Diastereoselective nucleophilic addition to aldehydes with polar α- And α,β-substituents

Article abstract of DOI:10.1002/adsc.201100173

The stereoselectivities obtained in Lewis acid-promoted Mukaiyama aldol additions and Sakurai allylations of mono-, and syn- and anti-disubstituted aldehydes possessing various polar α- and β-substituents under non-chelating conditions are presented. The

Full text of DOI:10.1002/adsc.201100173

FULL PAPERS
DOI: 10.1002/adsc.201100173
Diastereoselective Nucleophilic Addition to Aldehydes with Polar
a- and a,b-Substituents
Tessie Borg,a Jakob Danielsson,a Maziar Mohiti,a Per Restorp,a
and Peter Somfaia,b,*
a
KTH Chemical Science and Engineering, Organic Chemistry, Royal Institute of Technology, S-10044 Stockholm, Sweden
Fax : (+46)-8-791-2333; e-mail: somfai@kth.se
Institute of Technology, University of Tartu, Nooruse 1, 504 41 Tartu, Estonia
b
Received: March 11, 2011; Revised: May 2, 2011; Published online: August 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100173.
Abstract: The stereoselectivities obtained in Lewis In contrast, the selectivitites obtained from addition
acid-promoted Mukaiyama aldol additions and Sa- of sterically demanding nucleophiles to a-chloro-sub-
kurai allylations of mono-, and syn- and anti-disubsti- stituted aldehydes cannot be rationalized by the
tuted aldehydes possessing various polar a- and b- same models and an alternative is discussed. The
substituents under non-chelating conditions are pre- stereochemichal outcome in the additions to a,b-dis-
sented. The stereochemical outcome in the nucleo- ubstituted aldehydes is more complex and cannot be
philic addition to a-substituted aldehydes containing predicted using current models.
an a-benzyloxy, a-fluoro or a-sulfonamide substitu-
ent are accurately predicted by current stereoinduc- Keywords: aldol reaction; allylation; diastereoselec-
tion models.
tivity; induction model
Introduction
polar Felkin–Anh (PFA) model predicts the forma-
tion of the anti product and this is in accord with ex-
Nucleophilic addition to chiral carbonyl compounds is perimental observations.[5]
an important tool for stereoselective C C bond for-
ꢀ
mation,[1] and the aldol reaction is an integral part of
the arsenal of reactions for the total synthesis of natu-
ral products.[2] In these reactions the addition to the
diastereotopic p-faces of a C=O moiety give rise to
stereoisomeric products. Thus an integral aspect of
these reactions is the ability to predict and control the
stereochemical outcome, which is of great importance
for the design and synthesis of complex molecules.
Consequently, much work has been expended on de-
veloping models that accurately predict the p-facial
selectivities for this type of reaction.[3] For additions
to a-substituted aldehydes under non-chelation con-
trolled conditions the Felkin–Anh model, in which
torsional strain and hyperconjugation are important
controlling elements and govern the conformation of
the transition state, has been used with great suc-
cess.[4] Application of these criteria to aldehydes
having an a-heteroatom substituent results in struc-
ture A (Scheme 1) having a staggered conformation
where the best vicinal acceptor is oriented antiperi-
Scheme 1. The polar Felkin–Anh (A) and Cornforth–Evans
(B) models for the addition to a-heteroatom substituted al-
planar to the forming s-bond. It can be seen that the dehydes, and the polar 1,3-asymmetric induction model (C).
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Diastereoselective Nucleophilic Addition to Aldehydes with Polar a- and a,b-Substituents
Recently the validity of the PFA model was ques-
tioned by Evans and co-workers who showed that the
stereochemical outcome in the addition of E and Z
boron enolates to a-alkoxy aldehydes was best ration-
alized by the modified Cornforth model (B) (Corn-
forth–Evans).[6,7] Structure B is based on the assump-
tion that, in addition to having a staggered conforma-
tion, minimization of dipole interactions is an impor-
ꢀ
tant transition state control element. Hence, the C X
bond in B is almost antiparallel to the carbonyl
group. A recent computational study supports the im-
portance of the Cornforth–Evans model in the addi-
tion of enol boranes to a-heteroatom-substituted al-
dehydes having electronegative substituents (X=F,
OMe, Cl), while those having less electronegative sub-
stituents (X=NMe2, SMe, PMe2) favor the PFA reac-
tion manifold.[8]
In contrast, no general models have been advanced
for the prediction of the stereochemical outcome in
nucleophilic additions to b-substituted aldehydes in
the absence of chelation. However, Evans has pro-
posed that for the particular case when the b-substitu-
Scheme 2. The merged FA-polar 1,3-asymmetric induction
model (D) and the Cornforth–Evans transition state struc-
tures for addition to an anti- and syn-a,b-bisalkoxy aldehyde
ent is a polar heteroatom moiety (OR, Cl) structure (E and F).
C, in which steric and electrostatic effects are mini-
mized, accounts for the observed anti selectivity in
the BF3·OEt2-mediated addition of enolsilanes to
these substrates.[9]
The considerably more complex task of rationaliz- hyde should proceed with high selectivity. Experimen-
ing the stereochemical outcome in the addition of nu- tally, however, it was found that the Mukaiyama aldol
cleophiles to a,b-disubstituted aldehydes has been ad- reactions with anti-a,b-bisalkoxy aldehydes in most
dressed by the Evans group for a-alkyl-b-alkoxy sub- cases exhibited good diastereoselectivities, while the
strates. Superficially, it can be expected that the rela- corresponding syn isomer displayed lower selectivi-
tive stereochemistry of the major product can be pre- ties. To rationalize the stereochemical outcome both
dicted by analyzing the individual directing effects of PFA and Cornforth–Evans transition states conforma-
the a- and b-stereocenters, respectively. In this scenar- tions were analyzed, and by considering the inherent
io one stereoisomer of the aldehyde will have a and the developing syn-pentane interactions,[1d,11] it
matched combination of the a- and b-stereocenters, was concluded that the Cornforth–Evans model most
which will mutually reinforce the formation of a par- accurately predicted the observed stereochemical
ticular stereoisomeric product, while the other combi- trends. Thus, for the BF3·OEt2-mediated addition of
nation will be mismatched. Indeed, Mukaiyama aldol silyl enol ethers to anti-a,b-bisalkoxy aldehydes tran-
additions to anti-a-methyl-b-alkoxy aldehydes, where sition state structure E was proposed, while the syn
both stereodirecting elements promote addition to the isomer should react through transition state F, which
same diastereotopic C=O p-face, afforded the prod- suffers from an unfavorable R$H interaction. It is
ucts in high selectivity, and transition state (TS) con- evident from these studies that prediction of the ste-
formation D was suggested (Scheme 2).[9b] As can be reochemical outcome in the nucleophilic addition to
seen in structure D, both the a- (Felkin–Anh) and b- a,b-disubstituted aldehydes is far from trivial and
stereocenters (polar 1,3-asymmetric induction model) cannot be addressed by simple additive analysis of the
are acting in concert which favors addition to the C= participating stereocontrolling elements.
O Re face. As expected, addition to the corresponding
As parts of an ongoing investigation we have pre-
mismatched syn aldehyde proceeded with varying dia- viosly described a diastereoselective aldol addition a-
stereoselectivity. However, in a continuation of this amino-b-silyloxy aldehydes and an unexpected syn se-
investigation the addition of silyl enol ethers to a,b- lectivity in the Mukaiyama aldol addition to a-chloro-
bisalkoxy aldehydes was also studied.[10] Based on substituted aldehydes.[12,13] Herein, we report our full
analysis of the individual stereodirecting contributions investigation of the nucleophilic addition to a- and
from both alkoxy substituents it was predicted that a,b-polar substituted aldehydes, including chloro-,
the syn-a,b-bisalkoxy diastereomer should be fluoro-, alkoxy- and amino-substituted aldehydes.
matched, and that nucleophilic addition to this alde-
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Tessie Borg et al.
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Results and Discussion
for additions to a-chloro-, a-alkoxy- and a-fluoro-sub-
stituted aldehydes was supported in a recent theoreti-
cal investigation of enol borane additions to a-hetero-
substituted aldehydes,[8] and for the latter two sub-
a-Substituted Aldehydes
The initial focus of this study was directed towards strates this has been verified experimentally.[6a,15] It
the investigation of the facial bias exerted by a polar was shown that a-substituted aldehydes reacting via
a-substituent in the Mukaiyama aldol addition. a- the Cornforth–Evans manifold confer a higher diaste-
Substituted aldehydes 1–5,[14] having varying electron- reoselectivity with boron Z(O)-enolates than with the
ic and steric properties were selected and subjected to corresponding E(O)-enolates due to a destabilizing
the Mukaiyama aldol addition and the results are syn-pentane interaction in the E(O)-enolate TS. The
summarized in Table 1. a-Alkoxy (entries 7–9)[10] and opposite trend was observed for substrates reacting
a-fluoro aldehydes (entries 10–12) gave generally via the PFA TS. In a similar vein a-chloro aldehyde 1
poor anti selectivity, the trend being that larger nucle- was subjected to boron enolates 22 and 23
ophiles gave lower dr. For a-chloro aldehydes (en- (Scheme 3).[12] Addition of E(O)-enolate 22[16] to alde-
tries 1-6) a similar but more pronounced trend was hyde 1 furnished adduct 24b in modest yield and se-
observed. Addition of the hindered pinacolone enol lectivity, while the use of Z(O)-enolate 23[16] afforded
silane (6a) to a-chloro aldehydes 1 and 2 gave the syn 25b in excellent yield and selectivity which indicates
isomer as the major product in good selectivities (en- that also 1 prefers to react through a Cornforth–
tries 1 and 4), which is unanticipated and cannot be Evans TS in boron-mediated aldol reactions.
predicted by the PFA or the Cornforth–Evans
Given these results it is then not clear why a-
models. A completely opposite trend was observed chloro-, a-alkoxy- and a-fluoro-substituted aldehydes
for the a-sulfonamide 5 (entries 13–15), where an in- react with poor Cornforth–Evans, or even anti-Corn-
crease in size of the nucleophile led to an enhanced forth–Evans, selectivity in the Mukaiyama aldol reac-
amount of the anti isomer, which is expected on the tion (Table 1, entries 1–12). It is generally accepted
basis of the PFA model.[3a]
that the reaction proceeds through an open TS,[6a,17]
In order to begin to decipher the observed results having either antiperiplanar or synclinal TS conforma-
an examination of the operative transition states was tions, although exceptions are known.[18] To rational-
needed. The validity of the Cornforth–Evans model ize the stereochemical outcome in the Mukaiyama
Table 1. Mukaiyama aldol reaction to aldehydes 1-5.[a]
Entry
Aldehyde
X
R
6
R’
Products[b] (Ratio)
Yield[c] [%]
1
2
3
4
5
6
1
1
1
2
2
2
3
3
3
4
4
4
5
5
5
Cl
Cl
Cl
Cl
Cl
Cl
OTBS
OTBS
OTBS
F
i-Pr
i-Pr
i-Pr
CH2Ph
CH2Ph
CH2Ph
i-Pr
i-Pr
i-Pr
CH2Ph
CH2Ph
CH2Ph
i-Pr
i-Pr
i-Pr
a
b
c
a
b
c
a
b
c
a
b
c
t-Bu
i-Pr
Me
t-Bu
i-Pr
Me
t-Bu
i-Pr
Me
t-Bu
i-Pr
Me
7a:7b (84:16)
8a:8b (35:65)
9a:9b (40:60)
99
92
94
99
97
94
66
69
66
43
35
63
85
94
60
10a:10b (78:22)
11a:11b (29:71)
12a:12b (40:60)
13a:13b (50:50)
14a:14b (25:75)
15a:15b (18:82)
16a:16b (43:57)
17a:17b (27:73)
18a:18b (36:64)
19a:19b (>2:98)
20a:20b (7:93)
21a:21b (22:78)
7[d]
8[d]
9[d]
10
11
12
13
14
15
F
F
NTsBn
NTsBn
NTsBn
a
b
c
t-Bu
i-Pr
Me
[a]
Reaction conditions: To a solution of the aldehyde (1 equiv.) in CH2Cl2 at ꢀ608C was added BF3·OEt2 (3 equiv.) and 6
(2 equiv.) and the mixture was stirred for 18 h.
[b]
[c]
[d]
1
Diastereomeric ratio was determined by H NMR spectroscopy of the crude reaction mixture.
Isolated yield.
See ref.[10] for experimental details.
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Diastereoselective Nucleophilic Addition to Aldehydes with Polar a- and a,b-Substituents
Scheme 3. E(O)- and Z(O)-boron enolate additions to a-chloro aldehyde 1.
