An efficient procedure for the direct nucleophilic substitution of the abiko-masamune auxiliary

Article abstract of DOI:10.1055/s-0029-1217819

An efficient method for the nucleophilic displace-ment of the Abiko-Masamune auxiliary is reported, which involves i-PrMgCl for intermediate ester activation.

Full text of DOI:10.1055/s-0029-1217819

LETTER
A
An Efficient Procedure for the Direct Nucleophilic Substitution of the
Abiko–Masamune Auxiliary
D
irec
t
N
uc
u
leophilic Su
n
bstitution of the
Ab
iko–Masamuni a
e
A
uxil
,
iary Pengfei Li,b Dirk Menche*b
a
Medizinische Chemie, Helmholtz-Zentrum für Infektionsforschung, Inhoffenstr. 7, 38124 Braunschweig, Germany
Institut für Organische Chemie, Ruprecht-Karls-Universität Heidelberg, INF 270, 69120 Heidelberg, Germany
Fax +49(6221); E-mail: dirk.menche@oci.uni-heidelberg.de
b
Received 29 April 2009
conditions enabling applications also to complex and sen-
sitive substrates.
Abstract: An efficient method for the nucleophilic displace-
ment of the Abiko–Masamune auxiliary is reported, which in-
volves i-PrMgCl for intermediate ester activation.
As shown in Scheme 1, our synthetic concept was based
on the use of Lewis acids for ester activation, which are
expected to coordinate internally to the aldol product by
chelation to the b-hydroxy ester, as schematically present-
ed in structure 3. Consequently, this sterically congested
ester should be activated and nucleophilic displacement
faciliated.
Key words: synthetic methodology, Lewis acid, ester cleavage,
aldol reaction, Abiko–Masamune auxiliary
The Abiko and Masamune aldol reaction presents one of
the most widely used methods for stereoselective propi-
onate aldol couplings.1,2 The method allows for both syn-
and anti-aldol connections with excellent diastereoselec-
tivities and yield. Furthermore, it has demonstrated its
broad substrate scope and, consequently, has been widely
applied in polyketide synthesis.3 A major drawback of the
method, however, are apparent difficulties to cleave the
norephedrin-derived auxiliary with nucleophiles other
than hydride (e.g., phsophonates or Weinreb amides) of-
ten resulting in extensive decomposition, namely through
retro-aldol or elimination pathways, which so far may
only be circumvented by resorting to an alternative auxil-
iary.4 As part of our synthesis of the natural product arc-
hazolid A,3d we encountered these problems first hand by
attempting the nonreductive nucleophilic cleavage of the
Abiko–Masamune aldol product 1 (Scheme 1) to access
products of type 2.
To test our notion, a variety of Lews acids were studied
in the nucleophilic displacement reaction of Abiko–
Masamune aldol product 4 with phosphonate 5 under mild
conditions (–78 to –20 °C, THF). As shown in Table 1,
best results were obtained with i-PrMgCl among those
evaluated (entries 1–6). To avoid hydrodehalogenation,
choice of base for phosphonate deprotonation was critical
(entries 6 and 7). After optimization of conditions,5 the
desired b-keto phosphonate 6a was obtained with useful
yields as the major product.6,7 Notably, the chiral auxiliary
may be readily recovered in 80–90% yield by column
chromatography after the reaction.5
To further expand this concept also to Weinreb amides,
the conversion of 4 to 8 was studied. As shown in Table 2,
a range of Lewis acids were evaluated for this purpose
(entries 1–5), under mild reaction conditions (–20 to –10 °C,
THF). As before, best results were obtained with i-PrMgCl,
giving the desired product 8 with preparatively useful
yields (entry 5).6,8 Use of BuLi mainly led to elimination
along the 2,3-bond under these reaction conditions.
Herein, we report an efficient procedure for the direct dis-
placement of the Abiko–Masamune auxiliary by sterically
hindered nucleophiles. The method uses i-PrMgCl for in
situ ester activation and is characterized by mild reaction
To evaluate the usefulness of these procedures, the con-
version of 4 to phosphonate 9 and methyl ketone 11 was
studied. As shown in Scheme 2, these derivatives may be
readily obtained following our protocols and further con-
ventional functional group interconversions. In contrast,
the direct transformation of 10 to either 9 and 12 proceed-
ed in only very low yields (9%, 16%), resulting mainly in
elimination products.9 Also, the likewise tested alterna-
tives of first removing the auxiliary reductively and then
introducing the required phosphonate or Weinreb amide
in four-step procedures (viz. conversions of 10 to 9 or 11)
were not comparable in terms of number of steps as well
as overall chemical yield with the direct method reported
herein.
Ph
O
OR
decomposition
(i.a. retro aldol,
elimination ...)
O
I
Nu– (≠ H–
)
N
Bn
SO2Mes
1
O
OR
Nu
I
L.A.
2
Ph
O
O
Nu: (MeO)2P(O)CH2,
MeO(Me)N
O
R
N
Bn
SO2Mes
L.A.: Lewis acid
3
Scheme 1
SYNLETT 2009, No. x, pp 000A–000D
Advanced online publication: xx.xx.2009
DOI: 10.1055/s-0029-1217819; Art ID: G14509ST
x
x
.xx.
2
0
0
9
Finally, the applicability of this procedure to an even more
challenging aldol product was demonstrated, as part of
© Georg Thieme Verlag Stuttgart · New York

