Stereoselectivity in the intramolecular Nozaki-Hiyama-Kishi reaction: Influence of the substitution pattern and protecting groups in the construction of 10-membered lactones

Article abstract of DOI:10.1016/S0040-4039(02)00347-7

The use of the intramolecular Nozaki-Hiyama-Kishi reaction to construct 10-membered lactones is described. The influence of the nature of the protecting groups at C3 and C4 and the presence of the methyl group at C9 on the stereochemistry of the newly formed stereogenic center at C7 was investigated. Matched induction led to the preparation of the decanolide moiety with high degree of stereoselection.

Full text of DOI:10.1016/S0040-4039(02)00347-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2815–2818
Stereoselectivity in the intramolecular Nozaki–Hiyama–Kishi
reaction: influence of the substitution pattern and protecting
groups in the construction of 10-membered lactones
Ronaldo A. Pilli* and Mauricio M. Victor
Instituto de Qu´ımica, UNICAMP, CP 6154, Campinas 13083-970, Brazil
Received 8 November 2001; revised 15 February 2002; accepted 18 February 2002
Abstract—The use of the intramolecular Nozaki–Hiyama–Kishi reaction to construct 10-membered lactones is described. The
influence of the nature of the protecting groups at C3 and C4 and the presence of the methyl group at C9 on the stereochemistry
of the newly formed stereogenic center at C7 was investigated. Matched induction led to the preparation of the decanolide moiety
with high degree of stereoselection. © 2002 Elsevier Science Ltd. All rights reserved.
the conformational bias of the acyclic precursor in the
stereochemical course of the reaction.
Decanolides have attracted special attention over the
last years.1 An important family of compounds are the
decarestrictines,2 mainly decarestrictine D due to its
ability as an inhibitor of cholesterol biosynthesis and
DNA-binding activity.3 Such significant biological
properties contributed to the interest in devising syn-
thetic approaches to this family of natural products.
The synthetic approach to lactones has traditionally
focused mainly on the use of fragmentation/ring expan-
sion reactions and on lactonization strategies in order
to build the lactone ring.4 Recently, examples of the
construction of lactones through the formation of the
CꢀC bond appeared5 and the intramolecular Nozaki–
Hiyama–Kishi (NHK) coupling reaction6 stands as a
promising protocol. The influence of the protecting
groups in the stereochemical outcome of the NHK
reactions has been reported previously.7 During our
studies on the total synthesis of decarestrictine D, we
observed loss of stereochemical control at C7 upon
changing the OTBS groups at C3 and C4 in (−)-4a for
the isopropylidene acetal group.5d These observations
prompted us to expand our study on the influence of
According to our approach, the construction of the
decanolide ring 1 would arise from the formation of the
C6ꢀC7 bond (Scheme 1). The acyclic precursors would
be prepared from the condensation of acid (−)-28 and
alcohols 3a–c. The change of the protecting groups at
C3 and C4 would arise from manipulation of the
protecting groups at these oxygenated positions in the
acyclic precursors. Our expectation to control the
stereogenic center to be created at C7 was based on the
interplay of transannular interactions and on the pro-
posal by Overman and coworkers of a well organized
arrangement in the transition state of the NHK reac-
tion. During the synthesis of (−)-deacetoxyalcionine,9
these authors proposed the chelation of the vinylic
chromium species to the carbonyl group of the alde-
hyde in order to explain the outstanding diastereoselec-
tivity observed in the formation of the 9-membered ring
(>20:1). As applied to our case, we would expect that:
(i) the methyl group at C9 would adopt a pseudo-
equatorial orientation in the transition state thus
R3
O
R4
O
R3
PO
R4
O
R1
R2
HO
+
9 O
9 O
HO
OTBS
3
7
3
I
4
I
6
4
OTBS
R5
OP
OP
(+)-3a R1=H, R2=Me
(-)-3b R1=Me, R2=H
3c R1=R2=H
R6
OTBS
(-)-2
OP
OP
1
Scheme 1.
* Corresponding author. E-mail: pilli@iqm.unicamp.br
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00347-7

