions of TMSCN
(2, 4, and 6 equiv) and TiCl in C D were concentrated in
4
6
6
(
vacuo (0.2 torr 1 torr = 133.322 Pa)) collecting the volatile
components in a cold trap. Analysis of the resulting yellow
erentially to the si face of both enantiomers of 4 as ex-
pected for this reagent (23) and indicating that the reagent
si face selectivity was higher than the substrate syn
diastereoselectivity. We also attempted cyanohydrin forma-
tion by replacing TADDOL with (R)-(+)-1,1>-bi-2-naphthol
1
residue by H NMR (in C D ) consistently showed the pres-
6
6
ence of a single signal at ca. 0.18 indistinguishable from
1
3
1
TMSCl. The H NMR spectrum (in C D ) of the volatile
6
6
components obtained from the 2:1 mixture of TMSCN:TiCl4
indicated the absence of both TMSCl and TMSCN, whereas
that from the 4:1 mixture showed the presence of ca. 2 equiv
(
BINOL) in the Narasaka protocol (25).12 Hydrocyanation of
1
with this modified procedure also showed double stereo-
13
differentiation but very low enantiotopic group selectivity
of TMSCl and that from the 6:1 mixture contained ca.
13,14
(
Table 1, entry 5).
2 equiv each of TMSCl and TMSCN d (–0.17).
These ex-
9
The configurational stability of the cyanohydrins under the reaction conditions was confirmed by control experiments.
1
0
Reaction of 1 with TMSCN (2 equiv) in the presence of (i-Pr-O) Cl Ti(IV) (1 equiv) at 0°C in CH Cl gave a 2.5:1 mixture of syn:anti
2
2
2
2
cyanohydrins 2s and 2a (cf. 4:1, syn:anti diastereoselectivity in TiCl mediated reaction of a-alkoxy aldehydes with TMSCN (17a)). As-
4
suming a reagent enantioselectivity of 4:1 and a substrate diastereoselectivity of 2.5:1, eq. [1] predicts an enantiotopic group selectivity of
1
.5:1.
1
1
1
1
Aldehyde 1 was recovered (50% yield) from a hydrocyanation reaction proceeding to 35% conversion ( H NMR) and found to have 15% ee in
1
favor of (R)-1 by H NMR of the Mosher’s ester of the corresponding alcohol (NaBH , 0°C, MeOH; quantitative). Using the equation in foot-
4
note 6, the calculated enantiotopic group selectivity from this data (C = 0.35, ee = 0.15) is 2:1.
2
Subsequent to our work, Nakai and co-workers (25) reported hydrocyanation of aldehydes with the reagent prepared by mixing (R)-BINOL
and (i-Pr-O) Ti(IV) (0.2 equiv each, rt, 0.5 h) in CH Cl followed by addition of TMSCN (2.5 equiv, 0°C, 0.5 h) (putative catalyst:
4
2
2
(
BINOL)(CN) Ti(IV)). With this reagent, addition of cyanide was re face selective giving (S) cyanohydrins (10–75% ee) from simple
2
aliphatic aldehydes.
1
1
3
Confirmed by addition of an authentic sample(s).
4
Experiments were conducted at least in triplicate. Quantification was achieved by addition of internal standards (TMSCN and (or) TMSCl).
1
Varying amounts of TMSOH (d 0.12) were observed; this signal was counted as being derived from TMSCl which was confirmed ( H
NMR) by adding controlled amounts of water to a C D solution of TMSCl and TMSCN. Variation of the calculated stoichiometry among
6
6
“
identical” experiments was ca. ±15%.
©
2001 NRC Canada

Ward et al.
Table 2. Hydrocyanation of 1 and benzaldehyde with TiCN reagents.
1779
Entry
Aldehyde
PhCHO
TiCN reagent (equiv)
15a,b (%)
2 (2s:2a)a,b (%)
1
2
3
4
5
6
7
8
9
1
1
TiCl (1)/TMSCN (1)c
50
78
92
4
c
TiCl (1)/TMSCN (2)
4
c
TiCl (1)/TMSCN (4)
4
d
1
TiCl (1)/TMSCN (1)
70 (4:1)
90 (4:1)
88 (3.3:1)
4
d
TiCl (1)/TMSCN (2)
4
d,e
TiCl (1)/TMSCN (2)
4
TiCl CN2 (TMS ) (0.16)g
2
–
+
f
21
50
PhCHO
1
PhCHO
1
1
4
2
TiCl CN2 (TMS ) (0.5)g
2
–
+
f
63 (2:1)
4
2
2
–
+
h
g
TiCl CN4 (TMS ) (0.16)
2 2
TiCl CN4 (TMS ) (0.5)g
2
–
+
h
92 (3:1)
75 (1:1.2)
0
1
2
2
g
i
(i-Pr-O) TiCN (1)
3
a
1
Determined by H NMR of the crude reaction mixture; the remainder is aldehyde.
Estimated relative error of ±10%.
b
c
Conditions: TMSCN was added to a CDCl solution of TiCl at room temperature. After 1 h, aldehyde was added; water was added
3
4
after an additional 1 h.
d
Aldehyde added at –78°C; reaction at –78 to –25°C over 3 h.
e
f
TMSCN added to 1 and TiCl at –78°C.
Prepared by concentration of a 2:1 mixture of TMSCN:TiCl4.
4
g
Reaction for 30 min at room temperature.
Prepared by concentration of a 4:1 mixture of TMSCN:TiCl4.
h
i
Prepared by concentration of a 6:1 mixture of TMSCN:(i-Pr-O) Ti.
4
a
Table 3. Hydrocyanation of 1 and with TiCN reagents in the presence of MgBr ·OEt (5 equiv).
2
2
Entry
Reagent (equiv)
2b,c (%)
(R)-2sc,d (%)
(R)-2ac,d (%)
(S)-2sc,d (%)
(S)-2ac,d (%)
kS/kRe
1
2
3
4
5
6
7
8
9
a
TMSCN (1.1) f
95
65
60
51
95
25
19
30
24
2s:2a = 9:1
2s:2a = 4:1
2s:2a = 3:1
2s:2a = 7.5:1
2s:2a = 8.8:1
6
4
5
f
Et NCN (1.1)
4
2
–
+
g
TiCl CN (TMS ) (1)
(i-Pr-O) TiCN (1)
2
4
2
h
3
i
(i-Pr-O) Ti (1) – Et NCN (1)
4
4
i
14b (0.3) – Et NCN (0.3)
45
46
45
31
43
46
44
34
1
6
4
5
17
0.95
1.0
0.98
1.05
4
j
14b (1) – TMSCN (6)
16 (1) – TMSCN (0.33)
17 (1) – TMSCN (0.33)
18
b
Conditions: cyanide reagent added to a suspension of Mg(II) and 1 in CH Cl solution, 0°C, 1 h. Determined by H NMR of the crude reaction
2
2
mixture.
c
Estimated relative error of ±10%.
