Saucy-Marbet rearrangements of alkynyl halides in the synthesis of highly enantiomerically enriched allenyl halides

Article abstract of DOI:10.1016/j.tetlet.2008.08.089

A stereospecific Saucy-Marbet rearrangement of alkynyl halides is described here. These rearrangements provide an entry to highly enantiomerically enriched allenyl bromides and chlorides through excellent chirality transfer and the preservation of optical integrity of alkynyl halides.

Full text of DOI:10.1016/j.tetlet.2008.08.089

Tetrahedron Letters 49 (2008) 6404–6409
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Saucy–Marbet rearrangements of alkynyl halides in the synthesis
of highly enantiomerically enriched allenyl halides
*
Yu Tang, Lichun Shen, Becky J. Dellaria, Richard P. Hsung
Division of Pharmaceutical Sciences and Department of Chemistry, 777 Highland Avenue, University of Wisconsin, Madison, WI 53705, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereospecific Saucy–Marbet rearrangement of alkynyl halides is described here. These rearrangements
provide an entry to highly enantiomerically enriched allenyl bromides and chlorides through excellent
chirality transfer and the preservation of optical integrity of alkynyl halides.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 6 August 2008
Accepted 21 August 2008
Available online 28 August 2008
Allenes are among the most powerful building blocks in organic
synthesis.1,2 Recently, both Trost3 and we4 communicated cop-
per(I)-catalyzed amidations of allenyl halides 2 en route to an
atom-economical synthesis of allenamides 4 (Scheme 1), a class
of heteroatom-substituted allenes that have attracted much atten-
tion from the synthetic community.1,2,5–8 Specifically in our work,4
the cross-coupling is completely stereospecific when employing
enantiomerically enriched allenyl halides 2-P and 2-M
(Scheme 1).
enantiomeric enrichment was at best modest even when employ-
ing known conditions starting from mesylation of optically pure
propargyl alcohols (R)-1 and (S)-1.1,2,11,12 Our interest13 in both
the Saucy–Marbet rearrangement for the synthesis of chiral
allenes9,14–16 and reactivities of alkynyl halides such as 517,18
prompted us to explore the synthesis of enantiomerically pure
allenyl halides 7 by uniting the two concepts.19 We communicate
here the concept of employing a stereospecific Saucy–Marbet
rearrangement of alkynyl halides in the synthesis of highly enantio-
merically enriched allenyl halides.
However, we were met with the challenge of preparing opti-
cally pure allenyl halides. With the exception of diastereoselective
examples,9,10 for axially chiral allenyl halides such as 2, the level of
Conditions for the proposed rearrangement could be readily
established using racemic alkynyl halides as shown in Table 1.
R
I
HO
Ph
R
H
P
O
N
R
•
P
•
R
H
H
R
(R)-
O
3
1
(a) mesylation
(b) LiI and CuI
~ 60% overall yield
2-P: 50% ee
O
H
Ph
O
4:
(P,R):(M,R) = 77:23
N
H
or
or
R
Ph
cat CuCN
O
N
HO
I
H
R
M
•
H
R
M
•
O
S
R
H
H
1
2-M: 70% ee
4: (P,R):(M,R) = 15:85
(S)-
Saucy-Marbet rearrangement of alkynyl halides
EtO
O
CH3C(OEt)3
acid and Δ
X
H
R
P/M
HO
[3,3]
O
•
X
X = I, Br, or Cl
X
R
OEt
R
(R) or (S)-5
6
7: ee?
Scheme 1. Access to optically enriched allenyl halide.
* Corresponding author. Tel.: +1 608 890 1063; fax: +1 608 262 5345.
E-mail address: rhsung@wisc.edu (R. P. Hsung).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.089

Y. Tang et al. / Tetrahedron Letters 49 (2008) 6404–6409
6405
Table 1
Alkynyl halides in Saucy–Marbet rearrangements
CH3C(OEt)3, cat
X
H
HO
Me
toluene [conc], 80 ºC,18 h
•
O
X
Me
Saucy-Marbet rearrangement
of halo alkynes
OEt
10
( )- : X=I
11
( )- : X= Br
( )-8: X=I
( )-9: X= Br
Entry
Halides
CH3C(OEt)3
Concentration (M)
Cat (mol %)
Allenes
Yielda (%)
1
2
3
4
5
6
( )-8
( )-9
( )-9
( )-9
( )-9
( )-9
Solventb
Solventb
2.0 equiv
2.0 equiv
2.0 equiv
2.0 equiv
—
—
0.10
0.10
0.10
0.10
None
None
p-TsOH [10]
EtCO2H
AcOH [10]
AcOH [10]
( )-10
( )-11
( )-11
( )-11
( )-11
( )-11
Trace + smc
10% + 85% sm
20% + 56%
20%+ 56% sm
24% + 54% sm
95%d
a
Isolated yields.
b
c
conc = 0.40 M.
Also decomp.