Scheme 4. Transition state structures in nucleophilic additions to a-chloro aldehydes 1 and 2.
aldol addition to a-chloro-substituted aldehydes 1 and TS H the major steric interaction is between the enol
2 TS structures G–J will be considered (Scheme 4). silane R’-substituent and the a-chloro substitu-
Structures G and H represent Cornforth–Evans struc- ent,[9b,22] while the relevant synclinal TSs G and I are
tures in which the enol silane has a synclinal or anti- characterized by a destabilizing interaction between
periplanar orientation, respectively, whereas struc- the enol silane and the Lewis acid coordinated to the
tures I and J are anti-Cornforth–Evans arrange- carbonyl oxygen.[9b,17,23]
ments,[19,20] in which the diastereotopic C=O face is
To differentiate between the synclinal and antiperi-
exposed for attack. Also, in structures I and J the di- planar TSs, aldehyde 1 was reacted with enol silanes
hedral angle between the carbonyl group and the a- 6a (R’=t-Bu) and 6c (R’=Me) in the presence of the
chloro substituent is relatively small, resulting in a de- sterically demanding Lewis acid trityl tetrafluorobo-
stabilizing dipole repulsion.[21] In the antiperiplanar rate (Scheme 5).[9b,24] By increasing the size of the
Scheme 5. Mukaiyama aldol addition to aldehyde 1 using trityl tetrafluoroborate.
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Tessie Borg et al.
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Lewis acid, the synclinal TSs are expected to be de- could then be rationalized as a manifestation of the
stabilized and changing the enol silane R’-substituent increased electronegativity of the a-heteroatom sub-
from Me (6c) to t-Bu (6a) is expected to further disfa- stituent, which should destabilize the TS structure cor-
vor this reaction pathway. However, when using responding to J, as is observed (Table 1, entries 7–12).
Ph3CBF4 the diastereoselectivity remains unchanged
The phenomenon discussed above should be specif-
within experimental error (compare with Table 1, en- ic for a-heteroatom-substituted aldehydes that prefer-
tries 1 and 3), suggesting that TS structures G and I entially react through Cornforth–Evans TS structures.
are not relevant in this reaction, and that the antiperi- For aldehydes reacting via the PFA manifold, it is
planar arrangements H and J are operative in the Mu- well established that smaller nucleophiles generally
kaiyama additions to aldehydes 1 and 2.
give lower levels of facial discrimination.[26] Hence,
It can then be argued that the BF3·OEt2-mediated substrates preferring the PFA conformation are ex-
addition of pinacolone enolsilane 6a to aldehydes 1 pected to show a reversed dependence of the selectiv-
and 2 will preferentially proceed through J in order ity on the sterics of the enolsilane.[27] Indeed, addition
to avoid steric interactions with the a-chloro substitu- of 6a and b to N-Ts-N-Bn-protected valinal (5) pro-
ent present in structure H (Table 1, Entries 1 and 4). ceed with excellent anti selectivity, while the addition
When decreasing the size of the enol silane R’ moiety of 6c displayed reduced levels of anti selectivity
the destabilizing steric interactions in H will be atte- (Table 1, entries 13–15, R=t-Bu!Me, syn:anti>
nuated, while the unfavorable dipole interaction in 2:98!22:78).
TS structure J remains unchanged, resulting in an in-
creased formation of the anti diastereomer (Table 1,
entries 2, 3, 5 and 6). It is also evident that both a-si- a,b-Disubstituted Aldehydes
lyloxy aldehyde 3[10] and a-fluoro aldehyde 4 follows
a similar trend in diastereoselectivity when changing In the continuation of this study additions to alde-
the size of the enol silane (Table 1, entries 7–9 and hydes having both polar a- and b-substituents were
10–12, respectively), and it is suggested that similar examined, the aim being to unravel any trends in the
factors as those outlined in Scheme 4 also dictate the diastereochemical outcomes. Three sets of aldehydes
outcome for these substrates.[25] The higher anti selec- were selected, all containing a b-alkoxy moiety, while
tivity obtained in the Mukaiyama aldol addition to 3 the steric and the electronic properties of the a-sub-
(X=O) and 4 (X=F) compared to 1 and 2 (X=Cl) stituent were varied: a,b-bisalkoxy aldehydes 28–31,
Table 2. Mukaiyama aldol reaction to a,b-disubstituted aldehydes 28-37.[a]
Entry
Aldehyde
a,b
X
P
R
Products[b] (Ratio)
Yield[c] [%]
1
2
3
4
5
6
28
29
30
31
32
33
34
35
36
37
anti
anti
syn
syn
anti
anti
syn
syn
anti
syn
OBn
OBn
OBn
OBn
NTsBn
NTsBn
NTsBn
NTsBn
Cl
Bn
Bn
Bn
Bn
TBS
TBS
TBS
TBS
TBS
TBS
CH2CH2Ph
n-C6H13
CH2CH2Ph
n-C6H13
CH2CH2Ph
c-C6H11
CH2CH2Ph
c-C6H11
38a:38b (14:86)
39a:39b (16:84)
40a:40b (49:51)
41a:41b (45:55)
42a:42b (> 2:98)
43a:43b (> 2:98)
44a:44b (53:47)
45a:45b (56:44)
46a:46b (95:5)
47a:47b (91:9)
99
93
90
92
92
81
91
49
99
94
7d)
8e)
9
CH2CH2Ph
CH2CH2Ph
10
Cl
[a]
Reaction conditions: To a solution of the aldehyde (1 equiv.) in CH2Cl2 at ꢀ608C was added BF3·OEt2 (3 equiv.) and 6a
(2 equiv.) and the mixture was stirred for 18 h.
[b]
[c]
[d]
[e]
1
Determined by H NMR spectroscopy of the crude reaction mixture.
Yields are reported for diastereomeric mixtures.
The reaction time was 40 h.
The reaction was run at ꢀ408C.
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Diastereoselective Nucleophilic Addition to Aldehydes with Polar a- and a,b-Substituents
a-amino-b-alkoxy derivatives 32–35 and a-chloro-b-si- salkoxy aldehydes 28–31,[10] it is assumed that the
lyloxy aldehydes 36 and 37. These substrates were ap- former aldehydes react through a PFA manifold
plied in the Mukaiyama aldol addition with silyl enol and,[8] consequently, that the Cornforth–Evans TS
ether 6a and the Sakurai allylation reaction with allyl- structures proposed for 28–31 do not apply. Although
trimethylsilane (48), and the results are detailed we can offer no explanation for the stereochemical
below.
outcome in additions to aldehydes 32–35 it is noted
Nucleophilic additions of TMS-enol ether 6a to that these results could not have been predicted by
anti-aldehydes 28, 29 proceeded in good yields and se- simply analyzing the individual contributions from the
lectivities to afford the corresponding 3,4-anti isomers a- and b-stereocenters, respectively. This point is fur-
(Table 2, entries 1, 2).[28] In contrast, additions to syn- ther highlighted by the p-facial selectivities obtained
aldehydes 30, 31 delivered triols 40 and 41 in equally in the Mukaiyama aldol reactions with a-chloro-b-si-
good yields but with poor diastereoselectivities (en- lyloxy aldehydes 36 and 37 (entries 9 and 10). Addi-
tries 3 and 4). Similar observations have been made tions to both anti-36 and syn-37 afforded the 3,4-syn
previously and were rationalized by invoking Corn- products 46a and 47a, respectively, in excellent yield
forth–Evans TS structures (e.g., see
E and F, and with high diastereoselectivity. Superficially, it ap-
Scheme 2).[10] In this scenario the lower diastereose- pears as the a-chloro substituent dictates the stereo-
lectivities obtained for the syn isomers 30 and 31 chemical outcome and that the b-substituent only has
were traced to an unfavorable syn-pentane interaction a minor influence. Once again, this outcome could
between R and the CHO proton in TS F, which is not have been predicted by applying the conventional
absent in structure E.
induction models. Taken together, the results in
Mukaiyama aldol additions to a-(N-benzyl-N-tosy- Table 2 highlight the increased complexity of predict-
lamino)-b-silyloxy aldehydes 32–35 follow a similar ing the stereochemical outcome in the Mukaiyama
trend.[13] Thus, addition of 6a to anti-aldehydes 32 and aldol addition to a,b-disubstituted aldehydes com-
33 afforded the corresponding 3,4-anti adducts 42b pared to a-substituted ones.
and 43b, respectively, in excellent yields and diaste-
In order to further investigate the nucleophilic ad-
reoselectivities (Table 2, entries 5 and 6) while aldol dition to these substrates, Sakurai allylations of alde-
additions to syn-aldehydes 34 and 35 resulted in lower hydes 28–37 were performed. The p-facial selectivities
yields and no appreciable selectivity (entries 7 and 8). in these additions are presented in Table 3. In general,
Although it would be tempting to speculate that the the stereochemical trends are in line with those ob-
stereochemical outcome for aldehydes 32–35 can be tained in the Mukaiyama aldol reaction. Allylation of
rationalized by applying similar models as for a,b-bi- aldehyde 28 and 29 proceeded with similar diastereo-
Table 3. Sakurai allylation reaction to a,b-disubstituted aldehydes 28–37.[a]
Entry
Aldehyde
a,b
X
P
R
Products (Ratio)[b]
Yield [%][c]
1
2
3
4
5
6
7
8
9
10
28
29
30
31
32
33
34
35
36
37
anti
anti
syn
syn
anti
anti
syn
syn
anti
syn
OBn
OBn
OBn
OBn
NTsBn
NTsBn
NTsBn
NTsBn
Cl
Bn
Bn
Bn
Bn
TBS
TBS
TBS
TBS
TBS
TBS
CH2CH2Ph
n-C6H13
CH2CH2Ph
n-C6H13
CH2CH2Ph
c-C6H11
CH2CH2Ph
c-C6H11
49a:49b (13:87)
50a:50b (16:84)
51a:51b (21:79)
52a:52b (33:67)
53a:53b (13:87)
95
93
83
87
67
decomp.[d]
54a:54b (45:55)
<5
decomp.[d]
CH2CH2Ph
CH2CH2Ph
55a:55b (60:40)
56a:56b (59:41)
88
94
Cl
[a]
Reaction conditions: To a solution of the aldehyde (1 equiv.) in CH2Cl2 at ꢀ608C was added BF3·OEt2 (3 equiv.) and allyl-
trimethylsilane (2 equiv.) and the mixture was stirred for 18 h.
ACHTUNGTRENNUNG
[b]
[c]
[d]
Isolated yield.
1
Determined by H NMR spectroscopy of the crude reaction mixture.
No allylation, even at elevated temperature, only decomposition of the aldehyde was observed.
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Tessie Borg et al.
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selectivity as in the addition of pinacolone enol silane Mukaiyama Aldol Reaction: Aldehydes 1, 2, 4, 5, 28–
(6a) to these substrates. In contrast, the additions to 37
the corresponding syn-aldehydes 30 and 31 proceeded
The experimental procedure for Mukaiyama aldol reaction
of aldehyde 1 with enol ether 6a is representative for all al-
with higher anti selectivities.[29] Sakurai allylation of
anti-a-amino-b-silyloxy aldehyde 32 displayed re-
duced selectivity compared with the Mukaiyama aldol
addition, which would be expected from a PFA-con-
trolled reaction.[26] All attempts to allylate aldehydes
33 and 35, even at elevated temperatures, were unsuc-
cessful and gave only decomposition products. The di-
minished diastereoselectivity in the allylations of alde-
hyde 36 and 37 compared with the Mukaiyama aldol
additions (Table 2, entries 11 and 12) should be noted
and indicates that the size of the nucleophile influen-
ces the selectivity in the addition to these substrates.
dehydes 1, 2, 6, 7, 9.
(5S*,6S*/5R*,6S*)-6-Chloro-5-hydroxy-2,2,7-tri-
methyloctan-3-one (7a, 7b)
To a stirred solution of 1 (19 mg, 156 mmol) in CH2Cl2
(1 mL) was added BF3·OEt2 (60 mL, 468 mmol) at ꢀ608C.
After 5 min. was added 6a (69 mL, 312 mmol) and the resul-
tant solution was stirred at ꢀ608C for 18 h. The reaction
was quenched by addition of H2O (5 mL) and allowed to
reach room temperature. The aqueous phase was extracted
with CH2Cl2 (3ꢁ7 mL), dried (MgSO4) and concentrated
under reduced pressure to afford 7a and 7b as a colorless
oil; yield: 34 mg (99%), dr 86:14 (syn:anti). The diastereo-
mers were separated by flash chromatography (pentane:E-
tOAc 12:1).
