2
Y. Yamamoto et al. / Tetrahedron Letters xxx (2018) xxx–xxx
to a stereoꢁenic sꢀlfꢀr atom, which was verifieu at a later staꢁe.
The cascaue reaction auuꢀct was converteu to the
8
corres-onuinꢁ TES ether 9 (89%; ur = 10:1± by a conventional
methou. The relative stereochemistry of 9 was confirmeu by
NMR analysis. Namely, a larꢁe coꢀ-linꢁ constant (10.4 Hz±
between H)5 anu H)6 inuicateu their 1,2)uiaxial relationshi-, anu
the NOE correlation between H)4 anu H)5 clearly sꢀꢁꢁesteu their
cis relationshi-. Thermal elimination of sꢀlfinic aciu from 9 was
sꢀccessfꢀlly -erformeu by heatinꢁ in xylenes in the -resence of
K CO to afforu 10 (81%± as the sole -rouꢀct [7]. This fact leu ꢀs
2 3
to the conclꢀsion that the above mentioneu uiastereoisomerism
in 8/9 is uꢀe to the sꢀlfꢀr atom.
With the key ketone 10 in hanu, the uiastereoselective auuition
of alkyllithiꢀm (Scheme 2, 10 ? 11± was carrieu oꢀt. Notably, Casey
et al. have synthesizeu the strꢀctꢀrally similar bicyclic ketones with
the 3,3)uimethyl)2,4)uioxabicyclo[3.1.1]nonan)9)one skeleton by a
rather similar methou (Fiꢁ. 2± [6b]. They have uetermineu that this
Scheme 1. Synthesis of the key intermeuiate 10.
-articꢀlar ketone exists in the Chair/Boat conformation as shown in
Fiꢁ. 2. Accoruinꢁly, oꢀr ketone 10 miꢁht also -refer -seꢀuo)Chair/
Boat conformation, in which the to- siue of the carbonyl ꢁroꢀ-
woꢀlu be blockeu by an acetoniue ꢁroꢀ-, thereby ex-osinꢁ the
bottom siue to nꢀcleo-hilic attack. Thꢀs, this auuition is ex-ecteu
to -roceeu with excellent uiastereoselectivity.
Table 2 sꢀmmarizes the re-resentative resꢀlts obtaineu for the
uiastereoselective auuition of alkyllithiꢀm. First, the most conven)
2
tional conuitions, i.e., n)C12H25Li in Et O, were examineu. However,
cascaue reaction of 6 with 7. The key cascaue reaction was investi)
ateu as shown in Table 1. First, -yrroliuine was selecteu as the
ꢁ
base, becaꢀse the formation of an enamine intermeuiate was con)
siuereu to be uesirable [6]. A weak aciu catalyst, e.ꢁ., PPTS [6a], was
also em-loyeu to accelerate the reaction. The first three entries
clearly revealeu the uifficꢀlty of this cascaue reaction. However, a
stoichiometric (or semi)stoichiometric± amoꢀnt of -yrroliuine
was recoꢁnizeu to be -referable, anu the auuition of PPTS miꢁht
be sliꢁhtly effective. However, all attem-ts to chanꢁe a base anu/
or an auuitive were not frꢀitfꢀl (entries 4–6±. By chanꢁinꢁ the
solvent or reaction tem-eratꢀre, remarkable im-rovement was
not observeu (entries 7–10±. Thꢀs, the reason for the low yielu
was reconsiuereu, which was thoꢀꢁht to be relateu to the
com-etitive uecom-osition of 6 caꢀseu by its instability. To
the uesireu auuition uiu not -roceeu at ꢀ78 °C, -robably uꢀe to the
low reactivity of 10 caꢀseu by steric hinurance (entry 1±. With the
increase in the tem-eratꢀre to 0 °C, qꢀite sꢀr-risinꢁly, the ꢀnue)
0
sireu e-imer 11 was isolateu in a consiuerable yielu, while the
uesireu auuꢀct 11 was obtaineu in a lower yielu (entry 2±. The rel)
0
ative stereochemistry of 11 was confirmeu by the observation of
0
NOE between one of the acetoniue Me ꢁroꢀ-s anu 1 )H
2
. Althoꢀꢁh
-
revent the uecom-osition of 6 ꢀnuer the reaction conuitions,
the reason for the ꢀn-reuictable reversal of uiastereoselectivity
was not certain [8], the reactivity of 10 was consiuerably lower
than ex-ecteu. Fortꢀnately, both the yielu anu uiastereoselectivity
the -yrroliuine enamine of 7 was -re-areu -rior to the auuition
of 6. Therefore, the -re)mixinꢁ of 7 with -yrroliuine was
attem-teu, afforuinꢁ 8 in a sliꢁhtly im-roveu yielu (28%; entry
2
were uramatically im-roveu by chanꢁinꢁ the solvent from Et O to
1
8
1±. Even thoꢀꢁh there was consiuerable room for o-timization,
was sꢀccessfꢀlly -re-areu by Michael–aluol cascaue reaction.