At 100 °C.
d
HO
Me
HO
R
Br
Me
H
P
R
Br
O
•
Me
OEt
12
(R)-
(R)-9
11-P: 55%
20 mol% AgNO3
2 equiv CH3C(OEt)3
1.1 equiv NBS
5 mol% HOAc
yields over
2 steps
or
or
acetone [1.0 M]
rt, overnight
toluene, sealed tube
100 ºC,18 h
HO
HO
Me
Br
H
M
•
O
Br
S
S
Me
Me
(S)-12
OEt
(S)-9
11-M:
51%
H
EtO
OEt
H
R
H
[3,3]
[3,3]
H
11-P
11-M
Me
S
Br
O
O
H
Br
Me
(S)-
H
13
13
(R)-
Scheme 2. Stereospecific Saucy–Marbet rearrangements.
Alkynyl iodide 8 was not as effective as alkynyl bromide 9 (entry 1
vs entry 2), and an acid catalyst such as AcOH was critical (entries
3–6) and so was the optimal temperature of 100 °C (entry 5 vs
entry 6). With these conditions in hand, enantiomerically pure
alkynyl bromides (R)- and (S)-920 were prepared from their respec-
tive chiral propargyl alcohol (R)- and (S)-12 using AgNO3 and NBS
(Scheme 2). Subsequent Saucy–Marbet rearrangements led to the
respective allenyl bromides 11-P and 11-M in good yields over
two steps. Given the ability of [3,3]-sigmatropic rearrangements
to conserve and transfer chirality, these reactions should be highly
stereoselective through intermediates (R)- and (S)-13, leading to
11-P and 11-M with high levels of enantiomeric purity. Represen-
tative examples of these rearrangements of allenyl halides are
shown in Figure 1, in which both allenyl bromides and chlorides
could be accessed.
To unambiguously confirm that these rearrangements indeed
gave allenyl halides possessing high levels of enantiomeric purity,
in the absence of a conclusive chiral HPLC analysis, we attained
enantiomeric ratios by examining ratios of the respective diaste-
reomeric derivatives. Reduction of allenyl bromide 11-P using
yields over 2 steps
X
n-pentyl
P
Br
O
HO
•
Ph
H
P
S
H
O
•
Br
Br
Ph
OEt
OEt
16-P: X = Br: 52% yield
17-P: X = Cl: 46% yield
14-P: 40% yield
(S)-15
X
H
M
Br
HO
Ph
O
•
H
M
•
n-pentyl
O
R
Ph
OEt
OEt
16-M: X = Br: 48% yield
14-M:
15
(R)-
17-M:
42% yield
X = Cl: 35% yield
Figure 1. Highly enantiomerically pure allenyl halides.

6406
Y. Tang et al. / Tetrahedron Letters 49 (2008) 6404–6409
Br
1) 2.2 equiv DIBAL-H
toluene, 0 ºC, 2 h
P
•
Me
H
Br
CbzN
O
P
•
Me
H
O
S
2) DCC, DMAP, CH2Cl2, rt
OEt
O
Cbz
O
N
11-P
18-P:
dr ≥95 : 5
44% overall yield
HO
S
Br
P
•
Ph
H
Br
P
•
Ph
H
1) DIBAL-H
O
O
2)
HO
O
S
O
OMe
OEt
S
OMe
14-P:
19-P:
R = Ph
86% overall [dr = 93 : 7]
yields over 2 steps
Br
H
M
•
Br
Ph
H
M
•
CbzN
O
O
Me
S
O
OMe
S
O
18-M: 42% yield [dr ≥95:5]
19-M: 85% yield [dr = 93 : 7]
X
X
P
•
n-pentyl
H
M
•
H
n-pentyl
O
O
OMe
O
OMe
O
S
S
20-P: X = Br: 70% yield [dr ≥95:5]
21-P: X = Cl: 80% yield [dr ≥95:5]
20-M: 85% yield [dr ≥95:5]
21-M: 83% yield [dr ≥95:5]
Scheme 3. Determination of enantiomeric purity.
DIBAL and subsequent esterification of the resulting alcohol using
Cbz-protected -proline led to homo-allenyl ester 18-P in 44%
In addition to their usage in amidative cross-couplings for the
synthesis of allenamides, allenyl halides are well known as highly
useful synthons in organic transformations.23 To showcase one of
the possible transformations with these enantiomerically pure
allenyl halides, we investigated the propargyl trichlorosilane addi-
tion to benzyaldehyde employing known conditions24 and allenyl
bromides 11-P and 11-M (Scheme 4). The respective addition
products, allenols 22-[P,S] and 22 -[M,R], were isolated in good
yields and high diastereoeselectivity.
The stereochemistry of the benzylic carbon was assigned using
Mosher’s ester analysis.25 The high degree of diastereoselectivity
suggests excellent chirality transfer from allenyl bromides 11-P
and 11-M. This chirality transfer likely proceeds through allenyl
copper intermediates 23-P and 23-M, and also through (S) and
(R)-propargyl tricholorosilanes shown in the Zimmermann–Traxler
transition states [TS-S and TS-R] for the ensuing addition.24
Stereochemical assignments of 22-[P,S] and 22-[M,R] also imply a
syn-facial transmetallation of copper intermediates 23-P and
23-M with HSiCl3 as shown in 24.