B
J. Li et al.
LETTER
Table 1 Direct Displacement by Phosphonate
O
MeO
MeO
O
P
O
OH
Ph
O
OH
P
MeO
MeO
5
Me
Bn
X
O
I
Lewis acid
N
THF
–78 to –20 °C
SO2Mes
6a: X = I
6b: X = H
4
Entry
Lewis acid
–
Nucleophilea
Yield (%)
b
1
2
3
4
5
6
7
5, BuLi
5, BuLi
5, BuLi
5, BuLi
5, BuLi
5, BuLi
5, KHMDS
–
b
BuLi
–
c
Me3Al
–
c
MeMgBr
EtMgBr
i-PrMgCl
i-PrMgCl
–
b
–
6b 86
6a 80
a Deprotonation of phosphonate 5 prior to addition to 4, see experimental procedure.5,
b Decomposition.
c No conversion.
this involved an optimized procedure for the Wittig reac-
tion of 15 to 14,11 which implied use of CH2Cl2 as solvent
and running the reaction at room temperature.12
Table 2 Direct Displacement by Weinreb Amide
O
Me
NH HCl
Ph
O
OH
O
OH
7
Me
Me
Bn
MeO
2
In summary, we have developed an efficient procedure for
the displacement of Abiko–Masamune aldol products.
The procedure uses i-PrMgCl for intermediate activation,
presumably by chelation of the b-hydroxy ester, facilitat-
ing the nucleophilic attack. It is expected that this method
will be useful in further expanding the scope and applica-
tions of Abiko–Masamune aldol reactions.
3
O
I
N
I
Lewis acid
N
Me
THF
SO2Mes
–20 to –10 °C
4
8
Entry
Lewis acid
Nucleophilea
7, i-PrMgCl
7, i-PrMgCl
7, i-PrMgCl
7, i-PrMgCl
7, i-PrMgCl
Yield (%)
b
1
2
3
4
5
Me3Al
–
b
Me2AlCl
–
b
Acknowledgment
DIBAL-H
BuLi
–
c
Generous financial support by the Volkswagenstiftung, the
Deutsche Forschungsgemeinschaft and the HZI is most gratefully
acknowledged. We thank Antje Ritter and Tatjana Arnold for tech-
nical support.
–
i-PrMgCl
72
a Compound 7 was treated with i-PrMgCl prior to addition to 4: see
experimental procedure.8,
b Mainly decomposition.
References and Notes
c Mainly, elimination along the 2,3-bond was observed giving the cor-
responding diene.
(1) (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc.
1997, 119, 2586. (b) Liu, J.-F.; Abiko, A.; Pei, Z.; Buske,
D. C.; Masamune, S. Tetrahedron Lett. 1998, 39, 1873.
(c) Inoue, T.; Liu, J.-F.; Buske, D. C.; Abiko, A. J. Org.
Chem. 2002, 67, 5250.
(2) For recent reviews on the aldol reaction and direct methods
for polypropionate synthesis, see: (a) Brodmann, R.;
Lorenz, M.; Schäckel, R.; Simsek, S.; Kalesse, M. Synlett
2009, 174. (b) Li, J.; Menche, D. Synthesis 2009, 2293.
(3) For selected recent examples, see: (a) Evano, G.; Schaus,
J. V.; Panek, J. S. Org. Lett. 2004, 6, 525. (b) Smith,
A. B. III; Simov, V. Org. Lett. 2006, 8, 3315. (c) White, J.
D.; Smits, H. Org. Lett. 2005, 7, 235. (d) Menche, D.;
Hassfeld, J.; Li, J.; Rudolph, S. J. Am. Chem. Soc. 2007, 129,
6100. (e) Jin, J.; Chen, Y.; Li, Y.; Wu, J.; Dai, W. Org. Lett.
2007, 9, 2585. (f) Ying, Y.; Hong, J. Tetrahedron Lett.
2007, 48, 8104.
our studies directed towards the total synthesis of etnang-
ien,10 as shown in Scheme 3. Substrate 16 contains a diene
moiety, in combination with an additional d-substitutent
and a labile primary allylic TBS-ether, rendering it even
more prone to elimination or alternative decomposition
pathways. Nevertheless, the direct conversion of diene 16
into 17 proceeded smoothly using our protocol, giving the
desired Weinreb amide in good yields.6 This demonstrates
the usefulness of our procedure also to particularly labile
and hindered substrates. Adduct 16 was readily available
by Abiko–Masamune propionate aldol reaction with alde-
hyde 13, which in turn was accessible from 15. Notably,
Synlett 2009, No. x, A–D © Thieme Stuttgart · New York