Conclusions
Major isomer 7a, white solid mp 40–458C. 1H NMR
(CDCl3, 500 MHz): d=4.37 (ddd, J=7.5, 4.5, 2.9 Hz, 1H),
3.68 (dd, J=7.6, 2.9 Hz, 1H), 2.89 (dd, J=17.7, 7.7 Hz, 1H),
2.76 (dd, J=17.8, 4.6 Hz, 1H), 2.68 (s, 1H), 2.14 (qd, J=
13.4, 6.7, 6.7, 6.7 Hz, 1H), 1.15 (s, 9H), 1.08 (t, J=6.9,
6.9 Hz, 6H); 13C NMR (CDCl3, 125 MHz): d=215.6, 74.3,
68.0, 44.4, 41.9, 32.4, 26.2, 20.3, 19.9; IR (film): nmax =3491,
2962, 1701, 737 cmꢀ1; HR-MS (FAB+): m/z=221.1303,
calcd. for C11H21ClO2 (M+H): 221.1308.
In conclusion, it has been shown that the stereochemi-
cal outcome in the Mukaiyama aldol addition to a-
chloro-substituted aldehydes is sensitive to the size of
the silyl enol ether and it is proposed that small nu-
cleophiles preferentially react through Cornforth–
Evans TS structures, while sterically more hindered
enol silanes preferentially react through anti-Corn-
forth–Evans TS. A similar relationship between the
size of the nucleophile and the stereochemical out-
come is also observed for a-alkoxy- and a-fluoro-sub-
stituted aldehydes, and it is proposed that similar fac-
tors govern the diastereofacial selectivity with this
class of substrates. It has also been shown that a-sul-
fonamide-substituted aldehydes, which preferentially
react through a PFA manifold, follow the opposite
trend, i.e., an increase in the size of the nucleophile
gives higher diastereoselectivity in favor of the anti
diastereomer. It has also been shown that the stereo-
chemical outcome in the Mukaiyama aldol addition
and Sakurai allylation of a,b-bisheteroatom-substitut-
ed aldehydes cannot be predicted using current
models for rationalizing stereoinduction.
Minor isomer 7b, colorless oil. 1H NMR (CDCl3,
500 MHz): d=4.05 (dt, J=8.6, 8.5, 2.4 Hz, 1H), 3.78 (dd,
J=8.9, 3.4 Hz, 1H), 3.72–3.55 (br s, 1H), 3.08 (dd, J=18.0,
2.4 Hz, 1H), 2.78 (dd, J=18.0, 8.1 Hz, 1H), 2.41 (m, 1H),
1.18–1.15 (s, 9H), 1.02 (d, J=6.8 Hz, 3H) , 0.97 (d, J=
6.6 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d=218.3, 71.3,
69.4, 44.6, 40.0, 29.0, 26.2, 20.7, 15.6; IR (film): nmax =3479,
2966, 1689, 725 cmꢀ1; HR-MS (FAB+): m/z=221.1303,
calcd. for C11H21ClO2 (M+H): 221.1308.
(5S*,6S*/5R*,6S*)-6-Chloro-5-hydroxy-2,7-di-
methyloctan-3-one (8a, 8b)
Prepared from aldehyde 1 and enol silane 6b as described
for 7a and 7b to afford 8a and 8b as a colorless oil; yield:
112 mg (83%); dr 35:65 (syn:anti). The diastereomers were
separated by flash chromatography (pentane:EtOAc 8:1).
Minor isomer 8a. 1H NMR (CDCl3, 500 MHz): d=4.37
(td, J=7.5, 3.7, 3.7 Hz, 1H), 3.68 (dd, J=7.3, 3.1 Hz, 1H),
2.86 (dd, J=17.5, 7.9 Hz, 1H), 2.71 (dd, J=17.5, 4.4 Hz,
1H), 2.67 (s br, 1H), 2.61 (m, 1H), 2.19–2.08 (m, 1H), 1.11
(d, J=7.0 Hz, 6H), 1.07 (dd, J=6.5, 5.4 Hz, 6H); 13C NMR
(CDCl3, 125 MHz): d=214.1, 74.4, 68.0, 45.2, 41.5, 32.3,
20.4, 19.7, 17.99, 17.95; IR (film): nmax =3479, 2970, 1709,
Experimental Section
1H and 13C NMR spectra were recorded in CDCl3 using the
residual peak of CHCl3 (1H: d=7.26; 13C d=77.0). Only the
strongest/structurally most important peaks (cmꢀ1), in the
IR spectra, are listed. Analytical TLC plates were visualized
with UV light and phosphomolybdic acid/cerium sulfate
staining reagent. Air- and moisture-sensitive reactions were
carried out in flame-dried, septum-capped flasks under an
atmospheric pressure of N2. All liquid reagents were trans-
ferred via oven-dried syringes. THF and CH2Cl2 were dried
using a Glass-contour solvent dispersion system.
741 cmꢀ1
; HR-MS (FAB+): m/z=207.1147, calcd. for
C10H19ClO2 (M+H): 207.1146.
Major isomer 8b. 1H NMR (CDCl3, 500 MHz): d=4.05
(dt, J=8.5, 8.5, 2.3 Hz, 1H), 3.74 (dd, J=8.7, 3.5 Hz, 1H),
3.51 (s br, 1H), 3.01 (dd, J=17.9, 2.5 Hz, 1H), 2.73 (dd, J=
18.0, 8.2 Hz, 1H), 2.61 (m, 1H), 2.42–2.31 (m, 1H), 1.10 (d,
J=6.9 Hz, 6H) , 1.00 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.6 Hz,
3H); 13C NMR (CDCl3, 125 MHz): d=214.1, 74.4, 68.0, 45.2,
41.5, 32.3, 20.4, 19.7, 17.99, 17.96; IR (film): nmax =3475,
2028
asc.wiley-vch.de
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 2022 – 2036

Diastereoselective Nucleophilic Addition to Aldehydes with Polar a- and a,b-Substituents
2970, 1704, 733 cmꢀ1; HR-MS (FAB+): m/z=207.1149,
calcd. for C10H19ClO2 (M+H): 207.1146.
J=14.0, 6.7 Hz, 1H), 3.10 (dd, J=14.0, 8.1 Hz, 1H), 2.90
(dd, J=17.8, 8.5, Hz, 1H), 2.75 (dd, J=17.8, 3.8 Hz, 1H),
2.61 (hept, J=6.9 Hz, 1H), 1.12 (d, J=6.9 Hz, 3H), 1.11 (d,
J=6.9 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d=214.6,
137.6, 129.3, 128.5, 126.9, 68.1, 66.8, 44.3, 41.5, 40.8, 17.96,
17.95; IR (film): nmax =3467, 2970, 1705, 702 cmꢀ1; HR-MS
(FAB+): m/z=255.1147, calcd. for C14H19ClO2 (M+H):
255.1146.
(5S*,6S*/5R*,6S*)-5-Chloro-4-hydroxy-6-methyl-
heptan-2-one (9a, 9b)
Prepared from aldehyde 1 and enol silane 6c as described
for 7a and 7b to afford 9a and 9b as a colorless oil; yield:
136 mg (94%); dr 40:60 (syn:anti). The diastereomers were
separated by flash chromatography (pentane:EtOAc 6:1).
Minor isomer 9a. 1H NMR (CDCl3, 500 MHz): d=4.36
(m, 1H), 3.67 (dd, J=7.1, 3.4 Hz, 1H), 2.85 (dd, J=17.3,
8.2 Hz, 1H), 2.67 (dd, J=17.3, 4.1 Hz, 1H), 2.62 (s br, 1H),
2.21 (s, 3H), 2.13 (qd, J=13.5, 6.7, 6.7, 6.7 Hz, 1H), 1.07
(dd, J=6.7, 3.4 Hz, 6H); 13C NMR (CDCl3, 125 MHz): d=
1
Major isomer 11b: H NMR (CDCl3, 500 MHz): d=7.34–
7.28 (m, 2H), 7.27–7.22 (m, 3H), 4.12–4.05 (m, 2H), 3.59 (br
s, 1H), 3.34 (dd, J=14.4, 3.3 Hz, 1H), 2.99–2.91 (m, 2H),
2.82 (dd, J=17.8, 7.9 Hz, 1H), 2.62 (hept, J=6.9 Hz, 1H),
1.12 (d, J=6.9 Hz, 3H), 1.11 (d, J=6.9 Hz, 3H).; 13C NMR
(CDCl3, 125 MHz): d=214.6, 137.6, 129.3, 128.5, 126.9, 68.1,
66.8, 44.3, 41.5, 40.8, 17.96, 17.95; IR (film): nmax =3479,
2970, 1709, 1466, 1045 cmꢀ1
; HR-MS (FAB+): m/z=
207.9, 74.3, 68.0, 48.4, 32.2, 30.9, 20.4, 19.5; IR (film): nmax
3456, 2966, 1712, 737 cmꢀ1
HR-MS (FAB+): m/z=
201.0653, calcd. for C8H15ClNaO2 (M+Na): 201.0653.
=
;
255.1145, calcd. for C14H19ClO2 (M+H): 255.1146.
Major isomer 9b: 1H NMR (CDCl3, 400 MHz): d=4.10
(dt, J=8.6, 8.6, 2.5 Hz, 1H), 3.75 (dd, J=8.6, 3.7 Hz, 1H),
3.36 (s br, 1H), 3.01 (dd, J=18.0, 2.4 Hz, 1H), 2.72 (dd, J=
18.0, 8.5 Hz, 1H), 2.35 (dtd, J=13.4, 6.7, 6.7, 3.7 Hz, 1H),
2.21 (s, 3H), 1.01 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.6 Hz,
3H); 13C NMR (CDCl3, 125 MHz): d=210.1, 71.3, 68.9, 46.7,
30.9, 29.0, 20.6, 15.8; IR (film): nmax =3448, 2966, 1708,
(5S*,6S*/5R*,6S*)-6-Chloro-5-hydroxy-2,2-dimethyl-
7-phenylheptan-3-one (12a, 12b)
Prepared from aldehyde 2 and enol silane 6c as described
for 7a and 7b to afford 12a and 12b as a colorless oil; yield:
354 mg (51%); dr 66:34 (syn:anti). The following ratios were
used: aldehyde 2 equiv., BF3·OEt2 2 equiv., enol silane
1 equiv. The diastereomers were separated by preparative
HPLC (hexanes 99.5%, 2-propanol 0.5%).
733 cmꢀ1
; HR-MS (FAB+): m/z=201.0651, calcd. for
C8H15ClNaO2 (M+Na): 201.0653.
1
Minor isomer 12a. H NMR (CDCl3, 500 MHz): d=7.35–
(5S*,6S*/5R*,6S*)-6-Chloro-5-hydroxy-2,2-dimethyl-
7.30 (m, 2H), 7.28–7.24 (m, 3H), 4.24–4.19 (ddd, J=8.7, 3.6,
2.3 Hz, 1H), 4.11 (ddd, J=8.0, 6.8, 2.3 Hz, 1H), 3.29 (dd,
J=14.0, 6.8 Hz, 1H), 3.09 (dd, J=14.0, 8.0 Hz, 1H), 2.90
(dd, J=17.8, 8.7 Hz, 1H), 2.71 (dd, J=17.8, 3.6 Hz, 1H),
2.19 (s, 3H); 13C NMR (CDCl3, 125 MHz): d=208.4, 137.5,
129.3, 128.6, 126.9, 67.9, 66.8, 47.6, 40.8, 30.7; IR (film):
nmax =3448, 2912, 1712, 702 cmꢀ1; HR-MS (FAB+): m/z=
227.0833, calcd. for C12H15ClO2 (M+H): 227.0833.
7-phenylheptan-3-one (10a, 10b)
Prepared from aldehyde 2 as described for 7a and 7b to
afford 10a and 10b as a colorless oil; yield: 575 mg (99%);
dr 78:22 (syn:anti). The diastereomers were separated by
flash chromatography (heptane:EtOAc 5:1!3:1).
1
Major isomer 10a. H NMR (CDCl3, 500 MHz): d=7.30
(m, 5H), 4.22 (ddd, J=8.3, 3.9, 2.2 Hz, 1H), 4.16 (ddd, J=
8.6, 6.6, 2.2 Hz, 1H), 3.32 (dd, J=14.0, 6.6 Hz, 1H), 3.12
(dd, J=14.0, 8.2 Hz, 1H), 3.03 (s br, 1H), 2.92 (dd, J=17.9,
8.3 Hz, 1H), 2.81 (dd, J=17.9, 4.0 Hz, 1H), 1.16 (s, 9H);
13C NMR (CDCl3, 125 MHz): d=216.0, 137.6, 129.3, 128.5,
126.8, 68.2, 66.8, 44.4, 41.0, 40.8, 26.2; IR (film): nmax =3479,
2970, 1701, 702 cmꢀ1; HR-MS (FAB+): m/z=269.1304,
calcd. for C15H21ClO2 (M+H): 269.1303.