L
overall yield with a diastereomeric ratio of P95:5, thereby reflect-
ing a high degree of optical purity of 11-P (Scheme 3). Likewise,
allenyl bromide 14-P could be transformed into homo-allenyl
ester19-P using (S)-2-(6-methoxynaphthalen-2-yl)-propanoic acid
[or naproxen].
Overall, with the exception of 14-P and 14-M (see 19-M for the
dr), all other allenyl halides are of high enantiomeric purity.
Currently, we are not certain as to the source of erosion during
the rearrangement of alkynyl bromides (R)- and (S)-15. Neverthe-
less, this new protocol allows better preservation and transference
of the optical integrity from chiral propargyl alcohols to allenyl
halides. It is also noteworthy that the concept that we have estab-
lished here is not limited to commercially available optically pure
propargyl alcohols. Asymmetric protocols such as asymmetric
reductions of acetylenic ketones21 and acetylenic additions to
aldehydes22 should in principle provide practical access to a
diverse array of allenyl halides (Fig. 2).
asy [H]
HO
X
X
R
P
•
O
X
X
O
H
Saucy-Marbet
rearrangement
H
P
R
OEt
R
or
X = Br or Cl
H
O
O
HO
•
M
R
M
R
asy add
OEt
R
Figure 2. A concept of accesing chiral allenyl halides.

Y. Tang et al. / Tetrahedron Letters 49 (2008) 6404–6409
6407
Ph
S
Br
Br
Me
H
P
OH
Me
P
OEt
•
2.0 equiv HSiCl3
10 mol% CuCl
and 2.0 equiv i-Pr2NEt
THF [0.50 M], 40 ºC, 6 h
•
H
CO2Et
O
11-P
22
-[P,S]: 57%: dr = 95 : 5
or
or
and then
1.0 equiv PhCHO
DMF-CH3CN [0.50 M, 1:1 v/v]
Ph
R
H
M
•
OH
OEt
O
H
M
•
Me
0 ºC for 18 h
Me
CO2Et
11-M
22-[M,R]: 51%: dr = 94 : 6
CuCl
CuIIILn HSiCl3
R
TS-S
Cl
Cl
Si
Me
H
P
Me
•
H
R
Cl
H
23-P
S
Cl
O
Cl
CuIIILn
Cl
Si
H
Ph
Cl
R = CH2CO2Et
R1
R2
•
Me
R
H
CuIIILn
R
Si
H
M
•
23-M
24
Cl
R
O
Me
Cl
R
HSiCl3
TS-R
Ph
H
Scheme 4. Chirality transfer via propargyl trichlorosilane addition.
8. For our recent efforts, see: (a) Antoline, J. E.; Hsung, R. P. Synlett 2008, 739; (b)
Song, Z.; Hsung, R. P.; Lu, T.; Lohse, A. G. J. Org. Chem. 2007, 72, 9722; (c) Song,
Z.; Hsung, R. P. Org. Lett. 2007, 9, 2199; (d) Huang, J.; Ianni, J. C.; Antoline, J. E.;
Hsung, R. P.; Kozlowski, M. C. Org. Lett. 2006, 8, 1565; (e) Huang, J.; Hsung, R. P.
J. Am. Chem. Soc. 2005, 127, 50; (f) Shen, L.; Hsung, R. P. Org. Lett. 2005, 7, 775;
(g) Berry, C. R.; Hsung, R. P.; Antoline, J. E.; Petersen, M. E.; Rameshkumar, C.;
Nielson, J. A. J. Org. Chem. 2005, 70, 4038.
We have described here the concept of employing a stereospe-
cific Saucy–Marbet rearrangement of alkynyl halides in the synthe-
sis of highly enantiomerically enriched allenyl bromides and
chlorides. Further applications employing these allenyl halides
are underway.
9. Ohno, H.; Nagoako, Y.; Tomioka, K. In Modern Allene Chemistry; Krause, N.,
Hashmi, A. S. K., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2004;
Vol. 1, pp 141–181. specifically see Refs. 21-25.
10. For a recent highlight, see: Krause, N.; Hoffman-Röder, A. Angew. Chem., Int. Ed.
2002, 41, 2933.
11. (a) Marshall, J. A.; Grant, C. M. J. Org. Chem. 1999, 64, 8214; (b) Elsevier, C. J.;
Mooiweer, H. H. J. Org. Chem. 1987, 52, 1536; (c) Elsevier, C. J.; Vermeer, P.;
Gedanken, A.; Runge, W. J. Org. Chem. 1985, 50, 364; and references cited
therein.
12. Also see: (a) Landor, S. R.; Demetriou, B.; Evans, R. J.; Grzeskowiak, R.; Davey, P.
J. Chem. Soc., Perkin Trans. 2 1972, 1995; (b) Muscio, O. J., Jr.; Jun, Y. M.; Philip, J.
B., Jr. Tetrahedron Lett. 1978, 19, 2379; (c) Montury, M.; Goré, J. Synth. Commun.
1980, 10, 873.
Acknowledgement
Authors thank NIH-NIGMS [GM066055] and UW-Madison for
financial support.
References and notes
1. For a compendium on the chemistry of allenes, see: (a) Krause, N.; Hashmi, A. S.
K. In Modern Allene Chemistry; Wiley-VCH Verlag GmbH
& Co. KGaA:
13. (a) Frederick, M. O.; Hsung, R. P.; Lambeth, R. H.; Mulder, J. A.; Tracey, M. R. Org.