Determined by H NMR of the corresponding Mosher’s esters.
d
1
e
Calculated according to footnote 5.
Reference 27.
f
g
h
i
Prepared by concentration of a 6:1 mixture of TMSCN:TiCl4.
Prepared by concentration of a 6:1 mixture of TMSCN:(i-Pr-O) TiCN.
4
Addition of Et NCN over 30 min
4
j
Concentrated prior to use.
periments suggest that reaction of TiCl with TMSCN pro-
from
a
2:1 mixture of TMSCN:TiCl4 (nominal
4
2
–
+
2–
+
duces an initial 1:2 adduct (e.g., TiCl CN (TMS ) ) and that
stoichiometry TiCl CN (TMS ) ) under similar condi-
4
2
2
4 2
2
additional TMSCN results in the substitution of two Cl lig-
tions produced 1.3 equiv of mandelonitrile (15); reaction of
the same reagent with 1 gave a 2:1 mixture of 2s and 2a.
We also briefly examined cyanohydrin formation using a
reagent prepared by addition of TMSCN (6 equiv) to a so-
lution of (i-Pr-O) Ti in C D . After 15 min, the pale yellow
2
–
+
ands with two CN ligands [e.g., TiCl CN (TMS ) ] with
2
4
2
concomitant formation of TMSCl. The capability of the resi-
dues obtained after concentration of mixtures of TiCl and
4
TMSCN to produce cyanohydrins was confirmed by reac-
tions with benzaldehyde and with 1 (Table 2, entries 7–10).
The reagents derived from 6:1 and from 4:1 mixtures of
4
6
6
solution was concentrated in vacuo to produce a residue
with a nominal stoichiometry of “(i-Pr-O) TiCN” based on
3
2
–
+
1
15
TMSCN:TiCl (nominal stoichiometry TiCl CN (TMS ) )
analysis of the volatile components by H NMR. Addition
4
2
4
2
generated 3 equiv (based on Ti) of mandelonitrile (15)
from benzaldehyde within 30 min at room temperature. Re-
action of excess benzaldehyde with the reagent obtained
of 1 (1 equiv based on Ti) to a CH Cl solution of the
above residue gave a 1:1.2 mixture of 2s and 2a (75%)
(Table 2, entry 11).
2
2
15The amounts of i-Pr-OR (R = H, TMS, 0.9 to 1.1 equiv), and TMSCN (4.5 to 5.1 equiv) in the “distillate” were quantified using an internal
standard.
©
2001 NRC Canada

1
780
Can. J. Chem. Vol. 79, 2001
To summarize, TMSCN reacts with TiCl and with (i-Pr-
analogous conditions, the reaction proceeded with very low
enantiotopic group selectivity and without double stereo-
differentiation.
4
O) Ti to give adducts that can generate cyanohydrins from
4
1
7
benzaldehyde and from 1. The low diastereoselectivity ob-
served in reactions with 1 can be rationalized by considering
the decreased Lewis acidity of these adducts due to the
strongly donating CN ligand(s) which disfavors a “chelation-
controlled” pathway. Furthermore, the formation of such
adducts suggests that the primary role of the Ti(IV) in these
reactions may be to activate the TMSCN rather than the al-
dehyde. In any event, it seemed apparent that realization of
enantiotopic group selective cyanohydrin formation from a-
alkoxy aldehydes would require conditions to achieve
cyanohydrin formation with much higher diastereo-
selectivity. We undertook a systematic investigation of
cyanohydrin formation from 1 using a variety of cyanide
sources (TMSCN, Et NCN, Et NAg(CN) ), Lewis acids
We briefly examined enantiotopic group selective hydro-
cyanation using TMSCN in the presence of “chiral versions”
of Mg(II). Hydrocyanations of 1 with TMSCN–MgBr ·OEt
2
2
in the presence or absence of the nonracemic bisoxazoline
ligand 16 (28) were virtually indistinguishable (cf. Table 3,
entries 1 and 8). Finally, the use of the nonracemic Mg(II)
reagent 17 (29) in place of MgBr ·OEt resulted in low
2
2
diastereoselectivity (2s:2a = 2:1), very low enantiotopic
group selectivity, and proceeded without double stereo-
differentiation (Table 3, entry 9).
In conclusion, attempted hydrocyanations of a-alkoxy al-
dehydes with TMSCN using chiral nonracemic alkoxy
Ti(IV) reagents proceeded with low enantiotopic group se-
lectivity (<2:1). It was established that TMSCN can react
with Ti(IV) reagents to produce TiCN adducts that are capa-
ble of hydrocyanation but with low substrate-controlled
diastereoselectivity in reactions with a-alkoxy aldehydes.
The poor enantiotopic group selectivity observed can be ra-
tionalized to result from this low diastereoselectivity despite
the respectable levels of enantioface selectivity associated
with these reagents in hydrocyanation of achiral aldehydes.
Highly diastereoselective hydrocyanation of a-alkoxy alde-
hydes can be achieved with TMSCN in the presence of ex-
cess MgBr ·OEt (27). High diastereoselectivity was also
4
4
2
(
BF ·OEt , TiCl , SnCl , ZnBr , MgBr ), and reaction condi-
3 2 4 4 2 2
tions (27). This study revealed Mg(II) as a unique promoter
of hydrocyanation as it is capable of chelation of 1 and does
not react appreciably with the cyanide source. Under opti-
mized conditions (27), the cyanohydrin 2 was obtained in
high yield as a 24:1 mixture of syn:anti diastereomers 2s
1
6
and 2a, respectively.
Adapting this diastereoselective
method to achieve enantiotopic group selectivity would re-
quire a chiral nonracemic version of MgBr and (or) a chiral
2
nonracemic cyanide source. The latter strategy appeared more
promising because optimal diastereoselectivity requires the
use of excess solid MgBr ·OEt (27) and chiral nonracemic
2
2
observed using achiral and chiral TiCN adducts in place of
TMSCN. Although the putative TiCN adducts obtained from
nonracemic alkoxy Ti(IV) reagents are implicated in
enantioface selective hydrocyanation, these reagents were
not enantiotopic group selective under these conditions and
showed no evidence of double stereodifferentiation. The use
of nonracemic bisoxazoline ligands for Mg(II) was also inef-
fective.
2
2
Ti(IV) cyanides are readily available and have been impli-
cated in enantioselective hydrocyanation (14d, 23, 25).