1
Major isomer 12b. H NMR (CDCl3, 500 MHz): d=7.35–
7.30 (m, 2H), 7.28–7.24 (m, 3H), 4.14–4.08 (m, 2H), 3.42 (br
s, 1H), 3.32 (dd, J=14.4, 3.3 Hz, 1H), 2.98–2.92 (m, 2H),
2.81 (dd, J=17.9, 8.1 Hz, 1H), 2.22 (s, 3H); 13C NMR
(CDCl3, 125 MHz): d=209.4, 137.2, 129.5, 128.4, 126.9, 70.4,
65.5, 45.9, 40.1, 30.9; IR (film): nmax =3440, 2931, 1701, 1408,
698 cmꢀ1
; HR-MS (FAB+): m/z=227.0834, calcd. for
1
Minor isomer 10b. H NMR (CDCl3, 500 MHz): d=7.37–
C12H15ClO2 (M+H): 227.0833.
7.22 (m, 5H), 4.12 (ddd, J=8.6, 7.2, 3.9 Hz, 1H), 4.07 (t, J=
7.5, 7.5 Hz, 1H), 3.69 (s br, 1H), 3.37 (dd, J=14.4, 3.8 Hz,
1H), 3.03–2.93 (m, 2H), 2.85 (dd, J=18.0, 8.0 Hz, 1H), 1.17
(s, 9H); 13C NMR (CDCl3, 125 MHz): d=217.5, 137.3, 129.6,
(5S*,6S*/5R*,6S*)-6-Fluoro-5-hydroxy-2,2-dimethyl-
7-phenylheptan-3-one (16a, 16b)
128.3, 126.8, 70.8, 65.5, 44.6, 40.1, 39.2, 26.2; IR (film): nmax
=
2475, 2970, 1701, 702 cmꢀ1
;
HR-MS (FAB+): m/z=
Prepared from aldehyde 4 as described for 7a and 7b to
afford 16a and 16b as a colorless oil; yield: 55.0 mg (43%),
dr 43:57 (syn:anti).
269.1305, calcd for C15H21ClO2 (M+H): 269.1303.
1
Minor isomer 16a. H NMR (CDCl3, 500 MHz): d=7.27–
(5S*,6S*/5R*,6S*)-6-Chloro-5-hydroxy-2-methyl-7-
phenylheptan-3-one (11a, 11b)
7.16 (m, 5H), 4.51 (dddd, J=47.0, 7.9, 5.9, 2.3 Hz, 1H), 4.01
(ddddd, J=16.2, 4.8, 3.1, 3.1, 3.0 Hz, 1H), 3.07 (d, J=
4.8 Hz, 1H), 3.09–2.95 (m, 2H), 2.81 (dd, J=17.9, 9.0 Hz,
1H), 2.66 (dd, J=17.9, 3.3 Hz, 1H), 1.08 (s, 9H); 13C NMR
(125 MHz, CDCl3): d=216.6, 136.9 (d, J=6.4 Hz), 129.4,
128.6, 126.7, 95.6 (d, J=177.1 Hz), 67.8 (d, J=20.0 Hz), 39.2
Prepared from aldehyde 2 and enol silane 6b as described
for 7a and 7b to afford 11a and 11b as a colorless oil; yield:
163 mg (97%); dr 29:71 (syn:anti). The diastereomers were
separated by flash chromatography (heptane:EtOAc 5:1).
1
Minor isomer 11a: H NMR (CDCl3, 500 MHz): d=7.36–
(d, J=3.6 Hz), 37.1 (d, J=22.2 Hz), 26.3; IR (film): nmax =
7.30 (m, 2H), 7.29–7.24 (m, 3H), 4.22 (ddd, J=8.5, 3.8,
2.4 Hz, 1H), 4.13 (ddd, J=6.7, 8.1, 2.4 Hz, 1H), 3.31 (dd,
3437, 2924, 1701, 1369, 1169 cmꢀ1; HR-MS (FAB+): m/z=
253.1597, calcd. for C15H21FO2 (M+H): 253.1598.
Adv. Synth. Catal. 2011, 353, 2022 – 2036
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2029

Tessie Borg et al.
FULL PAPERS
1
Major isomer 16b. H NMR (CDCl3, 500 MHz): d=7.35–
2.85 (unresolved ddd, J=18.0 Hz, 1H), 2.68 (dd, J=18.0,
8.8 Hz, 1H), 2.20 (s, 3H); 13C NMR (125 MHz, CDCl3): d=
209.7, 136.71 (d, J=1.7 Hz), 129.5, 128.5, 126.7, 94.9 (d, J=
174.2 Hz), 68.4 (d, J=24.9 Hz), 45.0 (d, J=3.6 Hz), 37.6 (d,
7.22 (m, 5H), 4.56 (dddd, J=47.9, 7.5, 7.5, 3.3 Hz, 1H),
4.04–3.97 (m, 1H), 3.55 (d, J=4.3 Hz, 1H), 3.15 (ddd, J=
32.9, 14.7, 3.3 Hz, 1H), 2.95 (ddd, J=23.0, 14.8, 7.9 Hz, 1H),
2.88 (ddd, J=18.0, 2.2, 2.2 Hz, 1H), 2.71 (dd, J=18.0,
8.6 Hz, 1H), 1.15 (s, 9H); 13C NMR (125 MHz, CDCl3): d=
217.7, 136.9 (d, J=1.6 Hz), 129.6, 128.4, 126.6, 94.9 (d, J=
174.0 Hz), 68.8 (d, J=24.9 Hz), 44.6, 38.4 (d, J=3.6 Hz),
37.7 (d, J=20.4 Hz), 26.2; IR (neat): nmax =3475, 2966, 1701,
1365, 1061 cmꢀ1; HR-MS (FAB+): m/z=253.1591, calcd. for
C15H21FO2 (M+H): 253.1598.
J=20.4 Hz), 30.9; IR (neat): nmax =3371, 1709, 1107 cmꢀ1
;
HR-MS (FAB+): m/z=211.1127, calcd. for C12H15FO2 (M+
H): 211.1129.
AHCTUNGTREG(NNUN 5R*,6S*)-6-(N-Benzyl-N-tosylamino)-5-hydroxy-
2,2,7-trimethyloctan-3-one (19b)[12]
Prepared from aldehyde 5 as described for 7a and 7b to
afford 19b as a colorless oil; yield: 90 mg (85%); dr>2:98
(syn:anti).
(5S*,6S*/5R*,6S*)-6-Fluoro-5-hydroxy-2-methyl-7-
phenylheptan-3-one (17a, 17b)
1
Major isomer 19b. H NMR (CDCl3, 400 MHz): d=7.68
(d, J=8.2 Hz, 2H), 7.46 (d, J=7.0 Hz, 2H), 7.35–7.21 (m,
5H), 4.61 (d, J=15.4 Hz, 1H), 4.36 (d, J=15.4 Hz, 1H),
4.01 (m, 1H), 3.43 (m, 1H), 3.26 (d, J=2.2 Hz, 1H), 2.53
(m, 2H), 2.42 (s, 3H), 1.91 (m, 1H), 1.04 (s, 9H), 0.74 (d,
J=6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz): d=217.5,
143.2, 138.2, 137.6, 129.6, 129.1, 128.4, 127.7, 127.3, 69.2,
44.2, 41.7, 29.3, 26.3, 22.3, 21.5, 20.2; IR (neat): nmax =3400,
2970, 1690, 1160 cmꢀ1; HR-MS (FAB+): m/z=446.2359,
calcd. for C25H35NO4S (M+H): 446.2365.
Prepared from aldehyde 4 and enol silane 6b as described
for 7a and 7b to afford 17a and 17b as a colorless oil; yield:
63.0 mg (35%); dr 27:73 (syn:anti).
1
Minor isomer 17a. H NMR (400 MHz, CDCl3): d=7.35–
7.22 (m, 5H), 4.57 (dddd, J=46.4, 8.0, 5.9, 2.5 Hz, 1H),
4.16–4.04 (m, 1H), 3.13–3.00 (m, 3H), 2.86 (dd, J=17.7,
9.0 Hz, 1H), 2.69 (dd, J=17.7, 3.4 Hz, 1H), 2.61 (hept, J=
6.9 Hz, 1H), 1.12 (d, J=6.9 Hz, 3H), 1.11 (d, J=6.9 Hz,
3H); 13C NMR (125 MHz, CDCl3): d=215.0, 136.8 (d, J=
6.3 Hz), 129.4, 128.6, 126.7, 95.6 (d, J=177.0 Hz), 67.7 (d,
J=20.1 Hz), 42.5 (d, J=3.5 Hz), 41.6, 37.0 (d, J=22.2 Hz),
18.0, 17.9; IR (neat): nmax =3341, 1709, 1643 cmꢀ1; HR-MS
(FAB+): m/z=239.1439, calcd. for C14H19FO2 (M+H):
239.1442.
AHCTUNGTREG(NNNU 5R*,6S*)-6-(N-Benzyl-N-tosylamino)-5-hydroxy-2,7-
dimethyloctan-3-one (20a, 20b)
Prepared from aldehyde 5 and enol silane 6b as described
for 7a and 7b to afford 20a and 20b as a colorless oil; yield:
140 mg (94%); dr 7:93 (syn:anti). The diastereomers were
separated by flash chromatography (heptane:EtOAc 6:1).
1
Major isomer 17b. H NMR (500 MHz, CDCl3): d=7.26–
7.15 (m, 5H), 4.56–4.48 (m, 1H), 3.96 (q, J=7.0 Hz, 1H),
3.41 (s, 1H), 3.06 (ddd, J=33.1, 14.8, 3.3 Hz, 1H), 2.88 (ddd,
J=22.9, 14.7, 8.0 Hz, 1H), 2.77 (dt, J=17.9, 2.3 Hz, 1H),
2.62 (dd, J=17.9, 8.6 Hz, 1H), 2.53 (hept, J=7.0 Hz, 1H),
1.04 (d, J=2.7 Hz, 3H), 1.03 (d, J=2.7 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=216.0, 136.8 (d, J=1.6 Hz), 129.5,
128.4, 126.6, 94.9 (d, J=174.2 Hz), 68.6 (d, J=24.8 Hz), 41.7
(d, J=3.6 Hz), 41.6, 37.6 (d, J=20.4 Hz), 17.9, 17.9; IR
(neat): nmax =3340, 2966, 1709, 1462, 1107 cmꢀ1; HR-MS
(FAB+): m/z=239.1440, calcd. for C14H19FO2 (M+H):
239.1442.
1
Major isomer 20b. H NMR (CDCl3, 500 MHz): d=7.69
(d, J=8.2 HZ, 2H), 7.48 (d, J=7.2 Hz, 2H), 7.34–7.24 (m,
5H), 4.63 (d, J=15.4 Hz, 1H), 4.33 (d, J=15.4 Hz, 1H),
3.99 (unresolved m, 1H), 3.43 (unresolved m, 1H), 3.27 (br
s, J=2.1 Hz, 1H), 2.55–2.35 (m, 6H), 1.96–1.77 (unresolved
m, 1H), 1.03 (d, J=6.8 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H),
0.97 (d, J=6.9 Hz, 3H), 0.73 (d, J=6.8 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): d=215.8, 143.2, 138.0, 137.5, 129.5,
129.0, 128.3, 127.6, 127.2, 69.12, 67.0 (br), 48.9 (br), 44.9,
41.0, 29.2, 22.2, 21.4, 20.0, 17.9, 17.8; IR (film): nmax
=
3521(br), 2970, 1705, 1335, 1157 cmꢀ1; HR-MS (FAB+):
m/z=432.2205, calcd. for C24H33NO4S (M+H): 432.2203.
(5S*,6S*/5R*,6S*)-5-Fluoro-4-hydroxy-6-phenyl-
hexan-2-one (18a, 18b)
AHCTUNGTREG(NNNU 4R*,5S*)-5-(N-Benzyl-N-tosylamino)-4-hydroxy-6-
methylheptan-2-one (21a, 21b)
Prepared from aldehyde 4 and enol silane 6c as described
for 7a and 7b to afford 18a and 18b as a colorless oil; yield:
112 mg (63%); dr 36:64 (syn:anti).
Prepared from aldehyde 5 and enol silane 6c as described
for 7a and 7b to afford 21a and 21b as a colorless oil; yield:
47.3 mg (60%); dr 22:78 (syn:anti). The following ratios
were used: aldehyde 2 equiv., BF3·OEt2 2 equiv., enol silane
1 equiv. The diastereomers were separated by flash chroma-
tography (heptane:EtOAc 8:1!4:1).