Lett. 2003, 5, 2663; (b) Kurtz, K. C. M.; Frederick, M. O.; Mulder, J. A.; Hsung, R.
P. Tetrahedron 2006, 62, 3928.
14. (a) Saucy, G.; Chopard-dit-Jean, L. H.; Guex, W.; Ryser, G.; Isler, O. Helv. Chim.
Acta 1958, 41, 160; (b) Marbet, R.; Saucy, G. Chimia 1960, 14, 361; (c) Saucy, G.;
Marbet, R. Helv. Chim. Acta 1967, 50, 1158.
15. For a recent leading reference on Saucy–Marbet rearrangement, see: Sherry, B.
D.; Toste, F. D. J. Am. Chem. Soc. 2005, 126, 15978.
16. For studies on stereoselectivity issues, see: (a) Heathcock, C. H.; Henderson, M.
A. J. Org. Chem. 1988, 53, 4736; (b) Fujisawa, T.; Maehata, E.; Kohama, H.; Sato,
T. Chem. Lett. 1985, 1457.
17. For amidations of alkynyl halides see: (a) Frederick, M. O.; Mulder, J. A.; Tracey,
M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem.
Soc. 2003, 125, 2368; (b) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.;
Vera, E. L. Org. Lett. 2004, 6, 1151.
18. For a cycloaddition method employing alkynyl halides, see: Yoo, W.-J.; Allen,
A.; Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 5853.
19. For a related concept in the synthesis of allenyl halides, see: (a) Corey, E. J.;
Boaz, N. W. Tetrahedron Lett. 1984, 25, 3055; (b) Saalfrank, R. W.; Welch, A.;
Haubner, M. Angew. Chem., Ed. Engl. 1995, 34, 2709.
20. General procedure for the synthesis and rearrangement of alkynyl halides. Alkynyl
bromides: A solution of the respective propargyl alcohol (1.0 equiv) and AgNO3
(20 mol %) in acetone (1.0 M) was stirred at rt for 25 min. After which, NBS
(1.1 equiv) was added. The reaction mixture was stirred at rt overnight before
Weinheim, 2004; Vols. 1 and 2; Also see: For general reviews on allenes, see:
(b) Krause, N.; Hashmi, A. S. K. In Modern Allene Chemistry; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, 2004; Vols. 1 and 2; (c) Brummond, K. M.; Kent,
J. L. Tetrahedron 2000, 56, 3263; (d) Ma, S. Chem. Rev. 2005, 105, 2829.
2. For earlier reviews, see: (a) Saalfrank, R. W.; Lurz, C. J. Heterosubstituierte
Allene and Polyallene. In Methoden Der Organischen Chemie (Houben-Weyl);
Kropf, H., Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1993; pp 3093–
3102; (b) Schuster, H. E.; Coppola, G. M. Allenes in Organic Synthesis; John Wiley
and Sons: New York, 1984.
3. Trost, B. M.; Dylan, S. T. Org. Lett. 2005, 7, 2117.
4. Shen, L.; Hsung, R. P.; Zhang, Y.; Antoline, J. E.; Zhang, X. Org. Lett. 2005, 7, 3081.
5. For a review, see: Hsung, R. P.; Wei, L.-L.; Xiong, H. Acc. Chem. Res. 2003, 36, 773.
6. For a review on the synthesis of allenamides, see: Tracey, M. R.; Hsung, R. P.;
Antoline, J.; Kurtz, K. C. M.; Shen, L.; Slafer, B. W.; Zhang, Y. In Science of
Synthesis; Weinreb, Steve M., Ed.; Houben-Weyl Methods of Molecular
Transformations; Georg Thieme Verlag KG, 2005. Chapter 21.4.
7. For recent reports on allenamide chemistry, see: (a) Fuwa, H.; Sasaki, M. Org.
Biomol. Chem. 2007, 5, 2214; (b) Watanabe, T.; Oishi, S.; Fuji, N.; Ohno, H. Org.
Lett. 2007, 9, 4821; (c) Hyland, C. J. T.; Hegedus, L. S. J. Org. Chem. 2006, 71,
8658; (d) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2006, 8,
621; (e) Fenández, I.; Monterde, M. I.; Plumet, J. Tetrahedron Lett. 2005, 46,
6029; (f) Alouane, N.; Bernaud, F.; Marrot, J.; Vrancken, E.; Mangeney, P. Org.
Lett. 2005, 7, 5797; de los (g) Rios, C.; Hegedus, L. S. J. Org. Chem. 2005, 70, 6541;
(h) Hyland, C. J. T.; Hegedus, L. S. J. Org. Chem. 2005, 70, 8628.