LETTER
Direct Nucleophilic Substitution of the Abiko–Masamune Auxiliary
C
O
P
O
OH
O
P
O
OMe
MeO
MeO
MeI, Ag2O
(87%)
MeO
MeO
I
I
9
6a
1. LiAlH4
2. DMP
3. 5, BuLi
5, KHMDS
i-PrMgCl
(80%)
5, BuLi
(9%)
4. DMP
(45%)
Ph
Ph
O
OH
O
OMe
MeI, Ag2O
(91%)
Me
Me
Bn
O
I
O
SO2Mes
I
N
N
Bn
SO2Mes
10
4
1. HN(Me)OMe,
1. LiAlH4
2. DMP
3. MeMgBr
4. DMP
HN(Me)OMe,
i-PrMgCl
(16%)
i-PrMgCl (72%)
2. MeI, Ag2O (85%)
3. MeMgBr (93%)
(82%,
4 steps)
O
OMe
O
OMe
MeMgBr
(93%)
MeO
N
I
I
Me
11
12
Scheme 2
the organic phase separated, and the aqueous phase
1. NaBH4
2. TBSCl
O
H
thoroughly extracted with EtOAc (4 × 6 mL). The combined
organic phases were dried over MgSO4 and concentrated
under reduced pressure. Silica gel chromatography
(hexanes–EtOAc = 1:2) afforded the phosphonate 6a
(40.9 mg, 0.109 mmol, 80%) as a colorless oil and the chiral
Masamune alcohol auxiliary as a white solid (50.6 mg,
0.120 mmol, 88%).
EtO2C
OTBS
3. DIBAL-H
4. MnO2
CHO
14
13
(66%)
O
CH2Cl2, r.t.
(80%)
Ph
O
Ph3P
Me
O
EtO2C
N
(6) All new compounds had spectroscopic data in support of the
assigned structures. Sample data follow.
(76%,
dr > 5:1)
CHO
Bn
SO2Mes
15
Compound 6a: 1H NMR (300 MHz, CDCl3): d = 0.93 (d,
J = 7.0 Hz, 3 H), 1.82 (s, 3 H), 3.06 (dq, J = 9.2, 7.0 Hz, 1
H), 3.17 (dd, J = 18.7, 13.8 Hz, 1 H), 3.25 (dd, J = 18.7, 13.8
Hz, 1 H), 3.76 (s, 3 H), 3.80 (s, 3 H), 4.25 (d, J = 9.2 Hz, 1
H), 6.30 (s, 1 H). 13C NMR (75 MHz, CDCl3): d = 13.7, 18.7,
41.2, 42.9, 50.2, 53.2, 53.3, 79.2, 80.9, 147.4, 205.4, 205.5.
HRMS: m/z calcd for C10H18IO5PNa [M + Na]+: 398.9834;
found: 398.9836.
Cy2BOTf,
Et3N
Ph
O
OH
Me
O
N
TBSO
O
16
Bn
SO2Mes
Compound 8: 1H NMR (400 MHz, CDCl3): d = 1.09 (d,
J = 7.1 Hz, 3 H), 1.81 (d, J = 1.0 Hz, 3 H), 3.15 (m, 1 H),
3.17 (s, 3 H), 3.58 (d, J = 6.1 Hz, 1 H), 3.69 (s, 3 H), 4.26 (t,
J = 6.4 Hz, 1 H), 6.30 (s, 1 H). 13C NMR (100 MHz, CDCl3):
d = 15.1, 20.1, 32.2, 38.2, 61.8, 79.0, 80.1, 148.1, 176.3.
HRMS: m/z calcd for C9H16INO3Na [M + Na]+: 336.0073;
found: 336.0075.
OH
HN(Me)OMe
i-PrMgCl
Me
N
(74%)
OMe
TBSO
17
Scheme 3
Compound 17: 1H NMR (400 MHz, CDCl3): d = 0.06 (s, 6
H), 0.90 (s, 9 H), 1.11 (d, J = 7.1 Hz, 3 H), 1.82 (s, 3 H), 2.94
(dq, J = 7.0, 7.1 Hz, 1 H), 3.04 (d, J = 5.6 Hz, 1 H), 3.20 (s,
3 H), 3.68 (s, 3 H), 4.24 (d, J = 5.1 Hz, 2 H), 4.60 (ddd,
J = 9.2, 7.0, 5.6 Hz, 1 H), 5.43 (d, J = 9.2 Hz, 1 H), 5.75 (dt,
J = 15.3, 5.1 Hz, 1 H), 6.24 (d, J = 15.3 Hz, 1 H). 13C NMR
(100 MHz, CDCl3): d = –5.1, 13.2, 14.4, 18.5, 26.0, 41.5,
61.5, 63.8, 70.7, 128.7, 131.8, 133.7, 136.0, 189.2. HRMS:
m/z calcd for C18H35NO4SiNa [M + Na]+: 380.2233; found:
380.2232.
(4) (a) Fanjul, S.; Hulme, A. N.; White, J. W. Org. Lett. 2006, 8,
4219. (b) Fanjul, S.; Hulme, A. N. J. Org. Chem. 2008, 73,
9788.
(5) Experimental Procedure
To a cold solution (–78 °C) of dimethyl methylphosphonate
(156 mL, 2.93 mmol, 11 equiv) in THF (1 mL) were added
KHMDS (0.5 M in toluene, 2.66 mL, 1.33 mmol, 10 equiv),
and the resulting suspension was stirred at –20 °C for 2 h. To
a cold solution (–78 °C) of the ester (92.1 mg, 0.136 mmol,
1.0 equiv) in THF (1 mL) was added i-PrMgCl (2.0 M in
Et2O, 204 mL, 0.409 mmol, 3.0 equiv). After 20 min the
above mixture was added via cannula. The reaction mixture
was warmed to –20 °C during 1.5 h and stirred at –20 °C for
30 min. Sat. aq NH4Cl (6 mL) and H2O (6 mL) were added,
(7) Using metalated ethyl congener of 5, i.e., diethyl
ethylphosphonate, resulted in only low conversion under
identical reaction conditions.
Synlett 2009, No. x, A–D © Thieme Stuttgart · New York