Initial experiments evaluated the possibility for diastereo-
selective cyanohydrin formation from 1 using an achiral
“
TiCN” reagent in the presence of MgBr ·OEt (Table 3).
2 2
Although the reagent obtained by concentration of a 6:1
mixture of TMSCN and TiCl (nominal stoichiometry
4
2
–
+
TiCl CN (TMS ) ) gave 2 with poor diastereoselectivity
2
4
2
(
Table 3, entry 3), the reagent prepared from a 6:1 mixture
Ph Ph
Ph Ph
1
4a X = Cl
14b X = O-i-Pr
of TMSCN and (i-Pr-O) Ti (nominal stoichiometry (i-Pr-
O) TiCN) generated 2 with a diastereoselectivity nearly as
4
O
O
O
O
OH
OH
O
O
X
X
3
Ti
high as that obtained with TMSCN (Table 3, cf. entries 1
and 4). The reagent obtained analogously from a 6:1 mixture
of TMSCN and 14b was also very diastereoselective in the
presence of MgBr ·OEt but produced 2 with very low
enantiotopic group selectivity and without evidence for dou-
ble stereodifferentiation (Table 3, entry 7). We also exam-
Ph
Ph
Ph Ph
Ph Ph
1
3
CN
O
O
2
2
OH
CN
O
O
N
N
N
N
Mg
Br
Ph
Ph
ined reagents derived from Et NCN and Ti(IV) alkoxides in
the presence of excess MgBr ·OEt for hydrocyanation. The
4
1
5
Ph
17
Ph
16
2
2
Mg(II) mediated hydrocyanation of 1 with Et NCN is a rela-
4
tively poor method (Table 3, entry 2) (27). However, slow
Experimental
addition of Et NCN to a suspension of 1 and MgBr ·OEt in
4
2
2
the presence of (i-Pr-O) Ti was as effective as TMSCN–
General methods
All solvents were distilled prior to use. Et N was distilled
4
MgBr ·OEt for stereoselective synthesis of 2s (Table 3, cf.
2
2
3
entries 1 and 5). The successful moderation of the reactivity
from CaH and stored over KOH pellets. Anhydrous solvents
2
of Et NCN towards MgBr (27) by (i-Pr-O) Ti suggests the
were distilled under argon as follows: ether and tetra-
hydrofuran (THF) from benzophenone potassium ketyl; ben-
zene, toluene, and CH Cl from P O and stored over 3 Å
4
2
4
possible formation of a TiCN reagent under these condi-
tions. Although the chiral titanium alkoxide 14b was also ef-
fective for diastereoselective hydrocyanation of 1 under
2
2
2
5
molecular sieves; MeOH from Mg(OMe) . Unless otherwise
2
1
6
Conditions: MgBr ·OEt (5 equiv), Et NAg(CN) (2 equiv) in CH Cl , –78 to –20°C, 2 h. This level of diastereoselectivity is five
2
2
4
2
2
2
times greater than previously reported for a-alkoxy aldehydes.
1
7
Reaction of benzaldehyde under these conditions gave 15 with <10% ee.
©
2001 NRC Canada

Ward et al.
1781
noted, reactions were carried out under an atmosphere of
argon and reaction temperatures refer to the bath. Concentra-
tion refers to removal of volatiles at water aspirator pressure
on a rotary evaporator.
(2.5 equiv), and DMAP (ca. 1 mg) in CH C (ca. 0.1 M in
2
l
alcohol) at room temperature. After stirring for 1–3 h, the
reaction mixture was concentrated to give the crude
1
Mosher’s esters (quantitative conversion was verified by H
Preparative TLC (PTLC) was carried out on glass plates
NMR).
(
20 × 20 cm) precoated (0.25 mm) with silica gel 60 F254.
General procedure for hydrocyanation with TMSCN–
Materials were detected by visualization under an ultraviolet
lamp (254 nm) and (or) by treating a 1 cm vertical strip re-
moved from the plate with a solution of phosphomolybdic
acid (5%) containing a trace of ceric sulfate in aqueous sul-
furic acid (5% v/v), followed by charring on a hot plate.
Flash column chromatography (FCC) was performed accord-
ing to Still et al. (30) with Merck silica gel 60 (40–63 ꢁm).
Dry FCC was performed according to Harwood (31). All
mixed solvent eluents are reported as v/v solutions.
(
i-Pr-O) TiCl –TADDOL (or BINOL)
2 2
A solution of (i-Pr-O)2TiCl2 (1.5 equiv) in toluene (ca. 0.5 M)
was added via syringe to a stirred solution of TADDOL
(1.5 equiv) in toluene (ca. 0.5 M) at room temperature. Af-
ter 1 h, MS4A (ca. 150 mg/mmol of aldehyde) and then
TMSCN (5 equiv) were added and the mixture was cooled
to –23°C. A solution of aldehyde (ca. 0.2 mmol) in toluene
(ca. 0.1 M) was added to the mixture. After the appropriate
time, phosphate buffer (pH 7) was added and the mixture was
allowed to warm to room temperature (ca. 25 min) and then was
Spectral data
®
filtered (Celite ) and extracted with EtOAc (×3). The combined
High resolution mass spectra (HRMS) and low resolution
mass spectra (LRMS) were obtained on a VG 70E double
focussing high resolution spectrometer; only partial data are
reported. EI ionization was accomplished at 70 eV and CI at
organic layers were washed with brine, dried over Na SO , and
2
4
concentrated to give the crude cyanohydrin. The conversion was
1
determined by H NMR of the crude by integrating signals due
to 1 (or 4) and 2 (or 5). Fractionation of the crude by PTLC
5
0 eV with ammonia as the reagent gas; only partial data are
(25% EtOAc in hexane) gave recovered 1 (or 4) and the cyano-
reported. IR spectra were recorded on a Fourier transform
interferometer using a diffuse reflectance cell (DRIFT); only
diagnostic and (or) intense peaks are reported. Unless other-
hydrins 2 (or 5) as a mixture of diastereomers; the stereoi-
1
someric composition was determined by H NMR of the
corresponding Mosher’s esters.