6408
Y. Tang et al. / Tetrahedron Letters 49 (2008) 6404–6409
TM
being filtered through a small pad of Celite . The filtrate was concentrated and
the crude bromo-propargyl alcohol was used for the next step without further
purification.
of DCC (1.5 equiv), in CH2Cl2 (0.6 M) at 0 °C. After which, the reaction
mixture was allowed to warm to rt and was stirred overnight being filtered
TM
through a small pad of Celite . The filtrate was concentrated under reduced
Alkynyl chlorides: To solution of respective propargyl alcohol (1.0 equiv) in THF
(0.2 M) was added n-BuLi (1.6 M in hexane) (2.2 equiv) at ꢀ78 °C, and after
10 min, NCS (2.2 equiv) was added into the mixture. The reaction mixture was
stirred at ꢀ78 °C for 1 h, and the ice bath was removed to allow the mixture to
warm up to rt. After which, the reaction mixture was stirred at r.t. for 10 min.
The mixture was then diluted with H2O (20 mL) and extracted with CH2Cl2
(150 mL). The organic layer was dried (MgSO4). The solution was distilled
under reduced pressure. The crude chloro-propargyl alcohol was used for the
next step without further purification.
Rearrangement: To a solution of an alkynyl halide, the preparation of which is
described above, in anhyd toluene (0.2 M) were added triethyl orthoacetate
(2.0 equiv) and acetic acid (5 mol %), and the reaction mixture was heated for
18 h at 100 °C in a sealed tube. The solvent was removed under reduced
pressure, and the crude residue was purified using flash silica gel column
chromatography (gradient eluent: 0–10% ether in pentane) to provide allenyl
bromide as yellow oil. For characterizations, see: Compound 11-P: (56.8 mg,
pressure, and the crude residue was purified using flash silica gel column
chromatography (gradient eluent: 0–10% EtOAc in hexanes) to provide the
corresponding ester.
For selected characterizations, see: Compound 18-P: (9.10 mg, 44% yield).
Rf = 0.57 (50% EtOAc in hexanes); ½a D20
ꢀ4.40 (c 3.15 in CH2Cl2); ‘&’ indicates
ꢁ
rotamers. 1H NMR (500 MHz, CDCl3) d 1.76 (t, 3H, J = 7.5 Hz), 1.90–2.02 (m,
3H), 2.19–2.02 (m, 1H), 2.56–2.59 (m, 1H), 2.70–2.74 (m, 1H), 3.46–3.56 (m,
1H), 3.59–3.65 (m, 1H), 4.01–4.16 (m, 1H), 4.23–4.31 (m, 1H), 4.36 & 4.40
(dd, 1H, J = 4.0, 9.0 Hz), 5.07–5.19 (m, 2 H), 6.26–5.33 (m, 1H), 7.29–7.37 (m,
5H); IR (thin film) cmꢀ1 2953w, 1698s, 1417m, 1350w, 1166m, 1116w,
1058w; mass spectrum (ESI): m/e (% relative intensity) 430.5 (100) (M+Na)+,
432.5 (98) (M+2+Na)+. Compound 18-M: (8.50 mg, 42% yield). Rf = 0.57 (50%
EtOAc in hexanes); ½a D20
ꢁ
ꢀ 63.0 (c 8.65 in CH2Cl2); ‘&’ indicates rotamers. 1H
NMR (500 MHz, Toluene-d8) d 1.38 (dd, 3H, J = 7.5, 33.0 Hz), 1.46–1.62 (m,
3H), 2.05–2.10 (m, 1H), 2.26–2.10 (m, 1H), 2.41–2.44 (m, 1H), 3.05–3.07 &
3.23–3.28 (m, 1H), 3.32–3.37 & 3.45–3.52 (m, 1H), 3.94 (t, 1H, J = 6.0 Hz),
4.04 (t, 1H, J = 6.0 Hz), 4.08–4.11 & 4.27–4.30 (m, 1H), 4.92–5.14 (m, 3H),
6.98–7.19 (m, 5H); IR (thin film) cmꢀ1 2955m, 1698s, 1417m, 1350m, 1167s,
1116w, 1085; mass spectrum (ESI): m/e (% relative intensity) 430.5 (100)
(M+Na)+, 432.5 (98) (M+2+Na)+.