D
J. Li et al.
LETTER
(8) Experimental Procedure
(9) The corresponding dienes of 9 and 12 were obtained in 38%
and 6% yield, respectively.
(10) Menche, D.; Arikan, F.; Perlova, O.; Horstmann, N.;
Ahlbrecht, W.; Wenzel, S. C.; Jansen, R.; Irschik, H.;
Müller, R. J. Am. Chem. Soc. 2008, 129, 14234.
(11) Famer, L. J.; Marron, K. S.; Koch, S. S. C.; Hwang, C. K.;
Kallel, E. A.; Zhi, L.; Nadzan, A. M.; Robertson, D. W.;
Bennani, Y. L. Bioorg. Med. Chem. Lett. 2006, 16, 2352.
(12) Experimental Procedure
To a solution of ester 4 (231 mg, 0.342 mmol, 1.0 equiv) in
THF (1 mL) was added i-PrMgCl (ca. 2 M in THF, 0.17 mL,
0.34 mmol, 1.0 equiv), after 10 min a suspension of
magnesium chloride methoxy(methyl)amide complex,
which was prepared by addition of i-PrMgCl (ca. 2 M in
THF, 3.42 mL, 6.84 mmol, 20 equiv) to a suspension of N,O-
dimethylhydroxylamine hydrochloride (334 mg, 3.42 mmol,
10 equiv) in THF (3 mL) at –20 °C, was added. The reaction
mixture was stirred at –20 °C for 2 h and warmed up to –10 °C
(1 h). The reaction was quenched by addition of sat. aq
NH4Cl (5 mL). The product amide was extracted into EtOAc
(3 × 20 mL), and the combined organic layers were dried
over MgSO4 and concentrated in vacuo. After flash
chromatography (hexanes–EtOAc = 2:1 to 1:1) amide 8
(77.0 mg, 0.246 mmol, 72%) was obtained as a white solid.
To a flask containing Ph3PCHCHO (146 mg, 0.481 mmol,
1.0 equiv) was added a solution of 15 (207 mL, 1.52 mmol,
3.0 equiv) in dry CH2Cl2 (100 mL). The reaction mixture was
stirred for 15 h at r.t. and purified direct by flash chromatog-
raphy (hexanes–Et2O = 6:1 to 1:1) to give aldehyde 14 (64.6
mg, 0.384 mmol, 80%) as colorless crystals.
Synlett 2009, No. x, A–D © Thieme Stuttgart · New York

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