wise noted, NMR spectra were measured in CDCl solution
at 300 MHz for H and 75 MHz for C. For H NMR, resid-
ual CHCl in CDCl was employed as the internal standard
3
1
13
1
General procedure for hydrocyanation with TMSCN–TiCl4
reagents
3
3
1
3
(
7.26 d); for C NMR, CDCl was employed (77.2 d). The
3
TiCl (11 mg, 0.06 mmol) in CDCl (40 ꢁL) was added
1
4
3
H NMR chemical shifts and coupling constants were deter-
via syringe to a solution of TMSCN (1, 2, or 4 equiv) in
mined assuming first-order behavior. Multiplicity is indi-
cated by one or more of the following: s (singlet), d
(
(
the order of the multiplicity assignment. H NMR spectra
were normally obtained with a digital resolution of
CDCl (0.5 mL). After standing at room temperature for 1 h,
3
PhCHO (6 mg, 0.06 mmol) or 1 (13 mg, 0.06 mmol) was
added. After standing at room temperature for 1 h, the mix-
doublet), t (triplet), q (quartet), m (multiplet), br (broad), ap
apparent); the list of couplings constants (J) corresponds to
ture was poured over H O, diluted with CH Cl , filtered
1
2
2
2
®
(
2
Celite ), dried over Na SO , and concentrated giving 15 or
2 4
as a yellow oil. Analysis and fractionation were performed
0
.244 Hz/pt (sweep width = 4000 Hz, FID = 32 K data
as described above.
points) and coupling constants are reported to the nearest
1
0
.5 Hz. The H NMR assignments were made on the basis of
General procedure for hydrocyanation with TiCN reagents
chemical shift and multiplicity and were confirmed, where
necessary, by homonuclear decoupling and (or) NOE experi-
TiCl (19 mg, 0.10 mmol) in C D (0.2 mL) was added
4
6
6
via syringe to a solution of TMSCN (2, 4, or 6 equiv) in
C D (0.3 mL) in an NMR tube (5 mm). After standing for
1
3
ments. The multiplicity of C NMR signals refers to the
number of attached Hs (i.e., s = C, d = CH, t = CH , q =
CH ) and was determined by J-modulation (32).
6
6
2
1
5 min, concentrated by freeze drying under high vacuum
3
(
0.2 torr (1 torr = 133.322 Pa)) with the volatile components
being collected in a liquid nitrogen cooled trap and analyzed
by H NMR. The yellowish solid residue was dissolved in
1
Materials
TMSCN (33), (i-Pr-O) TiCl (34), TADDOL (23), (i-Pr-
2
2
C D (0.5 mL) and PhCHO (63 mg, 0.60 mmol) or 1
6
6
O) Ti(TADDOL) (24), and 18 (29) were prepared according
2
(44 mg, 0.20 mmol) was added via syringe. After 30 min,
phosphate buffer (pH 7) was added and the mixture was ex-
tracted with CH Cl (×3). The combined organic extracts
to literature procedures. The aldehydes 1 and 4 were prepared
from hexanal and pivaldehyde, respectively, by addition of
vinlymagnesium bromide, benzylation, and ozonolyisis ac-
cording to the procedure of Midland and Koops (35). TiCl4
and (i-Pr-O) Ti were freshly distilled prior to use. All other
reagents were commercially available and, unless otherwise
noted, were used as received.
2
2
were dried over Na SO and concentrated to give a mixture
2
4
of 15 (or 2) as a yellow oil. Analysis and fractionation as de-
4
scribed above. Analogous procedures using (i-Pr-O) Ti or
4
1
4b in place of TiCl were employed to prepare and use (i-
4
Pr-O) TiCN or “(TADDOL)(i-Pr-O)TiCN”, respectively.
3
General procedure for preparation Mosher’s esters
A solution of (R)-MTPA-Cl (prepared (20) from (S)-
MTPA-OH; 1.2 to 1.5 equiv) in CH Cl (ca. 0.05 M) was
General procedure for hydrocyanation with TiCN reagents
in the presence of MgBr ·OEt
2
2
A solution of 1 (20 mg, 0.091 mmol) in CH Cl (0.5 mL)
2
2
2
2
added via syringe to a stirred solution of the alcohol, Et N
was added to a stirred suspension of MgBr .OEt (115 mg,
3
2
2
©
2001 NRC Canada

1
782
Can. J. Chem. Vol. 79, 2001
0
.45 mmol) in CH Cl (1.5 mL) at room temperature. After
(38), 91 (82). HRMS m/z calcd. for C H F NO : 463.1970;
2
2
25 28
3
4
–
1
stirring for 5 min, the reaction mixture was cooled to 0°C. A
solution of the cyanating reagent (TMSCN or Et NCN or
TiCN) (0.3–1 equiv) was added via syringe. After 1 h at
0
tion mixture processed as above to give the crude 2. For en-
try 8 of Table 3, 1 was added to a suspension the
MgBr ·OEt containing the ligand 16 (1 equiv). For entry 9
of Table 3, reagent 17 (1 equiv) was used instead of
MgBr ·OEt (5 equiv). Analysis and fractionation were per-
found: 463.1978 (EI). IR ꢂ
(cm ): 2953, 1763, 1453,
max
1
18
†
1172. H NMR d: 7.51–7.25 (10H, m, ArH), 5.67 (d, J =
4
‡
§
¶
4 Hz), 5.62 (d, J = 4.5 Hz), 5.57 (d, J = 6 Hz), and 5.52
†
¶
°C, phosphate buffer (pH 7, 5 mL) was added and the reac-
(d, J = 6.5 Hz) (1H, HC-1), 4.69 (d, J = 11 Hz), 4.65 (d,
‡
¶
§
J = 11 Hz), 4.63 (d, J = 11 Hz), 4.58 (d, J = 11 Hz), 4.53
†
§
(d, J = 11 Hz), 4.51 (d, J = 11 Hz), 4.47 (d, J = 11 Hz),
‡
†¶
and 4.42 (d, J = 11 Hz) (2H, H CAr), 3.81–3.71 (m), and
2
2
2
‡
§
‡§
†
3.71–3.61 (m) (1H, HC-2), 3.59 (br s), 3.54 (br s), and
¶
3.50 (br s) (3H, H CO), 1.70–1.14 (8H, m, H C-3, H C-4,
2
2
3
3
2
formed as described above.
H C-5, H C-6), 0.90–0.81 (3H, m, H C-7).