THF, afforuinꢁ 10 in 69% yielu with -erfect selectivity (entry 3±.
However, a lower yielu was observeu at 0 °C even in THF (entry
The relative stereochemistry of 8 was not certain, bꢀt it was
confirmeu by NMR analysis after conversion to the corres-onuinꢁ
TES ether 9. Notably, 8 was a uiastereomeric mixtꢀre (ur = ca.
4±. Fꢀrther attem-ts to ꢀse CeCl
no im-rovement in yielu.
3
or HMPA as an auuitive afforueu
Finally, the synthesis of (± ±)1 was com-leteu. After ue-rotection
1
0:1 in all cases±. However, this uiastereoisomerism was relateu
of TES ꢁroꢀ- (91%±, the resꢀltinꢁ alcohol was oxiuizeu with DMP to
Table 1
Stꢀuies on Michael–aluol cascaue reaction.
Entry
Conuitionsa,b
Yielu of 8c (%±
Base (eqꢀiv.±
Solvent
Auuitive (eqꢀiv.±
Tem-.; Time
1
2
3
4
5
6
7
8
9
1
1
Pyrroliuine (1.0±
Pyrroliuine (1.0±
Pyrroliuine (0.2±
Pyrroliuine (1.0±
DBU (0.2±
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
3
3
3
3
3
3
PPTS (0.2±
ꢀ
r.t.; 2 h
r.t.; 1 h
19
13
14
14
uecom-.
uecom-.
7
4
PPTS (0.2±
p)NP (0.2±
PPTS (0.2±
PPTS (0.2±
PPTS (0.2±
PPTS (0.2±
PPTS (0.2±
PPTS (0.2±
PPTS (0.2±
r.t.; 24 h
r.t.; 5.5 h
r.t.; 0.5 h
r.t.; 0.5 h
r.t.; 7.5 h
r.t.; 7.5 h
55 °C; 1 h
ꢀ20 °C; 1 h
r.t.; 2 h
TMG (0.2±
Pyrroliuine (1.0±
Pyrroliuine (1.0±
Pyrroliuine (1.0±
Pyrroliuine (1.0±
Pyrroliuine (0.8±
MeCN
CH Cl
2
2
CHCl
CHCl
CHCl
3
3
3
11
N.R.
28
u
0
1
e
p)NP: p)Nitro-henol; TMG: 1,1,3,3)Tetramethylꢁꢀaniuine.
a
Reaction conuitions ꢀnless otherwise stateu: A solꢀtion of 6 anu 7 (1.0–1.5 eqꢀiv.± was stirreu in the -resence of a base anu an auuitive ꢀntil the uisa--earance of 6.
Startinꢁ material 6 coꢀlu not be recovereu ꢀnless otherwise stateu.
Isolateu yielu in 2 ste-s from 5.
No reaction: Startinꢁ material 6 was not consꢀmeu by TLC analysis.
Before the auuition of 6, 7 was -re)mixeu with -yrroliuine (see Sꢀ--ortinꢁ Information±.
b
c
u
e