55% yield). Rf = 0.57 (25% EtOAc in hexanes); ½a D20
ꢁ
82.0 (c 0.64 in CH2Cl2); 1H
NMR (400 MHz, CDCl3) d 1.27 (t, 3H, J = 7.2 Hz), 1.77 (d, 3H, J = 7.2 Hz), 3.41 (d,
2H, J = 2.0 Hz), 4.18 (q, 2H, J = 7.2 Hz), 5.33 (qt, 1H, J = 7.2, 2.4 Hz); 13C NMR
(100 MHz, CDCl3) d 14.2, 14.3, 43.9, 61.3, 83.3, 94.6, 169.2, 202.1; IR (thin
film) cmꢀ1 2981w, 1734s, 1156w, 1033w; mass spectrum (ESI): m/e (% relative
intensity) 241.2 (100) (M+Na)+, 243.2 (83) (M+2+Na)+. Compound 11-M:
Compound 21-P: (19.0 mg, 80% yield). Rf = 0.10 (20% EtOAc in hexanes); ½a D20
ꢁ
38.0 (c 0.56 in CH2Cl2); 1H NMR (500 MHz, CDCl3) d 0.88 (t, 3H,J = 7.0 Hz),
1.20–1.39 (m, 6H), 1.57 (d, 3H,J = 7.5 Hz), 1.97 (dt, 2H, J = 7.5, 14.0 Hz), 2.56–
2.65 (m, 2H), 3.85 (q, 1H,J = 8.0 Hz), 3.91 (s, 3H), 4.17–4.28 (m, 2H), 5.32–
5.37 (m, 1H), 7.10–7.16 (m, 2H), 7.38–7.42 (m, 1H), 7.65–7.72 (m, 3H); 13C
NMR (125 MHz, CDCl3) d 14.3, 18.9, 22.7, 28.3, 29.3, 31.4, 36.0, 45.7, 55.6,
62.0, 101.2, 101.4, 105.8, 119.2, 126.2, 126.5, 127.4, 129.2, 129.5, 134.0,
135.8, 157.9, 174.7, 199.7; IR (thin film) cmꢀ1 2928w, 1734s, 1154m, 1032w;
mass spectrum (ESI): m/e (% relative intensity) 423.6 (100) (M+Na)+, 425.6
(29) (M+2+Na)+. Compound 21-M: (24.0 mg, 83% yield). Rf = 0.10 (20% EtOAc
(51.2 mg, 51% yield). Rf = 0.57 (25% EtOAc in hexanes); ½a D20
ꢀ83.0 (c 0.53 in
ꢁ
CH2Cl2); 1H NMR (500 MHz, CDCl3) d1.26 (t, 3H, J = 7.5 Hz), 1.78 (d, 3H,
J = 7.0 Hz), 3.41 (d, 2H, J = 2.0 Hz), 4.17 (q, 2 H, J = 7.5 Hz), 5.33 (qt, 1H, J = 7.5,
2.5 Hz); 13C NMR (125 MHz, CDCl3) d 14.2, 14.6, 44.1, 61.5, 83.3, 94.7, 169.3,
202.1; IR (thin film) cmꢀ1 2981w, 1939s, 1167s, 1032w; mass spectrum (ESI):
m/e (% relative intensity) 241.2 (100) (M+Na)+, 243.2 (83) (M+2+Na)+.
Compound 14-P: (22.1 mg, 40% yield). Rf = 0.68 (33% EtOAc in hexanes); ½a D20
ꢁ
85.0 (c 0.43 in CH2Cl2); 1H NMR (500 MHz, CDCl3) d 1.28 (t, 3 H, J = 7.5 Hz),
3.57 (dq, 2H, J = 2.0, 16.5 Hz), 4.21 (q, 2H, J = 7.0 Hz), 6.29 (t, 1H, J = 2.0 Hz),
7.25–7.41 (m, 5H); 13C NMR (125 MHz, CDCl3) d 14.4, 44.1, 61.7, 86.6, 101.4,
128.4, 128.9, 129.1, 132.3, 169.0, 202.4; IR (thin film) cmꢀ1 2981w, 1734s,
1235m, 1178s, 1027m; mass spectrum (ESI): m/e (% relative intensity) 303.3
(75) (M+Na)+, 305.3 (72) (M+2+Na)+. 14-M: (24.3 mg, 42% yield). Rf = 0.68 (33%
in hexanes); ½a 2D0
ꢁ
ꢀ1.50 (c 0.55 in CH2Cl2); 1H NMR (500 MHz, CDCl3) d 0.88
(t, 3H, J = 7.5 Hz), 1.20–1.34 (m, 6H), 1.29–1.31 (m, 2H), 1.57 (d, 3H,
J = 7.5 Hz), 1.93 (q, 2H, J = 7.0 Hz), 2.60 (dt, 2H,J = 2.5, 6.5 Hz), 3.85 (q, 1H,
J = 7.5 Hz), 3.92 (s, 3H), 4.17–4.27 (m, 2H), 5.23–5.29 (m, 1H), 7.10–7.16 (m,
2H), 7.39–7.42 (m, 1H), 7.65–7.73 (m, 3H); 13C NMR (125 MHz, CDCl3) d 14.3,
18.8, 22.7, 28.3, 29.3, 31.4, 36.0, 45.7, 55.6, 62.0, 101.2, 101.4 105.8, 119.3,
126.2, 126.5, 127.4, 129.2, 129.5, 134.0, 135.9, 157.9, 174.7, 199.6; IR (thin
film) cmꢀ1 2930w, 1733s, 1233w, 1174w, 1033w; mass spectrum (ESI): m/e
(% relative intensity) 423.6 (100) (M+Na)+, 425.6 (29) (M+2+Na)+.
EtOAc in hexanes); ½a D20
ꢁ
ꢀ123.0 (c 0.63 in CH2Cl2); 1H NMR (500 MHz, CDCl3) d
1.28 (t, 3 H, J = 7.5 Hz), 3.56 (dq, 2H, J = 2.5, 16.5 Hz), 4.21 (q, 2H, J = 7.5 Hz),
6.29 (t, 1H, J = 2.0 Hz), 7.26–7.41 (m, 5H); 13C NMR (125 MHz, CDCl3) d 14.4,
44.1, 61.7, 86.6, 101.4, 128.4, 128.9, 129.1, 132.3, 169.0, 202.4; IR (thin
film) cmꢀ1 1737s, 1220s, 1014m; mass spectrum (ESI): m/e (% relative
intensity) 303.3 (100) (M+Na)+; 305.3 (100) (M+2+Na)+.