2
2
3
2
-(Phenylmethoxy)heptanal (1): LRMS (CI, NH ) m/z (rela-
3,3-Dimethyl-2-(phenylmethoxy)butanal (4): LRMS (CI,
3
+
+
+
tive intensity): 238 ([M + 18] , 10), 221 ([M + 1] , 2), 191
NH ) m/z (relative intensity): 224 ([M + 18] , 100), 177
3
(
36), 108 (64), 91 (100). HRMS m/z calcd. for C H O :
(32), 108 (21), 91 (28). HRMS m/z calcd. for C H O :
1
4
21
2
13 18
2
+
–1
2
21.1542 (= [M + H] ); found: 221.1542 (CI, NH ). IR ꢂ
206.1307; found: 206.1298 (EI). IR ꢂ (cm ): 2960, 2870,
2714, 1727, 1454, 1110. H NMR d: 9.73 (1H, d, J = 3.5 Hz,
3
max
max
–
1
1
1
(
cm ): 3088, 2930, 1732, 1454, 1099, 736, 698. H NMR d:
.65 (1H, d, J = 2 Hz, HC-1), 7.39–7.28 (5H, m, ArH), 4.68
1H, d, J = 12 Hz, HCAr), 4.54 (1H, d, J = 12 Hz, HCAr),
.76 (1H, ddd, J = 2, 6.5, 6.5 Hz, HC-2), 1.72–1.62 (2H, m,
H C-3), 1.51–1.35 (2H, m, H C-4), 1.34–1.20 (4H, m, H C-5,
9
(
3
HC-1), 7.37–7.29 (5H, m, ArH), 4.65 (1H, d, J = 11.5 Hz,
HCAr), 4.43 (1H, d, J = 11.5 Hz, HCAr), 3.29 (1H, d, J =
1
3
3.5 Hz, HC-2), 1.01 (9H, s, (H C) C). C NMR d: 204.9 (d,
3 3
C-1), 137.8 (s, Ph), 128.2 (2d, Ph), 128.1 (3d, Ph), 90.7 (d,
C-3), 73.1 (t, CH O), 35.6 (s, C-4), 27.0 (3q, (H C) C).
2
2
2
1
3
H C-6), 0.92–0.83 (3H, t, J = 6.5 Hz, H C-7). C NMR d:
2
3
2
3
3
2
1
3
03.7 (d, C-1), 137.5 (s, Ph), 128.5 (2d, Ph), 128.3 (d, Ph),
(
2R*,3R*)-2-Hydroxy-4,4-dimethyl-3-(phenylmethoxy)
28.0 (2d, C-2), 83.5 (d, C-2), 72.5 (t, CH O), 31.6 (t, C-5),
2
pentanenitrile (5s) and (2S*,3R*)-2-hydroxy-4,4-dimethyl-
3
0.0 (t, C-3), 24.4 (t, C-4), 22.4 (t, C-6), 14.0 (q, C-7).
-(phenylmethoxy)pentanenitrile (5a)
(
2R*,3R*)-2-Hydroxy-3-(phenylmethoxy)octanenitrile (2s) and
TMSCN (173 mg, 1.74 mmol) and Et N (59 mg,
3
(2S*,3R*)-2-hydroxy-3-(phenylmethoxy)octanenitrile (2a):
0.58 mmol) were added to a stirred solution of aldehyde 4
(120 mg, 0.580 mmol) and MS4A (100 mg) in toluene
(2.5 mL) at room temperature. After 3 h, the mixture was fil-
tered and concentrated to give 8 (a 3:1 mixture of 8s and 8a,
+
LRMS (CI, NH ) m/z (relative intensity): 265 ([M + 18] ,
3
1
), 191 (8), 108 (13), 91 (100). HRMS m/z calcd. for
+
C H NO : 265.1916 (= [M + NH ] ); found: 265.1906 (CI,
1
5
21
2
4
–
1
1
1
NH ). IR ꢂ
(cm ): 3426, 3031, 2930, 1454, 1073, 744,
respectively, by H NMR; 160 mg, 90%). H NMR d for 8s:
7.44–7.22 (5H, m, ArH), 4.89 (1H, d, J = 11.5 Hz, HC-Ar),
4.63 (1H, d, J = 11.5 Hz, HC-Ar), 4.52 (1H, d, J = 5.5 Hz,
HC-2), 3.25 (1H, d, J = 5.5 Hz, HC-3), 1.04 (9H, s,
(H3C) C), 0.20 (9H, s, (H C) Si); d for 8a: 7.44–7.22
3
max
1
6
98. H NMR d for 2s: 7.43–7.32 (5H, m, ArH), 4.75 (1H, d,
J = 11.5 Hz, HCAr), 4.58 (1H, d, J = 11.5 Hz, HCAr), 4.46
1H, dd, J = 4, 9 Hz, HC-2), 3.63 (1H, ddd, J = 4, 7, 7 Hz,
HC-3), 2.95 (1H, d, J = 9 Hz, OH), 1.90–1.76 (1H, m, HC-4),
.75–1.58 (1H, m, HC-4), 1.47–1.23 (6H, m, H C-5, H C-6,
(
3
3
3
1
(5H, m, ArH), 5.00 (1H, d, J = 11.5 Hz, HC-Ar), 4.62 (1H,
d, J = 4 Hz, HC-2), 4.61 (1H, d, J = 11.5 Hz, HC-Ar), 3.25
(1H, d, J = 4 Hz, HC-3), 1.00 (9H, s, (H C) C), 0.25 (9H, s,
2
2
H C-7), 0.97–0.85 (3H, m, H C-8); d for 2a: 7.43–7.32
2
3
(
5H, m, ArH), 4.76 (1H, d, J = 11.5 Hz, HCAr), 4.71 (1H, d,
J = 11.5 Hz, HCAr), 4.38 (1H, dd, J = 3, 9 Hz, HC-2), 3.68
1H, dt, J = 3, 6.5 Hz, HC-3), 2.95 (1H, d, J = 9 Hz, OH),
.75–1.58 (2H, m, H C-4), 1.47–1.23 (6H, m, H C-5, H C-6,
3
3
(H C) Si). To a stirred solution of 8 (a 3:1 mixture of 8s and
3
3
(
1
8a, respectively; 160 mg) in Et O (10 mL) was added 1 M
2
HCl (10 mL). After 14 h, the mixture was diluted with Et O
2
2
2
2
1
3
H C-7), 0.97–0.85 (3H, m, H C-8). C NMR d for 2s: 137.2
and washed sequentially with H O and sat. NaCl, dried over
2
3
2
(
(
(
s, Ph), 128.6 (2d, Ph), 128.2 (d 2, Ph), 128.1 (d, Ph), 119.0
Na SO , and concentrated to give 5 as a colorless liquid
2
4
1
s, C-1), 79.4 (t, C-2), 73.4 (d, CH Ar), 63.2 (d, C-3), 31.6
(122 mg, 90%, 3:1 mixture of 5s and 5a by H NMR). The
residue was fractionated by FCC (10% EtOAc in hexane)
giving 5s as a clear liquid (75 mg, 55%) and 5a as a clear
liquid (10 mg, 8%).