1
Minor isomer 18a. H NMR (500 MHz, CDCl3): d=7.22
(m, 5H), 4.56 (dddd , J=46.7, 8.0, 5.8, 2.6 Hz, 1H), 4.10
(dddd, J=24.6, 9.1, 2.8, 2.8 Hz, 1H), 3.01 (m, 2H), 2.97 (br
s, 1H), 2.86 (dd, J=17.7, 9.1 Hz, 1H), 2.67 (dd, J=17.7,
3.3 Hz, 1H), 2.20 (s, 3H); 13C NMR (126 MHz, CDCl3): d=
209.6, 136.72 (d, J=1.7 Hz), 129.5, 128.5, 126.7, 94.9 (d, J=
174.2 Hz), 68.4 (d, J=24.9 Hz), 45.0 (d, J=3.7 Hz), 37.6 (d,
1
Major isomer 21b. H NMR (CDCl3, 400 MHz, 558C): d=
7.70 (d, J=8.1 Hz, 2H), 7.46 (d, J=7.0 Hz, 2H), 7.36–7.24
(m, 5H), 4.64 (d, J=15.5 Hz, 1H), 4.32 (d, J=15.5 Hz, 1H),
4.04 (unresolved m, 1H), 3.44 (dd, J=6.2, 6.2 Hz 1H), 3.09
(br s, 1H), 2.63–2.46 (m, 2H), 2.44 (s, 3H), 2.01 (s, 3H),
1.99–1.87 (m, 1H), 1.04 (d, J=6.7 Hz, 3H), 0.75 (d, J=
6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz, 458C): d=209.6,
143.3, 138.4, 137.6, 129.6, 129.2, 128.5, 127.8, 127.4, 69.5, 67.2
(br), 49.3 (br), 48.0, 30.3, 29.4, 22.3, 21.4, 20.0; IR (film):
J=20.5 Hz), 30.9; IR (neat): nmax =3371, 1709, 1107 cmꢀ1
;
HR-MS (FAB+): m/z=211.1127, calcd. for C12H15FO2 (M+
H): 211.1129.
1
Major isomer 18b. H NMR (500 MHz, CDCl3): d=7.34–
7.23 (m, 5H), 4.56 (dddd, J=47.8, 8.0, 7.5, 3.3 Hz, 1H),
4.10–4.02 (m, 1H), 3.30 (d, J=4.5 Hz, 1H), 3.12 (ddd, J=
33.0, 14.8, 3.3 Hz, 1H), 2.95 (ddd, J=22.9, 14.7, 8.0 Hz, 1H),
2030
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 2022 – 2036

Diastereoselective Nucleophilic Addition to Aldehydes with Polar a- and a,b-Substituents
nmax =3618 (br), 2962, 1709, 1334, 1157 cmꢀ1
ACTHNUGTRNE(NGU 6S*,7R*)-6,7-Bis(benzyloxy)-5-hydroxy-2,2-di-
;
HR-MS
(FAB+): m/z= 404.1890, calcd. for C22H29NO4S (M+H):
404.1890.
methyltridecan-3-one (39b, 39b)
Prepared from aldehyde 29 as described for 38 to afford 39a
and 39b as a colorless oil; yield: 92 mg (93%); dr 84:16
(syn:anti).
(5S*,6S*/5R*,6S*)-6-Chloro-5-hydroxy-2,2,7-tri-
methyloctan-3-one (7a, 7b)
1
Major isomer 39b. H NMR (500 MHz, CDCl3): d=7.32
(m, 10H), 4.79 (d, J=11.6 Hz, 1H), 4.67 (d, J=11.6 Hz,
1H), 4.62 (d, J=11.5 Hz, 1H), 4.55 (d, J=11.5 Hz, 1H),
4.13 (ddt, J=6.0, 3.6, 2.3 Hz, 1H), 3.72 (m, 1H), 3.62 (dd,
J=6.2, 3.5 Hz, 1H), 3.43 (d, J=3.7 Hz, 1H), 2.92 (dd, J=
18.1, 2.3 Hz, 1H), 2.58 (dd, J=18.2, 9.2 Hz, 1H), 1.69 (m,
1H), 1.59 (m, 1H), 1.48 (m, 1H), 1.30 (m, 7H), 1.07 (s, 9H),
0.88 (t, J=6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=
218.4, 138.6, 138.5, 128.36, 128.32, 128.1, 127.8, 127.6, 127.5,
81.7, 79.7, 73.6, 71.9, 68.2, 44.3, 39.4, 31.8, 29.9, 29.4, 26.2,
25.6, 22.6, 14.1; IR (film): nmax =3492(br), 1696, 1455,
To a solution of Ph3CBF4 (657 mg, 1.99 mmol) in CH2Cl2
(17 mL) at ꢀ608C was added 1 (80 mg, 0.66 mmol) and the
solution stirred for 15 min followed by addition of 6a
(229 mg, 1.33 mmol). The resultant mixture stirred for 18 h
and then quenched by addition of H2O (17 mL) and allowed
to reach room temperature. The aqueous phase was extract-
ed with CH2Cl2 (3ꢁ10 mL), dried (MgSO4) and concentrat-
ed under reduced pressure. The residue was purified by
flash chromatography (pentane:EtOAc 12:1) to afford 7a
and 7b as a colorless oil; yield: 117 mg (80%); dr 84:16
(syn:anti). See above for characterization details.
1089 cmꢀ1
C29H42O4 (M+Li): 461.3238.
; HR-MS (FAB+): m/z=461.3222, calcd. for
(5S*,6S*/5R*,6S*)-5-Chloro-4-hydroxy-6-methyl-
heptan-2-one (9a, 9b)
AHCTUNGTREG(NNUN 6R*,7R*)-6,7-Bis(benzyloxy)-5-hydroxy-2,2-di-
methyl-9-phenylnonan-3-one (40a, 40b)
Prepared from aldehyde 1 and enol silane 6c as described
for 7a and 7b. The mixture was purified by flash chromatog-
raphy (pentane:EtOAc 6:1) to afford 9a and 9b as colorless
oils; yield: 99 mg (83%); dr 37:63 (syn:anti). See above for
characterization details.
Prepared from aldehyde 30 as described for 38 to afford 40a
and 40b as a colorless oil; yield: 32 mg (90%); dr 51:49
(syn:anti).
1
Mixture of isomers. H NMR (400 MHz, CDCl3): d=7.26
(m, 15Hmaj, 15Hmin), 4.79 (AB-d, J=11.7 Hz, 1Hmaj), 4.72–
4.54 (m, 3Hmaj, 4Hmin), 4.28 (m, 1Hmin), 4.18 (qd, J=5.0,
3.7 Hz, 1Hmaj), 3.76 (ddd, J=8.1, 6.3, 3.9 Hz, 1Hmaj), 3.60
(m, 2Hmin), 3.51 (d, J=3.46 Hz, 1Hmin), 3.44 (dd, J=6.3,
3.6 Hz, 1Hmaj), 2.87 (d, J=5.2 Hz, 1Hmaj), 2.85–2.51 (m,
3Hmaj, 4Hmin), 2.44 (dd, J=17.9, 3.8 Hz, 1Hmaj), 2.09–1.96
(m, 1Hmaj, 2Hmin), 1.88 (m, 1Hmaj), 1.07 (s, 9Hmin), 1.04 (s,
9Hmaj); 13C NMR (125 MHz, CDCl3): d=216.8, 216.2, 142.1,
141.8, 138.5, 138.1, 138.2, 138.0, 128.46, 128.47, 128.40,
128.38, 128.36, 128.35, 128.2, 128.1, 128.21, 127.9, 127.8,
127.7, 125.3, 125.77, 81.5, 80.6, 79.1 78.5, 74.4, 73.7, 73.0,
72.5, 68.5, 67.4, 44.3, 44.2, 40.5, 39.6, 32.7, 31.9, 31.8, 31.7,
26.22, 26.18; IR (film): nmax =3489 (br), 1703, 1454,
Mukaiyama Aldol Reaction: Aldehydes 28–37
The experimental procedure for Mukaiyama aldol reaction
of aldehyde 28 is representative for all aldehydes 28–37.
ACHTUNGTRENNUNG(6S*,7R*)-6,7-Bis(benzyloxy)-5-hydroxy-2,2-dimethyl-
9-phenylnonan-3-one (38a, 38b)
To a stirred solution of 28 (27.3 mg, 72.9 mmol) in CH2Cl2
(1 mL) was added BF3·OEt2 (28 mL, 219 mmol) at ꢀ608C.
After 5 min. was added 6a (32 mL, 146 mmol) and the resul-
tant solution was stirred at ꢀ608C for 18 h. The reaction
was quenched by addition of H2O (5 mL) and allowed to
reach room temperature. The aqueous phase was extracted
with CH2Cl2 (3ꢁ7 mL), dried (MgSO4) and concentrated
under reduced pressure to afford 38a and 38b as a colorless
oil; yield: 34.5 mg (99%); dr 86:14 (syn:anti).
1070 cmꢀ1
C31H38O4 (M+H): 475.2848.
; HR-MS (FAB+): m/z=475.2838, calcd. for
AHCTUNGTREG(NNUN 6R*,7R*)-6,7-Bis(benzyloxy)-5-hydroxy-2,2-di-
methyltridecan-3-one (41a, 41b)
1
Major isomer 38b. H NMR (400 MHz, CDCl3): d=7.28
(m, 15H), 4.82 (d, J=11.7 Hz, 1H), 4.69 (d, J=8.1 Hz, 1H),
4.66 (d, J=7.9 Hz, 1H), 4.55 (d, J=11.5 Hz, 1H), 4.12 (ddt,
J=6.2, 3.5, 2.4 Hz, 1H), 3.79 (td, J=8.0, 3.4 Hz, 1H), 3.67
(dd, J=6.4, 3.4 Hz, 1H), 3.39 (d, J=3.7 Hz, 1H), 2.93 (dd,
J=18.1, 2.3 Hz, 1H), 2.86 (m, 1H), 2.67 (ddd, J=13.8, 10.1,
6.4 Hz, 1H), 2.57 (dd, J=18.2, 9.2 Hz, 1H), 2.06 (m, 1H),
1.94 (m, 1H), 1.08 (s, 9H); 13C NMR (100 MHz, CDCl3):
d=218.3, 142.4, 138.5, 128.48, 128.44, 128.42, 128.37, 128.1,
128.0, 127.72, 127.68, 125, 81.5, 79.1, 73.7, 71.9, 68.2, 44.4,
39.5, 31.9, 31.7, 26.3; IR (film): nmax =3485 (br), 1703, 1454,
Prepared from aldehyde 31 as described for 38 to afford 41a
and 41b as a colorless oil; yield: 49 mg (92%); dr 55:45
(syn:anti).
1
Minor isomer 41a. H NMR (400 MHz, CDCl3): d=7.30
(m, 10H), 4.67 (d, J=11.8 Hz, 4H), 4.29 (dq, J=6.2, 3.1 Hz,
1H), 3.59 (dt, J=6.4, 3.9 Hz, 1H), 3.54 (dd, J=5.8, 3.8 Hz,
1H), 3.50 (d, J=3.5 Hz, 1H), 2.82 (dd, J=17.7, 2.8 Hz, 1H),
2.63 (dd, J=17.7, 8.9 Hz, 1H), 1.66 (m, 2H), 1.29 (m, 8H),
1.08 (s, 9H), 0.88 (t, J=6.9 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=217.0, 138.3, 138.2, 128.4, 128.3, 128.2, 127.8,
128.2, 127.7, 80.9, 79.5, 73.8, 72.5, 68.6, 44.3, 39.7, 31.8, 30.2,
,29.4, 26.2, 25.9, 22.6, 14.1.
1073 cmꢀ1
; HR-MS (FAB+): m/z=475.2838, calcd. for
C31H38O4 (M+H): 475.2848.
1
Major isomer 41b. H NMR (400 MHz, CDCl3): d=7.30
(m, 10H), 4.83 (d, J=11.7 Hz, 1H), 4.63 (m, 3H), 4.16 (m,
1H), 3.73 (ddd, J=7.8, 6.4, 4.2 Hz, 1H), 3.39 (dd, J=6.3,
3.5 Hz, 1H), 2.88 (d, J=5.1 Hz, 1H), 2.73 (dd, J=17.9,
8.5 Hz, 1H), 2.45 (dd, J=17.9, 3.7 Hz, 1H), 1.66 (m, 2H),
Adv. Synth. Catal. 2011, 353, 2022 – 2036
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asc.wiley-vch.de
2031

Tessie Borg et al.