General Procedure for addition of allenyl bromides 11-P to benzaldehyde: To a
stirred solution of allenyl bromide 11-P (1.0 equiv) in THF (0.5 M) were
added CuCl (0.10 equiv), HSiCl3 (2.0 equiv), and iPr2NEt (2.0 equiv)
successively at rt. The mixture was stirred at 40 °C for 6 h. After which,
DMF-CH3CN (0.5 M, 1:1 v/v) was added and the mixture was cooled to 0 °C.
Then benzaldehyde (1.0 equiv) was added, and the mixture was kept at 0 °C
for 18 h before being quenched with cold H2O and extracted with ether. The
extract was washed with sat aq NaCl, dried over Na2SO4, and concentrated
under reduced pressure. The crude residue was purified using flash silica gel
column chromatography (gradient eluent: 0–50% EtOAc in hexanes) to
provide the allenylic alcohol. For characterizations, see: Compound 22-[P,S]:
Compound 16-P: (28.7 mg, 52% yield). Rf = 0.67 (33% EtOAc in hexanes); ½a D20
ꢁ
127.0 (c 0.96 in CH2Cl2); 1H NMR (500 MHz, CDCl3) d 0.89–0.92 (m, 3H), 1.26–
1.33 (m, 7 H), 1.46–1.48 (m, 2 H), 2.13 (dq, 2H, J = 3.0, 7.5 Hz), 3.44 (d, 2H,
J = 2.5 Hz), 4.20 (q, 2H, J = 7.0 Hz), 5.37–5.42 (m, 1H); 13C NMR (125 MHz,
CDCl3) d 14.0, 14.1, 22.3, 27.8, 28.4, 31.1, 43.9, 61.1, 83.7, 99.6, 168.9, 201.0; IR
(thin film) cmꢀ1 2928m, 1735s, 1157m, 1032m; mass spectrum (ESI): m/e (%
relative intensity) 297.3 (100) (M+Na)+, 299.3 (99) (M+2+Na)+. Compound 16-
M: (24.9 mg, 48% yield). Rf = 0.67 (33% EtOAc in hexanes); ½a D20
ꢀ106.0 (c 0.81
ꢁ
in CH2Cl2); 1H NMR (500 MHz, CDCl3) d 0.81–0.91 (m, 3H), 1.20–1.29 (m, 7H),
1.36–1.44 (m, 2H), 2.06 (dq, 2H, J = 3.0, 7.5 Hz), 3.36 (s, 2H), 4.13 (q, 2H,
J = 7.5 Hz), 5.31–5.35 (m, 1H); 13C NMR (125 MHz, CDCl3) d 14.0, 14.1, 22.4,
27.8, 28.4, 31.1, 43.9, 61.1, 83.8, 99.6, 168.8, 201.1; IR (thin film) cmꢀ1 2927 m,
1734s, 1156m, 1031m; mass spectrum (ESI): m/e (% relative intensity) 297
(100) (M+Na)+, 299.3 (98) (M+2+Na)+.
(7.10 mg, 57% yield). Rf = 0.23 (20% EtOAc in hexanes); ½a D20
ꢀ21.0 (c 1.05 in
ꢁ
CH2Cl2); 1H NMR(400 MHz, CDCl3)
d 1.23 (t, 3H, J = 7.2 Hz), 1.69 (d, 3H,
J = 7.2 Hz), 2.91 (dq, 2H, J = 2.0, 16.4 Hz), 3.20–3.22 (m, 1H), 4.10 (q, 2H,
J = 7.2 Hz), 5.28–5.30 (m, 1H), 5.31–5.37 (m, 1H), 7.24–7.39 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 14.4, 14.5, 35.5, 61.3, 74.6, 90.0, 101.2, 126.6, 127.8,
128.4, 142.1, 172.7, 203.4; IR (thin film) cmꢀ1 2981w, 1733m, 1716s, 1156m,
1025m; mass spectrum (MALDI): m/e (% relative intensity) 269 (100)
(M+Na)+; m/e calcd for C15H18O3Na+269.1148, found 269.1152. 22-[M,R]:
Compound 17-P: (25.5 mg, 46% yield). Rf = 0.65 (10% MTBE in hexanes); ½a D20
ꢁ
20.9 (c 2.5 in CH2Cl2); 1H NMR (500 MHz, CDCl3) d 0.88–0.91 (m, 3H), 1.23–
1.36 (m, 7H), 1.42–1.50 (m, 2H), 2.11 (q, 2H, J = 7.5 Hz), 3.32 (d, 2H, J = 2.0 Hz),
4.19 (q, 2H, J = 7.2 Hz), 5.60–5.63 (m, 1H); 13C NMR (125 MHz, CDCl3) d 14.3,
14.4, 22.7, 28.1, 29.2, 31.4, 42.9, 61.4, 98.3, 101.2, 169.2, 201.0; IR (thin
film) cmꢀ1 2929m, 2369s, 1734m, 1158w; mass spectrum (ESI): m/e (% relative
intensity) 253.4 (90) (M+Na)+. Compound 17-M: (9.3 mg, 46% yield). Rf = 0.65
(4.40 mg, 51% yield). Rf = 0.23 (20% EtOAc in hexanes); ½a D20
ꢁ
18.8 (c 1.85 in
CH2Cl2); 1H NMR (400 MHz, CDCl3) d 1.23 (t, 3H, J = 6.8 Hz), 1.69 (d, 3H,
J = 6.8 Hz), 2.91 (dq, 2H, J = 2.0, 16.4 Hz), 3.18–3.22 (m, 1H), 4.11 (q, 2H,
J = 7.2 Hz), 5.28–5.30 (m, 1H), 5.31–5.40 (m, 1H), 7.24–7.39 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 14.4, 14.5, 35.5, 61.3, 74.6, 90.0, 101.2, 126.6, 127.8,
128.4, 142.1, 172.7, 203.4; IR (thin film) cmꢀ1 2982w, 1733m, 1716m, 1157w,
1025m; mass spectrum (MALDI): m/e (% relative intensity) 269 (100)
(M+Na)+; m/e Calcd for C15H18O3Na+ 269.1148, found 269.1148.