2
t, C-4), 30.4 (t, C-6), 24.8 (t, C-5), 22.4 (t, C-7), 13.9 (q, C-8);
d for 2a: 137.4 (s, Ph), 128.6 (2d, Ph), 128.2 (2d, Ph), 128.0
(
(
7
7
d, Ph), 118.0 (s, C-1), 79.4 (t, C-2), 72.8 (d, CH Ar), 64.1
2
d, C-3), 31.7 (t, C-4), 30.4 (t, C-6), 24.7 (t, C-5), 22.4 (t, C-
Spectral data for 5s: LRMS (CI, NH ) m/z (relative inten-
), 13.9 (q, C-8). Elemental anal. calcd. for C H NO : C
3
1
5
21
2
+
sity): 251 ([M + 18] , 6), 224 (100), 108 (33), 91 (48).
2.84, H 8.56, N 5.66; found: C 72.54, H 8.53, N 5.62.
+
HRMS m/z calcd. for C H NO : 251.1760 (= [M + NH ] );
1
4
19
2
4
–
1
1
-Cyano-2-(phenylmethoxy)heptyl (2S)-3,3,3-trifluoro-2-methoxy-
found: 251.1760 (CI). IR ꢂ
(cm ): 3456, 2959, 2872,
max
1
2
-phenylpropanoate (3): Fractionation of the crude product
from reaction of 2 (a 2.4:1 mixture of racemic 2s and 2a;
mg, 0.03 mmol) with (R)-MTPA-Cl by PTLC (25% EtOAc
in hexane) gave a 2.6:2.6:1:1 mixture of (R)-3s, (S)-3s, (R)-
a, and (R)-3a isomers, respectively, as a colorless oil
13 mg, 88%). LRMS (CI, NH ), m/z (relative intensity):
2240 (w), 1395, 1089. H NMR d: 7.46–7.35 (5H, m, ArH),
5.00 (1H, d, J = 10.5 Hz, HCAr), 4.89 (1H, d, J = 10.5 Hz,
HCAr), 4.58 (1H, dd, J = 1.5, 10 Hz, HC-2), 3.47 (1H, d,
J = 1.5 Hz, HC-3), 3.29 (1H, d, J = 10 Hz, OH), 1.00 (9H, s,
8
1
3
3
(
4
H C). C NMR d: 137.0 (s, Ph), 128.6 (2d, Ph), 128.3 (d,
3
Ph), 128.2 (2d, Ph), 120.6 (s, C-1), 86.4 (d, C-2), 76.0 (t,
CH O), 59.3 (d, C-3), 35.9 (s, C-4), 26.4 (3q, CH ). Elemen-
3
+
81 ([M + 18] , 37), 373 (42), 279 (23), 189 (100), 108
2
3
18Legend: † = (R)-3a, ‡ = (S)-3a, § = (R)-3s, ¶ = (S)-3s.
©
2001 NRC Canada

Ward et al.
1783
tal anal. calcd. for C H NO : C 72.07, H 8.21l N 6.00;
found: C 72.06, H 8.18, N 5.93.
tracted with Et O (×3) and the combined organic layers were
1
4
19
2
2
washed with brine, dried over Na SO , concentrated, and the
2
4
residue fractionated by FCC (35% EtOAc in hexane) to give
the diol 9 as a 2:1 mixture of 9s and 9a, respectively,
Spectral data for 5a: LRMS (CI, NH ) m/z (relative inten-
3
+
sity): 251 ([M + 18] , 46), 224 (100), 108 (42), 91 (54).
(
54 mg, 58%). LRMS (CI, NH ) m/z (relative intensity): 175
3
+
HRMS m/z calcd. for C H NO : 251.1760 (= [M + NH ] );
+
1
4
19
2
4
([M + 18] , 5), 148 (100), 99 (36), 83 (17). HRMS m/z
calcd. for C H NO : 175.1447 (= [M + NH ] ); found:
–
1
found: 251.1763 (CI, NH ). IR ꢂ
(cm ): 3422, 2960,
+
3
max
8
15
2
4
1
2
872, 2250 (w), 1394, 1105. H NMR d: 7.44–7.30 (5H, m,
ArH), 4.80 (1H, d, J = 11.5 Hz, HCAr), 4.76 (1H, d, J =
1.5 Hz, HCAr), 4.58 (1H, d, J = 3 Hz, HC-2), 3.30 (1H, d,
–1
1
75.1447 (CI, NH ). IR ꢂ (cm ): 3421, 2929, 1465, 1077.
3 max
1
H NMR d for 9a: 4.42 (1H, d, J = 3.0 Hz, HC-2), 3.92–3.80
1
(
1H, m, HC-3), 1.72–1.43 (2H, m, H C-4), 1.42–1.24
2
1
3
J = 3 Hz, HC-3), 2.40 (1H, br s, OH), 1.05 (9H, s, H C).
C
3
(6H, m, H C-5, H C-6, H C-7), 0.94–0.85 (3H, t, J =
2 2 2
NMR d: 139.0 (s, Ph), 129.7 (2d, Ph), 129.2 (d, Ph), 129.0
6
.5 Hz, H C-8); for 9s: 4.33 (1H, d, J = 4.5 Hz, HC-2),
3
(
(
2d, Ph), 118.8 (s, C-1), 93.3 (d, C-2), 76.7 (t, CH O), 63.9
d, C-3), 35.7 (s, C-4), 26.9 (3q, CH3).
2
3.92–3.80 (1H, m, HC-3), 1.72–1.43 (2H, m, H C-4), 1.42–
2
1.24 (6H, m, H C-5, H C-6, H C-7), 0.94–0.85 (3H, t, J =
2
2
2
1
3
6
.5 Hz, H C-8). C NMR d for 9a: 117.9 (s, C-1), 72.6 (d,
3
1
-Cyano-3,3-dimethyl-2-(phenylmethoxy)butyl
(2S)-3,3,3-
C-3), 66.0 (d, C-2), 32.6 (t, C-4), 31.5 (t, C-6), 25.0 (t, C-5),
2.4 (t, C-7), 13.9 (q, C-8); d for 9s: 118.8 (s, C-1), 72.6 (d,
C-3), 64.9 (d, C-2), 32.1 (t, C-4), 31.5 (t, C-6), 25.0 (t, C-5),
2.4 (t, C-7), 13.9 (q, C-8).