FULL PAPERS
1.29 (m, 8H), 1.08 (s, 9H), 0.88 (t, J=6.9 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=216.3, 138.7, 138.43,
128.43, 128.3, 128.0, 127.8, 127.6, 81.9, 80.1, 74.5, 73.1, 67.5,
44.2, 40.6, 31.8, 31.0, 29.5, 26.2, 25.5, 22.6, 14.1; IR (film):
nmax =348 0(br), 1703, 1455, 1072 cmꢀ1; HR-MS (FAB+): m/
z=455.3154, calcd. for C29H42O4 (M+H): 455.3156.
3H); 13C NMR (100 MHz, CDCl3): d=216.3, 142.6, 141.5,
138.3, 137.8, 128.8, 128.7, 128.5, 128.3, 128.0, 127.9, 127.0,
125.9, 74.1, 65.3, 64.2, 49.7, 44.3, 41.2, 35.7, 32.3, 26.2, 25.9,
21.4, 18.0, ꢀ4.4, ꢀ4.5; IR (film): nmax =2960, 1700,
1160 cmꢀ1
; HR-MS (FAB+): m/z=652.3503, calcd. for
C37H53NO5SSi (M+H): 652.3492.
1
Minor isomer 44b. H NMR (400 MHz, CDCl3): d=7.43
(m, 2H), 7.32–7.18 (m, 8H), 7.07 (d, J=7.0 Hz, 2H), 6.91
(d, J=8.1 Hz, 2H), 4.79 (d, J=14.5 Hz, 1H), 4.61 (d, J=
14.5 Hz, 1H), 4.43 (dt, J=6.3, 2.3 Hz, 1H), 4.27 (m, 1H),
3.97 (dd, J=10.2, 2.3 Hz, 1H), 3.59 (d, J=3.2 Hz, 1H), 2.87
(d, J=18.5 Hz, 1H), 2.73–2.51 (m, 3H), 2.24 (s, 3H), 2.22
(m, 2H), 1.10 (s, 9H), 0.87 (s, 9H), 0.14 (s, 3H), 0.05 (s,
3H); 13C NMR (100 MHz, CDCl3): d=218.6, 142.8, 141.6,
138.3, 137.3, 129.8, 129.0, 128.4, 128.3, 128.0, 127.5, 127.3,
125, 72.4, 65.1, 63.5, 49.9, 44.3, 40.9, 36.7, 32.7, 26.4, 26.2,
21.4, 18.3, ꢀ4.2, ꢀ5.2; IR (film): nmax =2960, 1690,
N-Benzyl-N-{(1R*,2R*)-1-[(S*)-1-(tert-butyl)-
dimethylsilanyloxy-3-phenylpropyl]-2-hydroxy-5,5-
dimethyl-4-oxohexyl}-4-methylbenzenesulfonamide
(42b)
Prepared from aldehyde 32 as described for 38a and 38b to
afford 42b as a colorless oil; yield: 141 mg (92%); dr>2:98
(syn:anti). 1H NMR (400 MHz, CDCl3): d=7.75 (d, J=
8.0 Hz, 2H), 7.51 (d, J=6.8 Hz, 2H), 7.37–7.18 (m, 10H),
4.81 (d, J=15.2 Hz, 1H), 4.40 (d, J=15.2 Hz, 1H), 4.24 (m,
1H), 4.07 (m, 1H), 3.91 (m, 1H), 3.64 (d, J=2.3 Hz, 1H),
2.88 (dt, J=13.0, 4.6 Hz, 1H), 2.69 (m, 1H), 2.61 (dt, J=
13.0, 4.6 Hz, 1H), 2.45 (s, 3H), 2.21 (d, J=18.0 Hz, 1H),
2.00 (m, 1H), 1.63 (m, 1H), 1.03 (s, 9H), 0.92 (s, 3H), 0.02
(s, 3H), ꢀ0.02 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
215.6, 143.5, 142.6, 138.0, 137.7, 129.8, 129.0, 128.6, 128.5,
128.3, 127.7, 127.3, 125.6, 72.4, 68.9, 44.0, 41.6, 35.8, 28.8,
26.0, 21.4, 18.1, ꢀ4.3, ꢀ4.4; IR (film): nmax =2960, 1690,
1160 cmꢀ1
; HR-MS (FAB+): m/z=674.3324, calcd for
C37H53NO5SSi (M+Na): 674.3311.
N-Benzyl-N-{(1S*,2S*/1S*,2R*)-1-[(S*)-1-(tert-butyl)-
dimethylsilanyloxy-3-cyclohexylmethyl]-2-hydroxy-
5,5-dimethyl-4-oxohexyl}-4-methylbenzene-
sulfonamide (45a, 45b)
1160 cmꢀ1
; HR-MS (FAB+): m/z=652.3484, calcd. for
Prepared from aldehyde 35 as described for 38a and 38b to
afford 45a and 45b as a colorless oil; yield: 34 mg (49%); dr
56:44 (syn:anti). The diastereomers were separated by prep-
arative HPLC (hexane:i-PrOH 99:1).
C37H53NO5SSi (M+H): 652.3492.
N-Benzyl-N-{(1R*,2R*)-1-[(S*)-1-(tert-butyl)-
dimethylsilanyloxy-3-cyclohexyl-ethyl]-2-hydroxy-5,5-
dimethyl-4-oxohexyl}-4-methylbenzenesulfonamide
(43b)
1
Major isomer 45a. H NMR (400 MHz, CDCl3): d=7.51–
7.12 (m, 9H), 4.72 (d, J=16.2 Hz, 1H), 4.56 (d, J=16.2 Hz,
1H), 4.34 (m, 1H), 3.98 (dd, J=9.4, 3.0, 1H), 3.75 (t, J=3.5,
1H), 3.10 (d, J=17.3, 1H), 2.90 (d, J=4.6 Hz, 1H), 2.51
(dd, J=17.3, 9.0 Hz, 1H), 2.37 (s, 3H), 1.57–0.79 (m, 29H),
0.16 (s, 3H), 0.13 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
216.7, 142.6, 138.7, 137.7, 128.9, 128.7, 128.1, 127.9, 127.1,
79.7, 77.3, 65.2, 49.8, 44.3, 42.1, 39.7, 31.8, 28.6, 26.3, 26.2,
26.09, 26.05, 21.4, 18.5, ꢀ3.3, ꢀ4.7; IR (film): nmax =3490,
1700, 1340, 1100 cmꢀ1; HR-MS (FAB+): m/z=630.3651,
calcd. for C35H55NO5SSi (M+H): 630.3648.
Prepared from aldehyde 33 as described for 38a and 38b to
afford 43b as a colorless oil; yield: 29 mg (81%); dr>2:98
1
(syn:anti). H NMR (500 MHz, d8-PhMe, 908C): d=7.61 (d,
J=8.2 Hz, 2H), 7.41 (d, J=7.4 Hz, 2H), 7.13–6.82 (m, 5H),
4.68 (d, J=15.4 Hz, 1H), 4.50 (m, 1H), 4.34 (d, J=15.4,
1H), 4.04–3.90 (m, 2H), 3.47 (s, 3H), 2.71 (dd, J=17.0,
9.6 Hz, 1H), 2.27 (d, J=17.0 Hz, 1H), 1.99–0.94 (m, 29H),
0.17 (s, 3H), ꢀ0.02 (s, 3H); 13C NMR (125 MHz, DMSO-
d6): d=213.8, 137.9, 134.8, 130.4, 129.1, 128.6, 127.8, 127.6,
75.6, 67.9, 62.7, 43.8, 43.2, 30.1, 27.0, 26.3, 24.5, 21.4, 19.1,
ꢀ1.7, ꢀ4.5; IR (film): nmax =3450, 2970, 1690, 1340,
1
Minor isomer 45b. H NMR (400 MHz, CDCl3): d=7.31–
7.01 (m, 9H), 4.82 (d, J=14.5 Hz, 1H), 4.48 (d, J=14.5 Hz,
1H), 4.33 (m, 1H), 4.13 (m, 2H), 3.36 (s, 1H), 2.91 (m, 1H),
2.69 (m, 1H), 2.33 (s, 3H) 1.99–0.80 (m, 29H), 0.21 (s, 3H),
0.13 (s, 3H); 13C NMR (125 MHz, CDCl3); d=218.6, 142.6,
138.5, 136.8, 129.7, 128.9, 127.9, 127.5, 127.3, 109.0, 64.9,
62.1, 50.3, 44.4, 41.2, 39.8, 31.1, 29.7, 29.4, 26.9, 26.4, 26.3,
26.0, 21.3, 18.7, ꢀ3.5, ꢀ4.5; IR (film): nmax =3500, 1690,
1160 cmꢀ1
; HR-MS (FAB+): m/z=630.3643, calcd. for
C35H55NO5SSi (M+H): 630.3648.
N-Benzyl-N-{(1S*,2S*/1S*,2R*)-1-[(S*)-1-(tert-butyl)-
dimethylsilanyloxy-3-phenylpropyl]-2-hydroxy-5,5-
dimethyl-4-oxohexyl}-4-methylbenzenesulfonamide
(44a, 44b)
1100 cmꢀ1
; HR-MS (FAB+): m/z=630.3648, calcd. for
C35H55NO5SSi (M+H): 630.3648.
(5S*,6S*,7R*)-6-Chloro-5-yloxy-(tert-butyl)-
dimethylsilane-7-hydroxy-2,2-dimethyl-9-phenyl-
nonan-3-one (46a)
Prepared from aldehyde 34 as described for 38a and 38b to
afford 44a and 44b as a colorless oil; yield: 45 mg (91%); dr
53:47 (syn:anti). The diastereomers were separated by flash
chromatography (pentane:EtOAc 20:1).
Prepared from aldehyde 36 as described for 38 to afford 46a
as a colorless oil; yield: 16 mg (99%); dr 95:5 (syn:anti).
1
Major isomer 44a. H NMR (400 MHz, CDCl3): d=7.49–
1
7.02 (m, 14H), 4.72 (d, J=16.0 Hz, 1H), 4.62 (d, J=16.0 Hz,
1H), 4.30 (m, 1H), 4.11 (dd, J=8.9, 2.5 Hz, 1H), 3.94 (dt,
J=6.1, 2.5 Hz, 1H), 2.97 (d, J=4.5 Hz, 1H), 2.82 (dd, J=
18.0, 2.0 Hz, 1H), 2.57 (m, 3H), 2.43 (s, 3H), 1.96 (m, 1H),
1.62 (m, 1H), 1.11 (s, 9H), 0.82 (s, 9H), 0.08 (s, 3H), 0.04 (s,
Major isomer 46a. H NMR (500 MHz, CDCl3): d=7.13
(m, 5H), 4.56 (ddt, J=6.3, 2.7, 1.2 Hz, 1H), 4.04 (dd, J=
11.0, 5.4 Hz, 1H), 3.90 (dd, J=5.5. 1.2 Hz, 1H), 3.40 (d, J=
2.8 Hz, 1H), 2.76 (dd, J=6.2, 5.7 Hz, 2H), 2.66 (ddd, J=
13.5, 11.3, 5.1 Hz, 1H), 2.55 (ddd, J=13.5, 11.1, 6.0 Hz, 1H),
2032
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 2022 – 2036

Diastereoselective Nucleophilic Addition to Aldehydes with Polar a- and a,b-Substituents
1.95 (m, 2H), 1.05 (s, 9H), 0.81 (s, 9H), 0.14 (d, J=20.9 Hz,
6H); 13C NMR (125 MHz, CDCl3): d=215.3, 141.5, 129.3,
128.4, 128.3, 125.9, 74.8, 65.7, 65.4, 44.3, 41.4, 36.7, 30.3, 26.2,
25.8, 18.0, ꢀ4.5, ꢀ4.7; IR (film): nmax =3436 (br), 1702, 1644,
1255, 1095, 837, 777 cmꢀ1; HR-MS (FAB+): m/z=427.2428,
calcd for C23H39ClO3Si (M+H): 427.2430.