21. For leading references on such asymmetric reductions, see: (a) Bach, J.;
Berenguer, R.; Garcia, J.; Loscertales, T.; Vilarrasa, J. J. Org. Chem. 1996,
61, 9021; (b) Helal, C. J.; Magriotis, P. A.; Corey, E. J. J. Am. Chem. Soc. 1996, 118,
10938; (c) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1997, 119, 8738; (d) Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61,
3214.
(10% MTBE in hexanes); ½a D20
ꢁ
ꢀ18.5 (c 1.90 in CH2Cl2); 1H NMR (500 MHz,
CDCl3) d 0.88–0.92 (m, 3H), 1.25–1.40 (m, 7H), 1.42–1.50 (m, 2H), 2.12 (q, 2H,
J = 7.2 Hz), 3.33 (d, 2H, J = 1.8 Hz), 4.20 (q, 2H, J = 6.9 Hz), 5.59–5.67 (m, 1H);
13C NMR (125 MHz, CDCl3) d 14.0, 14.1, 22.4, 27.8, 28.9, 31.2, 42.6, 61.2, 98.0,
100.9, 168.9, 200.8; IR (thin film) cmꢀ1 2929m, 2364s, 1734m, 1158w; mass
spectrum (ESI): m/e (% relative intensity) 253.4 (18) (M+Na)+.
General procedure of DIBAL-H reduction and esterification: A solution of the
respective allenyl bromide (or chloride) in toluene (0.2 M) was cooled to 0 °C
followed by the addition of DIBAL-H (2.2 equiv). The reaction mixture was
stirred for 2 h at 0 °C before it was quenched with MeOH and diluted with
EtOAc. A sat aq K/Na–tartrate solution was then added, and the mixture was
stirred for another 2–4 h until it was separated as two clear layers. The
aqueous layer was extracted twice with EtOAc (equal volume) after separation.
The combined organic extracts were concentrated under reduced pressure,
and the crude alcohol was used for the next step without further purification.
22. For reviews on asymmetric additions of acetylenes to carbonyl systems, see:
(a) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757; (b) Pu, L. Tetrahedron 2003, 59,
9873; (c) Walsh, P. J. Acc. Chem. Res. 2003, 36, 739.
23. For a review, see: (a) Marshall, J. A.; Gung, B. W.; Grachan, M. L. In Modern
Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH Verlag GmbH &
Co. KGaA: Weinheim, 2004; Vol. 1, pp 493–592; (b) Marshall, J. A. Chem. Rev.
1996, 96, 31.
To
a solution of the above mentioned crude alcohol, carboxylic acid
(1.5 equiv), and DMAP (0.1 equiv) in CH2Cl2 (0.2 M) was added a solution

Y. Tang et al. / Tetrahedron Letters 49 (2008) 6404–6409
6409
24. For leading references on allenyl silane chemistry employingHSiCl3 and CuCl,
see: (a) Kobayashi, S.; Nisho, K. J. Am. Chem. Soc. 1995, 117, 6392; (b)
Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620; (c) Becker, D. A.;
Danheiser, R. L. J. Am. Chem. Soc. 1989, 111, 389; (d) Calas, R. J. Organomet.
Chem. 1980, 200, 11; (e) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1997, 62,
8976.
25. Respective proton chemical shifts are in the brackets.
[1.54]
[6.57]
[1.59]
[6.56]
Me
Me
O
H
[4.07]
[2.93]
O
H
S
[2.83]
OCH2CH3
R
F3C
S
F3C
Ph
S
O
P
P
O
Ph
OCH2CH3
[4.05]
Ph
O
MeO
H
Ph
OMe
H
O
[5.24-5.32]
[5.12-5.20]
Mosher Esters of 22-[P,S]
[6.55]
H
[6.57]
O
[1.60]
Me
[1.55]
Me
O
R
Ph
H
O
R
F3C
O
R
Ph
S
F3C
Ph
Ph
MeO
O
O
M
M
OMe
H
OCH2CH3
[4.06]
[5.25-5.30] [2.92]
OCH2CH3
[4.07]
Mosher Esters of 22-[M,R]
[2.83]
H
[5.14-5.17]