trifluoro-2-methoxy-2-phenylpropanoate (6): Fractionation
of the crude product from reaction of 5 (a 1.5:1 mixture of
2
5
a and 5s, respectively; 10 mg, 0.043 mmol) with (R)-
MTPA-Cl by PTLC (25% EtOAc in hexane) gave 6 as a
.5:1.5:1:1 mixture of (R)-6a, (S)-6a, (R)-6s, and (R)-6s
isomers, respectively, as a colorless oil (16 mg, 83%). IR ꢂ
2
1
(
2R*,3R*)-2,3-Dihydroxy-4,4-dimethylpentanenitrile (10s):
max
A solution of TiCl (0.030 mL, 52 mg, 0.27 mmol) in
4
–1
1
(
cm ): 2959, 1761, 1453, 1227, 1171, 1108, 1021. H NMR
CH Cl (0.2 mL) was added via syringe to a stirred solution
2
2
1
9
‡
†
d: 7.57–7.18 (10H, m, ArH), 5.83 (d, J = 2 Hz), 5.77 (d,
of 4s (32 mg, 0.14 mmol) in CH Cl (2.3 mL) at 25°C. After
2
2
§
¶
J = 2 Hz), 5.590 (d, J = 4 Hz), and 5.587 (d, J = 5.5 Hz)
0
.5 h, H O was added and the mixture was extracted with
2
¶
†
(
1H, HC-1), 4.83 (d, J = 11 Hz), 4.76 (d, J = 11 Hz),
CH Cl (×3). The combined organic layers were filtered
2
2
§
‡
¶
®
4
1
4
.73 (d, J = 11 Hz), 4.64 (d, J = 11 Hz), 4.58 (d, J =
(
Celite ), and the filtrate was dried over Na SO , concen-
2 4
§
†
1 Hz), 4.52 (d, J = 11 Hz), 4.38 (d, J = 11 Hz), and
trated, and the residue (29 mg) fractionated by dry FCC (0–
‡
†¶
‡
.25 (d, J = 11 Hz) (2H, H CAr), 3.61 (m), 3.52 (m),
2
50% Et O in hexane, gradient elution) to give 10s as a white
2
§
¶
§
and 3.45 (m) (3H, H CO), 3.53 (d, J = 5.5 Hz), 3.45 (d,
3
solid (10 mg, 51%). LRMS (CI, NH ) m/z (relative inten-
3
†
‡
+
J = 4 Hz), 3.33 (d, J = 2 Hz), and 3.18 (d, J = 2) (1H,
HC-2), 1.04 (s), 1.03 (s), 0.98 (s), and 0.89 (s), (9H,
sity): 161 ([M + 18] , 62), 134 (100). HRMS m/z calcd. for
C H NO : 161.1290 (= [M + NH ] ); found: 161.1284 (CI,
(cm ): 3416, 3291, 2959, 2873, 2238 (w),
110, 1020. H NMR d: 4.61–4.56 (1H, br s, HC-2), 3.59–
¶
†
‡
§
+
7
13
2
4
+
–
1
(
H C) ). LRMS (EI) m/z (relative intensity): 449 ([M] , 5),
3 3
NH ). IR ꢂ
3
max
1
1
89 (22), 91 (100), 57 (21). HRMS m/z calcd. for
1
1
3
C H F NO : 449.1814; found: 449.1812 (EI). Elemental
2
4
26
3
4
3.55 (1H, br s, HC-3), 1.00 (9H, br s, J = 1 Hz, (H C) ).
C
3
3
anal. calcd. for C H F NO : C 64.13, H 5.83, N 3.12;
2
4
26
3
4
NMR: 120.1 (s, C-1), 78.9 (d, C-2), 61.8 (d, C-3), 35.2 (s,
C-4), 26.4 (3q, (CH ) ). Elemental analysis calcd. for
found: C 64.42, H 5.82, N 3.13.
3
3
C H NO : C 58.72, H 9.15, N 9.78; found: C 58.86,
H 8.95, N 9.51.
7
13
2
2
,3-Dihydroxyoctanenitrile (9): TMSCN (100 mg, 1.01 mmol)
and Et N (41 ꢁL, 30 mg, 0.30 mmol) was added to a stirred
3
(
(
4
4R*,5R*)-2,2-Dimethyl-5-pentyl-1,3-dioxolane-4-carbonitrile
11t) and (4R*,5S*)-2,2-dimethyl-5-pentyl-1,3-dioxolane-
-carbonitrile (11c)
TsOH (24 mg, 0.13 mmol) was added to a stirred solution
of 9 (a 2:1 mixture of 9s and 9a; 50 mg, 0.32 mmol) in
dimethoxypropane (10 mL) at room temperature. After 12 h,
the reaction mixture was diluted with CH Cl (15 mL),
washed sequentially with sat. NaHCO (×2) and H O, dried
over Na SO , and concentrated giving a colorless oil the
2 4
2
2
3 2
1
crude 11 as 2:1 ratio of trans:cis diastereomers by H NMR
67 mg). The residue was fractionated by FCC (10% EtOAc
(
in hexane) giving 11t (25 mg), a 1:1 mixture of 11t and 11c
(13 mg), and 11c (12 mg, 80%).
tion of one drop of DCl to the NMR sample resulted in hy-
drolysis of 7 to give a 2:1 mixture of 2s and 2a, respectively.
To a stirred solution of 7 (2:1 mixture of 7s:7a; 190 mg,
Spectral data for 11t: LRMS (CI, NH ) m/z (relative inten-
sity): 215 ([M + 18] , 8), 198 ([M + 1] , 26), 182 (78), 171
3
+
+
(19), 61 (100). HRMS m/z calcd. for C H NO : 215.1760
1
1
19
2
+
–1
0
1
.596 mmol) in CH Cl (20 mL) was added TiCl (71 ꢁL,
23 mg, 0.65 mmol). After 1 h, the reaction was quenched
by addition of NH Cl (1 M, 20 mL). The mixture was ex-
(= [M + NH ] ); found: 215.1758 (CI). IR ꢂ (cm ): 2933,
2
2
4
4 max
1
1460, 1383, 1218, 1067. H NMR d: 4.36 (1H, ddd, J = 6, 6,
6 Hz, HC-5), 4.15 (1H, d, J = 6 Hz, HC-4), 1.72–1.63
4
19Legend: † = (R)-6a, ‡ = (S)-6a, § = (R)-6s, ¶ = (S)-6s.
©
2001 NRC Canada

1
784
Can. J. Chem. Vol. 79, 2001
(
1
(
2H, m, H C-1>), 1.49 (3H, s, H CC-2), 1.45 (3H, s, H CC-2),
4. (a) D.E. Ward, Y. Liu, and C.K. Rhee. Can. J. Chem. 72, 1429
(1994); (b) D.E. Ward, Y. Liu, and C.K. Rhee. Synlett, 561
2
3
3
.40–1.27 (6H, m, H C-2>, H C-3>, H C-4>), 0.93–0.87
2 2 2
3H, m, H C-5>). C NMR d: 117.9 (s, CN), 112.3 (s, C-2),
1
3
(
1993).
. (a) D.E. Ward, D. How, and Y. Liu. J. Am. Chem. Soc. 119,
884 (1997); (b) D.E. Ward, Y. Liu, and D. How. J. Am.