2816
R. A. Pilli, M. M. Victor / Tetrahedron Letters 43 (2002) 2815–2818
dimethoxypropane and PPTS in CH2Cl2, in 78% overall
yield.
determining the relative position of the C9ꢀC7
moiety and influencing carbonyl face-selection,
assuming that a chair–chair–chair conformation
would prevail;
At this point we were ready to apply the intramolecular
NHK reaction to the aldehydes derived from 4a–c and
6a–c. The primary TBS groups in compounds 4a–c
were selectively removed and oxidized to the corre-
sponding aldehydes with Dess–Martin periodinane,
while the PMB-group in 6a–b was removed by treat-
ment with DDQ and the corresponding alcohols were
oxidized as already described. Alcohol (−)-6c was oxi-
dized with Dess–Martin periodinane (Scheme 3). All
the aldehydes obtained were not purified but immedi-
ately used in the NHK coupling step. The coupling
required 15 equiv. of CrCl2 (containing 0.5% of NiCl2)
in degassed DMF at high dilution and at room temper-
ature. The results are described below (Table 1).
(ii) the judicious choice of the protecting group at C3
and C4 could dictate the relative positioning of the
C5ꢀC6 and C2ꢀOꢀC7 fragments: OTBS groups
which are bound to adopt anti relative orientation
would enforce gauche orientation of the C2ꢀC3/
C4ꢀC5 bonds while the cyclic isopropylideneacetal
as protecting group would keep the side chains
apart.
The synthesis of the acyclic precursors began with the
coupling of acid (−)-2 with alcohols 3a–c employing the
Yamaguchi protocol, which furnished the TBS-protect-
ing acyclic precursors 4a–c in 64–83% yield (Scheme 2).
In order to prepare the isopropylideneacetal-protected
precursors, different strategies were employed. The C9-
methyl substituted esters (−)-4a and (−)-4b required10
changing the primary hydroxyl protecting group from
TBS to PMB, and after removal of the secondary TBS
groups of (−)-5a and (−)-5b with HF·pyridine complex,
the diols obtained were treated with 2,2-
dimethoxypropane and PPTS in DMF to give (−)-6a
and (+)-6b in 63 and 40% overall yield, respectively.
The C9 unsubstituted (−)-6c was obtained directly from
(−)-4c after removal of TBS-groups with a large excess
of HF·pyridine complex and treatment with 2,2-
The assignment of the stereochemistry at C7 was
achieved by 1H NMR as described for (−)-7a: H7
appeared as a triplet of doublets at l 4.21 with two
large coupling constants (10.8 and 8.4 Hz, trans-diaxial
orientation for H6 and H8ax) and a small one (3.4 Hz,
H8eq), suggesting a chair–chair–chair conformation
(Fig. 1). Such an assignment was supported by nOe
experiments: 4.3% increment at H7 was observed upon
irradiation of H9 and eventually by its conversion to
(−)-decarestrictine D.5a,5d Accordingly, the 1H NMR
spectra of (−)-11b displayed H7 as a triplet of doublets
R3
I
TBSO
R4
O
O
HO
O
(-)-2
+
d
a
O
R1 R2
I
OTBS
OTBS
O
HO
OTBS
O
(+)-3a R1=H, R2=Me
(-)-3b R1=Me, R2=H
3c R1=R2=H
(-)-4a R3=Me, R4=H
(-)-4b R3=H, R4=Me
(-)-4c R3=R4=H
(-)-6c
b
R3
I
PMBO
R4
O
O
R3
I
PMBO
R4
O
O
c
O
OTBS
OTBS
O
(-)-6a R3=Me, R4=H
(+)-6b R3=H, R4=Me
(-)-5a R3=Me, R4=H
(-)-5b R3=H, R4=Me
Scheme 2. Key: (a) (i) (−)-2, 2,4,6-trichlorobenzoyl chloride, Et3N, THF. (ii) 3, benzene, DMAP [(−)-4a 83%, (−)-4b 64%, (−)-4c
74%]. (b) (i) HF·pyridine, pyridine, THF. (ii) PMB–trichloroacetimidate, Et2O, TfOH (cat) [(−)-5a 74%, (−)-5b 53%, two steps].
(c) (i) HF·pyridine, pyridine, THF. (ii) 2,2-Dimethoxypropane, PPTS, DMF [(−)-6a 85%, (+)-6b 75%, two steps]. (d) (i)
HF·pyridine, pyridine, THF. (ii) 2,2-Dimethoxypropane, PPTS, CH2Cl2 (78%, two steps).
R2
I
R2
R2
R1O
R3
O
O
R3
O
O
R3
O
O
a
+
OR5
HO
OR5 HO
OR5
7R
7S
OR4
OR4
OR4
Re face attack
Si face attack
Scheme 3. Key: (a) (i) R1 deprotection (except for (−)-6c). (ii) Dess–Martin oxidation. (iii) NHK cyclization. For yields, see Table
1.