(4R*,5R*,6S*)-6-Chloro-5-hydroxy-2,4,7-trimethyl-
octan-3-one (25b)
To 2-methyl-3-pentanone (41 mL, 332 mmol) in Et2O
(0.6 mL) at 08C was added 9-BBNOTf (730 mL, 0.5M in
hexane) and DIPEA (69 mL, 398 mmol). The solution
turned yellow and was allowed to reach room temperature
and stirred for 1 h before it was cooled down to ꢀ788C and
1 (40 mg, 332 mmol) dissolved in Et2O (0.7 mL) was added
dropwise. The resultant mixture was stirred at ꢀ788C for
2 h, allowed to warm up to 08C and after 10 min. quenched
by sequential addition of phosphate buffer pH 7 (1.5 mL),
MeOH (1.5 mL) and H2O2 (1.5 mL). The mixture was
stirred for additional 30 min at room temperature, then di-
luted with buffer (5 mL) and CH2Cl2 (5 mL). The aqueous
phase was extracted (CH2Cl2, 3ꢁ5 mL), the combined or-
ganic phases were washed (1:1 NaS2O3, 20 wt%, aqueous
and NaHCO3 saturated, aqueous), dried (Na2SO4) and con-
centrated. The residue was purified by flash chromatography
(pentane:EtOAc 16:1) to afford 25b as a colorless oil; yield:
61 mg (99%); dr 94:6 (syn:anti).
(5S*,6S*,7R*)-6-Chloro-5-yloxy-(tert-butyl)-
dimethylsilane-7-hydroxy-2,2-dimethyl-9-
phenylnonan-3-one (47a)
Prepared from aldehyde 37 as described for 38 to afford 47a
as a colorless oil; yield: 24 mg (94%); dr 91:9 (syn:anti).
1
Major isomer 47a. H NMR (CDCl3, 500 MHz): d=7.25
(m, 5H), 4.41 (m, 1H), 4.01 (dd, J=4.7, 2.7 Hz, 1H), 3.14
(d, J=4.1 Hz, 1H), 2.85 (m, 2H), 2.67 (m, 2H), 2.14 (s, 1H),
1.91 (m, 1H), 1.16 (s, 9H), 0.93 (s, 9H), 0.12 (d, J=2.6 Hz,
6H); 13C NMR (CDCl3, 125 MHz): d=215.2, 141.5, 128.5,
128.3, 126.0, 74.8, 68.2, 68.1, 44.4, 41.4, 35.7, 31.2, 26.4, 26.2,
25.8, 18.1, ꢀ4.1, ꢀ4.4; IR (film): nmax =3488, 1703, 1255,
1095, 1072, 837, 778 cmꢀ1; HR-MS (FAB+): m/z=427.2431,
calcd for C23H39ClO3Si (M+H): 427.2430.
1
Major isomer 25b. H NMR (CDCl3, 500 MHz): d=3.93
(td, J=10.1, 1.7, 1.7 Hz, 1H), 3.77 (dd, J=10.1, 2.2 Hz, 1H),
3.61 (d, J=1.9 Hz, 1H), 3.35 (dq, J=7.3, 7.3, 7.3, 1.5 Hz,
1H), 2.82 (sept., J=6.9, 6.9, 6.9, 6.9, 6.9, 6.9 Hz, 1H), 2.46
(dtd, J=13.4, 6.7, 6.7, 2.2 Hz, 1H), 1.38–1.10 (m, 9H), 1.04
(d, J=6.8 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): d=221.3, 71.1, 67.8, 43.9, 40.0, 28.1,
20.9, 18.7, 17.8, 14.5, 8.6; IR (film): nmax =3451 (br), 1681,
1090, 1017, 735 cmꢀ1; HR-MS (FAB+): m/z=221.1301,
calcd for C11H21ClO2 (M+H): 221.1303.
Boron Enolate Addition to Aldehyde 1: (4R,5S/
4S,5R)-6-Chloro-5-hydroxy-2,4,7-trimethyloctan-3-one
(24a, 24b)
To
a stirred solution of 2-methyl-3-pentanone (41 mL,
332 mmol) in Et2O (0.6 mL) was added (c-Hex)2BCl
(349 mL, 1M in hexane) and Et3N (51 mL, 365 mmol) at
08C. The solution turned white and was stirred for 1 h
before it was cooled down to ꢀ788C and 1 (40 mg,
332 mmol) dissolved in Et2O (0.4 mL) was added dropwise.
The resultant mixture was stirred at ꢀ788C for 2 h, allowed
to warm up to 08C and after 10 min. quenched by sequential
addition of phosphate buffer pH 7 (1.5 mL), MeOH
(1.5 mL) and H2O2 (1.5 mL). The mixture was stirred for ad-
ditional 30 min at room temperature and diluted with buffer
(5 mL) and CH2Cl2 (5 mL). The aqueous phase was extract-
ed (CH2Cl2, 3ꢁ5 mL), the combined organic phases were
washed (1:1 NaS2O3, 20 wt%, aqueous and NaHCO3, satu-
rated, aqueous), dried (Na2SO4) and concentrated to afford
24a and 24b as a colorless oil; yield: 30 mg (50%); dr 13:87
(syn:anti). The diastereomers were separated by flash chro-
matography (pentane:EtOAc 16:1).
Sakurai Allylation Reaction of Aldehydes 28–37
The experimental procedure for Sakurai allylation of alde-
hyde 28 is representative for all aldehydes 28–37.
AHCTUNGTREG(NNNU 5S*,6R*)-5,6-Bis(benzyloxy)-8-phenyloct-1-en-4-ol
(49a, 49b)
To a stirred solution of 28 (22.2 mg, 59.3 mmol) in CH2Cl2
(1 mL) was added BF3·OEt2 (23 mL, 178 mmol) at ꢀ608C.
After 5 min. was added allyl trimethylsilane (19 mL,
119 mmol) and the resultant solution was stirred at ꢀ608C
for 18 h. The reaction was quenched by addition of H2O
(5 mL) and allowed to reach room temperature. The aque-
ous phase was extracted with CH2Cl2 (3ꢁ2.5 mL), dried
(MgSO4) and concentrated under reduced pressure. Flash
chromatography (pentane:EtOAc 8:1) of the residue gave
49a and 49b as colorless oil; yield: 23.4 mg (95%); dr 87:13
(syn:anti).
1
Minor isomer 24a. H NMR (CDCl3, 400 MHz): d=3.67
(dd, J=8.6, 1.7 Hz, 1H), 4.03 (d, J=7.9, 1H), 3.06 (m, 1H),
2.74 (sept, J=6.9 Hz, 1H), 2.11 (m, 1H), 1.08 (m, 9H), 1.01
(m, 6H); 13C NMR (CDCl3, 125 MHz): d=218.1, 73.1, 71.8,
48.6, 41.1, 32.7, 20.8, 20.1, 18.0, 17.9, 13.9; HRMS (FAB+):
m/z=221.1302, calcd. for C11H21ClO2 (M+H): 221.1303.
1
Major isomer 49b. H NMR (500 MHz, CDCl3): d=7.27
(m, 15H), 5.82 (m, 1H), 5.13 (m, 2H), 4.77 (d, J=11.4 Hz,
1H), 4.65 (dd, J=11.4, 8.5 Hz, 2H), 4.56 (d, J=11.5 Hz,
1H), 3.79 (m, 2H), 3.57 (dd, J=6.6, 3.6 Hz, 1H), 2.86 (m,
1H), 2.67 (m, 1H), 2.52 (m, 1H), 2.24 (m, 2H), 2.10 (ttd,
J=11.6, 9.0, 4.5 Hz, 1H), 1.99 (m, 1H); 13C NMR
(125 MHz, CDCl3): d=142.2, 138.4, 138.3, 135.0, 128.43,
128.41, 128.36, 128.3, 127.95, 127.89, 127.70, 127.67, 125.7,
118.1, 81.9, 79.5, 73.63, 72.0, 71.0, 38.0, 32.2, 31.8; IR (film):
nmax =3428 (br), 1640, 1454, 1095, 1071, 916 cmꢀ1; HR-MS
(FAB+): m/z=417.2423, calcd. for C28H32O3 (M+H):
417.2424.
1
Major isomer 24b. H NMR (CDCl3, 500 MHz): d=3.99
(s, 1H), 3.64 (dd, J=10.1, 2.3 Hz, 1H), 3.52 (d, J=10.2 Hz,
1H), 3.46 (dq, J=7.4, 2.8 Hz, 1H), 2.77 (sept, J=6.9 Hz,
1H), 2.54 (dsept, J=6.7, 2.32 Hz, 1H), 1.32 (d, J=7.35 Hz,
3H), 1.14 (d, J=7.0 Hz, 3H), 1.10 (d, J=6.82 Hz, 3H), 1.01
(d, J=6.85 Hz, 3H), 0.92 (d, J=6.58 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): d=223.1, 76.3, 70.8, 43.3, 40.9, 28.8,
20.9, 18.1, 17.6, 15.7, 14.5; IR (film): nmax =3413 (br), 1641,
1065, 1025, 742 cmꢀ1; HR-MS (FAB+): m/z=221.1302,
calcd for C11H21ClO2 (M+H): 221.1303.
Adv. Synth. Catal. 2011, 353, 2022 – 2036
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2033

Tessie Borg et al.
14.1; IR (film): nmax =3451 (br), 1640, 1455, 1069, 915 cmꢀ1
FULL PAPERS
;
ACHTUNGTRENNUNG
HR-MS (FAB+): m/z=397.2737, calcd. for C26H36O3 (M+
H): 397.2737.
50b)
Prepared from aldehyde 29 as described for 49 to afford 50a
and 50b as a colorless oil; yield: 118 mg (93%); dr 84:16
(syn:anti).
(3R*,4S*,5S*)-4-N-Benzyl-N-tosylamino-1-phenyloct-
7-ene-3-yloxy-(tert-butyl)dimethylsilane-5-ol (53a,
53b)
1
Major isomer 50b: H NMR (500 MHz, CDCl3): d=7.45–
7.29 (m, 10H), 5.95 (m, 1H), 5.23–5.13 (m, 2H), 4.78 (d, J=
11.4 Hz, 1H), 4.70–4.54 (m, 3H), 3.85 (d, J=8.2 Hz, 1H),
3.80–3.73 (m, 1H), 3.54 (dd, J=6.6, 3.8 Hz, 1H), 2.65–2.55
(m, 1H), 2.38 (d, J=7.9 Hz, 1H), 2.28 (dd, J=14.2, 8.3 Hz,
1H), 1.82–1.69 (m, 2H), 1.58–1.46 (m, 1H), 1.44–1.25 (m,
7H), 0.93 (t, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=138.4, 135.2, 127.92, 127.88, 127.7, 127.6, 118.0, 82.2, 80.4,
73.6, 72.1, 71.3, 38.0, 31.8, 30.5, 29.5, 25.5, 22.6, 14.1; IR
(film): nmax =3473 (br), 1640, 1455, 1069, 914 cmꢀ1; HR-MS
(FAB+): m/z=397.2742, calcd. for C26H36O3 (M+H):
397.2737.
Prepared from aldehyde 32 as described for 49 to afford 53a
and 53b as a colorless oil; yield: 37 mg (67%); dr 87:13
(syn:anti).
1
Major isomer 53b. H NMR (500 MHz, CDCl3): d=7.70
(d, J=8.2, 2H), 7.38 (d, J=7.3, 2H), 7.24 (m, 10H), 5.61
(tdd, J=17.0, 10.1, 6.9 Hz, 1H), 5.02 (dd, J=10.3, 1.1 Hz,
1H), 4.93 (dd, J=17.1, 1.4 Hz, 1H), 4.73 (d, J=15.6 Hz,
1H), 4.39 (d, J=15.6 Hz, 1H), 4.01 (br s, 1H), 3.89 (br s,
1H), 3.68 (br s, 1H), 3.09 (br s, 1H), 2.75 (dt, J=12.8, 4.6,
1H), 2.56 (dt, J=12.9, 4.1 Hz, 1H), 2.43 (s, 3H), 2.10 (m,
2H), 1.93 (m, 1H), 1.63 (m, 1H), 0.88 (s, 9H), ꢀ0.00 (s,
3H), ꢀ0.01 (s, 3H); 13C NMR (125 MHz, CDCl3): d=143.6,
142.1, 137.8, 135.1, 129.7, 128.5, 128.5, 128.3, 127.6, 127.4,
125.7, 117.0, 73.3, 72.6, 40.1, 36.0, 28.8, 25.9, 21.4, 18.0, ꢀ3.8,
ACHTUNGTRENNUNG(5R*,6R*)-5,6-Bis(benzyloxy)-8-phenyloct-1-en-4-ol
(51a, 52b)
ꢀ4.6; IR (film): nmax =3478 (br), 1341, 1160, 836, 778 cmꢀ1
;
Prepared from aldehyde 30 as described for 49 to afford 51a
and 51b as a colorless oil; yield: 5 mg (83%); dr 79:21 (syn:-
anti).
HR-MS (FAB+): m/z=616.2887, calcd. for C34H47NO4SSi
(M+Na): 616.2893.