3
5
8
2
0.3 (d, C-4), 67.7 (d, C-5), 32.8 (t, C-1>), 31.5 (t, C-3>),
1
6.8 (t, C-2>), 25.0 (2q, CH C-2), 22.4 (t, C-4>), 13.9 (q, C-5>).
3
Chem. Soc. 118, 3025 (1996).
Elemental anal. calcd. for C H NO : C 66.97, H 9.70,
1
1
19
2
6
7
. D.E. Ward and W.-L. Lu. J. Am. Chem. Soc. 120, 1098 (1998).
. A.H. Hoveyda, D.A. Evans, and G.C. Fu. Chem. Rev. 93, 1307
N 7.10; found: C 67.21, H 9.86, N 6.89.
(
1993).
Spectral data for 11c: LRMS (CI, NH ) m/z (relative inten-
sity): 215 ([M + 18] , 8), 198 ([M + 1] , 26), 182 (78), 171
3
+
+
8. (a) S. Masamune, W. Choy, J.S. Petersen, and L.R. Sita.
Angew. Chem. Int. Ed. Engl. 24, 1 (1985); (b) K. Nakayama.
J. Chem. Ed. 67, 20 (1990); (c) W.R. Roush, L.K. Hoong,
M.A.J. Palmer, J.A. Straub, and A.D. Palkowitz. J. Org. Chem.
(
(
2
5
1
19), 61 (100). HRMS m/z calcd. for C H NO : 215.1760
11 19 2
+
–1
= [M + NH ] ); found: 215.1759 (CI, NH ). IR ꢂ (cm ):
4 3 max
1
935, 1467, 1374, 1227, 1064. H NMR d: 4.73 (1H, d, J =
Hz, HC-4), 4.15 (1H, ddd, J = 5, 6, 7 Hz, HC-5), 1.97–
.86 (1H, m, HC-1>), 1.81–1.70 (1H, m, HC-1>), 1.56 (3H, s,
5
5, 4117 (1990).
9
. C.H. Heathcock, M.C. Pirrung, J. Lampe, C.T. Buse, and S.D
Young. J. Org. Chem. 46, 2290 (1981).
0. E. Fischer. Ber. Dtsch. Chem. Ges. 23, 2611 (1890).
11. Z. Györgydeá and I. F. Pelyvás. Monosaccharide sugars. Aca-
demic Press, San Diego. 1998. Chap. 1. pp. 18–30.
H CC-2), 1.52–1.44 (1H, m, HC-2>), 1.37 (3H, s, H CC-2),
3
3
1
1
.39–1.32 (5H, m, HC-2>, H C-3>, H C-4>), 0.90 (3H, br t,
2 2
1
3
J = 7 Hz, H C-5>). C NMR d: 116.5 (s, CN), 111.8 (s,
3
C-2), 77.5 (d, C-4), 68.2 (d, C-5), 31.6 (t, C-3>), 30.3 (t, C-1>),
1
2. (a) W.R. Jackson, H.A. Jacobs, G.S. Jayatilake, B.R. Matthews,
and K.G. Watson. Aust. J. Chem. 43, 2045 (1990); (b) C.G.
Kruze. In Chirality in industry. Edited by A.N. Collins, G.N.
Sheldrake, and J. Crosby. Wiley, New York. 1992. pp. 279–299.
3. (a) M. North. Synlett, 807 (1993); (b) F. Effenberger. Angew.
Chem. Int. Ed. Engl. 33, 1555 (1994); (c) H. Griengl, A.
Hickel, D.V. Johnson, C. Kratky, M. Schmidt, and H. Schwab.
Chem. Commun. 1933 (1997); (d) F. Effenberger. Chimia, 53,
3 (1999).
14. (a) C.-D. Hwang, D.-R. Hwang, and B.-J. Uang. J. Org. Chem.
63, 6762 (1998); (b) Y. Hamashima, D. Sawada, M. Kanai, and
M. Shibisaki. J. Am. Chem. Soc. 121, 2641 (1999); (c) Y.N.
Belokon’, S. Caveda-Cepas, B. Green, N.S. Ikonnikov, V.N.
Khrustalev, V.S. Larichev, M.A. Moscalenko, M. North, C.
Orizu, V.I. Tararov, M. Tasinazzo, G.I. Timofeeva, and L.V.
Yashkina. J. Am. Chem. Soc. 121, 3968 (1999); (d) M. Kanai,
Y. Hamashima, and M. Shibasaki. Tetrahedron Lett. 41, 2405
(2000).
2
7.2 (t, CH C-2), 25.8 (q, C-2>), 25.5 (q, CH C-2), 22.4 (t,
3
3
C-4>), 13.9 (q, C-5>).
(
4R*,5R*)-2,2-Dimethyl-5-(1>,1>-dimethylethyl)-1,3-
1
dioxolane-4-carbonitrile (12t):
A solution of 10s (16 mg, 0.11 mmol) and TsOH (ca.
mg) in dimethoxypropane (1.5 mL) was stirred a room
2
temperature for 17 h. The reaction mixture was diluted with
CH Cl , washed sequentially with sat. NaHCO (×2) and
2
2
3
H O, dried over Na SO , and concentrated to give a yellow
2
2
4
oil (19 mg). Bulb-to-bulb distillation (Kugelrohr, 15 torr
1 torr = 133.322 Pa), 90°C) of the residue distillation
(
gave 12t as a colorless oil (12 mg, 60%). LRMS (CI, NH )
m/z (relative intensity): 201 ([M + 18] , 79), 168 (100), 157
3
+
(
92). HRMS m/z calcd. for C H O N: 201.1603 (= [M +
10 17 2
+
–1
NH ] ); found: 201.1606 (CI, NH ). IR ꢂ (cm ): 2961,
2
4
3
max
1
874, 2250 (w), 1479, 1379, 1214, 1072. H NMR d: 4.56
1
5. (a) R. Nishizawa and T. Saino. J. Med. Chem. 20, 510 (1977);
b) D.H. Rich, B.J. Moon, and A.S. Boparai. J. Org. Chem. 45,
(
(
(
1H, d, J = 7 Hz, HC-4), 4.13 (1H, d, J = 7 Hz, HC-5), 1.50
(
3H, s, H C-C-2), 1.45 (3H, s, H C-C-2), 0.96 (9H, s,
3
3
1
3
2288 (1980); (c) J.R. Luly, C. Hsiao, N. BaMaung, and J.J.
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3 3
(
2
d, C-4), 64.2 (d, C-5), 33.1 (s, C(CH ) ), 26.4 (q, CH C-2),
3
3
3
5.4 (3q, (CH ) C), 24.5 (q, CH C-2).
3
3
3
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