R. A. Pilli, M. M. Victor / Tetrahedron Letters 43 (2002) 2815–2818
Table 1. Diastereoselectivity in the NHK cyclization (see Scheme 3)
2817
Entry
Precursor
R1
R2
R3
R4
R5
Yield (%)a
Compound
Ratio 7S/7Rc
1
2
3
4
5
6
(−)-4a
(−)-4b
(−)-4c
(−)-6a
(+)-6b
(−)-6c
TBS
TBS
TBS
PMB
PMB
H
Me
H
H
Me
H
H
H
Me
H
H
Me
H
TBS
TBS
TBS
ꢀC(Me)2ꢀ
ꢀC(Me)2ꢀ
ꢀC(Me)2ꢀ
TBS
TBS
TBS
31
32
27
29
44
59b
7a/7b
8a/8b
9a/9b
\97:3
1:2
1.3:1
1:2
10a/10bd
11a/11b
12a/12b
1:22
1:3.3
a Overall yield, three steps.
b Overall yield, two steps.
c Determined by 1H NMR.
d Not separable by column chromatography.
(-)-7a
facial selection. A methyl group at C9 with R configu-
ration enforces the Re face attack as indicated when
one compares the results for (−)-4a (entry 1) and (−)-4c
(entry 3) and for (−)-6a (entry 4) and (−)-6c (entry 6).
Meanwhile, the bias for Si face addition in the 9S
methyl substituted substrate is evident upon compari-
son of the results observed for the NHK cyclization of
(−)-4a (entry 1) and (−)-4b (entry 2) and for the cycliza-
tion of (−)-6a (entry 4) and (+)-6b (entry 5). It is
reasonable to describe the combined influence of a 9R
methyl group and of TBS protecting group at C3 and
C4, as well as that of a 9S methyl group and an
isopropylidene acetal at C3 and C4 as matched cases.
These results imply that the construction of the decano-
lide skeleton can be achieved with high degree of
diastereoselection either to afford the (7S,9R) or
(7R,9S) configuration (Scheme 4).
H8ax
H6
OTBS
H4
Me
O
H8eq
H3
HO
O
H9
H7
OTBS
H5
δ 4.21 ppm
(J=10.8, 8.4, 3.4 Hz)
δ 4.19 ppm
(J=10.0, 10.0, 3.9 Hz)
H9
H7
H3
O
H5
Me
O
Me
Me
O
O
HO
H4
H6
(-)-11b
Figure 1.
In conclusion, some key factors that control the stereo-
chemistry of NHK cyclization in the construction of
decanolides were investigated. The proper choice of
protecting group associated with the correct stereo-
chemistry at C9 allowed the construction of decanolide
moiety with high degree of diastereoselection. Further
studies are underway.
at l 4.19 (10.0, 10.0 and 3.9 Hz) and 1.7% nOe incre-
ment upon irradiation of H9.11
When the NHK cyclization was carried out on the
TBS-protected esters without substitution at C9 ((−)-4c,
entry 3), a slight preference for the Re face attack was
observed. The isopropylidene acetal group at C3/C4
positions steered the addition to the Si face albeit with
moderate preference (entry 6, Table 1). These results
suggest that the judicious choice of the protecting
group can determine and influence the carbonyl facial
selection. Moreover, the presence of a methyl substitu-
tion at C9 also plays an important role in the carbonyl
Acknowledgements
This work was supported by grants from CNPq
(Brazil), Volkswagen Stiftung (Germany) and Interna-
tional Foundation for Science (Sweden).
Si face
attack
Re face
attack
R1O
O
O
R1O
O
O
matched
HO
matched
O
O
9S
O
O
9R
I
I
7R
O
O
OTBS
OTBS
HO
OTBS
OTBS
(-)-7a
Single product
7S
O
O
(+)-6b
(-)-11b
Major (22:1)
(-)-4a
Re face
attack
Si face
attack
Scheme 4.

2818
R. A. Pilli, M. M. Victor / Tetrahedron Letters 43 (2002) 2815–2818
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3440, 1722 cm−1; 1H NMR (500 MHz, CDCl3) l 5.88 (dd,
J=15.5, 9.6 Hz, 1H), 5.47 (dd, J=15.5, 9.4 Hz, 1H), 4.97
(dqd, J=11.2, 6.5, 1.6 Hz, 1H), 4.19 (td, J=10.0, 3.9 Hz,
1H), 4.02 (t, J=8.9 Hz, 1H), 3.76 (ddd, J=11.2, 8.6, 2.7
Hz, 1H), 2.79 (dd, J=11.5, 2.7 Hz, 1H), 2.39 (t, J=11.4
Hz, 1H), 1.94 (ddd, J=14.2, 4.0, 1.6 Hz, 1H), 1.82 (dt,
J=14.2, 10.8 Hz, 1H), 1.44 (s, 3H), 1.43 (s, 3H), 1.26 (d,
J=6.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) l 170.4,
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26.8, 21.4.; MS (EI): m/z 43 (100%), 241 (2%, [M−CH3]+);
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