1
Mixture of isomers. H NMR (400 MHz, CDCl3): d=7.32–
7.09 (m, 15Hmaj, 15Hmin), 5.89 (dddd, J=23.1, 11.1, 7.7,
6.4 Hz, 1Hmin), 5.78 (tdd, J=17.3, 10.3, 7.1 Hz, 1Hmaj), 5.12
(m, 2Hmin), 5.05 (m, 2Hmaj), 4.74 (AB-d, J=11.2 Hz, 1Hmaj),
4.64–4.43 (m, 3Hmaj, 4Hmin), 3.92 (ddd, J=11.1, 7.7, 3.5 Hz,
1Hmin), 3.77 (ddd, J=13.6, 6.7, 3.2 Hz, 1Hmaj), 3.69–3.61 (m,
1Hmaj, 1Hmin), 3.51–3.42 (m, 1Hmaj, 2Hmin), 2.84–2.73 (m,
(3R*,4S*,5S*)-4-Chloro-1-phenyloct-7-ene-3-yloxy-
[(tert-butyl)dimethylsilane]-5-ol (55a, 55b)
Prepared from aldehyde 36 as described for 49 to afford 55a
and 55b as a colorless oil: yield: 12 mg (88%); dr 40:60
(syn:anti).
1
1Hmaj, 1Hmin), 2.59 (m, 1Hmaj, 1Hmin), 2.67–2.52 (m, 1Hmaj
,
Mixture of isomers. H NMR (500 MHz, CDCl3): d=7.25
1Hmin), 2.44 (dddd, J=14.3, 6.3, 3.6, 1.6 Hz, 1Hmin), 2.30 (dd,
J=13.6, 6.9 Hz, 2Hmaj), 2.37–2.17 (m, 2Hmin), 2.11–1.85 (m,
2Hmaj, 2Hmin); 13C NMR (125 MHz, CDCl3): d=142.0, 141.7,
138.4, 138.1, 137.9, 137.5, 135.1, 134.8, 128.51, 128.46, 128.49,
128.44, 128.41, 128.38, 128.33, 128.1, 128.0, 127.9, 127.8,
127.7, 125.9, 125, 117.5, 117.2, 81.0, 78.8, 78.6, 78.4, 74.4,
73.0, 72.9, 72.4, 70.7, 70.2, 39.3, 38.1, 32.5, 31.95, 31.86, 31.0;
IR (film): nmax =3452 (br), 1640, 1454, 1067, 915 cmꢀ1; HR-
MS (FAB+): m/z=417.2424, calcd. for C28H32O3 (M+H):
417.2430.
(m, 1H), 5.88 (dddd, J=16.8, 10.3, 7.9, 6.3 Hz, 1Hmin), 5.78
(m, 1Hmaj), 5.22–5.12 (m, 2Hmaj, 2Hmin), 4.17–4.10 (m, 2Hmaj
,
1Hmin), 3.97–3.91 (m, 2Hmaj, 1Hmin), 2.85 (d, J=5.0 Hz,
1Hmaj), 2.76 (ddd, J=13.4, 11.6, 5.5 Hz, 1Hmin), 2.66 (m,
2Hmaj), 2.58 (m, 1Hmin), 2.49–2.40 (m, 1Hmaj, 1Hmin), 2.35–
2.27 (m, 1Hmaj, 1Hmin), 2.14–2.05 (m, 1Hmaj, 1Hmin), 1.98–
1.87 (m, 1Hmaj, 1Hmin), 0.94 (s, 9Hmin), 0.93 (s, 9Hmaj), 0.16–
0.12 (m, 6Hmaj, 1Hmin); 13C NMR (125 MHz, CDCl3): d=
141.8, 141.5, 133.9, 133.8, 129.3, 128.5, 128.4, 128.3, 128.2,
126.0, 125.9, 118.6, 118.2, 74.5, 74.0, 71.5, 68.9, 66.8, 65.7,
39.3, 37.7, 36.5, 35.9, 30.6, 30.4, 25.8, 18.1, 18.0, ꢀ4.2, ꢀ4.4,
ꢀ4.5, ꢀ4.7; IR (film): nmax =3449 (br), 1645, 1457, 1257,
1083, 919, 837, 777 cmꢀ1; HR-MS (FAB+): m/z=369.2013,
calcd. for C20H33ClO2Si (M+H): 369.2011.
ACHTUNGTRENNUNG(5R*,6R*)-5,6-Bis(benzyloxy)dodec-1-en-4-ol (52a,
52b)
Prepared from aldehyde 31 as described for 49 to afford 52a
and 52b as a colorless oil; yield: 122 mg (87%); dr 67:33
(syn:anti).
(3R*,4S*,5S*)-4-Chloro-1-phenyloct-7-ene-3-yloxy-
[(tert-butyl)dimethylsilane]-5-ol (56a, 56b)
1
Mixture of isomers. H NMR (400 MHz, CDCl3): d=7.38–
7.22 (m, 10Hmaj, 10Hmin), 5.95–5.86 (m, 1Hmin), 5.85–5.76 (m,
1Hmaj), 5.14–5.03 (m, 2Hmaj, 2Hmin), 4.81 (AB-d, J=11.3,
1Hmaj), 4.67–4.51 (m, 3Hmaj, 4Hmin), 3.92 (m, 1Hmin), 3.75
(m, 1Hmaj), 3.63 (m, 1Hmaj, 1Hmin), 3.43 (dd, J=7.3, 3.9 Hz,
1Hmin), 3.40 (dd, J=6.0, 3.2 Hz, 1Hmaj), 3.30 (d, J=3.4 Hz,
1Hmin), 2.44 (m, 1Hmin), 2.35–2.20 (m, 2Hmaj, 2Hmin), 1.75–
1.49 (m, 2Hmaj, 1Hmin), 1.47–1.36 (m, 1Hmaj, 1Hmin), 1.35–
1.16 (m, 7Hmaj, 7Hmin), 0.88 (m, 3Hmaj, 3Hmin); 13C NMR
(100 MHz, CDCl3): d=138.6, 138.3, 135.2, 134.9, 128.44,
128.42, 128.3, 128.2, 128.02, 128.00, 127.98, 127.9, 127.8,
127.6, 117.4, 81.6, 79.9, 79.5, 79.1, 74.6, 73.2, 72.9, 72.4, 70.6,
70.5, 39.2, 38.2, 31.8, 31.7, 30.8, 29.4, 29.3, 26.0, 25.6, 22.6,
Prepared from aldehyde 37 as described for 49 to afford 56a
and 56b as a colorless oil: yield: 21 mg (95%); dr 59:41
(syn:anti).
1
Mixture of isomers. H NMR (CDCl3, 500 MHz): d=7.23–
7.16 (m, 5Hmaj, 5Hmin), 5.90 (dddd, J=16.6, 10.3, 8.1, 6.2 Hz,
1Hmaj), 5.79 (tdd, J=17.2, 10.2, 7.1 Hz, 1Hmin), 5.21–5.17 (m,
2Hmaj, 2Hmin), 4.15 (ddd, J=7.7, 4.5, 3.0 Hz, 1Hmaj), 4.03–
3.91 (m, 1Hmaj, 3Hmin), 3.78 (dd, J=9.2, 2.9 Hz, 1Hmaj), 3.27
(d, J=2.6 Hz, 1Hmin), 2.76 (ddd, J=13.5, 11.4, 5.3 Hz,
1Hmaj), 2.70–2.55 (m, 2Hmaj, 2Hmin), 2.48 (d, J=5.3 Hz,
1Hmin), 2.40–2.27 (m, 1Hmaj, 1Hmin), 2.25–2.11 (m, 1Hmaj
,
1Hmin), 1.91 (m, 2H), 0.93 (s, 9Hmaj), 0.92 (s, 9Hmin), 0.14 (d,
2034
asc.wiley-vch.de
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 2022 – 2036

Diastereoselective Nucleophilic Addition to Aldehydes with Polar a- and a,b-Substituents
J=6.9 Hz, 6Hmaj), 0.11 (d, J=4.9 Hz, 6Hmin); 13C NMR
(CDCl3, 125 MHz): d=141.4, 133.8, 133.7, 128.5, 128.3,
126.0, 118.5, 118.4, 74.5, 74.2, 71.3, 70.8, 68.0, 63.5, 39.5, 38.8,
35.5, 34.1, 32.4, 31.5, 25.82, 25.79, 18.1, 18.0, ꢀ4.0, ꢀ4.4,
ꢀ4.5; IR (film): nmax =3471 (br), 1602, 1462, 1256, 1090, 997,
837, 777 cmꢀ1; HR-MS (FAB+): m/z=369.2009, calcd. for
C20H33ClO2Si (M+H): 369.2011.
by other groups. See, for example: b) S. Diaz-Oltra, J.
Murga, E. Falomir, M. Carda, G. Peris, J. A. Marco, J.
Org. Chem. 2005, 70, 8130–8139.
[7] J. W. Cornforth, R. H. Cornforth, K. K. Mathew, J.
Chem. Soc. 1959, 112–127.
[8] V. J. Cee, C. J. Cramer, D. A. Evans, J. Am. Chem. Soc.
2006, 128, 2920–2930.
[9] a) D. A. Evans, J. L. Duffy, M. J. Dart, Tetrahedron
Lett. 1994, 35, 8537–8540; b) D. A. Evans, M. J. Dart,
J. L. Duffy, M. G. Yang, J. Am. Chem. Soc. 1996, 118,
4322–4343; c) M. T. Reetz, K. Kessler, A. Jung, Tetra-
hedron Lett. 1984. 25, 729–732.
Acknowledgements
[10] D. A. Evans, V. J. Cee, S. J. Siska, J. Am. Chem. Soc.
This work was financially supported by the Swedish Research
Council, the Knut and Alice Wallenberg foundation and the
Estonian Science Foundation (Grant No. 7808). We wish to
thank P. Villo for her contribution.
2006, 128, 9433–9441.
[11] For discussions of the role of syn-pentane interactions
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[13] P. Restorp, P. Somfai, Org. Lett. 2005, 7, 893–895.
[14] For the synthesis of aldehydes 1, 2, 4, 5 and 28–37 see
Supporting Information.
[15] S. Dꢃaz-Oltra, M. Carda, J. Murga, E. Falomir, J. A.
Marco, Chem. Eur. J. 2008, 14, 9240–9254.
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[19] For steric and/or electronic reasons all other synclinal
structures has been excluded. For a discussion, see
ref.[8b], footnote 31.
[20] The aldehyde rotamer having the a-chloro substituent
perpendicular to the C=O moiety (anti-PFA TS) is
judged less likely since it would result in a destabilizing
steric interaction between R and one substituent on the
enol silane (Rꢄ or OTMS).
[21] For 2-chloropropanal the corresponding conformation
ꢀ
having a 308 angle between the C=O and C Cl bonds
is about 1.9 kcalmolꢀ1 higher in energy than the most
stable conformer. Notable is that this energy is dramat-
ically reduced when the angle is decreased. See ref.[7]
[22] C. H. Heathcock, S. H. Davidsen, K. T. Hug, L. A. Flip-
pin, J. Org. Chem. 1986, 51, 3027–3037.
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105, 1667–1668.
[24] T. Mukaiyama, S. Kobayashi, M. Murakami, Chem.
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[25] For an example where a TS structure similar to J has
been invoked to rationalize the stereochemical out-
come in the addition to an a-silyloxy aldehyde, see:
A. B. Smith III, S. M. Condon, J. A. McCauley, J. L.
Leazer Jr, J. W. Leahy, R. E. Maleczka Jr, J. Am.
Chem. Soc. 1997, 119, 947–961.
[5] See, for example: K. Nakai, M. Kaneko, T.-P. Loh, M.
Terada, T. Nakai, Tetrahedron Lett. 1990, 31, 3909–
3912.
[6] a) D. A. Evans, S. J. Siska, V. J. Cee, Angew. Chem.
2003, 115, 1803–1807; Angew. Chem. Int. Ed. 2003, 42,
1761–1765. Similar observations have also been made
Adv. Synth. Catal. 2011, 353, 2022 – 2036
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Tessie Borg et al.
FULL PAPERS
[26] C. Alvarez-Ibarra, O. Arjona, R. Pꢂrez-Ossorio, A.
Pꢂrez-Rubalcaba, M. L. Quiroga, M. J. Santesmases, J.
Chem. Soc. Perkin Trans. 2 1983, 1645–1648. For more
examples on diminished selectivities with smaller nu-
cleophiles, see ref.[4]
[28] For determination of the relative stereochemistry, see
Supporting Information.
[29] This trend has previously been observed in the addi-
tions of small nucleophiles to a,b-bisalkoxy aldehydes,
see ref.[9]
[27] Theoretical studies suggest that a-amino-substituted al-
dehydes react through PFA TS structures in the boron
aldol reaction. See ref.[7]
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